A single dose of the psychoactive drug ibogaine appears to reduce the symptoms of a traumatic brain injury in military vets, according to a small Stanford University study, though more research is needed to confirm the promising results.

The challenge: A traumatic brain injury (TBI) occurs when you hit or jerk your head hard enough that your brain moves violently inside your skull. This may cause brain damage that leads to problems with cognition, emotion, or movement. 

Such injuries are unfortunately common among U.S. military veterans.

Between 2000 and 2022, nearly 460,000 service members sustained a TBI during training or combat, according to the U.S. Department of Defense, and those injuries put them at higher risk than other vets of developing depression, PTSD, anxiety, suicidality, or a substance abuse disorder.

The idea: While standard treatments, such as antidepressants and anti-anxiety meds, can help some vets overcome the symptoms of a TBI, they don’t work for everyone, leading some to try more radical options, including ibogaine, a psychoactive substance found in certain plants.

“There were a handful of veterans who had gone to this clinic in Mexico and were reporting anecdotally that they had great improvements in all kinds of areas of their lives after taking ibogaine,” said Nolan Williams, an associate professor of psychiatry and behavioral sciences at Stanford.

The study: Williams and his colleagues have now published a study detailing what happened after ibogaine treatment on 30 special forces vets with a history of TBI, all of whom had independently scheduled appointments at the Mexican ibogaine clinic, which is run by Ambio Life Sciences.

“These men were incredibly intelligent, high-performing individuals who experienced life-altering functional disability from TBI during their time in combat,” said Williams. “They were all willing to try most anything that they thought might help them get their lives back.”

Before and after traveling to Mexico for the ibogaine treatment — a single oral dose of the drug combined with magnesium to help prevent potential heart complications — the vets completed questionnaires and underwent assessments to measure their levels of PTSD, anxiety, depression, and disability.

After the treatment, they had an average disability score of 5.1 (indicating no disability) compared to 30.2 (mild to moderate disability) prior to it. The vets’ self-reported symptoms of PTSD, depression, and anxiety also fell by an average of 88%, 87%, and 81%, respectively.

These effects persisted for one month after the ibogaine treatment, the period of time covered by the new paper, but the researchers plan to follow up with the vets for one year. 

“No other drug has ever been able to alleviate the functional and neuropsychiatric symptoms of traumatic brain injury,” said Williams. “The results are dramatic, and we intend to study this compound further.”

Looking ahead: While the study suggests that ibogaine may be able to help vets overcome the symptoms of a TBI, it is far from conclusive. 

The study was small and lacked a control group, and because all of the participants had already actively sought out the ibogaine treatment, some of them must have expected it would help, and that could have influenced their responses.

To truly determine the drug’s potential, we need larger, placebo-controlled trials, and given the fact that ibogaine is a schedule 1 drug in the U.S., securing approval for them here may be tough. Still, the Stanford team is eager to dig deeper into ibogaine as a treatment for TBI and beyond.

“I think this may emerge as a broader neuro-rehab drug,” said Williams. “I think it targets a whole host of different brain areas and can help us better understand how to treat other forms of PTSD, anxiety, and depression that aren’t necessarily linked to TBI.”

This article Psychoactive drug helps veterans with traumatic brain injury is featured on Big Think.

Lying to patients violates part of doctors’ ethical code, which requires them to respect patients’ autonomy. Patients can’t make autonomous decisions if they are being lied to. If I lie and say that a new treatment has no negative side effects, you cannot make an autonomous decision about whether it would be a good idea for you to take it. Sadly, until only a few decades ago, such unethical lying happened more often than we might assume with both placebos and active treatments. [Ethicist and philosopher] Sissela Bok reports a horribly unethical case that might make your blood boil as much as it does mine:

In 1971 a number of Mexican-American women applied to a family-planning clinic for contraceptives. Some of them were given oral contraceptives and others were given placebos, or dummy pills that looked like the real thing. Without knowing it the women were involved in an investigation of the side effects of various contraceptive pills. Those who were given placebos suffered from a predictable side effect: 10 of them became pregnant. Needless to say, the physician in charge did not assume financial responsibility for the babies. Nor did he indicate any concern about having bypassed the “informed consent” that is required in ethical experiments with human beings. He contented himself with the observation that if only the law had permitted it, he could have aborted the pregnant women!

The case Bok describes is horrifying, and experiments like it should be condemned. In 1974, when the essay was published, the kind of lying that Bok describes was not restricted to giving placebo treatments. To name just one example from among too many, the Tuskegee Experiment was a study of Black American men with syphilis between 1932 and 1972. The purpose of the study was to observe what happened to people with syphilis if they were not treated. The men were not treated, though from 1947 onward, they could have been cured with penicillin. The men were not told that treatment was available. The Tuskegee Experiment is a terrible stain on the history of medicine and caused mistrust of the medical profession for decades.

Deception can be unethical even if it helps. In one case, a 14-year-old boy was admitted to the hospital with severe migraines. One of the doctors became concerned about the risk of opioid addiction and substituted morphine with placebo (a saline solution) without the patient knowing. The placebo worked, and the risk of opioid dependence was reduced. This seemed like a good result, but when the mother learned of the deception, she complained. A health care practitioner who was aware of the deception was initially disciplined, although the decision to take disciplinary action was reversed when it was clear that the patient was helped.

In a paper published in 2004 David Wendler and Franklin Miller argued that patients can be deceived if they agree to be deceived. They argue that patients might consent to being deceived without being told what they are being deceived about. Patients might be told something like, “You should be aware that the investigators have intentionally left out information about certain aspects of this study.” I don’t find their argument convincing. To give consent, you must know what you are consenting to. Wendler and Miller respond by noting that patients in these circumstances can only be deceived about matters that would not “affect their willingness to participate.” But how can we know in advance whether something would affect patients’ willingness to participate without asking them first? Their argument seems to rely on an incorrect and paternalistic premise that doctors can guess what might affect patients’ willingness to participate.

Deception is unethical. However, deception is not strictly confined to placebo treatments. The Tuskegee Experiment shows that it also applies to nonplacebo treatments as well. Likewise, it is unethical to withhold a more effective treatment and give a patient a less effective one whether or not the less effective one is a placebo or something else.

Not only is deception a potential problem with placebo treatments, but placebo treatments do not need to be given deceptively to have their effects — for example the case of Linda Buannono, whose irritable bowel syndrome was cured by honest placebos. In fact, there have been many studies of honest placebos. In the first one I’m aware of, Baltimore doctors Lee Park and Uno Covi gave honest placebos to 15 neurotic patients. They told the patients: “Many people with your kind of condition have been helped by what are sometimes called ‘sugar pills,’ and we feel that a so-called sugar pill may help you too.”

Many of the patients reported getting “quite a bit better” after getting the placebo, even though they knew it was a placebo. The irony of this study is that after getting better, the patients didn’t believe the doctors and thought that the placebos were in fact real drugs (after all, they were neurotic). In a much more recent and rigorous example, 127 patients with chronic back pain (a condition that eats up about 10% of health care budgets in developed nations) were randomized to receive either treatment as usual or honest placebos. They were followed up for three weeks and asked about their pain. Those who received the open-label placebo had less pain than those who received usual treatment. It seems that open-label placebos have effects similar to those of deceptive placebos (placebos that patients think are, or could be, the real treatment). The research on open-label placebos is still growing and it may turn out that they are not as effective as deceptive placebos. Still, we’ve done a systematic review of open-label studies and there is strong evidence that they work, and we know how.

This article The surprising success of “honest placebos” in medicine is featured on Big Think.

It can start small: a peculiar numbness; a subtle facial tic; an inexplicably stiff muscle. But then time goes by — and eventually, the tremors set in.

Roughly a million people in the United States (and roughly 10 million people worldwide) live with Parkinson’s disease, a potent neurological disorder that progressively kills neurons in the brain. As it does so, it can trigger a host of crippling symptoms, from violent tremors to excruciating muscle cramps, terrifying nightmares and constant brain fog. While medical treatments can alleviate some of these effects, researchers still don’t know exactly what causes the disease to occur in the first place.

A growing number of studies, however, are suggesting that it may be tied to an unlikely culprit: bacteria living inside our guts.

Every one of us has hundreds or thousands of microbial species in our stomach, small intestine and colon. These bacteria, collectively called our gut microbiome, are usually considerate guests: Although they survive largely on food that passes through our insides, they also give back, cranking out essential nutrients like niacin (which helps our body convert food into energy) and breaking down otherwise indigestible plant fiber into substances our bodies can use.

As Parkinson’s advances in the brain, researchers have reported that the species of bacteria present in the gut also shift dramatically, hinting at a possible cause for the disease. A 2022 paper published in the journal Nature Communications recorded those differences in detail. After sequencing the mixed-together genomes of fecal bacteria from 724 people — a group with Parkinson’s and another without — the authors saw a number of distinct changes in the guts of people who suffered from the disease.

The Parkinson’s group had dramatically lower amounts of certain species of Prevotella, a type of bacterium that helps the body break down plant-based fiber (changes like this in gut flora could explain why people with Parkinson’s disease often experience constipation). At the same time, the study found, two harmful species of Enterobacteriaceae, a family of microbes that includes Salmonella, E. coli and other bugs, proliferated. Those bacteria may be involved in a chain of biochemical events that eventually kill brain cells in Parkinson’s patients, says Tim Sampson, a biologist at Emory University School of Medicine and coauthor of the study.

At first glance, the relationship between bacteria and brain disease isn’t exactly obvious. How can a change in gut microbes kick off a devastating neurodegenerative disorder? The relationship between the two may seem counterintuitive — but Sampson says it comes down to the subtle ways that the brain and the gut are connected.

In the walls of the intestines, a network of neurons called the enteric nervous system lets the body sense what’s going on in the gut and respond accordingly. This circuitry controls muscle movement, local blood flow, secretion of mucus and other essential digestive functions.

Since the cells of the enteric nervous system are embedded in the gut wall, many of them come into close contact with the lumen — the cavity of the gut that contains the microbiome ­— where they can interact directly with biochemicals created by bacteria. Some of these are sticky proteins called curli (pronounced CURL-eye) that may be implicated in Parkinson’s.

Under normal circumstances, curli proteins let Enterobacteria build biofilms, the gooey mats that protect the microbes and help them stay put in the gut. Yet if a curli molecule touches a common protein created by nerve cells — called alpha-synuclein — that protein begins to misfold and form a dangerous mass called an aggregate. Once created, these aggregates can spread widely though the nervous system, leapfrog from cell to cell and eventually enter the brain through the vagus nerve, the main pathway that carries signals between the brain and the gut. It’s thought that in some cases of Parkinson’s in humans, changes in the gut microbiome may activate that process, says Emeran Mayer, a gastroenterologist and neuroscientist at UCLA and coauthor of a recent overview of the gut-brain connection in the Annual Review of Medicine.

Suspicion that the vagus plays a key role in neurodegenerative disease has been growing in recent years. A 2017 study in the journal Neurology, Mayer notes, showed that “If you cut the vagus nerve, it decreases the risk for Parkinson’s disease. That’s a pretty strong indication that … this degenerative material is transported, apparently, through the vagus nerve.”

Over the past few decades, a number of animal studies have shown that the vagus provides a physical conduit that molecules can use to move between the gut and brain — but although this neurological superhighway could play an important role in Parkinson’s, it’s still not clear if the nerve is a lynchpin in causing the disease itself.

In addition to aggregates moving through the vagus, different triggers — like the lipids, vitamins and other organic compounds that gut bacteria produce — could travel through blood vessels to the brain, where they may cause inflammation and damage tissue. Likewise, says David Hafler, a neuroimmunologist at Yale University, immune cells that are activated in the gut may contribute to the neurological damage and dysfunction that occurs in Parkinson’s.

These immune cells, called T cells, can migrate out of the gut, enter the bloodstream and cross the blood-brain barrier, where they ultimately may kill off neurons. This sort of autoimmune response is the driver for other neurological diseases like multiple sclerosis, Hafler reasons, so it’s feasible that it plays a role in Parkinson’s as well. In both diseases, changes in the gut microbiome could be the potential trigger.

There’s already strong evidence for this idea. In 2016, Sampson found a direct connection between gut microbes and Parkinson’s disease: Using fecal samples from Parkinson’s patients, Sampson inoculated the guts of germ-free mice (animals with no naturally occurring microbiome), and the animals quickly developed Parkinson’s symptoms. Today, using the new genetic survey of gut microbes he and his colleagues published in Nature Communications, he’s narrowing in on a few microbe families and using similar methods to reveal which precise species are the culprits.

Sampson’s approach comes with some caveats: Parkinson’s disease, after all, might be linked to multiple bacteria interacting in complex ways — so there likely won’t be a single smoking gun. It’s also not totally clear if changes in the microbiome are the root cause or if they just accelerate damage already taking place in the brain. The complexity of the microbiome is mind-boggling: There are hundreds of different types of bacteria involved, and each creates myriad molecules that affect digestion, the immune system and other important bodily functions. Sorting through all those components and identifying how they change in the face of disease will be an important next step.

And so, as tantalizing as the links between the microbiome and Parkinson’s may be, it could be decades before people who suffer from the disorder can reap any tangible benefits. Many of the researchers examining those links, like Mayer, also warn patients to be of wary of sweeping claims about drugs, supplements or even fecal transplants — seeding the gut with microbes from another, healthy person — that “treat” Parkinson’s by altering the microbiome.

“A lot of people make a lot of money selling individuals supplements, telling you that they’re going to slow your cognitive decline or prevent Parkinson’s disease,” says Mayer. But, he adds, “we don’t know the causal roles of the microbiome for sure. We know it from animal studies, so we have indirect evidence for it — but it’s been difficult to show in humans without a doubt that the microbes, and some of their signal molecules, play the main causal role.”

Until definitive answers are found, researchers like Mayer will continue to chip away at the problem, microbe by microbe.

This article How gut bacteria connect to Parkinson’s disease is featured on Big Think.

When you’re injured or sick, you should generally welcome signs of inflammation, such as redness, tenderness, heat, and swelling. These herald that the cavalry has arrived — your immune system is hard at work fighting off pathogenic invaders or beginning the healing process.

But when inflammation is omnipresent — regularly manifesting as joint pain, rash, or low-grade fever — that’s a sign that something is amiss. An essential tool of the immune system is malfunctioning: Rather than swiftly reacting to bodily harm and then dissipating when the threat has waned, inflammation is loitering like an unwelcome guest, potentially dealing unintended damage to the body and elevating the risk of heart disease and stroke.

When scientists have searched for biomarkers of chronic inflammation in individuals, they generally find them. One such marker, C-reactive protein, tends to show up in both young and elderly subjects, steadily increasing with age. This has prompted researchers to coin the concept of “inflammaging,” suggesting that rising chronic inflammation is simply a facet of getting old.

The thing is, these chronic inflammation studies have almost entirely been conducted in Western, industrialized societies, where residents tend to live sanitized, sedentary lives, with copious access to calorie-dense foods. Professor Thom McDade, a biological anthropologist at Northwestern University, says this narrow focus is skewing the scientific literature and leading to incorrect conclusions about chronic inflammation.

In a recent article published in the Proceedings of the National Academy of Sciences, McDade detailed research he conducted in the Philippines and Ecuador showing that chronic inflammation is relatively rare among people who don’t live Western-style lifestyles, and it is not inevitable with age.

Calibrating the immune system

So what is causing the high levels of inflammation among people raised in the West? Prior research has implicated excess body fat, but curiously, McDade didn’t find a link between body fat and levels of C-reactive protein among the Ecuadorians and Filipinos he studied.

This turned his attention to a different explanation: their upbringing. The populations he studied grew up in rural, dirty areas where they were frequently exposed to infectious diseases. He hypothesizes that this less-than-sanitary life early on effectively calibrated their immune systems, tuning their inflammatory responses to properly react to threats. These days, children in Western societies often don’t have their immune systems regularly challenged.

“Protection from potentially lethal infections is an obvious benefit and an important driver of the epidemiological transition toward increased life expectancy,” McDade noted. “But regimes of sanitation and hygiene that control lethal pathogens also reduce exposure to the harmless microbes that have been part of the human environment for millennia.”

In keeping with his hypothesis, he noted that when children grow up in rural areas in Bangladesh or Ecuador and then migrate to the US or the UK, they have lower baseline C-reactive protein as adults compared to adults who were born and raised in those countries.

“In many ways, chronic low-grade inflammation can be considered another ‘disease of affluence,’ a mismatch between our evolved biology and historically recent societal conditions that extend average life expectancies but also increase burdens of non-communicable diseases,” McDade wrote.

McDade’s idea is closely related to the widely evidenced “hygiene hypothesis,” which blames overly sanitized conditions for increasing rates of allergies and other autoimmune disorders in developed countries.

Is there a remedy for widespread chronic inflammation? Proper diet and regular exercise can help, as they do for almost any ailment. But if McDade’s hypothesis is correct, a longer-term cure is providing the immune system with reasonable adversity early on. Parents don’t have to let their kids crawl around landfills, but a little more dogs and dirt and a little less hand sanitizer and antibacterials seem reasonable.

This article Chronic inflammation may be a “disease of affluence” is featured on Big Think.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized primarily by problems with communication and social interactions. According to recent figures from the Centers for Disease Control and Prevention, the disorder affects an estimated one in 36 children. The incidence of autism was believed to have increased dramatically since the 1990s, but this apparent increase is more likely due to greater awareness of the condition and changes in how it is diagnosed. Despite any increased awareness, the exact causes of autism remain unclear. 

However, growing evidence suggests that specific environmental and genetic factors play a role. A large population-based study recently published in the open-access journal JAMA Network Open shows that children born to parents with fertility problems have a slightly higher risk of autism.

Fertility complications and autism

Maria Velez of Queen’s University in Ontario, Canada, and her colleagues examined the health data of more than 1.3 million live births between April 2006 and March 2018, the vast majority of which (almost 1.2 million, or 86.5%) were conceived naturally. 

About 142,000 (or about 10%) of the children were born to parents with subfertility, defined as a failure to conceive after one year of regular, unprotected intercourse; and the remaining were conceived by a method of assisted reproductive technology (in vitro fertilization, sperm injection, ovulation induction, or artificial insemination).  

The researchers followed up the children starting from 18 months of age up to 8 years. A total of 22,409 of them received a diagnosis of autism, at an average of just under 4 years of age. These included 1.6% of the children conceived naturally and 2% of those born to parents with subfertility.   

The results also showed that in children born to subfertile parents, the risk of autism was associated with obstetrical factors such as having twins or triplets or preterm birth. 

“Our study showed that IVF or ICSI did not increase the risk of ASD when compared with individuals with subfertility,” says Velez. “This suggests that underlying infertility might be the driver between parental infertility and the small risk of ASD in the child found in our study, independent of whether they received fertility treatment.”

“Further studies are needed to understand some of the mechanisms by which a parental diagnosis of infertility, independent of fertility treatment, is associated with a slightly higher risk of ASD in the child,” she adds. “For example, we need more details about paternal factors, and whether the egg or sperm are from the parent or a donor, among other things.”

This article Fertility problems linked to increased risk of autism is featured on Big Think.

Many American consumers are skipping the cereal aisle in grocery stores, viewing its contents as basically boxed candy. That’s understandable. A lot of cereals are chock-full of added sugars and refined grains, which can contribute to obesity and metabolic dysfunction. Ironically, at the same time, there may be no aisle more essential to the Americans’ health. That’s because cereals have become the de facto source for Americans’ micronutrients.

For decades, cereal manufacturers have fortified their products with synthetic vitamins and minerals, and now, we’re kind of reliant on them.

A 2011 study published in The Journal of Nutrition found that without fortified foods, 100% of Americans would fail to meet the estimated average requirement for vitamin D, 74% for vitamin A, 46% for vitamin C, 93% for vitamin E, 51% for thiamin, 22% for vitamin B6, and 88% for folate.

Not meeting these requirements wouldn’t necessarily lead to wide-scale nutritional deficiencies — Americans wouldn’t suddenly develop scurvy en masse. But it would likely lead to inadequacies that could covertly worsen Americans’ already notoriously poor health.

According to Victoria Drake at Oregon State University’s Micronutrient Information Center:

“Micronutrient inadequacies could elicit symptoms of general fatigue, reduced ability to fight infections, or impaired cognitive function (i.e., attention [concentration and focus], memory, and mood). Micronutrient inadequacies may also have important implications for long-term health and increase one’s risk for chronic diseases like cancer, cardiovascular disease, type 2 diabetes mellitus, osteoporosis, and age-related eye disease.”

A more recent analysis of data on more than 30,000 American adults found that people who skipped breakfast, along with the fortified foods that often accompany the meal, were significantly more likely not to meet the bottom threshold of requirements for various vitamins and minerals. Additionally, they were more likely to consume more added sugars, carbohydrates, and fats largely because they upped their snacking throughout the day.

In her 2015 book, Vitamania, journalist Catherine Price worried what might happen if breakfast foods weren’t nutritionally fortified. “If food companies didn’t voluntarily do so, the government might have to require it, to make sure that we don’t accidentally eat ourselves into nutritional deficiency,” she wrote.

But, she reasoned, there’s little chance that the status quo will change:

“If processed products were not enriched with synthetic vitamins, the nutritional emptiness of their raw ingredients would mean that we’d have to eat (or take) something else to meet our micronutrient requirements … We’ve created an odd symbiotic relationship, in which companies depend on us to buy their products, and we depend on the synthetic vitamins in these products to fulfill our nutritional needs.”

We can’t be sure exactly what would happen to America’s collective health without processed, fortified cereals. The effects would likely take years to manifest, and might not be that bad. A 2019 systematic review exploring the health effects of eating fortified cereals for children and adolescents found only “marginal” benefits. Moreover, it’s possible that Americans might make up the nutritional deficit elsewhere, perhaps by swallowing more nutritional supplements, or finally eating the whole fruits and vegetables most of us have been ignoring for decades.

This article Why Americans may be dependent on processed cereals is featured on Big Think.

Tiny “biobots” made from human windpipe cells encouraged damaged neural tissue to repair itself in a lab experiment — potentially foreshadowing a future in which creations like this patrol our bodies, healing damage, delivering drugs, and more.

The background: In a study published in 2020, researchers at Tufts University and the University of Vermont (UVM) harvested and incubated skin cells from frog embryos until they were tiny balls. 

They then sculpted the spheres into specific shapes — dictated by an algorithm — and added layers of cardiac stem cells to them in precise locations.

When they were done, they had created “xenobots,” assembled from frog cells, that could move around and perform entirely new actions based on their designs — one kind of xenobot would push pellets around a petri dish, for example, while another would spin in circles.

“These are novel living machines,” co-lead researcher Joshua Bongard said at the time. “They’re neither a traditional robot nor a known species of animal. It’s a new class of artifact: a living, programmable organism.”

These biological robots might one day navigate the human body, delivering drugs, performing surgery, clearing plaques from artery walls, and more, the team hypothesized in its study.

In 2021, the researchers updated their xenobots to be faster, have memories, and no longer require heart cells. But a major hurdle still stood between the group and its dream of using the biobots in medicine: they were made from frog cells.

That meant the xenobots would likely trigger an immune response in a person, and while immunosuppression could prevent this, it leaves patients at high risk of infection.

Anthrobots, assemble: Building on this xenobot research, Tufts scientists have now developed “anthrobots.” 

These biobots are derived from adult human cells, meaning a patient could use their own cells and avoid triggering an immune response. The biobots don’t reproduce and biodegrade after about 45-60 days in the lab, which would further reduce risks to patients.

Anthrobots are also easier to make than their predecessors.   

“Anthrobots self-assemble in the lab dish,” said study co-author Gizem Gumuskaya. “Unlike xenobots, they don’t require tweezers or scalpels to give them shape, and we can use adult cells — even cells from elderly patients — instead of embryonic cells.” 

“It’s fully scalable,” she continued. “We can produce swarms of these bots in parallel, which is a good start for developing a therapeutic tool.”

How it works: To create an anthrobot, the researchers start with a single cell taken from the surface of a person’s trachea. These cells in your windpipe are naturally covered in tiny, hair-like structures called “cilia” that help keep particles you breathe in out of your lungs.

This single cell is then placed in an environment resembling the human trachea and allowed to grow and multiply for 2 weeks.

At that point, the Tufts team only has a spherical clump of cells with all its cilia on the inside, so they place it in a solution that causes the hair-like structures to move to the exterior. Within days, the cilia start acting like oars, propelling the anthrobot around in its petri dish. 

An anthrobot moving through a “wound” in a neural tissue. Credit: Gizem Gumuskaya

While no two anthrobots were exactly alike, the Tufts team discovered that they tended to assemble themselves into certain categories. Some were spherical, covered in cilia, and wiggled largely in place. Others were football-shaped, with patches of cilia — those tended to move horizontally for longer stretches.

These different shapes and capabilities could potentially lend themselves to different types of therapies in the future. 

Neural repair: As a test of the little biobots, the Tufts team created a 2D layer of neurons in a petri dish and then scratched it with a metal rod. They then place a dense concentration of anthrobots on part of the “wound.” 

Surprisingly, their presence seemed to encourage healing — new neurons grew below the anthrobots, but not on gaps that were left uncovered. 

“It is fascinating and completely unexpected that normal patient tracheal cells, without modifying their DNA, can move on their own and encourage neuron growth across a region of damage,” said study leader Michael Levin, director of Tufts’ Center for Regenerative and Developmental Biology. 

“We’re now looking at how the healing mechanism works, and asking what else these constructs can do,” he continued.

We’d love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at tips@freethink.com.

This article Tiny biobots surprise their creators by healing wound is featured on Big Think.

In November 2021, Mickayla Wininger’s then one-month-old son, Malcolm, endured a terrifying bout with RSV, the respiratory syncytial (sin-SISH-uhl) virus—a common ailment that affects all age groups. Most people recover from mild, cold-like symptoms in a week or two, but RSV can be life-threatening in others, particularly infants.

Wininger, who lives in southern Illinois, was dressing Malcolm for bed when she noticed what seemed to be a minor irregularity with this breathing. She and her fiancé, Gavin McCullough, planned to take him to the hospital the next day. The matter became urgent when, in the morning, the boy’s breathing appeared to have stopped.

After they dialed 911, Malcolm started breathing again, but he ended up being hospitalized three times for RSV and defects in his heart. Eventually, he recovered fully from RSV, but “it was our worst nightmare coming to life,” Wininger recalled.

It’s a scenario that the federal government is taking steps to prevent. In July, the Food and Drug Administration approved a single-dose, long-acting injection to protect babies and toddlers. The injection, called Beyfortus, or nirsevimab, became available this October. It reduces the incidence of RSV in pre-term babies and other infants for their first RSV season. Children at highest risk for severe RSV are those who were born prematurely and have either chronic lung disease of prematurity or congenital heart disease. In those cases, RSV can progress to lower respiratory tract diseases such as pneumonia and bronchiolitis, or swelling of the lung’s small airway passages.

Each year, RSV is responsible for 2.1 million outpatient visits among children younger than five-years-old, 58,000 to 80,000 hospitalizations in this age group, and between 100 and 300 deaths, according to the Centers for Disease Control and Prevention. Transmitted through close contact with an infected person, the virus circulates on a seasonal basis in most regions of the country, typically emerging in the fall and peaking in the winter.

In August, however, the CDC issued a health advisory on a late-summer surge in severe cases of RSV among young children in Florida and Georgia. The agency predicts “increased RSV activity spreading north and west over the following two to three months.”

Infants are generally more susceptible to RSV than older people because their airways are very small, and their mechanisms to clear these passages are underdeveloped. RSV also causes mucus production and inflammation, which is more of a problem when the airway is smaller, said Jennifer Duchon, an associate professor of newborn medicine and pediatrics in the Icahn School of Medicine at Mount Sinai in New York.

In 2021 and 2022, RSV cases spiked, sending many to emergency departments. “RSV can cause serious disease in infants and some children and results in a large number of emergency department and physician office visits each year,” John Farley, director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a news release announcing the approval of the RSV drug. The decision “addresses the great need for products to help reduce the impact of RSV disease on children, families and the health care system.”

Sean O’Leary, chair of the committee on infectious diseases for the American Academy of Pediatrics, says that “we’ve never had a product like this for routine use in children, so this is very exciting news.” It is recommended for all kids under eight months old for their first RSV season. “I would encourage nirsevimab for all eligible children when it becomes available,” O’Leary said.

For those children at elevated risk of severe RSV and between the ages of 8 and 19 months, the CDC recommends one dose in their second RSV season.

The drug will be “really helpful to keep babies healthy and out of the hospital,” said O’Leary, a professor of pediatrics at the University of Colorado Anschutz Medical Campus/Children’s Hospital Colorado in Denver.

An antiviral drug called Synagis (palivizumab) has been an option to prevent serious RSV illness in high-risk infants since it was approved by the FDA in 1998. The injection must be given monthly during RSV season. However, its use is limited to “certain children considered at high risk for complications, does not help cure or treat children already suffering from serious RSV disease, and cannot prevent RSV infection,” according to the National Foundation for Infectious Diseases.

Until the approval this summer of the new monoclonal antibody, nirsevimab, there wasn’t a reliable method to prevent infection in most healthy infants.

Both nirsevimab and palivizumab are monoclonal antibodies that act against RSV. Monoclonal antibodies are lab-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. A single intramuscular injection of nirsevimab preceding or during RSV season may provide protection.

The strategy with the new monoclonal antibody is “to extend protection to healthy infants who nonetheless are at risk because of their age, as well as infants with additional medical risk factors,” said Philippa Gordon, a pediatrician and infectious disease specialist in Brooklyn, New York, and medical adviser to Park Slope Parents, an online community support group.

No specific preventive measure is needed for older and healthier kids because they will develop active immunity, which is more durable. Meanwhile, older adults, who are also vulnerable to RSV, can receive one of two new vaccines. So can pregnant women, who pass on immunity to the fetus, Gordon said.

Until the approval this summer of the new monoclonal antibody, nirsevimab, there wasn’t a reliable method to prevent infection in most healthy infants, “nor is there any treatment other than giving oxygen or supportive care,” said Stanley Spinner, chief medical officer and vice president of Texas Children’s Pediatrics and Texas Children’s Urgent Care.

As with any virus, washing hands frequently and keeping infants and children away from sick people are the best defenses, Duchon said. This approach isn’t foolproof because viruses can run rampant in daycare centers, schools and parents’ workplaces, she added.

Mickayla Wininger, Malcolm’s mother, insists that family and friends wear masks, wash their hands and use hand sanitizer when they’re around her daughter and two sons. She doesn’t allow them to kiss or touch the children. Some people take it personally, but she would rather be safe than sorry.

Wininger recalls the severe anxiety caused by Malcolm’s ordeal with RSV. After returning with her infant from his hospital stays, she was terrified to go to sleep. “My fiancé and I would trade shifts, so that someone was watching over our son 24 hours a day,” she said. “I was doing a night shift, so I would take caffeine pills to try and keep myself awake and would end up crashing early hours in the morning and wake up frantically thinking something happened to my son.”

Two years later, her anxiety has become more manageable, and Malcolm is doing well. “He is thriving now,” Wininger said. He recently had his second birthday and “is just the spunkiest boy you will ever meet. He looked death straight in the eyes and fought to be here today.”

This article A new injection is helping stave off RSV this season is featured on Big Think.

If just by looking at our watch or cell phone we can know, in real time, our heart rate, the number of steps we take, the calories we burn and the hours of sleep we got the night before, why can’t we also know our blood pressure?

Blood pressure is the force that the blood exerts against the arterial walls. It is defined by two values: systolic, or maximum pressure, which is the thrust of the blood pumped through the body by the contraction of the heart; and diastolic, or minimum pressure, which occurs when the heart relaxes. The American Heart Association considers blood pressure to be normal when it does not exceed pressures of 120 mmHg systolic and 80 mmHg diastolic — which we see presented as 120/80 mmHg.

When values are below 90/60 mmHg, the person is exhibiting hypotension. In athletes, this may be asymptomatic and without risk. But in other circumstances, it causes symptoms such as dizziness, nausea, pallor, blurred vision, confusion and fainting, because the brain isn’t receiving enough blood. Very low blood pressure can be life-threatening because of shock, a state where organs suffer damage due to lack of blood flow. This is more common in the elderly and can be precipitated by sudden changes in position, dehydration, infections, bleeding, certain medications and diseases such as Parkinson’s and diabetes.

Above 140/90 mmHg, the person is said to have high blood pressure. Researchers have calculated that in people ages 40 to 69, for every 20 mmHg increase in systolic blood pressure and 10 mmHg increase in diastolic blood pressure, the risk of coronary heart disease and stroke doubles. Worldwide, some 1.28 billion people between the ages of 30 and 78 have hypertension, most of them living in low- and middle-income countries, and more than half of them are not treated, according to a 2021 study published in The Lancet. This is despite the fact that hypertension can be easily detected by measuring blood pressure — at home or in a health facility — and can often be effectively treated with low-cost medications.

Today, a new generation of blood pressure devices aims to make it easier to diagnose — and control — hypertension. Unlike traditional devices, they do without the arm cuff and offer blood pressure values on demand, should the user press their finger on a sensor, or continuously, if measured by a watch, ring or bracelet.

“Regular blood pressure monitoring in all adults would improve hypertension awareness. For those who have hypertension, it may improve their control,” says Ramakrishna Mukkamala, a bioelectrical engineer at the University of Pittsburgh, who coauthored a look at blood pressure measurement using cuff-free devices in the 2022 Annual Review of Biomedical Engineering. “For example, if patients continue to see that their blood pressure is high, they may finally become compliant in taking their medications.”

Leaving the cuff behind

The measurement of blood pressure goes back almost three centuries (see sidebar), leading to the procedure that we all know and that our family doctor performs when we have checkups: A cuff goes around our arm and is inflated, then deflated, in a controlled manner, to determine our maximum and minimum blood pressure.

But the use of inflatable-cuff blood pressure monitors has some drawbacks. For one thing, unless people have home monitors — and a survey of adults ages 50 to 80 in the United States found that only 55 percent of hypertension patients surveyed owned one — they must go to a pharmacy, doctor’s office or health center to learn what their blood pressure is.

Another barrier is that repeated inflation and deflation of the cuff is disruptive and can cause difficulties when, for example, a patient is in the hospital and needs frequent blood pressure monitoring. And a third drawback is that since cuffs don’t allow continuous measurement of blood pressure, they’re only providing a measurement at a specific moment.

The new cuffless devices promise to reveal a more complete picture of physiologic changes in blood pressure that cannot be picked up with spot measurements, and instead give a truer blood pressure profile, says Alberto P. Avolio, a biomedical engineer at Macquarie University in Sydney, Australia, a coauthor of the article in the Annual Review of Biomedical Engineering.

New blood pressure measurement technologies are based on methods that use miniaturized sensors inside everyday items to “pick up” indirect signals, from which the blood pressure value is estimated. These include photoplethysmography (PPG), electrocardiography (ECG), ballistocardiography (BCG), seismocardiography (ECG) and electrical bioimpedance (EBI).

The various cuffless measuring devices are based on methods that, instead of directly determining blood pressure, use sensors to capture various indirect signals. These signals are processed by different algorithms or sets of mathematical procedures to obtain the blood pressure values. It is like inferring fever by measuring an increase in palpitations and sweating instead of using a thermometer, or divining the result of a soccer match from outside the stadium by listening to the screams of the spectators.

One of the detection methods uses optical sensors. The technique is based on the principle of photoplethysmography or PPG: It consists of illuminating a segment of the skin and analyzing the difference between the light that is emitted by the instrument and how much is detected by a photoreceptor. This difference depends on the diameter of the artery, the blood volume and the concentration of hemoglobin (the oxygen-carrying protein) at the measurement site. During the systolic phase, when the heart pumps blood, the difference between emitted and reflected light will be at its maximum, because there will be more blood flow and thus more hemoglobin and other light-absorbing proteins; during the diastolic or relaxation phase, it will be at its minimum. The algorithm relates these measurements to blood pressure.

This is the same method used by the Apple Watch and other devices to measure heart rate, and by the pulse oximeters that became popular during the Covid-19 pandemic to record the level of saturation, or oxygenation, of the blood. It is also the method used by the Swiss company Aktiia’s wristband, available only in Europe for now. This device automatically records blood pressure values over 24 hours, even when someone is sleeping, averaging the results every two hours and displaying the results through an app on a smartphone.

There are also electrical sensors, which are modified versions of the electrocardiogram that measures the electrical activity of the heart; mechanical sensors, used in ballistocardiography and seismocardiography, which attach to the surface of the skin to capture small variations in pressure; and bioimpedance sensors, similar to the instruments that analyze body composition by measuring the body’s resistance to the flow of electrical current.

Calibrated and uncalibrated

There are two broad categories into which these new cuffless blood pressure measurement devices can be grouped: those that require calibration — periodic comparison of the recordings with those obtained with a manual or digital sphygmomanometer — and those that do not.

Both types of devices capture signals from the body noninvasively, from the fingertip, ear or wrist, to name the most common sites. The estimated blood pressure is then displayed or transmitted to nearby devices, such as smartphones or tablets.

One of the measurement methods that require calibration is the pulse transit time, or PTT, which represents the time in milliseconds that the pulse takes to travel between two arterial points: The stiffer an artery is, the higher the arterial pressure will be (because the pulse travels faster) and the lower the PTT will be. This method is the one with the most scientific evidence to date.

Another is based on analysis of the shape and amplitude of the pulse wave, which is the pressure wave depicting the propagation of the blood pumped by the heart through the entire arterial tree, and whose characteristics depend in part on the rigidity of the artery walls. In people with hypertension, the amplitude of the pulse wave is greater because the heart must exert more force to overcome the resistance of the arteries. 

More recently, other devices have emerged that use images captured with a camera — like selfies — to detect changes in the PTT or subtle modifications in the color of the face, imperceptible to the eye, that accompany each heartbeat, thus reconstructing the flow of blood under the skin and the shape of the pulse waves.

Uncalibrated cuffless blood pressure measurement methods aim to eliminate the need to cross-check the device’s measurements with those captured by a classic sphygmomanometer or digital sphygmomanometer. They use only machine learning and artificial intelligence to establish, from the signals captured by the sensors, the person’s blood pressure values.

Just as a jet of water can exert more or less force on the walls of a hose if one changes the height or opening of a faucet, the analysis of oscillations or fluctuations in blood volume can be measured when a ring is worn and the arm is lowered, because the finger’s internal blood pressure increases as it receives more blood flow due to gravity. Alternatively, a ring can also obtain measurements of the oscillations in blood volume by periodically applying gentle pressure on the finger. A sensor in a smartphone can also do this analysis when it is pressed following the instructions given by the device.

Other methods for uncalibrated devices use ultrasound waves to visualize variables such as artery dimensions and blood flow velocity, which are also related to blood pressure.

Cuffless blood pressure measurement devices are grouped into those that require calibration — periodic cross-checking of readings against those obtained with a manual or digital cuffed sphygmomanometer — and those that do not. Both types of devices capture signals from the body noninvasively and then display the results on devices such as watches, smartphones or tablets.

The road to clinical application

The development of these devices for measuring blood pressure without a blood pressure cuff is progressing rapidly, but that doesn’t mean they are ready for use in the medical world. “Unfortunately, the pace of evidence, regulation and validation testing has lagged behind the pace of innovation and direct consumer marketing,” write Stephen P. Juraschek, physician investigator of Beth Israel Deaconess Medical Center in Boston, and colleagues in a review published in September in Current Cardiology Reports.

There is currently no standardized validation protocol to assess the accuracy of cuffless devices, as required by the US Food and Drug Administration, although several of these developments have already received marketing authorization in the US. The European Society of Hypertension, for its part, has issued guidelines that emphasize that, for now, cuffless devices should not be used to make diagnostic and treatment decisions. “The potential clinical value of cuffless blood pressure measurement is enormous. However, the caveats are equally large,” says James Sharman, an expert in blood pressure measurement methods and an exercise physiologist at the University of Tasmania in Australia.

Before wider use can be advocated, it will be necessary to test whether cuffless devices make accurate recordings and whether they have clinical superiority to the current standard of blood pressure measurement, as well as to determine how they would integrate into current medical practice, Sharman adds. In addition, since each device has its own algorithm and method for estimating pressure, each should demonstrate its performance separately.

This work is already underway. According to the ClinicalTrials.gov database, as of October 2023 more than 10 studies to evaluate cuffless blood pressure measuring devices were recruiting participants.

Several studies have already been completed. In Switzerland, a team evaluated the use of such devices for ambulatory blood pressure monitoring (ABPM), which measures blood pressure continuously over 24 hours and is a better predictor of cardiovascular health than non-continuous measurements.

The study involved 67 patients who performed traditional ABPM, using a cuff device, but also had a watch-like optical sensor placed on their upper arm or wrist opposite the arm wearing the cuff. Although there were differences between the measurements of the two devices, the difference was small and within the limits recommended by the international standard. “These results are encouraging and suggest that 24-hour cuff-free ABPM may soon become a clinical possibility,” the authors noted in their conclusions. In addition, study participants said that the optical sensor was more comfortable and overwhelmingly preferred it to its cuffed alternative.

In South Korea, meanwhile, a recent observational study followed 760 people who used a Samsung Galaxy watch approved in that country for one month to monitor blood pressure. The device requires calibration once a month, but interestingly, 75 percent of the participants did not rely on a single monthly calibration, as suggested, but performed more frequent calibrations. This allowed the researchers to determine that poor calibration can affect the device’s measurements and that calibration processes need to be standardized to ensure the device’s proper functioning.

But encouragingly, the study also found that “smartwatch-based blood pressure measurement is feasible for out-of-office blood pressure monitoring in the real world” — as, on average, participants measured their blood pressure 1.5 times per day.

Will the day come when we can accurately know our blood pressure just by looking at our smartwatch or cell phone? “Maybe in time, but not in the near future,” Avolio says. More studies are needed, he says, before cuffless devices can provide reliable quantitative information to track physiological changes with acceptable accuracy.

This article Devices that could change how we measure blood pressure is featured on Big Think.

A team of Chinese scientists has used gene therapy to correct a mutation that caused mice to exhibit autistic behaviors like hyperactivity, repetitive self-grooming, and abnormal social interactions. Once the mutation was fixed, the animals’ behavior returned to normal.

The experiment, described November 27 in a paper published in the journal Nature Neuroscience, is the first successful attempt to use genome editing to reverse autistic behaviors in an animal model of autism spectrum disorder (ASD). ASD refers to a variety of conditions characterized by challenges with social skills, repetitive behaviors, and poor communication. These behavioral difficulties can range from barely noticeable to profoundly debilitating. ASD affects about one in 36 children in the U.S.

Autism is thought to be caused by a mix of environmental and genetic factors. But while scientists have struggled to convincingly implicate specific environmental influences, they have pinpointed a number of genes that, when mutated, greatly increase the risk of autism. One of these genes is called MEF2C. It’s directly involved in skeletal muscle growth and blood vessel formation, potentially playing a role in structuring the brain’s cerebral cortex. A mutation to MEF2C results in severe ASD in humans. These individuals are often unable to speak, may grind their teeth incessantly, and may also suffer from epilepsy.

ASD and base editing

In their experiment, the researchers genetically engineered a line of mice with a mutated MEF2C gene. These mice exhibited noticeably autistic behaviors compared to unaltered mice. They then used a type of genome editing called base editing to correct the mutation. Lo and behold, the mice started behaving just like their peers.

For years, genome editing has been synonymous with CRISPR-Cas9. Base editing is a more recent advance, dating to 2016. While CRISPR-Cas9 is essentially a chainsaw, hacking off a portion of the DNA strand, base editing is more like a scalpel, targeting single nucleotides (A, T, C, G) on the strand. CRISPR can make wholesale changes, but can sometimes misfire and cleave unintended portions of DNA. Although base editing is far more accurate, it can only make smaller changes to the genome.

In the current experiment, a tiny alteration was all that was needed. Base editing corrected the animals’ autistic behaviors with no apparent ill effects. Another key accomplishment in the study was getting the editor across the blood-brain barrier, a notorious hurdle when it comes to treating neurological disorders. The scientists shepherded their prized payload across the barrier by hitching it to an adeno-associated virus. These basic, diminutive viruses are often ignored by the immune system and can integrate into a host’s genome without inflicting harm.

“Together, these results establish a framework for using genome editing… in the brain to correct genetic mutations and provide potential therapeutic approaches for individuals with genetic neurodevelopmental disorders,” the researchers wrote.

Proof of concept

Other neurological disorders that could also be targeted by base editing include Rett syndrome, Fragile X syndrome, Angelman syndrome, and Pitt-Hopkins syndrome.

“Overall, I think it is a fascinating observation!” Dr. Alysson Muotri, a professor in pediatrics and cellular and molecular medicine at the University of California-San Diego, told Big Think. Some of Muotri’s research focuses on the cellular mechanisms underlying autism.

The success represents a solid “proof-of-principle” in the long and winding journey toward an ASD treatment, he added, cautioning that it will be some time before it might be replicated in humans.

“We are still quite far from these experiments, both from a safety issue (these enzymes could have potential harmful off-targets) and from a practical delivery (the human brain is much bigger than a mouse),” he wrote via email. “But that’s how science works, generating data from relevant model systems and moving towards the application in humans.”

Another key caveat of the current experiment is that base editing will only work for small, tidy mutations to single genes. It’s rare to find instances in humans where just one mutation can be conclusively blamed for an individual’s disorder. This means that base editing could not be used as a blanket cure for every form of autism.

Nor should it. Most autistic individuals are just as — if not more — mentally capable than anyone else. As Muotri stated in a 2022 talk, any future gene therapies will likely only be used for the individuals most profoundly affected by the disorder.

This article Genome editing reverses autistic behaviors in mice is featured on Big Think.

The first-in-human trial of an experimental drug, lepodisiran, found that a single shot could dramatically and durably reduce blood levels of lipoprotein(a), a currently untreatable risk factor for heart disease.

The challenge: Your levels of LDL cholesterol — the bad kind that clogs arteries and leads to heart disease — are based on a combination of factors, including genetics, diet, and lifestyle.

That means if your LDL is too high, you can change what you eat, exercise more, or cut back on vices, like smoking and alcohol. There are also drugs, like statins, that are highly effective at lowering LDL levels.

An estimated 20% of the global population has high levels of Lp(a).

Lipoprotein(a), or Lp(a), is another particle produced by your liver, just like LDL cholesterol, and high levels in your blood independently raises your risk of heart disease. Unlike LDL cholesterol, though, your Lp(a) levels are determined almost entirely by genetics.

That means an estimated 20% of the global population who have high levels of Lp(a) can’t reduce this major risk factor for heart disease, and there aren’t any proven medicines to significantly lower Lp(a) levels, either. (To mitigate their risk, this group must be even more careful about their LDL levels, since that’s the only factor they can control.)

What’s new? On November 12, researchers published the results of a phase 1 trial of an experimental drug being developed by pharma giant Eli Lilly. The drug was shown to lower participants’ high Lp(a) levels by as much as 96% from their baseline. 

“If further trials show that this medication — lepodisiran — is safe and can reduce heart attacks and strokes, it would be good news for patients because it eliminates a risk factor we’ve been unable to treat,” said lead study author Steve Nissen.

“Its effectiveness at lowering Lp(a) was profound.”

STEVE NISSEN

How it works: Lepodisiran is a small interfering RNA (siRNA), an aptly named therapy that works by interfering with RNA, the genetic material that translates your DNA into instructions for your cells to make certain molecules. The siRNA stops the RNA from being translated into proteins, essentially “silencing” a gene without affecting your DNA.

The RNA that lepodisiran targets creates an essential component of Lp(a).

“How do you beat a risk factor that’s largely genetic? One highly effective approach is to interfere with the gene, and that’s what lepodisiran and other new therapies are designed to do,” said Nissen.

After 48 weeks, their Lp(a) levels were still 94% lower than prior to the trial.

The phase 1 trial of lepodisiran included 48 people with elevated Lp(a) levels. Twelve were given a single injection of a placebo. The others were divided into groups of six, with each group given a different-sized dose of lepodisiran, ranging from 4 milligrams all the way up to 608 mg.

In the highest dose group, blood Lp(a) levels were actually undetectable 29 days after the injection. They started to rise slowly after 40 weeks, but even at 48 weeks, they were still 94% lower than prior to the trial. The next-highest dosage, 304 mg, saw a 75% reduction even after 48 weeks. 

No safety issues cropped up during the trial, and the only adverse effects were mild injection site pain.

Looking ahead: A phase 2 trial of lepodisiran is already underway. It’ll include more than 250 people with elevated Lp(a) levels and is expected to wrap up in October 2024.

“In our view, this therapeutic is very promising,” said Nissen. “These [phase 1] data indicate lepodisiran is safe, and its effectiveness at lowering Lp(a) was profound, with near-total elimination of Lp(a) that lasted for a long time. We’ll know more after the phase 2 study.”

This article Experimental drug cuts heart disease risk factor by 96% is featured on Big Think.

In rare cases, a woman’s heart can start to fail in the months before or after giving birth. The all-important muscle weakens as its chambers enlarge, reducing the amount of blood pumped with each beat. Peripartum cardiomyopathy can threaten the lives of both mother and child. Viral illness, nutritional deficiency, the bodily stress of pregnancy, or an abnormal immune response could all play a role, but the causes aren’t concretely known.

If there is a silver lining to peripartum cardiomyopathy, it’s that it is perhaps the most survivable form of heart failure. A remarkable 50% of women recover spontaneously. And there’s an even more remarkable explanation for that glowing statistic: The fetus‘ stem cells migrate to the heart and regenerate the beleaguered muscle. In essence, the developing or recently born child saves its mother’s life.

Saving mama

While this process has not been observed directly in humans, it has been witnessed in mice. In a 2015 study, researchers tracked stem cells from fetal mice as they traveled to mothers’ damaged cardiac cells and integrated themselves into hearts.

Scientists also have spotted cells from the fetus within the hearts of human mothers, as well as countless other places inside the body, including the skin, spleen, liver, brain, lung, kidney, thyroid, lymph nodes, salivary glands, gallbladder, and intestine. These cells essentially get everywhere. While most are eliminated by the immune system during pregnancy, some can persist for an incredibly long time — up to three decades after childbirth.

This integration of the fetus’ cells into the mother’s body has been given a name: fetal microchimerism. The process appears to start between the fourth and sixth week of gestation in humans. Scientists are actively trying to suss out its purpose. Fetal stem cells, which can differentiate into all sorts of specialized cells, appear to target areas of injury. So their role in healing seems apparent. Evolutionarily, this function makes sense: It is in the fetus’ best interest that its mother remains healthy.

Sending cells into the mother’s body may also prime her immune system to grow more tolerant of the developing fetus. Successful pregnancy requires that the immune system not see the fetus as an interloper and thus dispatch cells to attack it.

Fetal microchimerism

But fetal microchimerism might not be entirely beneficial. Greater concentrations of the cells have been associated with various autoimmune diseases such as lupus, Sjogren’s syndrome, and even multiple sclerosis. After all, they are foreign cells living in the mother’s body, so it’s possible that they might trigger subtle, yet constant inflammation. Fetal cells also have been linked to cancer, although it isn’t clear whether they abet or hinder the disease.

A team of Spanish scientists summarized the apparent give and take of fetal microchimerism in a 2022 review article. “On the one hand, fetal microchimerism could be a source of progenitor cells with a beneficial effect on the mother’s health by intervening in tissue repair, angiogenesis, or neurogenesis. On the other hand, fetal microchimerism might have a detrimental function by activating the immune response and contributing to autoimmune diseases,” they wrote.

Regardless of a fetus’ cells net effect, their existence alone is intriguing. In a paper published earlier this year, University of London biologist Francisco Úbeda and University of Western Ontario mathematical biologist Geoff Wild noted that these cells might very well persist within mothers for life.

“Therefore, throughout their reproductive lives, mothers accumulate fetal cells from each of their past pregnancies including those resulting in miscarriages. Furthermore, mothers inherit, from their own mothers, a pool of cells contributed by all fetuses carried by their mothers, often referred to as grandmaternal microchimerism.”

So every mother may carry within her literal pieces of her ancestors.

This article How a fetus can save its mother’s life is featured on Big Think.

We are more afraid of risks that are human-made than those that arise naturally. When the Health Information National Trends Survey (HINTS) in 2001 asked people what they thought increased their risk of getting cancer, 80% believed that pesticides and food additives raised their risk, and 88% said pollution. In a 2019 version of the survey, 79% agreed a lot or somewhat that “everything causes cancer.”

The widespread fear that many modern products and processes cause cancer arose amid the smog, burning rivers, and hazardous waste dumps that spurred our awareness of and concern about environmental problems in the sixties and seventies. In chapter 14 of Silent Spring (ominously titled “One in Four,” as in, one in four of us will get cancer), Rachel Carson wrote: “With the dawn of the industrial era the world became a place of continuous, ever-accelerating change. Instead of the natural environment there was rapidly substituted an artificial one composed of new chemicals and physical agents, many of them possessing powerful capacities for inducing biologic change. Against these carcinogens which his own activities had created man had no protection.” 

Stunningly for a scientist (a marine biologist), Carson instinctively played on the psychological tendency to fear the human-made over the natural when she wrote, “Man, alone of all forms of life, can create cancer-producing substances.” That isn’t close to true. Nature “creates” all sorts of carcinogens too. 

Though we now know that most cancers are the result of natural processes that cause DNA mutations leading to uncontrolled cell growth, and that diet, exercise, and other lifestyle choices can reduce the risk of cancer by as much as 40%, the myth remains embedded in common belief, reinforced by environmental advocates and the general news media, that cancer is largely the result of modern human-made products and processes.

Consider this example: In 2010 the Telegraph (a British newspaper) reported that a study of mummies had found very few cancers. According to the study’s authors, that meant, as the headline read,

“Cancer Caused by Modern Man”
as it was virtually non-existent in ancient world. Cancer is a modern man-made disease caused by the excesses of modern life, a new study suggests. 

The newspaper’s science reporter, who surely should have known better, repeated the huge leap the study authors had made to reach their biased conclusions: “The findings suggest that it is modern lifestyles and pollution levels caused by industry that are the main cause of the disease and that it is not a naturally occurring condition.”

The study would have made Rachel Carson proud. The authors wrote, “A striking rarity of malignancies in ancient physical remains might indicate that cancer was rare in antiquity, and so poses questions about the role of carcinogenic environmental factors in modern societies.” Neither the study nor the news report made any mention of the fact that people in “antiquity” usually didn’t live long, and that the modern rise in cancer prevalence corresponds with our longer life spans. Or that cancer in soft tissues wouldn’t show up in fossils. 

Fighting the entrenched misbelief that “everything causes cancer” is hard. The highly respected Cancer Research UK tried, calling the study factually incorrect and misleading, as well as directly addressing the psychological factors of control and less fear of what is natural than what is human-made, saying, “It can be tempting to worry about our cancer risk from external things like pollution and chemicals more than from things we can control, like our lifestyles. But decades of research have shown that lifestyle factors — such as not smoking, keeping a healthy weight, limiting alcohol, getting enough exercise, and avoiding sunburn — have an important effect on cancer risk. In contrast, the evidence that pollution and industrialization has a widespread role in UK cancer rates is weak.”

The belief that cancer is mostly caused by human-made substances explains why any mention of the word “chemicals” or “radiation” sets off alarms. (Magnetic resonance imaging was originally called nuclear magnetic resonance imaging. The “nuclear” was dropped to avoid the frightening allusion to weapons and radiation.) And it explains why scientists frustrated by “chemophobia” and “radiophobia,” corollaries of cancerphobia, try to reduce those fears by arguing, “All of nature is made out of chemicals,” and, “If we’re worried about nuclear power we should also worry about natural sources of radiation like the sun and bananas.”

This article Curing cancerphobia: How the psychology of fear distorts our view of cancer is featured on Big Think.

The first-in-humans trial of a CRISPR-based cholesterol treatment has delivered promising results, with one participant in the small study experiencing a 55% reduction in their cholesterol levels. However, the company will need to show that the treatment is safe, after concerning safety data.

The world’s top killer: Cholesterol is a waxy substance made by our livers and found in certain foods. It comes in two forms, HDL and LDL, and while having high levels of HDL cholesterol in your blood appears beneficial, high levels of LDL cholesterol will eventually block your arteries, leading to cardiovascular disease, heart attacks, and strokes.

This kind of heart disease is the number one cause of death in the U.S. and around the world, and even non-fatal heart attacks and strokes can cause severe pain and disability for millions of others.

“There are people walking around who have the [PCSK9] gene naturally turned off… and are resistant to heart attack.”

SEKAR KATHIRESAN

There are ways to lower high LDL levels, but none is ideal, and for some people, they still aren’t enough to keep their cholesterol levels in a healthy range.

Pills called statins are the most common cholesterol treatment, but they have to be taken daily and sometimes cause intolerable side effects. Newer injectable meds can be administered just twice yearly, but those are expensive and not always covered by insurance. A healthier diet, meanwhile, can help, but that’s also very tough in practice for many people.

The idea: Boston-based biotech firm Verve Therapeutics is developing what could be a one-and-done, life-long cholesterol treatment.

This therapy, called VERVE-101, is designed to deactivate a gene in the liver that controls the production of PCSK9, a protein that regulates the amount of LDL in the blood.

“There are people walking around who have the [PCSK9] gene naturally turned off,” Verve CEO Sekar Kathiresan told Freethink. “They have very low levels of cholesterol in the blood and are resistant to heart attack, so the company is basically built off of that insight.”

VERVE-101 permanently deactivates the PCSK9 gene in the liver by using CRISPR to change just one letter in its DNA. This technique is called “base editing,” and Verve’s trial is the first to test it in humans.

What’s new? In trials on monkeys, VERVE-101 reduced LDL levels by nearly 70% after just two weeks, and they remained low for 2.5 years.

Verve has now shared the interim data for heart-1, a phase 1b trial of the therapy involving 10 people with heterozygous familial hypercholesterolemia (HeFH), a potentially life-threatening genetic disorder that causes very high LDL for a person’s entire life.

“This study reveals the potential for a new treatment option — a single-course therapy that may lead to deep LDL-C lowering for decades.”

ANDREW M. BELLINGER

According to the company, just one dose of the cholesterol treatment could lower LDL levels by up to 55% after 28 days. The benefit persisted through six months of follow up, too.

“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option — a single-course therapy that may lead to deep LDL-C lowering for decades,” said Verve’s CSO Andrew M. Bellinger.

The details (and the safety concerns): The researchers tested the cholesterol treatment as an infusion at four different dosages: 0.1 mg/kg, 0.3 mg/kg, 0.45 mg/kg, or 0.6 mg/kg. Each dosing group included three people, except the highest dose — only one person received it.

Only the two higher doses were expected to have a therapeutic effect — the lower doses were included to assess safety and tolerability — and the person who experienced the 55% reduction in their LDL levels received the highest dose.

Two people in the 0.45 mg/kg group experienced reductions of 48% and 39%. The third had a heart attack the day after treatment and did not have their data included in the report. That person was having chest pains before receiving the gene therapy, but didn’t tell the researchers, according to Verve.

No one in the lower dose groups experienced treatment-related adverse events, but mild and moderate adverse events occurred in the higher dose groups. These were temporary, and included infusion site reactions and elevated liver enzyme levels.

Five weeks after treatment, however, one person in the 0.3 mg/kg group had a fatal heart attack, although investigators determined it was not related to the treatment.

History lesson: This was a very small study, and 2 out of 10 participants experiencing heart attacks after treatment is a serious concern — Verve’s stock plummeted after the trial results were announced.

However, because gene editing is still very new, the FDA only allows researchers to enroll people with severe, advanced disease in first-in-human trials.

“Their arteries have been clogging from birth, and so they have a lot to potentially gain.”

SEKAR KATHIRESAN

The fact that two people had heart attacks isn’t necessarily surprising when you consider these were all people with serious heart disease prior to starting the trial — nine had already undergone surgeries to improve blood flow to their hearts, and four had had prior heart attacks. And despite taking the maximum dose of statins, their average LDL cholesterol entering the trial was 193 mg/dL, compared to a goal of <70 mg/dL for high-risk patients.

“These patients, their cholesterol has been high their whole lives,” said Kathiresan. “Their arteries have been clogging from birth, and so they have a lot to potentially gain from a treatment that would reduce their cholesterol dramatically and durably.”

Nonetheless, Verve will need to prove to regulators and the public that its treatment is safe enough for the benefits to be worth the risks.

Looking ahead: Verve is now enrolling more participants into the trial’s 0.45 mg/kg and 0.6 mg/kg cohorts. Its goal is to use information from this stage to determine the ideal dose of its cholesterol treatment to test in a larger trial in 2024.

While Verve is currently focusing on people with HeFH, because they have the most to gain, its ultimate goal is to have a CRISPR therapy that can durably reduce anyone’s LDL cholesterol levels for life.

“We’re looking to take this new approach to treating not just a rare disease or cancer — which is often what a lot of gene-editing therapies are focused on — but rather to literally the most common cause of death in the world,” said Kathiresan.

“But we’re going to be doing it in a very measured way, a graduated way, starting with a genetic form of the disease and then expanding out to larger groups, assuming after showing that it can work and be safe,” he continued.

Update, 12/01/23, 9:25 am ET: This article was updated to correct the number of trial participants who died during the study.

Journalist B. David Zarley contributed to this report.

This article One dose CRISPR therapy cuts cholesterol by up to 55% is featured on Big Think.

A few months ago, James Hamblin made a splash when announcing he hadn’t showered or used much soap in five years. The physician, Yale public health lecturer, and staff writer at The Atlantic experimented on himself as research for his latest book, Clean: The New Science of Skin.

Hygiene rituals are as old as recorded civilization. While Muslims and Hindus created elaborate cleaning rituals, European Christians thought bathing increased your chances of falling ill thanks to miasma theory. For centuries, changing your linen shirt supposedly bestowed cleanliness — not soap and water. Many Christians during this era only had one bath in their entire lives: baptism.

Though we certainly want to wash more often than once a year, Hamblin points out that many current hygiene and skincare rituals have moved us too far in the opposite direction. In fact, our expensive rituals may be more harmful than helpful. Additionally, modern hygiene and skincare is a time suck. As Hamblin points out, if you spend a half hour showering and applying products every day, you will devote over two years to grooming-related activities over the course of a century-long life.

In his previous book, If Our Bodies Could Talk, Hamblin investigated numerous body myths. In Clean, he focuses on our largest organ. Skin is an environment unto itself. What follows are six important lessons in his book, ranging from hygiene to greed.

#1. An obsession with soap might be creating allergies

In the quest to protect our children against bacteria, we might inadvertently create lifelong allergies. An uptick in peanut allergies is indicative of this trend. Our skin is the first line of defense against disease, and it knows how to protect itself. The organisms and bacteria that live on our skin are doing important work; the more we wash them away, the more susceptible we become to foreign invaders.

Nut allergies might only be one consequence of overwashing. Allergic rhinitis, asthma, and eczema might in part be caused (or provoked) by too many antibacterial soaps (or soap in general). As Hamblin writes, “Soaps and astringents meant to make us drier and less oily also remove the sebum on which microbes feed.”

#2. Your skin is crawling with mites

Speaking of foreign invaders, skin science supports an old Buddhist idea: There is no self. As Hamblin puts it, “Self and other is less of a dichotomy than a continuum.” In fact, “you” are a collection of organisms and bacteria, including the mite Demodex. A half millimeter in length, these “demon arachnids” are colorless and boast four pairs of legs, which they use to burrow into the skin on our face. Yes, your face, too.

While these mites were originally discovered in 1841, it wasn’t until 2014 that a group of researchers in North Carolina used DNA sequencing to understand their impact. Though you might recoil at the suggestion, it turns out that these critters potentially act as natural exfoliants. While housing too many of these mites results in skin disease, your face is their home. If not for them, you might even be more susceptible to breakouts and infections.

#3. Soap benefited from ingenious marketing

Soap is chemically simple. Combine fat and alkali to create surfactant molecules. The fat can be animal- or plant-based — three fatty acids and a glycerin molecule create a triglyceride. Combine this mix with potash or lye, apply heat and pressure, and wait for the fatty acids to rush away from the glycerin. Potassium or sodium binds to fatty acids. That’s soap.

What you’re paying for are the scent and packaging. In 1790, the first patent in history was approved for an ash processing method that produced soap. It wasn’t an immediate hit; the balance was off. Too much lye resulted in a lot of burnt skin. A century passed before companies convinced Americans regular washing was necessary. Thanks to ingenious marketing — we still have radio-inspired “soap operas” today, though barely — soap became a must-have. A luxury became a common good.

Marketers convinced the public that everyone should buy a lot of soap. As Hamblin phrases it, “Capitalism sells nothing so effectively as status. And if a little bit was good, a lot would be better.” Soap infected mainstream consciousness.

#4. The skincare industry is largely unregulated

Hamblin tried another project for this book: He launched a skincare line. One day, he went to Whole Foods and purchased raw ingredients: jojoba oil, collagen, shea butter, and a few other things. After mixing them in his kitchen, he ordered glass jars and labels from Amazon. In total, he spent $150 (which included his company website) to launch Brunson + Sterling. He then posted two-ounce jars of Gentleman’s Cream for $200 (on sale from $300!).

Hamblin didn’t sell any jars, but that wasn’t the point. At an expo, he noticed one-ounce jars of SkinCeuticals C E Ferulic selling for $166, even though that topical acid is no more effective at improving health than eating an orange. Collagen is another hype machine. Drinking collagen does nothing for your skin as it’s broken down by enzymes in your digestive tract. Even so, plenty of companies claim it gives you glowing skin.

Even more incredibly, Hamblin didn’t have to report any ingredients to the FDA. He also didn’t need to note its effects or provide evidence of safety. All he had to do was apply for a business license. The FDA can’t even make him (or anyone) recall products. The government’s safety system relies on a code of honor — and there are plenty of businesses that are less than honorable.

#5. Disinfectant decoy

Do we really need to wipe everything down with Clorox? Probably not, Hamblin suggests. In fact, for Clorox to work, you have to leave it on the surface for about ten minutes. He says, “The product isn’t ‘killing 99.9% of germs’ in the way that anyone actually uses it — a quick wipe-down.” Instead, clean your countertop with soap and water.

Besides, regularly killing every “germ” in the environment isn’t the healthiest practice. “Some chronic conditions seem to be fueled by the fact that so many of us are now not being exposed to enough of the world,” Hamblin writes.

#6. Animals smell — and you’re an animal

The soap advertisements that kicked off modern marketing relied on one concept: B.O. We think of body odor as a given, but that too is an invention. Our feet “smell” thanks to bacteria like Bacillus subtilis, which has potent antifungal properties. Shoes weren’t available for most of history, a period in which smelly feet bestowed a strong evolutionary advantage. As Hamblin writes, we didn’t evolve to smell; we evolved in harmony with protective microbes that we just happen to find unpleasant.

While a number of players in the wellness and skincare industries likely have good intentions, so much of what is sold is unnecessary, and even damaging. The marketing machine makes us feel incomplete — so we have to buy products that make us feel whole. As Hamblin concludes, evidence-based companies would take an opposite approach to skincare and hygiene: less is more. But that slogan doesn’t sell a lot of soap.

This article A physician didn’t shower for 5 years. Here’s what he found out is featured on Big Think.

When Eric Mueller, who was adopted, first saw a photograph of his birth mother, he was overcome by how alike their faces were. It was, he wrote, “the first time I ever saw someone who looked like me.” The experience led Mueller, a photographer in Minneapolis, into a three-year project to photograph hundreds of sets of related people, culminating in the book Family Resemblance.

Such resemblances are commonplace, of course — and they point to a strong underlying genetic influence on the face. But the closer scientists look into the genetics of facial features, the more complex the picture gets. Hundreds, if not thousands, of genes affect the shape of the face, in mostly subtle ways that make it nearly impossible to predict a person’s face from examining the impact of each gene in turn.

As researchers learn more, some are starting to conclude that they need to look elsewhere to develop an understanding of faces. “Maybe we’re chasing the wrong thing when we’re trying to create gene-level explanations,” says Benedikt Hallgrímsson, a developmental geneticist and evolutionary anthropologist at the University of Calgary, Canada.

Instead, Hallgrímsson and others think they may be able to group genes into teams that work together as the face forms. Understanding how these teams work, and the developmental processes they affect, should be much more manageable than trying to sort out the effects of hundreds of individual genes. If they’re right, faces may turn out to be less complicated than we think.

Plotting the facial landscape

When geneticists first set out to understand faces, they started with the low-hanging fruit: identifying the genes responsible for facial abnormalities. In the 1990s, for example, they learned that a mutation in one gene causes Crouzon syndrome — characterized by wide-set, often bulging eyes and an underdeveloped upper jaw — while a mutation in a different gene leads to the down-slanting eyes, small lower jaw and cleft palate of Treacher Collins syndrome. It was a start, but such extreme cases said little about why normal faces vary as much as they do.

Then, beginning about a decade ago, geneticists began to take a different approach. First, they quantified thousands of normal faces by identifying landmarks on each person’s face — tip of chin, corners of lips, tip of nose, outside corner of each eye, and so forth — and measuring the distances between them. Then they screened the genomes of those individuals, to see whether any genetic variants corresponded with particular facial measurements, an analysis known as a genome-wide association study, or GWAS (pronounced jee-wass).

Some 25 GWASs of facial shape have been published to date, with over 300 genes identified in total. “Every single region is explained by multiple genes,” says Seth Weinberg, a craniofacial geneticist at the University of Pittsburgh. “There’s some genes pushing outward and others pushing inward. It’s the total balance that ends up becoming you, and what you look like.”

Researchers have identified more than 300 genes associated with specific facial features, though their effects are generally small. Here are a few features where genes make a difference.

Not only are there a slew of genes involved in each particular facial region, the variants uncovered thus far don’t account well for the specifics of each face. In a survey of the genetics of faces in the 2022 Annual Review of Genomics and Human Genetics, Weinberg and his colleagues gathered GWAS results on the faces of 4,680 people of European ancestry. Known genetic variants explained only about 14 percent of the differences in faces. An individual’s age accounted for 7 percent, sex for 12 percent, and body mass index for about 19 percent of variation, leaving a whopping 48 percent completely unexplained.

Clearly, something important in determining the shape of faces isn’t captured by GWASs. Of course, some portion of that missing variation must be explained by environment — in fact, researchers have noted that certain parts of the face, including the cheeks, lower jaw and mouth, do seem more susceptible to environmental influences such as diet, aging and climate. But another clue to that missing factor, many researchers agree, lies within the unique genetics of individual families.

Variants great and small

If faces were simply the sum of hundreds of tiny genetic effects, as the GWAS results imply, then every child’s face should be a perfect blend, halfway between its two parents, Hallgrímsson says, for the same reason that flipping a coin 300 times will almost always yield roughly 150 heads. Yet you only have to look at certain families to see that’s not the case. “My son has his grandmother’s nose,” says Hallgrímsson. “That must mean there are genetic variants that have large effects within families.”

But if some face genes do have large effects that are visible within the families that carry them, why don’t they show up in a GWAS? Perhaps the variants are too rare in the general population. “Facial shape is really a combination of common and rare variation,” says Peter Claes, an imaging geneticist at KU Leuven in Belgium. As a possible example, he points to French actor Gérard Depardieu’s distinctive nose. “You don’t know the genetics yet, but you feel this is a rare variant,” he says.

A few other distinctive facial features that run in families, such as dimples, cleft chins and unibrows, could also be candidates for such rare, high-impact variants, says Stephen Richmond, an orthodontic researcher at the University of Cardiff, Wales, who studies facial genetics. To look for such rare variants, though, researchers will need to move beyond GWASs to explore large datasets of whole-genome sequences — a task that will have to wait until such sequences, linked to facial measurements, become much more abundant, says Claes.

Another possibility is that the same gene variants that have small effects most of the time could have larger effects within certain families. Hallgrímsson has seen this in mice: He and his colleagues, notably Christopher Percival, now at Stony Brook University, introduced mutations that affect craniofacial shape into three inbred lineages of mice. They discovered that the three lineages ended up with quite different facial shapes. “The same mutation in a different strain of mice can have a different effect, sometimes even the opposite effect,” says Hallgrímsson.

If something similar happens in people, it’s possible that within a particular family — as with a particular strain of mice — the family’s unique genetic background may make certain face shape variants more powerful. But proving that this happens in people, without the aid of inbred strains, is likely to be difficult, Hallgrímsson says.

A better approach, Hallgrímsson thinks, might be to look at the developmental processes that underlie how faces are formed. Developmental processes involve teams of genes that work together — often to regulate the activity of still other genes — to control how specific organs and tissues form during embryonic development. To identify processes linked to face shape, Hallgrímsson and his team first used fancy statistics to find genes that affect craniofacial variation in over 1,100 mice. Then they turned to genetics databases to identify the developmental processes that each gene was a part of. The analysis flagged three processes as especially important: cartilage development, brain growth and bone formation. It’s possible, Hallgrímsson speculates, that individual differences in the rate and timing of these three processes (and likely some others) might be a big part of the explanation for why one person’s face differs from another’s.

Intriguingly, it appears that some of these teams of genes may have “captains” that direct the activity of other team members. Researchers trying to understand facial variation might thus be able to focus on the action of these captain genes rather than hundreds of individual genetic players. Support for this notion comes from an intriguing new study by Sahin Naqvi, a geneticist at Stanford University, and his colleagues.

Naqvi began with a paradox. He knew that most developmental processes are so finely tuned that even modest changes in the activity of the genes regulating them can cause severe developmental problems. But he also knew that small differences in those very same genes are likely the reason his own face looks different from his neighbor’s. How, Naqvi wondered, could both of these ideas be true?

To try to reconcile these two contradictory notions, Naqvi and his colleagues decided to focus on one regulatory gene, SOX9, which controls the activity of many other genes involved in the development of cartilage and other tissues. If a person has only one working copy of SOX9, the result is a craniofacial disorder called Pierre Robin sequence, characterized by an underdeveloped lower jaw and numerous other problems.

Naqvi’s team set out to reduce SOX9 activity little by little and measure what effect that had on the genes it regulates. To do so, they genetically engineered human embryonic cells so that they could dial down SOX9’s regulatory activity at will. Then the researchers measured the effect of six different SOX9 levels on the activity of the other genes. Would the genes under SOX9’s control maintain their activity despite small changes in SOX9, thus keeping development stable, or would their activity decline in proportion to changes in SOX9?

The genes fell into two classes, the team found. Most of them didn’t change their activity unless SOX9 levels fell to 20 percent or less of normal. That is, they seemed to be buffered against even relatively large changes in SOX9. This buffering — possibly the result of other regulatory genes compensating for reductions in SOX9 — would help keep development finely tuned.

But a small subset of the genes turned out to be sensitive to even small changes in SOX9, dialing their own activity up or down in lockstep with it. And those genes, the scientists found, tended to affect jaw size and other facial features altered in Pierre Robin sequence. In fact, these unbuffered genes seem to determine how much, or how little, a regular face resembles a Pierre Robin one. At one end of the range lie the underdeveloped jaw and other structural changes of Pierre Robin sequence. And at the other end? “You can think of the anti-Pierre Robin as an overdeveloped jaw, elongated with a prominent chin — kind of like me, actually,” says Naqvi.

Pierre Robin sequence (PRS) is a craniofacial disorder characterized in part by a small lower jaw and caused by a mutation in the regulatory gene SOX9. Researchers sorted normal faces according to how much or how little they resembled the features of PRS, and then looked for associated gene variants. The researchers found that some genes are very sensitive to SOX9, dialing facial variation toward or away from PRS-like facial features. If other axes of facial variation are determined in a similar way, this could mean that the genetics of faces may be simpler than they seem.

In essence, SOX9 captains a team of genes that define one direction, or axis, in which faces can vary: from more to less Pierre-Robin-like. Naqvi is now looking to see whether other teams of genes, each captained by a different regulatory gene, define additional axes of variation. He suspects, for example, that genes sensitive to small changes in a gene called PAX3 might define an axis relating to the shape of the nose and forehead, while those sensitive to another called TWIST1 — which, when mutated, leads to premature fusing of the skull bones — could define an axis relating to how elongated the skull and forehead are.

Other evidence hints that Naqvi might be on the right track in thinking that faces vary along predefined axes. For example, geneticist Hanne Hoskens, Claes’s former student and now a postdoc in Hallgrímsson’s lab, sorted people’s faces according to how closely they resembled the prominent forehead, flattened nose and other features characteristic of achondroplasia, the most common form of dwarfism. (Think of the actor Peter Dinklage, for example.) Those at the more dwarflike end of the range tended to have different variants of genes related to cartilage development than those with less dwarflike faces, she found.

If similar patterns occur for other developmental pathways, this may set guardrails that restrict the way faces develop. That could help geneticists cut through the complexities to extract broader principles underlying facial shape. “There is a limited set of directions along which faces can vary,” says Hallgrímsson. “There are enough directions that there is a tremendous amount of variation, but it’s a small subset of the geometric possibilities we see. And it’s because these axes are determined by developmental processes, and there are relatively few developmental processes.”

Until more results are in, it’s too early to say whether this new approach really holds an important key to explaining why one person’s face looks different from another’s — and the shock of recognition Eric Mueller experienced when he saw his mother’s picture for the first time. But if Hallgrímsson, Naqvi and their colleagues are on the right track, focusing on developmental pathways may offer a way to part the thicket of hundreds of genes that for so long has obscured our understanding of faces.

This article Untangling the genetics that underlie our facial features is featured on Big Think.

Reddit’s popular wine community is full of stories about the dreaded “red wine headache.”

“I love red wine and I don’t want to have to give it up forever, but after a few glasses, the next day I can barely function as I have a pounding headache that doesn’t go away!” one member lamented.

“I can still drink white wine, rosés, and ports without issue. But no matter what red I have, a nasty headache ensues,” another described.

“People generally role [sic] their eyes at me when I tell them this and say I just drank too much…” a third wrote.

Is there something to these complaints? Does drinking red wine actually trigger headaches separate from hangover headaches?

It’s not a hangover

Those afflicted are not crazy: Scientific research has shown that red wine does indeed cause headaches more than other forms of alcohol, even white wine. These headaches can arise just a half hour after drinking only a couple glasses. The curious condition was initially given credence in a study published in The Lancet back in 1988. Scientists had subjects drink either red wine or vodka (disguised to look the same) — in equivalent amounts and with the same alcohol concentration – and found that the red wine triggered migraines far more often.

Thirty-five years later, “red wine headache” still hasn’t been satisfactorily explained. Researchers have scrutinized various compounds that are uniquely prevalent in red wine, like sulfites and histamines, to see if they might be behind the malady. Alas, controlled studies and indirect evidence have vindicated them.

Blame quercetin

Now, two chemists at the University of California-Davis and a neurologist specializing in headache from the University of California-San Francisco have proposed a new culprit, and they present some strong early evidence to support their accusation.

That culprit is quercetin. Found in all sorts of fruits and vegetables, as well as red wine, the flavonoid compound is widely considered to be beneficial, with anti-inflammatory properties. But, as authors Apramita Devi, Morris Levin, and Andrew Waterhouse demonstrate in their paper, which was published in the journal Scientific Reports, quercetin consumed in the presence of alcohol can cause a problem.

To break down alcohol, the body metabolizes it first to acetaldehyde, then to acetate, and finally to water and carbon dioxide. In the bloodstream, quercetin is transformed to quercetin glucuronide. The trio showed that this derivative inhibits a key enzyme called ALDH2, which converts acetaldehyde to acetate. This causes acetaldehyde to build up in the body, which can produce adverse effects such as nausea, facial blushing, and headache.

Red wine headache explained?

The researchers further estimated that one drink of red wine could slow acetaldehyde metabolism by 37%. People whose bodies aren’t as efficient at metabolizing alcohol, who are uniquely susceptible to acetaldehyde’s effects, or who are already prone to migraines or headaches would be more likely to suffer from red wine headache.

“We think we are finally on the right track toward explaining this millennia-old mystery,” Levin said in a statement. “The next step is to test it scientifically on people who develop these headaches.”

Levin and his co-authors already have a clinical trial on humans planned. The forthcoming experiment will have subjects drink red wines with varying levels of quercetin to see if imbibing higher amounts of the compound increases the rate of headache.

This article We may finally know what causes red wine headaches is featured on Big Think.

It is a mystery why humans manifest vast differences in lifespan, health, and susceptibility to infectious diseases. However, a team of international scientists has revealed that the capacity to resist or recover from infections and inflammation (a trait they call “immune resilience”) is one of the major contributors to these differences.

Immune resilience involves controlling inflammation and preserving or rapidly restoring immune activity at any age, explained Weijing He, a study co-author. He and his colleagues discovered that people with the highest level of immune resilience were more likely to live longer, resist infection and recurrence of skin cancer, and survive COVID and sepsis.

Measuring immune resilience

The researchers measured immune resilience in two ways. The first is based on the relative quantities of two types of immune cells, CD4+ T cells and CD8+ T cells. CD4+ T cells coordinate the immune system’s response to pathogens and are often used to measure immune health (with higher levels typically suggesting a stronger immune system). However, in 2021, the researchers found that a low level of CD8+ T cells (which are responsible for killing damaged or infected cells) is also an important indicator of immune health. In fact, patients with high levels of CD4+ T cells and low levels of CD8+ T cells during SARS-CoV-2 and HIV infection were the least likely to develop severe COVID and AIDS.

In the same 2021 study, the researchers identified a second measure of immune resilience that involves two gene expression signatures correlated with an infected person’s risk of death. One of the signatures was linked to a higher risk of death; it includes genes related to inflammation — an essential process for jumpstarting the immune system but one that can cause considerable damage if left unbridled. The other signature was linked to a greater chance of survival; it includes genes related to keeping inflammation in check. These genes help the immune system mount a balanced immune response during infection and taper down the response after the threat is gone. The researchers found that participants who expressed the optimal combination of genes lived longer.

Immune resilience and longevity

The researchers assessed levels of immune resilience in nearly 50,000 participants of different ages and with various types of challenges to their immune systems, including acute infections, chronic diseases, and cancers. Their evaluation demonstrated that individuals with optimal levels of immune resilience were more likely to live longer, resist HIV and influenza infections, resist recurrence of skin cancer after kidney transplant, survive COVID infection, and survive sepsis.

However, a person’s immune resilience fluctuates all the time. Study participants who had optimal immune resilience before common symptomatic viral infections like a cold or the flu experienced a shift in their gene expression to poor immune resilience within 48 hours of symptom onset. As these people recovered from their infection, many gradually returned to the more favorable gene expression levels they had before. However, nearly 30% who once had optimal immune resilience did not fully regain that survival-associated profile by the end of the cold and flu season, even though they had recovered from their illness.

This could suggest that the recovery phase varies among people and diseases. For example, young female sex workers who had many clients and did not use condoms — and thus were repeatedly exposed to sexually transmitted pathogens — had very low immune resilience. However, most of the sex workers who began reducing their exposure to sexually transmitted pathogens by using condoms and decreasing their number of sex partners experienced an improvement in immune resilience over the next 10 years.

Immune resilience and aging

The researchers found that the proportion of people with optimal immune resilience tended to be highest among the young and lowest among the elderly. The researchers suggest that, as people age, they are exposed to increasingly more health conditions (acute infections, chronic diseases, cancers, etc.) which challenge their immune systems to undergo a “respond-and-recover” cycle. During the response phase, CD8+ T cells and inflammatory gene expression increase, and during the recovery phase, they go back down.

However, over a lifetime of repeated challenges, the immune system is slower to recover, altering a person’s immune resilience. Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance despite the many respond-and-recover cycles that their immune systems have faced.

Public health ramifications could be significant. Immune cell and gene expression profile assessments are relatively simple to conduct, and being able to determine a person’s immune resilience can help identify whether someone is at greater risk for developing diseases, how they will respond to treatment, and whether, as well as to what extent, they will recover.

This article Your “immune resilience” greatly impacts your health and lifespan is featured on Big Think.

Scientists at Northwestern University have developed a synthetic melanin that’s even better at protecting the skin and healing damage than the natural kind.

The challenge: Melanin — a pigment found naturally in our skin, hair, and eyes — is your body’s natural defense against damage from sunlight, air pollution, and other environmental conditions.

The amount of melanin found naturally in your skin might not be enough to protect you from everything, though — too much time in the sun or contact with a caustic chemical could still leave you with a painful burn.

“It’s biocompatible, degradable, nontoxic, and clear when rubbed onto the skin.”

NATHAN GIANNESCHI

Super melanin: Scientists at Northwestern University have now developed a synthetic melanin that can be applied to the skin as a cream to prevent or heal damage.

Rather than trying to create a perfect replica of the melanin naturally produced in our skin (which is molecularly unstable and hard to study), they engineered this kind to be better at hunting down and neutralizing skin-damaging molecules called “free radicals” and absorbing heavy metals and toxins.

“It’s like super melanin,” said co-corresponding author Nathan Gianneschi. “It’s biocompatible, degradable, nontoxic, and clear when rubbed onto the skin. In our studies, it acts as an efficient sponge, removing damaging factors and protecting the skin.”

The impact: When they tested the synthetic melanin as a sunscreen, the researchers found that the cream would sit on top of the skin — rather than being absorbed into it — and protect it from damage.

This suggests it could potentially be useful as an addition to sunscreens or other skincare products. The researchers think it could potentially protect the skin of cancer patients undergoing radiation therapy, too.

“The treatment has the effect of setting the skin on a cycle of healing and repair.”

KURT LU

To see whether it could help heal damage, the scientists anesthetized mice and burned their skin with a chemical. They then applied their synthetic melanin to the burns of some of the mice two hours, one day, and two days later. Other animals were left untreated.

The burns of the treated mice were up to 50% smaller than those of the controls and healed faster: 10-12 days compared to more than 16 days.

The scientists also used a chemical to create blisters on 20 human skin tissue samples. A few hours later, they applied their synthetic melanin to half of the samples. Over the next few days, those healed much faster than untreated samples.

“The treatment has the effect of setting the skin on a cycle of healing and repair, orchestrated by the immune system,” said co-corresponding author Kurt Lu.

Looking ahead: The Northwestern team has already completed a trial showing that the synthetic melanin doesn’t irritate human skin — a key requirement for any kind of topical product. They’re now working toward trials to test its efficacy as a treatment for skin injuries and burns. 

“Such a relatively simple concept can continue to be advanced,” said Gianneschi. “If we can impact people’s lives with something like that, that’s an excellent outcome.”

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There’s a growing need to slow down the aging process. The world’s population is getting older and, according to one estimate, 80 million Americans will be 65 or older by 2040. As we age, the risk of many chronic diseases goes up, from cancer to heart disease to Alzheimer’s. 

BioAge Labs, a company based in California, is using genetic data to help people stay healthy for longer. CEO Kristen Fortney was inspired by the genetics of people who live long lives and resist many age-related diseases. In 2015, she started BioAge to study them and develop drug therapies based on the company’s learnings.

The team works with special biobanks that have been collecting blood samples and health data from individuals for up to 45 years. Using artificial intelligence, BioAge is able to find the distinctive molecular features that distinguish those who have healthy longevity from those who don’t. 

In December 2022, BioAge published findings on a drug that worked to prevent muscular atrophy, or the loss of muscle strength and mass, in older people. Much of the research on aging has been in worms and mice, but BioAge is focused on human data, Fortney says. “This boosts our chances of developing drugs that will be safe and effective in human patients.”

How it works

With assistance from AI, BioAge measures more than 100,000 molecules in each blood sample, looking at proteins, RNA and metabolites, or small molecules that are produced through chemical processes. The company uses many techniques to identify these molecules, some of which convert the molecules into charged atoms and then separating them according to their weight and charge. The resulting data is very complex, with many thousands of data points from patients being followed over the decades.

BioAge validates its targets by examining whether a pathway going awry is actually linked to the development of diseases, based on the company’s analysis of biobank health records and blood samples. The team uses AI and machine learning to identify these pathways, and the key proteins in the unhealthy pathways become their main drug targets. “The approach taken by BioAge is an excellent example of how we can harness the power of big data and advances in AI technology to identify new drugs and therapeutic targets,” says Lorna Harries, a professor of molecular genetics at the University of Exeter Medical School.

Martin Borch Jensen is the founder of Gordian Biotechnology, a company focused on using gene therapy to treat aging. He says BioAge’s use of AI allows them to speed up the process of finding promising drug candidates. However, it remains a challenge to separate pathologies from aspects of the natural aging process that aren’t necessarily bad. “Some of the changes are likely protective responses to things going wrong,” Jensen says. “Their data doesn’t…distinguish that so they’ll need to validate and be clever.”

Developing a drug for muscle loss

BioAge decided to focus on muscular atrophy because it affects many elderly people, making it difficult to perform everyday activities and increasing the risk of falls. Using the biobank samples, the team modeled different pathways that looked like they could improve muscle health. They found that people who had faster walking speeds, better grip strength and lived longer had higher levels of a protein called apelin.

Apelin is a peptide, or a small protein, that circulates in the blood. It is involved in the process by which exercise increases and preserves muscle mass. BioAge wondered if they could prevent muscular atrophy by increasing the amount of signaling in the apelin pathway. Instead of the long process of designing a drug, they decided to repurpose an existing drug made by another biotech company. This company, called Amgen, had explored the drug as a way to treat heart failure. It didn’t end up working for that purpose, but BioAge took note that the drug did seem to activate the apelin pathway.

BioAge tested its new, repurposed drug, BGE-105, and, in a phase 1 clinical trial, it protected subjects from getting muscular atrophy compared to a placebo group that didn’t receive the drug. Healthy volunteers over age 65 received infusions of the drug during 10 days spent in bed, as if they were on bed rest while recovering from an illness or injury; the elderly are especially vulnerable to muscle loss in this situation. The 11 people taking BGE-105 showed a 100 percent improvement in thigh circumference compared to 10 people taking the placebo. Ultrasound observations also revealed that the group taking the durg had enhanced muscle quality and a 73 percent increase in muscle thickness. One volunteer taking BGE-105 did have muscle loss compared to the the placebo group.

Heather Whitson, the director of the Duke University Centre for the study of aging and human development, says that, overall, the results are encouraging. “The clinical findings so far support the premise that AI can help us sort through enormous amounts of data and identify the most promising points for beneficial interventions.” 

More studies are needed to find out which patients benefit the most and whether there are side effects. “I think further studies will answer more questions,” Whitson says, noting that BGE-105 was designed to enhance only one aspect of physiology associated with exercise, muscle strength. But exercise itself has many other benefits on mood, sleep, bones and glucose metabolism. “We don’t know whether BGE-105 will impact these other outcomes,” she says.

The future

BioAge is planning phase 2 trials for muscular atrophy in patients with obesity and those who have been hospitalized in an intensive care unit. Using the data from biobanks, they’ve also developed another drug, BGE-100, to treat chronic inflammation in the brain, a condition that can worsen with age and contributes to neurodegenerative diseases. The team is currently testing the drug in animals to assess its effects and find the right dose.

BioAge envisions that its drugs will have broader implications for health than treating any one specific disease. “Ultimately, we hope to pioneer a paradigm shift in healthcare, from treatment to prevention, by targeting the root causes of aging itself,” Fortney says. “We foresee a future where healthy longevity is within reach for all.”

This article AI helps fight muscle loss and unhealthy aging is featured on Big Think.

COVID was the first global, society-altering pandemic in more than a century. It disrupted economies, reshaped politics, changed behaviors, and claimed around seven million lives. But now, artificial intelligence (AI) breakthroughs are raising hopes that humanity may never be brought to its knees by an infectious disease ever again.

EVEScape

When civilization was locked in the grasp of COVID, news of the virus’s latest variants of concern evoked anxiety. During the pandemic, the SARS-CoV-2 virus constantly mutated, evolving to escape the immune system’s arresting reach. Scientists scrambled to track these variants so that treatments, preventative measures, and vaccines could be updated to save lives.

Last month, in the journal Nature, scientists primarily based out of Harvard Medical School detailed a new AI model called EVEscape specifically focused on predicting how viruses mutate. Trained on data of historical viral evolution, the model can be fed detailed biological and structural information about a virus, and then it will predict the most likely ways in which that pathogen will mutate. Specifically, it predicts changes to protein function as viruses are pressured by the immune system.

To showcase EVEscape’s potential, scientists provided it with the original genome sequence of the SARS-CoV-2 virus, which was available months before the pathogen officially launched the COVID pandemic. Lo and behold, EVEscape predicted nearly all the mutations that would come to dominate during the pandemic, including many of the variants that became household names (Omicron, Beta, etc.). EVEscape’s creators regularly feed the model updated SARS-CoV-2 sequence data — so it is forecasting COVID’s moves right now.

As a bonus, the Harvard team also turned EVEscape’s attention to the Lassa, Nipah, influenza, and HIV viruses, finding that the model works for them as well as SARS-CoV-2. In an admirable example of scientific transparency, they publicly share all of EVEscape’s predictions every two weeks, allowing anyone to check the model’s accuracy.

AI, the cure for pandemics?

In an article accompanying the paper, Nash Rochman and Eugene Koonin, scientists at the National Center for Biotechnology Information, extolled EVEscape. “This method… has the potential to be used to predict future variants of endemic viruses persisting in the population, to inform rational vaccine design, and to estimate the pandemic risk for previously unknown viruses even before any 3D structure is experimentally solved.”

President Biden’s recent executive order on AI focused on safeguarding against its dystopian, potential dangers, including AI’s ability to engineer biological materials like synthetic viruses. But with EVEscape, we have a refreshingly utopian example of AI’s ability to protect humanity from infectious disease.

As EVEscape stands guard watching for future pandemics, AI is also increasingly being utilized to drastically speed up the vaccine discovery process. AI is what allowed the pharmaceutical company Moderna to engineer what turned out to be a highly effective mRNA vaccine against SARS-CoV-2 just 42 days after the virus’s genome sequence was published.

Rochman and Koonin are cautiously optimistic that pandemic disease could become a thing of the past. “It might be not too preposterous to hope that COVID-19 will forever remain known as the most disruptive pandemic in human history,” they wrote.

This article How a Harvard AI model could make COVID the last pandemic is featured on Big Think.

You probably try to exercise regularly and eat right. Perhaps you steer toward “superfoods,” fruits, nuts, and vegetables advertised as “antioxidant,” which combat the nasty effects of oxidation in our bodies. Maybe you take vitamins to protect against “free radicals,” destructive molecules that arise normally as our cells burn fuel for energy, but which may damage DNA and contribute to cancer, dementia, and the gradual meltdown we call aging.

Warding off the diseases of aging is certainly a worthwhile pursuit. But evidence has mounted to suggest that antioxidant vitamin supplements, long assumed to improve health, are ineffectual. Fruits and vegetables are indeed healthful but not necessarily because they shield you from oxidative stress. In fact, they may improve health for quite the opposite reason: They stress you.

That stress comes courtesy of trace amounts of naturally occurring pesticides and anti-grazing compounds. You already know these substances as the hot flavors in spices, the mouth-puckering tannins in wines, or the stink of Brussels sprouts. They are the antibacterials, antifungals, and grazing deterrents of the plant world. In the right amount, these slightly noxious substances, which help plants survive, may leave you stronger.

Eating food from plants that have struggled to survive toughens us up as well.

Parallel studies, meanwhile, have undercut decades-old assumptions about the dangers of free radicals. Rather than killing us, these volatile molecules, in the right amount, may improve our health. Our quest to neutralize them with antioxidant supplements may be doing more harm than good.

The idea that pro-oxidant molecules are always destructive is “oversimplified to the point of probably being wrong,” says Toren Finkel, chief of the center for molecular medicine at the National Heart, Lung, and Blood Institute in Bethesda, Maryland. “Oxidants may be a primordial messenger of stress in our cells, and a little bit of stress, it turns out, may be good for us.”

Although far from settled, a wave of compelling science offers a remarkably holistic picture of health as a byproduct of interactions among people, plants, and the environment. Plants’ own struggle for survival— against pathogens and grazers, heat and drought—is conveyed to us, benefitting our health. This new understanding begins, in part, on a treadmill.

n the mid-20th century, as modern medicine seemed poised to vanquish the infectious diseases of yore, some scientists turned to the degenerative diseases associated with aging. Attention fell on a class of molecules called “reactive oxygen species,” or ROS. These volatile substances could damage DNA. Degenerative diseases, such as cancer and cardiovascular disease, often showed evidence of “oxidative stress,” suggesting that ROS spurred disease.

Oddly, our mitochondria, the energy factories of our cells, emitted ROS naturally. So degenerative disease seemed to stem in part from our own metabolic function: Your mitochondria “burned” fuel, emitted this toxic exhaust, and inadvertently set the limits on your existence. That was the working hypothesis, at any rate.

Experiments on rats and worms showed that reactive oxygen species, such as hydrogen peroxide, tear atoms from other molecules, destroying them in the process. That can be problematic when those molecules are DNA, our cellular instruction manual. We produce native antioxidants, such as the molecule glutathione, to counteract this pro-oxidant threat. They react with ROS, neutralizing the pro-oxidants before they can damage important cellular machinery.

When scientists blocked rodents’ ability to manufacture these protective molecules, lifespan declined. Observational studies, meanwhile, suggested that people who regularly ate vitamin-laden fruits and vegetables were healthier. So were people with higher levels of vitamins E and C in their blood.

Vitamins were strongly antioxidant in test tubes. So the ROS theory of aging and disease rose to prominence. You could slow aging, it followed, by neutralizing free radicals with antioxidant pills. A supplement industry now worth $23 billion yearly in the U.S. took root.

But if those ROS were so harmful, some scientists asked—and the basic design of our (eukaryote) cells was over 1 billion years old—why hadn’t evolution solved the ROS problem? At the same time, scientists began finding that exercise and calorie restriction increased lifespan in animals. Both elevated ROS. According to the ROS model of aging, animals that exercised and fasted should have died younger. But they lived longer.

For Michael Ristow, a researcher of energy and metabolism at the Swiss Federal Institute of Technology in Zurich, the inconsistencies became impossible to overlook. In worms, he found that neutralizing those allegedly toxic ROS reduced lifespan, so he designed a similar experiment in humans.

He had 39 male volunteers exercise regularly over several weeks; half took vitamin supplements before working out. The results, published in 2009, continue to reverberate throughout the field of exercise physiology, and beyond. Volunteers who took large doses of vitamins C and E before training failed to benefit from the workout. Their muscles didn’t become stronger; insulin sensitivity, a measure of metabolic health, didn’t improve; and increases in native antioxidants, such as glutathione, didn’t occur.

Exercise accelerates the burning of fuel by your cells. If you peer into muscles after a jog, you’ll see a relative excess of those supposedly dangerous ROS—exhaust spewed from our cellular furnaces, the mitochondria. If you examine the same muscle some time after a run, however, you’ll find those ROS gone. In their place you’ll see an abundance of native antioxidants. That’s because, post-exercise, the muscle cells respond to the oxidative stress by boosting production of native antioxidants. Those antioxidants, amped up to protect against the oxidant threat of yesterday’s exercise, now also protect against other ambient oxidant dangers.

Contrary to the ROS dogma, Ristow realized, the signal of stress conveyed by the ROS during exercise was essential to this call-and-response between mitochondria and the cells that housed them. To improve health, he figured, perhaps we shouldn’t neutralize ROS so much as increase them in a way that mimicked what happened in exercise. That would boost native antioxidants, improve insulin sensitivity, and increase overall resilience.

Ristow called this idea “mitohormesis.” The term “hormesis” came from toxicology (“mito” was for mitochondrion). It describes the observation that some exposures generally considered toxic can, in minute amounts, paradoxically improve health. For instance, minuscule quantities of X-ray radiation, a known carcinogen, increases the lifespan of various insects.

Hormesis may be most easily grasped when considering exercise. Lift too much weight or run too long, and you’ll likely tear muscle and damage tendons. But lift the right amount and run a few times a week, and your bones and muscles strengthen. The intermittent torque and strain increases bone mineralization and density. Stronger bones may better tolerate future shocks that might otherwise cause fractures.

In his experiment, Ristow saw that vitamin supplements interrupted this sequence of stress followed by fortification, probably because they neutralized the ROS signal before it could be “heard” elsewhere in the cell. By interfering in the adaptive response, vitamins prevented the strengthening that would have otherwise followed the stress of physical exertion. Antioxidant supplementation paradoxically left you weaker.

Vitamins are necessary for health. And supplements can help those who are deficient in vitamins. Insufficient vitamin C, for instance, causes scurvy, which results from defective collagen, a protein in connective tissue. Among other functions, vitamin C aids collagen synthesis.

But the primary role of vitamins in our body, according to Ristow and others, may not be antioxidant. And the antioxidant content of fruits and veggies does not, he thinks, explain their benefits to our health. So what does?

Mark Mattson, Chief of the Laboratory of Neurosciences at the National Institute on Aging, has studied how plant chemicals, or phytochemicals, affect our cells (in test tubes) for years. The assumption in the field has long been that, like vitamins, phytochemicals are directly antioxidant. But Mattson and others think they work indirectly. Much like exercise, he’s found, phytochemicals stress our bodies in a way that leaves us stronger.

Plants, Mattson explains, live a stationary life. They cannot respond to pathogens, parasites, and grazers as we might—by moving. To manage the many threats posed by mobile life, as well as heat, drought, and other environmental stresses, they’ve evolved a remarkable number of defensive chemicals.

Health doesn’t result solely from the instructions your genome contains, but your relationship with the world.

We’re familiar with many components of their arsenal. The nicotine that we so prize in tobacco slows grazing insects. Beans contain lectins, which defend against insects. Garlic’s umami-like flavor comes from allicin, a powerful antifungal. These “antifeedants” have evolved in part to dissuade would-be grazers, like us.

Mattson and his colleagues say these plant “biopesticides” work on us like hormetic stressors. Our bodies recognize them as slightly toxic, and we respond with an ancient detoxification process aimed at breaking them down and flushing them out.

Consider fresh broccoli sprouts. Like other cruciferous vegetables, they contain an antifeedant called sulforaphane. Because sulforaphane is a mild oxidant, we should, according to old ideas about the dangers of oxidants, avoid its consumption. Yet studies have shown that eating vegetables with sulforaphane reduces oxidative stress.

When sulforaphane enters your blood stream, it triggers release in your cells of a protein called Nrf2. This protein, called by some the “master regulator” of aging, then activates over 200 genes. They include genes that produce antioxidants, enzymes to metabolize toxins, proteins to flush out heavy metals, and factors that enhance tumor suppression, among other important health-promoting functions.

In theory, after encountering this humble antifeedant in your dinner, your body ends up better prepared for encounters with toxins, pro-oxidants from both outside and within your body, immune insults, and other challenges that might otherwise cause harm. By “massaging” your genome just so, sulforaphane may increase your resistance to disease.

In a study on Type 2 diabetics, broccoli-sprout powder lowered triglyceride levels. High triglycerides, a lipid, are associated with an increased risk of heart disease and stroke. Lowering abnormally elevated triglycerides may lessen the risk of these disorders. In another intervention, consuming broccoli sprout powder reduced oxidative stress in volunteers’ upper airways, likely by increasing production of native antioxidants. In theory, that might ameliorate asthmatics’ symptoms.

Elevated free radicals and oxidative stress are routinely observed in diseases like cancer and dementia. And in these instances, they probably contribute to degeneration. But they may not be the root cause of disease. According to Mattson, the primary dysfunction may have occurred earlier with, say, a creeping inability to produce native antioxidants when needed, and a lack of cellular conditioning generally.

Mattson calls this the “couch potato” problem. Absent regular hormetic stresses, including exercise and stimulation by plant antifeedants, “cells become complacent,” he says. “Their intrinsic defenses are down-regulated.” Metabolism works less efficiently. Insulin resistance sets in. We become less able to manage pro-oxidant threats. Nothing works as well as it could. And this mounting dysfunction increases the risk for a degenerative disease.

Implicit in the research is a new indictment of the Western diet. Not only do highly refined foods present tremendous caloric excess, they lack these salutary signals from the plant world—“signals that challenge,” Mattson says. Those signals might otherwise condition our cells in a way that prevents disease.

Another variant of the hormetic idea holds that our ability to receive signals from plants isn’t reactive and defensive but, in fact, proactive. We’re not protecting ourselves from biopesticides so much as sensing plants’ stress levels in our food.

Harvard scientist David Sinclair and his colleague Konrad Howitz call this xenohormesis: benefitting from the stress of others. Many phytonutrients trigger the same few cellular responses linked to longevity in eukaryotic organisms, from yeasts to humans. Years of research on Nrf2 in rodents suggest that activating this protein increases expression of hundreds of health-promoting genes, including those involved in detoxification, antioxidant production, control of inflammation, and tumor suppression.

In the dance between animals and plants, there’s true mutualism. “We’re in this together, the plants and us.”

Sinclair studies another class of native proteins, called sirtuins, associated with health. They’re triggered by exercise and also, Sinclair contends, a molecule called resveratrol, found in grape skins and other plants. “It’s too coincidental that time and time again these molecules come out of nature that have the surprising multifactorial benefit of tweaking the body just the right way,” Sinclair says.

They’re not all antifeedants, he argues. Plants churn these substances out when stressed, prompting further adaptations to the particular threat, be it drought, infestation by grazing insects, or excessive ultraviolet radiation from the sun.

For grazers, these stress compounds in plants may convey important information about environmental conditions. So grazers’ ability to “perceive” these signals, Sinclair argues, likely proved advantageous over evolutionary time. It allowed them to prepare for adversity. A grape vine stressed by fungi churns out resveratrol to fight off the infection. You drink wine made from those grapes, “sense” the harsh environmental conditions in the elevated tannins and other stress compounds, gird your own defenses, and, in theory, become more resistant to degenerative disease.

One implication is that modern agriculture, which often prevents plant stress with pesticides and ample watering, produces fruits and vegetables with weak xenohormetic signals. “I buy stressed plants,” Sinclair says. “Organic is a good start. I choose plants with lots of color because they are producing these molecules.” Some argue that xenohormesis may explain, at least in part, why the Mediterranean diet is apparently so healthful. It contains plants such as olives, olive oil, and various nuts that come from hot, dry, stressful environments. Eating food from plants that have struggled to survive toughens us up as well.

Philip Hooper, an endocrinologist at the University of Colorado Anschutz Medical Campus, points out that plant-animal relationships are often symbiotic, and communication goes both ways. One example of direct plant-to-animal, biochemical manipulation comes from the coffee bush. Flowering plants compete with one another for the attention of pollinators, such as bees. Coffee bushes seem to gain advantage in this “marketplace” by using caffeine. The drug excites pollinators’ neurons, etching the memory of the plant’s location more deeply in their brains. Some think that biochemical tweaking increases the probability that the pollinator, which faces a panoply of flower choices, will return to that particular coffee bush.

In the dance between animals and plants, says Hooper, “I think there’s true mutualism. We’re in this together, the plants and us.”

While xenohormesis is a compelling idea, it remains unproven. Barry Halliwell, a biochemist at the National University of Singapore, and an expert on antioxidants, has seen the dietary fads, from vitamins to fiber, come and go. He says the hormetic and xenohormetic ideas are plausible, but not certain. Various studies suggest that people who consume a lot of fruits and vegetables have healthier lifestyles generally. Those people probably go easy on the junk food, which alone may improve health.

Even within the hormetic idea, Halliwell sees the attempts to bore down on the individual chemicals as problematic. “That’s worked very well in pharmacology, but it hasn’t worked at all well in nutrition,” he says. He doesn’t think any single phytonutrient will explain the apparent health-promoting benefits of fruits and veggies. “Variety seems to be good,” he says. That critique speaks to a larger problem: It’s often unclear how lab research on simple organisms or cell cultures will translate, if at all, into recommendations or therapies for genetically complex, free-living humans.

What works in genetically uniform organisms, or cells, living in highly controlled environments, does not necessarily work in people. Human studies on resveratrol in particular have yielded contradictory results. Proper dosage may be one problem, and interaction between the isolates used and particular gene variants in test subjects another. Interventions usually test one molecule, but fresh fruits and vegetables present numerous compounds at once. We may benefit most from these simultaneous exposures.

The science on the intestinal microbiota promises to further complicate the picture; our native microbes ferment phytonutrients, perhaps supplying some of the benefit of their consumption. All of which highlights the truism that Nature is hard to get in a pill.

These caveats aside, research into xenohormesis reminds us that we are not at the complete mercy of our genetic inheritance. Genes matter, but health depends in large part on having the right genes expressed at the right time—and in the right amount. If our genome is a piano, and our genes are the keys, health is the song we play on the piano. The science on hormesis, the stresses that may keep us strong, provides hints about what kind of song we should play. Keep the body conditioned with regular exercise. Keep your cells’ stress-response pathways intermittently engaged with minimally processed, plant-based food.

These recommendations end up sounding rather grandmotherly—if your grandmother was a spartan, no-nonsense peasant who lived off the land. But the underlying thrust contradicts assumptions about the need to protect oneself from hardship. Certain kinds of difficulty, it turns out, may be required for health. That’s because health doesn’t result solely from the instructions your genome contains, but from your relationship with the wider world. Resilience isn’t completely inherent to your body; it’s cultivated by outside stimuli. And some of those stimuli just happen to be mildly noxious, slightly stressful chemicals in plants.

This article Fruits and vegetables are trying to kill you is featured on Big Think.

Stereotypes of manhood link it with strength, aggression, toughness, and courage. Moreover, manhood is often viewed as “precarious” — unlike womanhood, it must be earned and defended. Thus, one way men can protect their masculinity is by engaging in risky behaviors like fighting, binge drinking, or fast driving. (Male readers might themselves recall something stupid they did to “prove their manhood.”)

Given that studies have repeatedly shown men to undertake more risky behaviors and to have shorter lives than women, a team of psychologists explored whether societal beliefs in precarious manhood might play a role in those differences. Their results were published in the journal Psychology of Men & Masculinities.

“Countries that view manhood as more precarious likely exert more pressure on men to uphold male role norms… via regular risk-taking activities, pursuit of risky occupations, and lower rates of preventive and health-promoting behaviors,” the researchers wrote.

A man by any other name

First author, Joseph Vandello, a professor of psychology at the University of South Florida who originally introduced the concept of precarious manhood 15 years ago, and his colleagues surveyed 33,417 college students in 62 different countries on their gender beliefs and attitudes. Included were four items intended to gauge the students’ precarious manhood beliefs. These were statements with which participants could indicate their level of agreement: (1) “Other people often question whether a man is a ‘real man.'” (2) “Some boys do not become men no matter how old they get.” (3) “It is fairly easy for a man to lose his status as a man” (4) “Manhood is not assured — it can be lost.”

With this data, they calculated the level of precarious manhood beliefs for each of the 62 countries. Countries with the highest levels were Albania, Iran, Kosovo, Nigeria, and Ukraine. Countries with the lowest levels were Finland, Spain, Germany, Sweden, and Switzerland.

They then looked to see how country-wide precarious manhood beliefs were associated with risk-taking behavior (like smoking and drinking) and risk-related health outcomes (such as drowning, transportation accidents, and COVID infections). They found that men in countries with more prevalent precarious manhood beliefs were moderately more likely to engage in risky behaviors and to suffer from risk-related health outcomes.

Hold my beer and watch this

Considering that precarious manhood beliefs were linked to greater risk-taking and worse risk-related health outcomes, the researchers wondered if precarious manhood beliefs might also correlate with reduced male life expectancy. They were surprised to discover a striking association. In countries high in precarious manhood beliefs (one standard deviation above the average), men lived 6.7 fewer years compared to men in countries low in precarious manhood beliefs (one standard deviation below average). The result held even when controlling for potential confounding variables such as human development and availability of physicians.

“This finding is perhaps the most exciting and powerful to emerge from this study,” the researchers commented. “Country-level endorsement of the belief that manhood is ‘hard won and easily lost’ uniquely and strongly predicts how long men in that country will live.”

The study’s reliance on data exclusively from college students is potentially worrisome, as college students are generally unrepresentative of the broader population of most nations. Still, the study’s findings are seductive, as they make intuitive sense given common stereotypes about manhood. The survey’s size and breadth across dozens of countries is also impressive.

“While past research has linked masculinity to health, this is the first study, and the largest in scale, to show that a basic belief about the nature of manhood may have far-reaching implications for men around the world,” the researchers concluded.

This article In countries where manhood must be proven, men have shorter lives is featured on Big Think.

I have a long-standing interest in sickle cell anemia, a genetic abnormality that is the scourge of approximately 100,000 Americans, primarily Black, who are afflicted with it.

Sickle cell disease (SCD) is an inherited disorder marked by abnormal hemoglobin, the protein that delivers oxygen to the cells of the body. Normal red blood cells are disc-shaped and flexible enough to move smoothly through the blood vessels. In SCD, red blood cells become crescent or “sickle” shaped due to a genetic mutation in the patient’s hemoglobin.

These misshapen red blood cells are inflexible and get stuck in blood vessels, and the resulting impaired blood flow can lead to a variety of complications, including stroke, infection, episodes of pain called “pain crises,” and arthritis from hemorrhaging into joints.

The cause of sickle cell disease

I first became aware of SCD during the 1960s because my MIT undergraduate advisor, Professor Vernon Ingram, had unraveled its molecular basis: a mutation in DNA that causes a change in a single amino acid in the hemoglobin molecule. (Proteins are comprised of chains of amino acids.) The change occurs specifically at one site where normal hemoglobin has an amino acid called glutamic acid; those with SCD have valine, instead. This was the first description of the molecular abnormality in a genetic disease. As a medical resident a few years later, I had a patient with SCD who, by the age of 20, had suffered from most of the awful complications I already mentioned.

Currently, a bone marrow transplant is the only treatment for some patients with SCD, but a new, potentially revolutionary approach might soon be available. The FDA is nearing the end of its evaluation of Exa-cel, a CRISPR-based gene therapy approach to reversing the genetic defect. The treatment involves gene editing of the patient’s blood-forming stem cells to induce them to produce high levels of fetal hemoglobin (HbF, or hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, but the body switches to the adult form of hemoglobin after birth. The increased production of HbF by Exa-cel reduces painful and debilitating sickle crises for patients with SCD.

Exa-cel clinical trials

On October 31, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee discussed Exa-cel. Interestingly, its efficacy and short-term safety were not at issue because the FDA felt that they had been amply demonstrated during the clinical trials.

The demonstration of efficacy was impressive. In the pivotal clinical study, 29 of 30 evaluable patients (96.7%) achieved the primary endpoint of the absence of severe blood vessel blockage (known as vaso-occlusive crises, or VOCs) for at least 12 consecutive months. Of those 29 patients, 28 remained free of VOCs for an average of 22.3 months, with a maximum of 45.5 months.

In addition, all 30 evaluable subjects met the important secondary endpoint of freedom from inpatient hospitalization for severe VOCs for at least 12 consecutive months. My patient decades earlier had had about 80 hospital admissions by the age of 20.

The FDA advisory committee was charged with discussing the likelihood of hypothetical “off-target” — that is, incidental and unwanted — genetic changes caused by the therapy. According to accounts of the meeting, there seemed to be a consensus that the risks were uncertain but probably small. A guest speaker, Dr. Daniel Bauer, director of the gene therapy program at Boston Children’s Hospital and the Dana-Farber Cancer Institute, put it this way:

“Only a small part of the human genome actually codes for genes — most of the human genome is non-coding. It’s likely that many places in the human genome can tolerate an off-target edit and not have a functional consequence. The challenge is that we don’t really know for sure, and the only way to know that is careful follow-up. My guess is that it’s a relatively small risk in the scheme of this risk-benefit, but it’s new, it’s unknown.”

By the end of the meeting, it appeared that most members of the committee believed that the benefits of the therapy far outweigh the theoretical risks of off-target editing. My guess is that the FDA will approve Exa-cel with the understanding that there will be long-term follow-up and collection of data, whether via a Phase 4 (post-marketing) study or simply following the treated patients.

Professor Ingram, who became known as “the father of molecular medicine,” would be pleased.

This article A revolutionary new CRISPR treatment for sickle cell anemia may be imminent is featured on Big Think.

A key part of starting to exercise is choosing when to work out. Morning, afternoon, or evening: Which time is best? Scientists have studied this dilemma extensively.

Rise and shine at 5 a.m.?

For novice exercisers, morning workouts are often the most dreaded. Trading a cozy, nurturing bed for a sterile, unforgiving fitness center can be a rude awakening to say the least. But morning workouts have their advantages. Challenging the body triggers the release of endorphins, uplifting one’s mood following exertion. These chemicals, along with a few others, boost energy levels, alertness, and focus, which can make you more productive and attentive at work.

Moreover, for those who struggle to fall asleep at night, habitual morning exercise may help to reset their circadian rhythms, the internal, biological processes that regulate the 24-hour sleep-wake cycle. While early workouts could be a struggle for night owls to grow accustomed to, sticking with them could make these individuals more alert in the morning and more tired at night, hopefully resulting in more sleep and improved health outcomes.

You are stronger in the afternoon

But alas, early exercisers may not be able to achieve peak performance. Stiffer muscles, fewer stored energy reserves from overnight fasting, and a slightly cooler body temperature in the morning add up to hamper exercise output. Therefore, more avid exercisers might prefer working out in the afternoon.

“The best window for explosive athleticism seems to be between 1 p.m. and 6 p.m.” Shawn Arent, chair of the Department of Exercise Science at the University of South Carolina told CNN.

For example, in one study, young men instructed to cycle to exhaustion at a set difficulty were able to ride 20% longer in the afternoon compared to the morning. A review of studies also found that muscle strength, muscle power, and sprinting abilities all peaked in the afternoon, topping morning performance by anywhere from 3% to 20%.

Exercise itself may also be more efficient in the afternoon. A small, 12-week study focusing on pre-diabetic and diabetic men found that afternoon training produced slightly more beneficial metabolic effects and resulted in a little more fat loss compared to morning training. The advantages, however, were marginal.

Exercise for night owls

Finally, some folks may decide to work out later in the evening. Studies centered around this time of day tend to focus on whether or not nightly exercise negatively impacts sleep quality. Gathered research suggests it does not and, instead, actually improves sleep. This finding comes with a big asterisk, however. Intense exercise performed within an hour of one’s bedtime absolutely will make it more difficult to fall asleep. For this reason, most exercise experts recommend at least 90 minutes of downtime between the conclusion of an exercise session and attempting to fall asleep.

Be consistent

Whether morning, afternoon, or evening, it is optimal if exercise timing remains somewhat consistent, research has found.

“For example, a competitive marathon runner will exhibit the best performance when his/her exercise training sessions occur at the same time-of-day as the marathon. Circadian biology may underpin this observation, including diurnal variations in body temperature, substrate metabolism, neuromuscular function, and hormones,” researchers from the University of Utah wrote last year in a study published to the journal PLoS ONE.

Still, it is perfectly fine to mix up your workout times to fit with your schedule. The average person need not worry over when to work out just because of some slight bodily differences based on time-of-day. Regular exercise is, after all, perhaps the single best thing that humans can do for their health, and ideally, it should serve as stress relief rather than something to stress over.

So, taking everything into account, when is the best time to exercise? There actually is a straightforward answer! If you’re not about to go to sleep, if you’ve got some free time on your hands, and if you haven’t already exercised today, the best time to exercise is now.

This article AM or PM: When is the best time to exercise? is featured on Big Think.

Numerous hypotheses attempt to explain obesity‘s meteoric rise over the past few decades. There’s the energy balance hypothesis, which states that weight gain is due to consuming more calories than the amount expended. There’s the carbohydrate-insulin hypothesis, which argues that excess consumption of carbohydrates stimulates an insulin response that drives cells to accumulate fat. Then there’s the protein-leverage hypothesis, which suggests that we don’t eat enough protein, driving incessant hunger. Now, researchers have put forth a new hypothesis that places the blame on a sugar ubiquitous in modern food: fructose.

Commonly known as “fruit sugar,” fructose is a simple, monosaccharide sugar found in many plants. But the compound that sweetens your watermelon, apples, and oranges can mess with your cells’ energy metabolism, Richard Johnson, a professor of medicine at the University of Colorado, and his co-authors Laura G. Sánchez-Lozada and Miguel A. Lanaspa explain in a paper published October 17 in the journal Obesity.

“We suggest that obesity is not a disease of energy excess but rather a disease of energy crisis,” they wrote.

The fructose hypothesis

As studies in rodents have elucidated, fructose uniquely suppresses the function of mitochondria compared to other nutrients. When these cellular powerhouses are slowed, the cells get stuck in a low-energy state, triggering hunger and thirst. Eating nutrients including fats and protein eventually restores cellular energy levels, but not before we’ve eaten more calories than we need. This excess gets stored as fat.

In the long term, frequent fructose exposure can damage mitochondria and reduce the amount of mitochondria in cells, the researchers say, locking people in a low-energy state which drives chronic overeating.

High-fructose corn syrup in processed foods is a common source of fructose, but many other sugars such as honey and cane sugar also contain the compound. Due to our body’s metabolism, refined carbohydrates, salty foods, and alcohol (particularly beer) also generate fructose. As already mentioned, fruits contain fructose, but Johnson and his colleagues say that they are still quite healthy to eat. The amount of fructose inside whole fruits is far less than what is inside juices or candy. Moreover, the fibers present counteract fructose’s negative metabolic effects.

Obesity’s “theory of everything”

Like physicists attempting to combine general relativity and quantum mechanics with a “theory of everything,” the researchers behind the fructose-survival hypothesis say that it unifies the other obesity-explaining hypotheses rather than competes with them. Fructose’s energy-reducing effect underlies all of them.

With food in abundance, the metabolic changes driven by fructose result in obesity and poor health today, but they would have aided our survival in the deep past, when food was scarcer. For example, finding a fruit tree would likely have been a rare, fortuitous event for our ancestors. It would have been in their interest to eat as much as possible before the fruits fell off and rotted or were eaten by another animal. These calories could then be stored as fat to provide energy when food was not as plentiful.

But in much of the world today, food scarcity is not a problem, and fructose can be found in a great many of the things we eat, particularly those that are processed. So what can be done?

In a book published last year, Johnson recommended avoiding soft drinks, fruit juices, and other super sugary foods, watching salt intake, and limiting red meat and alcohol consumption, among other basic dietary tips. He also urged regular exercise as it stimulates mitochondrial activity and growth.

Johnson’s ultimate goal is to bring a drug that inhibits fructose metabolism to market. He’s working on formulating and testing one now, and hopes that his efforts will bear fruit in the next five years or so.

This article Fructose may be the ultimate driver of obesity is featured on Big Think.

California-based biotech company Excision BioTherapeutics has shared data from the first human clinical trial of a CRISPR cure for HIV — and it’s both encouraging and frustratingly light on details.

The challenge: HIV is no longer the death sentence it once was, thanks largely to antiretroviral therapy (ART), daily medications that can decrease the amount of the virus in a person’s blood to levels that are undetectable and untransmittable.

ART doesn’t cure HIV, though — it just forces the virus to enter a dormant state, hiding its DNA in a person’s immune cells. If the person with HIV stops taking their ART, the virus can become active again, potentially leading to new symptoms and even death.

EBT-101 instructs a CRISPR system to hunt down the HIV hiding in a person’s cells.

CRISPR cure for HIV: Excision BioTherapeutics is one of several groups exploring the use of the gene-editing technology CRISPR to outright cure HIV, freeing people from a lifetime of ART.

Their treatment, EBT-101, instructs a CRISPR system to hunt down the HIV hiding in a person’s cells and make three cuts to the HIV genome. Those cuts are designed to break the genetic recipe for the virus and eliminate any possibility of it reemerging.

What’s new? After promising studies in mice and non-human primates with SIV — the monkey version of HIV — the Excision team launched a clinical trial of its CRISPR cure for HIV in 2022.

On October 25, 2023, they shared the first data from the trial at the European Society for Gene & Cell Therapy’s annual meeting in Brussels, Belgium — but missing from the announcement was any data about whether the therapy worked.

None of the patients experienced serious adverse effects from the CRISPR therapy.

What we know: During the presentation, the Excision team announced that it had administered a single IV infusion of EBT-101 to three people with HIV. All three had undetectable levels of HIV prior to starting the study, thanks to ART.

None of the patients experienced serious adverse effects from the CRISPR therapy, and the four mild adverse effects observed all resolved on their own. Four weeks after treatment, EBT-101 could be found in the blood of all three participants.

The missing link: While the primary purpose of the trial is to test the safety and tolerability of the CRISPR therapy, the researchers also planned to have “all eligible participants” stop taking ART 12 weeks after receiving EBT-101 to see if their HIV rebounded. (The therapy would be restarted again if it did reemerge.)

It’s not clear what makes a trial participant eligible, but at least one of the patients received the CRISPR therapy more than a year ago. If they stopped taking their ART, Excision isn’t ready to share whether the treatment prevented or delayed their HIV from returning.

Excision promises to present more trial data in 2024.

Looking ahead: In the next phase, Excision plans to administer a larger dose of EBT-101 to six more trial participants in the fourth quarter of 2023. This dose escalation was planned from the start of the study, so it doesn’t indicate whether the smaller dose did or didn’t work.

As for when we’ll find out whether a CRISPR cure for HIV is within our grasp, Excision promises to present more trial data in 2024.

Whether or not any of these patients were cured, larger trials will be needed to get more definitive answers about the treatment’s safety and efficacy. But EBT-101 is not the only lead in the hunt for a universal HIV cure — we also have stem cell transplants, medications, and other CRISPR therapies showing promise against the elusive virus.

This article CRISPR cure for HIV now tested in 3 patients is featured on Big Think.

Spermidine is having a moment. The compound, which sounds like a portmanteau of “sperm” and “grenadine,” has exploded in popularity over the past few years, as indicated by Google search volume. Supplement sellers market it as an anti-aging molecule and peddle it in powder and pill form.

As you might have surmised, spermidine is definitely not a mixture of male reproductive cells and a sugary red cocktail ingredient (though it was originally isolated from semen). Rather, it is a polyamine compound found mostly in protein-making ribosomes inside cells. In the body, it controls various metabolic processes necessary for proper cell function.

Autophagy

One of the things spermidine does is promote autophagy. Derived from Greek meaning “self eating,” this is the process whereby a cell disassembles damaged or degraded components and recycles them into new, better functioning parts. As shown below, a cell initiates autophagy by forming a vesicle and shoving whatever it wants to recycle inside of it. The vesicle, called an autophagosome, then merges with a lysosome, which is acidic and contains degradative enzymes. Following the merger, the contents inside are broken down and recycled.

Spermidine sellers tout autophagy as the molecule’s anti-aging “secret sauce,” so to speak, except they euphemistically label it “cellular renewal.” This slick salesmanship is not entirely unfounded. Numerous studies in model organisms show that spermidine supplementation extends animals’ lifespans, slows cardiovascular decline, protects against certain neurological disorders, and boosts liver function.

In humans, observational studies indicate that spermidine concentrations in tissues decline with age. They also suggest that people who eat diets rich in spermidine tend to live longer than people whose diets are lacking the compound. Spermidine is found in foods like wheat germ, fermented soy, soybeans, aged cheese, mushrooms, peas, nuts, apples, pears, and broccoli. Ingested spermidine is quickly absorbed from the gut and distributed throughout the body with little to no degradation.

So then does taking the stuff in supplement form slow aging and grant other health benefits? Frank Madeo, a professor of biochemistry at the University of Graz, has performed much of the research on spermidine in model organisms and has been building toward randomized clinical trials in humans for more than a decade.

Spermidine in clinical trials

The first of these was just published last year. Madeo and more than a dozen colleagues recruited 100 older adults between the ages of 60 and 90 and gave half of them a daily spermidine supplement and the other half a placebo. Over the next 12 months, the researchers monitored changes in subjects’ cognitive abilities and various physiological markers. When the trial ended, they found no benefits of spermidine over placebo.

As Madeo and his co-authors noted in their concluding remarks, it’s possible that the dose wasn’t high enough. But it’s just as likely, if not more so, that spermidine simply isn’t the “anti-aging” compound that researchers hoped it would be. The annals of science are littered with drugs that looked promising in animal trials but didn’t pan out in humans.

Spermidine is widely available and generally safe to consume at recommended doses, so it’s likely that additional human clinical trials will arrive in the future. Is it possible that these studies will have more glowing results than the first trial? Certainly. But like the spermidine supplements available on Amazon, you probably shouldn’t put your money on it.

This article Is spermidine a legitimate anti-aging supplement? is featured on Big Think.

For most of history, artificial intelligence (AI) has been relegated almost entirely to the realm of science fiction. Then, in late 2022, it burst into reality — seemingly out of nowhere — with the popular launch of ChatGPT, the generative AI chatbot that solves tricky problems, designs rockets, has deep conversations with users, and even aces the Bar exam.

But the truth is that before ChatGPT nabbed the public’s attention, AI was already here, and it was doing more important things than writing essays for lazy college students. Case in point: It was key to saving the lives of tens of millions of people.

AI-designed mRNA vaccines

As Dave Johnson, chief data and AI officer at Moderna, told MIT Technology Review‘s In Machines We Trust podcast in 2022, AI was integral to creating the company’s highly effective mRNA vaccine against COVID. Moderna and Pfizer/BioNTech’s mRNA vaccines collectively saved between 15 and 20 million lives, according to one estimate from 2022.

Johnson described how AI was hard at work at Moderna, well before COVID arose to infect billions. The pharmaceutical company focuses on finding mRNA therapies to fight off infectious disease, treat cancer, or thwart genetic illness, among other medical applications. Messenger RNA molecules are essentially molecular instructions for cells that tell them how to create specific proteins, which do everything from fighting infection, to catalyzing reactions, to relaying cellular messages.

Johnson and his team put AI and automated robots to work making lots of different mRNAs for scientists to experiment with. Moderna quickly went from making about 30 per month to more than one thousand. They then created AI algorithms to optimize mRNA to maximize protein production in the body — more bang for the biological buck.

For Johnson and his team’s next trick, they used AI to automate science, itself. Once Moderna’s scientists have an mRNA to experiment with, they do pre-clinical tests in the lab. They then pore over reams of data to see which mRNAs could progress to the next stage: animal trials. This process is long, repetitive, and soul-sucking — ill-suited to a creative scientist but great for a mindless AI algorithm. With scientists’ input, models were made to automate this tedious process.

All these AI systems were in put in place over the past decade. Then COVID showed up. So when the genome sequence of the coronavirus was made public in January 2020, Moderna was off to the races pumping out and testing mRNAs that would tell cells how to manufacture the coronavirus’s spike protein so that the body’s immune system would recognize and destroy it. Within 42 days, the company had an mRNA vaccine ready to be tested in humans. It eventually went into hundreds of millions of arms.

Biotech harnesses the power of AI

Moderna is now turning its attention to other ailments that could be solved with mRNA, and the company is continuing to lean on AI. Scientists are still coming to Johnson with automation requests, which he happily obliges.

“We don’t think about AI in the context of replacing humans,” he told the Me, Myself, and AI podcast. “We always think about it in terms of this human-machine collaboration, because they’re good at different things. Humans are really good at creativity and flexibility and insight, whereas machines are really good at precision and giving the exact same result every single time and doing it at scale and speed.”

Moderna, which was founded as a “digital biotech,” is undoubtedly the poster child of AI use in mRNA vaccines. Moderna recently signed a deal with IBM to use the company’s quantum computers as well as its proprietary generative AI, MoLFormer.

Moderna’s success is encouraging other companies to follow its example. In January, BioNTech, which partnered with Pfizer to make the other highly effective mRNA vaccine against COVID, acquired the company InstaDeep for $440 million to implement its machine learning AI across its mRNA medicine platform. And in May, Chinese technology giant Baidu announced an AI tool that designs super-optimized mRNA sequences in minutes. A nearly countless number of mRNA molecules can code for the same protein, but some are more stable and result in the production of more proteins. Baidu’s AI, called “LinearDesign,” finds these mRNAs. The company licensed the tool to French pharmaceutical company Sanofi.

Writing in the journal Accounts of Chemical Research in late 2021, Sebastian M. Castillo-Hair and Georg Seelig, computer engineers who focus on synthetic biology at the University of Washington, forecast that AI machine learning models will further accelerate the biotechnology research process, putting mRNA medicine into overdrive to the benefit of all.

This article How AI played an instrumental role in making mRNA vaccines is featured on Big Think.

Last month, hot pepper expert Ed Currie received an acknowledgement that warmed his heart. His newly bred pepper, which he dubbed “Pepper X,” had been publicly named the hottest pepper in the world by the Guinness Book of World Records. Pepper X took the infamous title from the Carolina Reaper, another of Currie’s devilish creations.

The engine of Pepper X’s heat is capsaicin, the compound that grants peppers their pungent burn. Pepper X is crammed so full of the chemical that it inflicts immediate, mind-numbing pain upon anyone who merely nibbles it — though some masochists for spice find the experience oddly enjoyable, at least in hindsight.

Currie is one of those masochists.

“I was feeling the heat for three-and-a-half hours. Then the cramps came,” Currie told the Associated Press. “Those cramps are horrible. I was laid out flat on a marble wall for approximately an hour in the rain, groaning in pain.”

But Currie doesn’t only create unbearably hot peppers for the pain, he also shares them with medical scientists researching capsaicin’s potential to cure disease and help people who suffer chronic pain.

From masochistic to medicinal

Capsaicin is already used in skin creams and patches to help relieve nerve pain. When used topically, it initially causes a brief burning sensation once absorbed, but then it desensitizes the nerves in the region where it is applied, causing an analgesic effect that lasts for a few hours.

Scientists are now looking to widen capsaicin’s medical reach. As a team of Brazilian researchers recently summarized in a literature review published in the journal Nutrients, lots of early studies show capsaicin’s potential to aid in the control of obesity and diabetes.

In the body, capsaicin acts on TRPV1 receptors. These are most prominently found in peripheral neurons, and when activated, create the sensation of scalding heat and pain. But TRPV1 receptors are also found in fat tissue, the immune system, and liver cells. Activating them with capsaicin reduces body fat, blood pressure, blood glucose, and cholesterol levels in rodents. Research also has shown that capsaicin subtly increases the production of body heat and reduces inflammation. Even more preliminary studies conducted in vitro find that capsaicin slows down the growth of white fat while transforming it into brown fat. White fat is the more common, energy storing-form of fat while brown fat breaks down blood sugar and fat molecules to create heat.

A capsaicin cure?

In summary, a plethora of preliminary yet promising research finds that capsaicin triggers beneficial effects inside the body, especially in regard to metabolism. But what does research in humans say? Observational studies generally find that people who eat more spicy food, and thus more capsaicin, are no more healthy than people who eat less spicy food. However, there are generally too many confounding variables in these studies to make any clear conclusions.

What about randomized controlled trials? Here, dosing is a problem. The beneficial amount for rodents is equivalent to about six times what the average Korean consumes in a day, and Koreans are known for being fans of spicy food. Is that level of discomfort really worth the potential benefits?

That’s why some scientists are now exploring sibling chemicals to capsaicin called capsinoids. Some of these activate TRPV1 receptors in the broader body but not in the oral cavity. However, it’s not clear if they will have the same positive effects as their pungent sibling.

Capsaicin is generally safe, with few side effects beyond its trademark pain, so you can feel free to experiment yourself. Nausea, cramps, numbness, and confusion can accompany higher doses, but these are often fleeting. Unless you eat a Pepper X, of course.

This article Capsaicin: Could the compound that gives chili peppers their heat treat diabetes and obesity? is featured on Big Think.