Gut bacteria may offer a treatment for autism

Autism affects people’s social behaviour and communication, and may impair their ability to learn things. All this is well known. Less familiar to most, though, are the gastrointestinal problems associated with the condition. The intestines of children with autism often harbour bacteria different from those in the guts of the neurotypical. As a consequence, such people are more than three times as likely as others are to develop serious alimentary-canal disorders at some point in their lives.

Unfortunate though this is, the upset gut floras of autistic people are seen by some investigators as the key to the condition—and to treating it. Recent research has shown that altering animals’ intestinal bacteria can have dramatic effects on their nervous systems. Ameliorating autism by tinkering with the ecology of the gut might thus be a fruitful line of inquiry.

A study just published in Neuron suggests that it is. In it, Mauro Costa-Mattioli of Baylor College of Medicine, in Texas, and his colleagues demonstrate that introducing a particular bacterium into the guts of mice that display autistic symptoms can abolish some of those symptoms. The bug in question is Lactobacillus reuteri. It is commonly found in healthy digestive systems and helps regulate acidity levels. And it is also easily obtainable for use as a probiotic from health-food shops.

Mens sana in corpore sano

Dr Costa-Mattioli and his team first reported L. reuteri’s effects on autism in 2016, after conducting experiments with obese female mice. These animals have a tendency to give birth to offspring with autistic traits familiar from people—unwillingness to socialise, repetitive behaviour and unwillingness to communicate (in the case of mice, via ultrasonic squeaking). The researchers noted that the guts of both the obese mothers and their young were bereft of L. reuteri. They wondered what effect transplanting these bugs into the animals might have. They found, when they did so to the offspring, that the youngsters’ autism-like traits vanished.

That led to the latest experiments, on mice that have autistic symptoms induced in four other, different ways. Some were genetically edited to be autistic. Some were exposed to valproic acid, a drug used to treat bipolar disorder and migraines that is known to induce autism in fetuses. Some had their guts cleared of all bacteria. And some belonged to a strain called btbr, individuals of which display autism-like traits that have no known cause.

Martina Sgritta, one of Dr Costa-Mattioli’s colleagues, analysed the bacteria in the guts of all of these animals. She found that, while the genetically engineered mice and the btbr mice had, as expected, reduced levels of L. reuteri, and those with bacteria-free guts were (obviously) free of the bug altogether, the valproic-acid mice had normal amounts of the bacterium.

This last result was unexpected, but the team carried on regardless. They arranged for between seven and 15 mice of each of the four types to have, starting at the age of three weeks, their drinking water laced with L. reuteri. Equivalent numbers of each type continued to be given ordinary water as a control. During the course of the experiment the mice had their faeces collected regularly, so that their bacteria could be tracked. And, at the age of seven weeks, they were given two sorts of social tests.

The first test involved putting each experimental mouse into a perspex container from which it could go either into a chamber where there was an empty wire cup or into one where there was a similar cup containing an unfamiliar mouse. Subject mice were left in the container for ten minutes and were monitored to see how long they spent with the empty cup and with the other mouse.

The second test placed a mouse in an arena where another, unfamiliar mouse was already present. An observer, who did not know which mice were controls and which had been given L. reuteri in their water, then noted how often over the course of ten minutes the two mice touched, sniffed, groomed and crawled on one another.

In both tests, all the mice that had had their water laced with L. reuteri, regardless of how their autism had been induced, were more sociable than equivalents that had been drinking unlaced water. In the first, they spent twice as much time with the mouse under the wire cup. In the second, they engaged in many more social interactions with the unfamiliar mouse.

The team’s initial hypothesis had been that the supplementary L. reuteri were somehow changing the gut flora of the mice exposed to them into something more normal. But they weren’t. Indeed, L. reuteriproved able to abolish autistic behaviour even in those mice which had guts otherwise devoid of microbes—as well as in those with valproic-acid-induced autism, which already had normal levels of the bug. That suggests boosting levels of this bacterial species is shaping behaviour all by itself.

Their next hypothesis was that the bacterium was doing this by interacting somehow with oxytocin, a hormone that shapes behaviour and plays a part in the ways in which people and other mammals form social bonds. Dr Costa-Mattioli knew from work published in 2013 that spraying oxytocin into the noses of mice with autistic symptoms helps to ameliorate some of those symptoms. Dr Sgritta therefore ran the experiments again, but this time on autistic mice that had had the oxytocin receptors on the relevant neurons disabled by genetic engineering. In these new experiments, the presence of L. reuteri in drinking water had no effect.

Follow-up examinations of the mice in all these experiments looked at the strengths of connections between nerve cells within part of the brain called the ventral tegmental region. This region regulates, among other things, motivation and reward-related social behaviour. Nerve signals are carried by the movement of ions (electrically charged atoms), so the team were able to measure connection-strength by monitoring the flow of ions at the junctions between nerve cells in this region. Strong connections, with lots of ion flow, indicated that social experiences were rewarding. These were normal in the mice exposed to L. reuteri, which makes sense since animals treated with the bacterium sought out more social experiences. Conversely, weak connections (those with little ion flow) indicated that social experiences were not triggering a reward. Such weak connections were found in animals that had not been exposed to the bacterium.

The researchers suspected that such effects were controlled by signals from the gut that are being transmitted by the vagus nerve, which connects gut and brain. To test this idea they cut that nerve in selected animals. In these animals, subsequent treatment with L. reuteri failed to abolish their autistic symptoms.

The crucial aspect of this work is L. reuteri’s wide availability—an availability approved by regulators such as America’s Food and Drug Administration. This existing approval, which means L. reuteri poses no known health hazard, simplifies the process of organising clinical trials.

Clearly, autism in people is more complicated than a mere willingness to associate with others. And getting too excited about a mouse trial is usually a mistake. But in Dr Costa-Mattioli’s view his results, which have been replicated in part by Evan Elliot’s laboratory in Bar-Ilan University, Israel, would justify embarking on at least preliminary trials intended to determine whether L. reuteri has positive effects on people with autism, and might thus be worth pursuing.

Others agree. Sarkis Mazmanian of the California Institute of Technology works in the same area. He says of these results: “I think the bar is now very low for getting this research moved on to human trials since most people already have these bacteria inside them and we know there are few, if any, safety or toxicity issues.”

The general availability of L. reuteri does, however, bring with it another possibility—that people will conduct their own, “off label” trials, either on themselves or on their children. Dr Mazmanian is cautious about that idea. “I don’t know if there is a barrier to people buying and using this stuff now. It may be strain-specific and the paper does not state which strain or strains were used,” he says.

At the moment, Dr Costa-Mattioli is unwilling to divulge that information. He is expecting to publish another paper soon, though, with more details. In practice, it may be hard to discourage people from testing L. reuteri’s effects themselves. All the more reason to do properly conducted trials quickly.

 

 

 

This article was originally published in The Economist. Read the original article.

The Placenta, an Afterthought No Longer

The placenta may be dismissed as “afterbirth,” deemed an afterthought in discussions about pregnancy and even relegated, literally, to the trash bin. But at long last it is beginning to get its due.

In the past three weeks, scientists have published three significant studies of this ephemeral organ. One gave a detailed analysis of all the genes expressed, or converted into functioning proteins, in the placenta; another experimented with a way to silence that expressionwhen it causes trouble. In the third, researchers created mini-placentas, three-dimensional clusters of cells, or organoids, that mimic the real thing in the lab, and can be used as models for studying it.

In addition, at a recent meeting in Bethesda, Md., of the Human Placenta Project, several teams of researchers showed off sophisticated new techniques that enable the placenta to be studied in real time. That work could help doctors diagnose dangerous complications in pregnancy — including pre-eclampsia (a form of high blood pressure), preterm birth and fetal growth restriction — early enough to intervene. It might also help to reveal why boys are much more vulnerable than girls to disorders of brain development, including schizophrenia, A.D.H.D., autism, dyslexia and Tourette syndrome.

“The missing link between complications during pregnancy and development of the fetal brain has been hiding in plain sight for a long time,” said Dr. Daniel R. Weinberger, director of the Lieber Institute for Brain Development in Baltimore, Md. “It’s the placenta.”

During the course of human pregnancy, the placenta grows from a few cells into an organ weighing more than a pound. It often is compared to an aggressive cancer. But a more apt metaphor might be a military invasion, as 90 percent of the placenta is made up of cells not from the mother but from the fetus.

Early in gestation, the fertilized egg implants itself in the mother’s uterine lining and sends out a few cells to breach it. These foot soldiers produce proteins that disarm the mother’s defenses, destroy the smooth muscles that line her blood vessels and dilate and redirect the vessels to feed the embryo. As the placental beachhead grows, its cells specialize to do the work of heart, lungs, liver and kidneys until the fetus can fend for itself. Groups of cells exchange oxygen for carbon dioxide; provide nutrients and hormones; protect the fetus from harmful stress, germs and chemicals; and remove waste.

This incursion fails as often as 20 percent of the time, and when it does, it can cause severe complications for the fetus, at birth and afterward. It may also forecast trouble for the mother’s health later in life: pre-eclampsia can portend heart disease and stroke, and gestational diabetes can signal later obesity and metabolic disease.

“There is nothing in medicine that can return so much on an investment as a healthy pregnancy and delivery, because that has years and years of impact later,” said Dr. George R. Saade, chief of obstetrics at the University of Texas Medical Branch. “And placental health is critical to the health of a pregnancy.”

Not all placentas develop equally. In the last few years Tracy Bale, director of the University of Maryland’s Center for Epigenetic Research in Child Health and Brain Development, has found that the placenta of a male fetus is more vulnerable to external stress than the placenta of a female fetus. This vulnerability, in turn, may transfer to the embryo, Dr. Bale said. Male fetuses typically are larger than females throughout gestation, but they also have higher rates of spontaneous abortions, stillbirth, premature birth and neurodevelopmental conditions.

It’s not yet clear what makes female fetuses more resilient. But during the first trimester, 58 genes are expressed differently in male fetuses than in females, according to an analysis published in January, in the journal Biology of Sex Differences.

Several of these genes are on the X chromosome. A female fetus has two X chromosomes and two copies of these genes, with one copy typically staying silent. But the analysis showed that many of these gene copies are activated regardless, and so they become a larger factor in female placentas than in males. (The more detailed analysis of gene expression published three weeks ago did not look at sex differences, but provides a framework for similar analyses.)

In May, Dr. Weinberger’s team at the Lieber Institute looked specifically at genes implicated in schizophrenia. They found that many of these genes are abundantly expressed in the fetal placenta, and are activated at even higher levels when the pregnancy is under stress; the effect is more dramatic in male fetuses than in females.

“We suggested that placentas of male fetuses seem to be more susceptible at a genetic level,” Dr. Weinberger said. “I’m very confident the same story is going to be there for autism, A.D.H.D. and other developmental behavioral problems.”

Technological limitations have obscured the central role that the placenta plays in the health of both baby and mother. The placenta is a dynamic organ, but it usually has been studied by dissecting it after delivery.

“That’s too late,” said Dr. Saade of the University of Texas. “It’s like studying cardiac disease or any other medical condition just by doing an autopsy.”

Problems with the placenta often begin in the spiral arteries of the mother — the arteries that the fetus commandeers to feed itself. If they are blocked or too narrow, the fetus may not get enough oxygen and nutrients, and the mother’s blood pressure may spike toward pre-eclampsia. This can begin as early as the first trimester, but few tools are available to diagnose it at that stage.

 

“The tests that are available today are all designed for the third trimester, and that’s way too late,” said Dr. Alfred Z. Abuhamad, chair of the department of obstetrics and gynecology at Eastern Virginia Medical School in Norfolk, Va.

In 2014, the child-health division of the National Institutes of Health set out to find noninvasive methods to identify complications earlier. An infusion of $80 million into placenta research prompted Dr. Abuhamad and others to adapt technologies used in other fields, and has already provided valuable insights into early pregnancy.

Some scientists are betting on magnetic resonance imaging scans, or M.R.I.s, as the most sensitive detectors of placental problems. They are using a method that measures oxygen levels in the blood; it is quick and, so far, seems to catch problems as early as the second trimester. Several teams worldwide are evaluating the technique, each in hundreds of women.

But M.R.I. is not widely in use in obstetricians’ offices, Dr. Abuhamad said, in contrast with ultrasound machines, which would be a more practical option. Traditional ultrasounds can show the structure and location of the placenta, not how well the organ is functioning. But advances over the past five years have sharpened the machine’s focus. One enables the device to detect tiny blood vessels; another, called elastography, was developed to examine the liver, and can help measure the density of placental tissue.

Dr. Abuhamad’s team is using these advances in ultrasound to chart placental health in about 500 pregnant women, including 300 at high risk of complications. They are collecting ultrasound data and blood samples from the women at eight time points during pregnancy to see which early features track with problems later on.

Other teams are trying to identify particles the placenta may release into the bloodstream because that could lead to a simple blood test for diagnosing problems. And one group of researchers is developing an oximeter, a device that quantifies the light reflected back through layers of fat as a measure of blood oxygen.

It will be at least five years before any of these tests makes their way to doctors’ offices. But when they are ready, they are likely to have a huge impact on obstetric practice, said Dr. Diana W. Bianchi, director of the National Institute of Child Health and Human Development.

“The way that prenatal care is currently structured, you hardly see your obstetrician in the first trimester,” she said. “And by the time you get to the third trimester, you’re seeing the obstetrician weekly.”

Instead, when placental screening identified a problem, women might be encouraged to see their doctors frequently through the first trimester. “Knowing that this starts early in the first trimester,” said Dr. Abuhamad, “could we then intervene in the first trimester — identify early, intervene early and prevent the complications?”

 

This article was originally published in The New York Times. Read the original article.

Narrower Skulls, Oblong Brains: How Neanderthal DNA Still Shapes Us

People who sign up for genetic testing from companies like 23andMe can find out how much of their DNA comes from Neanderthals. For those whose ancestry lies outside Africa, that number usually falls somewhere between 1 percent and 2 percent.

Scientists are still a long way from understanding what inheriting a Neanderthal gene means to people. Some Neanderthal genes may be helpful — improving our defenses against infections, for example — but other bits may leave carriers slightly more prone to certain diseases.

On Thursday, a team of scientists revealed that two pieces of Neanderthal DNA may have another effect: They may change the shape of our brains.

The study, published in the journal Current Biology, wasn’t designed to determine how Neanderthal genes influence thought — if they do so at all. Instead, the value of the research lies in its unprecedented glimpse into the genetic changes influencing the evolution of the human brain.

“This study is surely a milestone,” said Emiliano Bruner, a paleoanthropologist researcher at Spain’s National Research Center on Human Evolution, who was not involved in the research.

Neanderthals and modern humans are evolutionary cousins whose ancestors diverged about 530,000 years ago, possibly somewhere in Africa. Neanderthals left Africa long before modern humans, and their bones were found across Europe, the Near East, and even Siberia.

Before they disappeared about 40,000 years ago, Neanderthals left behind signs of sophistication: spears used to hunt big game, for instance, and jewelry made of shells and eagle talons.

Yet scientists still wonder just how much like us these cousins were. Did they speak a full-blown language? Did they think in symbols?

One thing is clear: They were not short on brains. By measuring the volume inside Neanderthal skulls, researchers have found that their brains were as big as ours, on average, perhaps bigger.

But their brains did not mimic ours. “We have roundish brains,” said Philipp Gunz, a paleoanthropologist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. “All other human species have elongated brain cases.”

Dr. Gunz and his colleagues study CT scans of fossil skulls to track brain evolution. As it turns out, the oldest skulls of modern humans, dating back 300,000 years, held elongated brains — more like those of Neanderthals than our own.

Skulls from about 120,000 years ago show that brains had gotten somewhat rounder by then, but were still outside the range observed in people today.

But there’s a gap in the fossil record after that period; the next oldest skulls that Dr. Gunz and his colleagues have studied are just 36,000 years old. These have the distinctive roundedness of living humans.

Modern human skulls got rounder because certain regions of the brain changed size. At the back of the brain, for example, a part called the cerebellum dramatically expanded.

Dr. Gunz and his colleagues wondered what sort of genetic changes drove this shift. It occurred to them that an answer might be found in a natural experiment that took place about 60,000 years ago: the interbreeding of modern humans and Neanderthals.

As they left Africa, modern humans encountered and mated with Neanderthals, producing healthy children who inherited a set of chromosomes from each parent. Neanderthal DNA has persisted through the generations in people of non-African descent.

 

Did Neanderthal genes affect the shape of modern human brains? The effect of any one gene would be exquisitely subtle, and so Dr. Gunz and his colleagues needed to compare a lot of brains to find it.

Fortunately, a number of scientific teams had already begun building databases of brain scans and DNA from volunteers.

Dr. Gunz’s team studied 4,468 people in the Netherlands and Germany. They searched the DNA of the volunteers for over 50,000 common genetic markers inherited from ancient Neanderthals.

Then the researchers compared the shapes of people’s brains to see whether any Neanderthal gene variants were associated. Two genetic markers jumped out: People who carry them have unusual patterns of gene activity in their brains.

One marker is linked to a gene called PHLPP1. It’s unusually active in the cerebellum of people who carry the Neanderthal version. This gene controls the production of an insulating sleeve that wraps around neurons. Known as myelin, it is crucial for long-range communication in the brain.

The other marker is linked to a gene called UBR4, which in carriers is less active in a region deep in the brain called the putamen. UBR4 helps neurons divide in the brains of children.

These findings suggest that PHLPP1 and UBR4 evolved to work differently in modern human brains. The modern human version of PHLPP1 may have produced extra myelin in the cerebellum. And our version of UBR4 may have made neurons grow faster in the putamen.

Why these changes? Simon Fisher, a co-author of the new study at the Max Planck Institute for Psycholinguistics in the Netherlands, speculated that modern humans evolved more sophisticated powers of language. They may have also become better at making tools.

“Things like tool use and speech articulation are hugely dependent on motor circuitry,” said Dr. Fisher.

Both require the brain to send fast, precise commands to muscles. And it may be no coincidence that the cerebellum and putamen are crucial parts of our motor circuitry — the very regions that helped change the overall shape of the modern human brain.

What does this research mean for people who carry the Neanderthal versions of these brain-shaping genes? There are limits to what genetics can tell us, said John Anthony Capra, an evolutionary biologist at Vanderbilt University who was not involved in the study.

It’s very hard to predict people’s behavior from their genes, he noted — let alone try to account for a few Neanderthal genes. To learn what they are doing in the brain will require that scientists discern very faint signals amid the noise of the human genome.

“That’s a long way off, if ever possible,” Dr. Capra said

 

This article was originally published in The New York Times. Read the original article.

A species of spider that suckles its young

Superficially, individuals of a species of jumping spider called Toxeus magnus look like ants. This protects them from the attentions of spider wasps—a group of insects that catch and paralyse spiders in order to lay their eggs on the arachnids’ bodies, which thus act as a living larder for the wasps’ larvae. Ants are not, however, the only group of unrelated animals that T. magnus resembles. They are also quite like mammals. That, at least, is the conclusion of a study just published in Science by Quan Ruichang of the Xishuangbanna Tropical Botanical Garden, in Yunnan, China.

Female mammals produce milk to suckle their young. Before modern gene-based phylogeny developed, that was indeed the definition of a mammal. A few other types of animal do something similar. Pigeons, for example, generate a milklike secretion in their throats, which they feed to their squabs. But until now, only in mammals (or some of them, anyway) was lactation thought to be the basis of an extended relationship between parent and offspring. Dr Quan and his colleagues have changed that thinking.

Their study was stimulated by the observation that wild T. magnus seem to remain in the maternal nest far longer than most other spider species. They wondered why. They therefore brought some specimens into their laboratory for a closer look. This showed that the mother of a brood exudes fluid from her epigastric furrow, the canal through which she lays her eggs. For the first week of her hatchlings’ lives, she deposits this fluid in drops around the nest, from which the young spiders drink. After that, until they are about 40 days old, she suckles the spiderlings directly.

Experiments that measured the growth and survival of young spiders, some of which involved sealing the mother’s epigastric furrow using typing-correction fluid, showed that the spiderlings did, indeed, depend on the secretion for nutrition. They relied on it completely until they were 20 days old, at which point they started leaving the nest to hunt on their own account. Even after this, though, the fluid formed an important dietary supplement until they were about 40 days old. And chemical analysis showed that it is a rich source of nutrients. It contains four times as much protein as cow’s milk does.

Even when weaned, young spiders, like many young mammals, returned home regularly after they had been out searching for food of their own—and experiments that removed the mother showed she was in some way contributing to their health and survival even then. Young spiders continued to return until they were 60 days old, and thus sexually mature. At that point, the mother started attacking returning sons, thus driving them away—presumably to avoid the risk of them mating with their sisters and producing inbred offspring. Daughters, though, she continued to tolerate. At what point those daughters, too, left to set up shop by themselves the study did not investigate.

Whether epigastric lactation and its consequent prolongation of family life is confined to T. magnus, or is more widespread among jumping spiders, remains to be looked at. But unless the strategy has evolved very recently it seems likely that at least some of T. magnus’s relatives will also employ it. Either way, Dr Quan’s discoveries serve as a reminder that if something works well in one part of the animal kingdom, the chances are that it will do so elsewhere, too.

 

 

 

This article was originally published in The Economist. Read the original article.

The era of human gene-editing may have begun. Why that is worrying

Humanity’s power to control the four-letter code of life has advanced by leaps and bounds. A new gene-editing technology called crispr-Cas9, which was not discovered until 2012, has been the subject of particular excitement. It allows dnato be edited easily, raising hopes that it could eventually be used to relieve human suffering. This week, however, crispr has caused more unease than optimism, because of claims by a Chinese scientist that he edited the genomes of twin girls when they were embryos, as part of ivf treatment.

He Jiankui, of the Southern University of Science and Technology, in Shenzhen—which was not involved in the work—says he edited a gene, ccr5, that allows hiv to infect human cells (see article). Mr He claims to have created one baby resistant to hiv infection, and a twin who is not. (Another woman is apparently carrying an edited embryo.) If reproductive cells were affected, any such modifications will be passed on to subsequent generations. There is still uncertainty over what Mr He has done. But it is just a matter of time before someone, somewhere, edits human embryos that are grown into babies. Governments and regulators need to pay heed.

Presume that Mr He’s assertions are truthful. One day it may make sense to edit an embryo—to cure genetic diseases, say. That day has not arrived. The technology is so new that the risks to human subjects cannot possibly justify the benefits. Scientists do not fully understand the scope of the unintended damage crispr does to dna elsewhere in the genome or how deactivating ccr5 might leave you vulnerable to other diseases (it may, for instance, make death from flu more likely).

Mr He’s work appears to have had the scantiest oversight and a vice-minister says it violates regulations. Mr He told delegates at a gene-editing conference in Hong Kong this week that he had run the idea for the trial past four people. It seems likely that Mr He himself was largely responsible for deciding whether his human experiment was worth the risks. It is not clear that the babies’ parents gave their informed consent.

Nor did the procedure fulfil any unmet medical need. For the child whose genome was edited to confer resistance, the claimed benefit is protection from a virus that she may never encounter (although her father is hiv-positive, his sperm were washed to prevent infection during fertilisation) and for which there is a good, and improving, standard of care. If the reports are correct, the second child has been exposed to the potential risks of an edited genome but can still be infected by hiv.

The idea that one scientist could make the leap towards editing reproductive cells has been condemned, but it has not been ruled out. Even if Mr He turns out to be a fraud, others have the means, the motive and the opportunity to do similar work. crispr is not a complex technology. That leads to two responses.

The first is practical: better oversight of places such as fertility clinics, where back-room genome-tinkerers may lurk. That applies not just in China, where Mr He has attracted vocal condemnation, but also in America, where ivf clinics could use greater regulatory scrutiny.

The second is proper debate about when gene-editing is warranted. Editing the unhealthy cells of those suffering from genetic diseases such as Duchenne’s muscular dystrophy and cystic fibrosis will alleviate their suffering. It is less clear when it is necessary to edit embryos, but Mr He’s experiment obviously fails the test. Fertility treatments already screen embryos for unwanted genes.

It may even be that editing will one day be used on embryos to enhance genomes (to make people cleverer, say), rather than to cure disease. But that requires regulators, policymakers, scientists and civil society to think through deep ethical questions. Work is already under way to develop principles for editing reproductive cells. Earlier this year the Nuffield Council on Bioethics, a think-tank in Britain, outlined two: that the changes brought about by gene-editing should not increase “disadvantage, discrimination or division in society” and that such changes should not harm the welfare of the future person. Such debate was always going to be needed. Now it is urgent.

 

 

This article was originally published in The Economist. Read the original article.

Project Baseline Aims to Ward Off Illness Before We Get Sick

One of the sobering facts about cancer treatment is that it often begins when it is already too late: Studies show that an alarming number of treatable cancers are diagnosed in the advanced stages of disease.

That has long bothered Dr. Sam Gambhir, a top cancer researcher at Stanford University who lost his teenage son to brain cancer in 2015. Dr. Gambhir wondered if there were some surefire way to detect cancer long before people got sick.

“In the cancer field we often find problems long after people have symptoms,” he said. “We rarely find things early.”

Now Dr. Gambhir is leading a large study that seeks to better understand the transition from normal health to disease. The study, called Project Baseline, could lead to the identification of new markers in the blood, stool or urine of healthy people that help predict cancer, cardiovascular disease and other leading killers of Americans. It is a joint effort between Stanford and Duke Universities and Verily, a life sciences company owned by Alphabet, the parent company of Google. Researchers are recruiting 10,000 adults across the United States who will be examined in extreme detail and followed intensively for at least four years.

Many of the people joining the study are healthy adults, which differs from traditional medical trials that focus largely on people who are already ill. Another key difference is that the researchers are collecting a staggering amount of medical data on their subjects: analyzing their microbiomes, sequencing their genomes, subjecting them to a variety of scans and assessing their cognitive health. They are also equipping volunteers with new wearable technology from Verily that records their nightly sleep patterns and tracks their heart rhythms and physical activity.

In another unusual move, the Project Baseline investigators are sharing the research results with their subjects, everything from how much plaque or calcium they find in their arteries to which bacterial strains inhabit their guts.

Some experts worry, however, that providing such detailed medical data to healthy adults could lead to new problems. Dr. Eric Topol, a professor of genomics at the Scripps Research Institute in California, cautioned that the sheer amount of testing, scans and other “deep interrogations” could produce incidental findings that cause unnecessary anxiety. “Sometimes it leads to unwarranted further testing that could even be harmful,” he said.

Dr. Topol is involved in a similar study, called All of Us and financed by the National Institutes of Health, which is building a “biobank” of health information collected from a million Americans. The researchers intend to return genetic data and some other results to participants but are figuring out the best way to do that.

“This is the new challenge in a democratized world of medical research,” Dr. Topol said. “I’m really in favor of it, but it sets up this new issue of dealing with unexpected results that are difficult to interpret.”

The Project Baseline researchers are learning this firsthand. They say they have discovered and promptly alerted participants to potentially lethal conditions that might otherwise have gone unnoticed, like cancer and aortic aneurysms, so they can seek appropriate medical care. But some of the participants have also been frightened by fairly innocuous findings, like chest X-rays that reveal small, usually benign nodules in their lungs that they may look up on the internet and think are cancerous, said Dr. Charlene Wong, a Project Baseline investigator. “For most of our participants, it will not be cancer. But we’re still in the process of working with participants to find out if we can return that data in the right way so that we minimize the anxiety it can cause,” she said.

Dr. Ken Mahaffey, a Project Baseline investigator and cardiologist at Stanford, said that he and his colleagues have “a responsibility, socially, morally and ethically, to get systems in place so we can share the results with participants in ways that they can understand them and then help them engage with their own physicians and clinical providers.”

Despite the anxiety it can cause, many people welcome such data. Studies like Project Baseline are especially appealing to the so-called Quantified Self movement, the growing community of people who track their every biometric with smartphone apps, high-tech gadgets and direct-to-consumer health tests. Some 2,000 people have enrolled in Project Baseline so far, and thousands more have signed up in a registry of potential volunteers who may be called on as the project expands to additional medical centers.

While there have been plenty of longitudinal studies in the past, many of the largest and most important were not very diverse. The landmark Framingham heart study that began in 1948, for example, focused mostly on white adults. Dr. Svati Shah, an associate professor of medicine at Duke, said Project Baseline is recruiting many people who are black, Hispanic, Asian and other ethnicities so the study can shed light on differences in disease risk factors among people of different backgrounds.

That includes people like Rosa Gonzalez, 57, a nurse who lives in Concord, N.C. Ms. Gonzalez, who is Mexican-American, joined the study earlier this year and has encouraged at least a dozen Latino friends and acquaintances to join it as well.

“Other studies present data and talk about Latinos, but they don’t have Latinos in the study,” she said. “I’m trying to set an example so other Latinos see that it’s good to take part so that we can have data that shows how we’re the same or different.”

Dr. Gambhir said the idea for Project Baseline was hatched in 2013, when Google executives approached him and said they wanted to do a landmark study on human health. Dr. Gambhir proposed a study to find early markers of cancer in people who are otherwise healthy.

“We have always thought that if we learn more about what your body is doing before you become ill, then we would have a much better chance of ideally preventing or at least detecting things early,” he said. Google liked the idea but suggested broadening the scope to include other diseases.

Verily declined to say how much it is spending on Project Baseline. But the company is investing in several areas of health care, including the development of contact lenses and miniature sensors that monitor blood sugar levels so patients with diabetes can better manage their disease.

In addition to sharing results with study volunteers, Project Baseline is hosting events and webinars in which study participants can ask the researchers questions and give them suggestions. “This isn’t research that’s happening in a black box,” said Dr. Jessica Mega, Verily’s chief medical officer. “People on the ground are part of this movement.”

This article was originally published in The New York Times. Read the original article.

 

Studies Warn Against Minimally Invasive Surgery for Cervical Cancer

Two new studies revealed bad news about minimally invasive surgery for cervical cancer, a widely used procedure performed through small slits in the abdomen instead of a big incision.

Compared with the older, open abdominal operation, the minimally invasive approach was more likely to result in recurrence of the cancer and death, researchers found, in the first study that rigorously tested the two methods.

The results, published on Wednesday in The New England Journal of Medicine, had been circulating among cancer specialists in recent months and are already changing medical practices. Minimally invasive surgery for cervical cancer had been regarded as an advance that would help women: It lets patients recover faster, and since it had proved safe for other cancers, it was expected to be safe for cervical cancer, too.

“At M.D. Anderson, we have completely stopped performing minimally invasive surgery for cervical cancer,” said Dr. Pedro T. Ramirez, a leading expert in minimally invasive surgery for gynecologic cancers, and the lead author of one study. “Throughout the gynecologic oncology community, we’re seeing a transition back to the predominance of open surgery.”

But he also said that some surgeons, who had invested a lot of time, energy and money in learning the less invasive approach, did not want to give it up.

Dr. Ramirez and other researchers said the surprise findings show why it is essential to conduct clinical trials that test one treatment against another.

Surgery is not regulated the way drugs are. Although the Food and Drug Administration must approve new surgical devices, it does not control the way they are used. A tool approved for one purpose can be used for another. Surgeons can try new approaches, and innovations can catch on and spread, as long as hospitals allow it.

Some innovations have backfired. Morcellators, power tools that mince up tissue for extraction through small openings, were originally approved for orthopedic surgery and other procedures, but came into widespread use in operations to remove fibroids, a type of benign tumor, from the uterus.

But fibroids sometimes hide malignant tumors, and morcellation was found to spread cancer in some women, increasing their risk of death.

In that case, the F.D.A. did step in and recommend that the devices not be used “in the vast majority of women” undergoing fibroid surgery. Their use fell off sharply.

Morcellation is not used in surgery for cervical cancer. When minimally invasive surgery is performed, the uterus is removed intact through the vagina.

The study included 631 women and 33 hospitals in the United States, Colombia, Brazil, Peru, Italy, China, Australia and Mexico.

The results affect a relatively small number of women in the United States, where screening has reduced the incidence of cervical cancer to about 13,000 cases a year, with about 4,000 deaths. But worldwide, cervical cancer is the fourth most common malignancy and cause of cancer death in women, with 570,000 cases a year and 270,000 deaths.

The disease is caused in nearly all cases by the human papillomavirus, HPV, an extremely common, sexually transmitted virus. In most people, the immune system clears the virus and they never knew they were infected. But in some it persists, and can cause cervical cancer and other malignancies.

Dr. Ramirez said women with cervical cancer should discuss the types of surgery with their doctors, and should “question the approach of having minimally invasive surgery if that is what is suggested to them.”

Dr. Amanda N. Fader, director of the Kelly Gynecologic-Oncology Service at Johns Hopkins University, and the author of an editorial that accompanies the studies, said the results had “dealt a great blow” to the minimally invasive surgical method for cervical cancer. Johns Hopkins has also halted the procedure, reverting to open surgery “for the time being,” she said.

One question the findings raise is whether women who have already had minimally invasive surgery for cervical cancer have a higher risk of recurrence than previously thought. Dr. Ramirez said most recurrences happen within the first two years after surgery, so women who had the operation more than two years ago may have little to worry about.

For those who had the surgery more recently, doctors are still trying to determine whether extra follow-up is needed. In any case, doctors said, long-term survival rates after both types of surgery are still high.

Dr. Ginger Gardner, a gynecologic oncologist at Memorial Sloan Kettering Cancer Center in New York, said the studies were important, and her hospital was examining its own surgical results and discussing the findings with patients. She said decisions were being made on a case-by-case basis, and that the minimally invasive approach might still be appropriate for some women.

“This turns us on our heads a bit,” said Dr. Lee-may Chen, director of the gynecologic oncology division of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. “We thought laparoscopic surgery would be good for this patient population.”

She said that because of the findings, she now encourages most patients to have open surgery for cervical cancer. But she discusses the information with them, and would consider the minimally invasive approach for women who refuse open surgery, or for those who have a high risk of serious complications from open surgery.

Research had found that the minimally invasive approach, in use since around 2006, worked as well as open surgery to treat cancer of the uterus, which convinced many doctors that it would also be safe for cervical cancer.

But uterine cancer and cervical cancer are different diseases, and require different operations. Uterine cancer needs a simple hysterectomy, which means removing only the uterus.

Cervical cancer requires a radical hysterectomy, a more complex operation that takes out the uterus, part of the vagina and other surrounding tissues.

Dr. Ramirez and his team wanted to compare open and minimally invasive surgery, to find out if they were equally effective at eliminating cervical cancer. The research was paid for by M.D. Anderson and Medtronic, which makes instruments for minimally invasive surgery.

To ensure that all the surgeons were skilled in minimally invasive procedures, the team leaders required them to submit reports on at least 10 operations, and unedited videos of two.

Patients were recruited from June 2008 through June 2017, and were assigned at random to have either open or laparoscopic surgery, about half to each group. Their average age was 46, and all had early-stage cervical cancer (surgery is not used in advanced cases).

As the study progressed, it was monitored by an independent safety board that looked at the data to make sure patients were not being harmed. Partway through the project, the board saw too many deaths in the minimally invasive group. It recommended that the researchers temporarily stop adding new patients so the findings could be more closely examined.

A deeper analysis confirmed the higher death rate. The board said that no more patients should be enrolled, and that the hospitals should be told that minimally invasive surgery carried a higher risk of death. The original plan had been to include 740 patients, but the study stopped at 631.

After 4.5 years, 96.5 percent of the patients who had open surgery were free of cancer, as opposed to 86 percent in the minimally invasive group. At three years, 99 percent of the open-surgery patients were alive, compared with 93.8 percent of those who had minimally invasive operations.

With a median follow-up time of 2.5 years, 27 patients in the minimally invasive group had a cancer recurrence, compared with seven who had open surgery. There were 19 deaths in the minimally invasive group (14 from cancer), and three in the open group (two from cancer).

The researchers were stunned. Dr. Ramirez said they had expected to find that the two methods were equivalent.

Researchers do not know why there was a difference, but offer several theories. One is that an instrument passed through the cervix during some laparoscopic operations may inadvertently spread cancer cells. Another is that carbon dioxide, used to inflate the abdomen so that surgeons can see better during minimally invasive procedures, may help cancer cells invade tissue. Still another idea is that laparoscopic surgery may miss some cancerous tissue.

Dr. Fader said that if more research could explain the bad outcomes, it might become possible to identify patients for whom the minimally invasive approach would be safe.

A second study also found problems with minimally invasive surgery. It was not a clinical trial. Rather, it used information from databases to compare the results of the two surgical methods. It was paid for by the National Institutes of Health and charitable foundations.

In one analysis, 1,225 of 2,461 women had minimally invasive surgery, and the rest had open surgery. At four years, 9.1 percent in the minimally invasive group had died, compared with 5.3 percent who had open surgery.

Another analysis looked at the survival rate for cervical cancer surgery over time, and found that it began to decline when minimally invasive surgery was introduced, dropping by 0.8 percent a year after 2006.

“None of us expected this,” said, Dr. Jason D. Wright, an author of the study and the chief of gynecologic oncology at NewYork-Presbyterian/Columbia University Irving Medical Center. “We expected to find it was as safe.”

He said that because of the findings, most women at his hospital who need operations for cervical cancer are now having open surgery.

 

This article was originally published in The New York Times. Read the original article.

Yes, the Octopus Is Smart as Heck. But Why?

To demonstrate how smart an octopus can be, Piero Amodio points to a YouTube video. It shows an octopus pulling two halves of a coconut shell together to hide inside. Later the animal stacks the shells together like nesting bowls — and carts them away.

“It suggests the octopus is carrying these tools around because it has some understanding they may be useful in the future,” said Mr. Amodio, a graduate student studying animal intelligence at the University of Cambridge in Britain.

But his amazement is mixed with puzzlement.

For decades, researchers have studied how certain animals evolved to be intelligent, among them apes, elephants, dolphins and even some birds, such as crows and parrots.

But all the scientific theories fail when it comes to cephalopods, a group that includes octopuses, squid and cuttlefish. Despite feats of creativity, they lack some hallmarks of intelligence seen in other species.

“It’s an apparent paradox that’s been largely overlooked in the past,” said Mr. Amodio. He and five other experts on animal intelligence explore this paradox in a paper published this month in the journal Trends in Ecology and Evolution.

For scientists who study animal behavior, intelligence is not about acing a calculus test or taking a car apart and putting it back together. Intelligence comprises sophisticated cognitive skills that help an animal thrive.

That may include the ability to come up with solutions to the problem of finding food, for example, or a knack for planning for some challenge in the future. Intelligent animals don’t rely on fixed responses to survive — they can invent new behaviors on the fly.

To measure animal intelligence, scientists observe creatures in the wild — watching a dolphin stick a sponge on its beak to avoid getting cuts from sharp rocks and coral, for example. Or they bring animals into the lab and offer them puzzles to solve, such as rewarding crows when they learn to rip paper into strips of just the right size.

Only a few species stand out in these studies, and by comparing them, scientists have identified some shared factors. The animals have big brains relative to their body size, they live for a long time, and they can form long-lasting social bonds.

Those similarities have led to some promising explanations for how certain animals evolved to be smart.

One is known as the ecological intelligence hypothesis. It holds that intelligence evolves as an adaptation for finding food. While some animals have a reliable food supply, others have to cope with unpredictability.

“If you eat fruit, you have to remember where the fruiting trees are and when they’re ripe,” said Mr. Amadio. “It can be much more cognitively challenging than eating leaves.”

Tools allow animals to get to food that they couldn’t reach otherwise. And if they can make plans for the future, they can store food to survive hard times.

Other researchers have argued for what’s known as the social intelligence hypothesis: Smarter animals “cooperate and learn from other members of the same species,” said Mr. Amadio.

Together, these forces appear to have encouraged the development of bigger, more powerful brains.

Smart animals also tend to live for a long time, and it’s possible that bigger brains drove the evolution of longevity. It takes years for juveniles to develop these complex organs, during which time they need help from adults to get enough food.

Cephalopods behave in ways that certainly suggest they’re highly intelligent. An octopus named Inky, for example, made a notorious escape recently from the National Aquarium of New Zealand, exiting his enclosure and slithering into a floor drain and, apparently, out to sea.

Cuttlefish can scare off predators by forming eyespots on their bodies in order to look like giant fish. But they only use this trick against predators that rely on vision to find prey. If a predator that depends on smell shows up, the cuttlefish are smart enough just to flee.

Octopuses show the same flexibility when scientists bring them into labs. In one study, researchers at Hebrew University presented octopuses with an L-shaped box with food inside. The animals figured out how to push and pull the morsel through a tiny hole in the wall of their tank.

Another feature that cephalopods share with other smart animals is a relatively big brain. But that’s where the similarities appear to end. Most of the neurons that do the computing, for example, are in the octopus’s arms.

Most strikingly, cephalopods die young. Some may live as long as two years, while others only last a few months. Nor do cephalopods form social bonds.

They get together to mate, but males and females don’t stay together for long or care for their young. While chimpanzees and dolphins may live in societies of dozens of other animals, cephalopods seem to be loners.

Mr. Amodio and his colleagues think the evolutionary history of cephalopods may explain this intelligence paradox. About half a billion years ago, their snaillike ancestors evolved to use their shells as a buoyancy device. They could load chambers in the shell with gas to float up and down in the ocean.

A cousin of cephalopods, the nautilus, still lives this way. Like cephalopods, it has tentacles. It also has a somewhat enlarged brain, although it doesn’t seem to be anywhere as intelligent as an octopus.

About 275 million years ago, the ancestor of today’s cephalopods lost the external shell. It’s not clear why, but it must have been liberating. Now the animals could start exploring places that had been off-limits to their shelled ancestors. Octopuses could slip into rocky crevices, for example, to hunt for prey.

On the other hand, losing their shells left cephalopods quite vulnerable to hungry predators. This threat may have driven cephalopods to become masters of disguise and escape. They did so by evolving big brains, the ability to solve new problems, and perhaps look into the future — knowing that coconut or clam shells may come in handy, for example.

An octopus pulls together two empty shells in order to hide off the coast of Sulawesi, Indonesia.CreditEthan Daniels, via Getty Images

Image
An octopus pulls together two empty shells in order to hide off the coast of Sulawesi, Indonesia.CreditEthan Daniels, via Getty Images

Yet intelligence is not the perfect solution for cephalopods, Mr. Amodio suggested. Sooner or later, they get eaten. Natural selection has turned them into a paradox: a short-lived, intelligent animal.

Mr. Amodio said that scientists still need to learn a lot more about cephalopods before they can know if this hypothesis is sound. But the research may do more than shine a light on octopuses and their cousins: It could give us a deeper understanding of intelligence in general.

“We can’t take for granted that there’s just one way to intelligence,” Mr. Amodio said. “There could be different paths.”

 

 

This article was originally published in The New York Times. Read the original article.