DNA Gets a New — and Bigger — Genetic Alphabet

In 1985, the chemist Steven A. Benner sat down with some colleagues and a notebook and sketched out a way to expand the alphabet of DNA. He has been trying to make those sketches real ever since.

On Thursday, Dr. Benner and a team of scientists reported success: in a paper, published in Science, they said they have in effect doubled the genetic alphabet.

Natural DNA is spelled out with four different letters known as bases — A, C, G and T. Dr. Benner and his colleagues have built DNA with eight bases — four natural, and four unnatural. They named their new system Hachimoji DNA (hachi is Japanese for eight, moji for letter).

Crafting the four new bases that don’t exist in nature was a chemical tour-de-force. They fit neatly into DNA’s double helix, and enzymes can read them as easily as natural bases, in order to make molecules.

“We can do everything here that is necessary for life,” said Dr. Benner, now a distinguished fellow at the Foundation for Applied Molecular Evolution in Florida.

Hachimoji DNA could have many applications, including a far more durable way to store digital data that could last for centuries. “This could be huge that way,” said Dr. Nicholas V. Hud, a biochemist at Georgia Institute of Technology who was not involved in research.

It also raises a profound question about the nature of life elsewhere in the universe, offering the possibility that the four-base DNA we are familiar with may not be the only chemistry that could support life.

The four natural bases of DNA are all anchored to molecular backbones. A pair of backbones can join into a double helix because their bases are attracted to each other. The bases form a bond with their hydrogen atoms.

But bases don’t stick together at random. C can only bond to G, and A can only bond to T. These strict rules help ensure that DNA strands don’t clump together into a jumble. No matter what sequence of bases are contained in natural DNA, it still keeps its shape.

Working at the Swiss university ETH Zurich at the time, Dr. Benner tried to make some of those imaginary bases real.

“Of course, the first thing you discover is your design theory is not terribly good,” said Dr. Benner.

Once Dr. Benner and his colleagues combined real atoms, according to his designs, the artificial bases didn’t work as he had hoped.

Nevertheless, Dr. Benner’s initial forays impressed other chemists. “His work was a real inspiration for me,” said Floyd E. Romesberg, now of the Scripps Research Institute in San Diego. Reading about Dr. Benner’s early experiments, Dr. Romesberg decided to try to create his own bases.

Dr. Romesberg chose not to make bases that linked together with hydrogen bonds; instead, he fashioned a pair of oily compounds that repelled water. That chemistry brought his unnatural pair of bases together. “Oil doesn’t like to mix with water, but it does like to mix with oil,” said Dr. Romesberg.

In the years that followed, Dr. Romesberg and his colleagues fashioned enzymes that could copy DNA made from both natural bases and unnatural, oily ones. In 2014, the scientists engineered bacteria that could make new copies of these hybrid genes.

In recent years, Dr. Romesberg’s team has begun making unnatural proteins from these unnatural genes. He founded a company, Synthorx, to develop some of these proteins as cancer drugs.

At the same time, Dr. Benner continued with his own experiments. He and his colleagues succeeded in creating one pair of new bases.

Like Dr. Romesberg, they found an application for their unnatural DNA. Their six-base DNA became the basis of a new, sensitive test for viruses in blood samples.

They then went on to create a second pair of new bases. Now with eight bases to play with, the researchers started building DNA molecules with a variety of different sequences. The researchers found that no matter which sequence they created, the molecules still formed the standard double helix.

Because Hachimoji DNA held onto this shape, it could act like regular DNA: it could store information, and that information could be read to make a molecule.

For a cell, the first step in making a molecule is to read a gene using special enzymes. They make a copy of the gene in a single-stranded version of DNA, called RNA.

Depending on the gene, the cell will then do one of two things with that RNA. In some cases, it will use the RNA as a guide to build a protein. But in other cases, the RNA molecule floats off to do a job of its own.

Dr. Benner and his colleagues created a Hachimoji gene for an RNA molecule. They predicted that the RNA molecule would be able to grab a molecule called a fluorophore. Cradled by the RNA molecule, the fluorophore would absorb light and release it as a green flash.

Andrew Ellington, an evolutionary engineer at the University of Texas, led the effort to find an enzyme that could read Hachimoji DNA. He and his colleagues found a promising one made by a virus, and they tinkered with it until the enzyme could easily read all eight bases.

They mixed the enzyme in test tubes with the Hachimoji gene. As they had hoped, their test tubes began glowing green.

“Here you have it from start to finish,” said Dr. Benner. “We can store information, we can transfer it to another molecule and that other molecule has a function — and here it is, glowing.”

In the future, Hachimoji DNA may store information of a radically different sort. It might someday encode a movie or a spreadsheet.

Today, movies, spreadsheets and other digital files are typically stored on silicon chips or magnetic tapes. But those kinds of storage have serious shortcomings. For one thing, they can deteriorate in just years.

DNA, by contrast, can remain intact for centuries. Last year, researchers at Microsoft and the University of Washington managed to encode 35 songs, videos, documents, and other files, totaling 200 megabytes, in a batch of DNA molecules.

With eight bases instead of four, Hachimoji DNA could potentially encode far more information. “DNA capable of twice as much storage? That’s pretty amazing in my view,” said Dr. Ellington.

Beyond our current need for storage, Hachimoji DNA also offers some clues about life itself. Scientists have long wondered if our DNA evolved only four bases because they’re the only ones that can work in genes. Could life have taken a different path?

“Steve’s work goes a long way to say that it could have — it just didn’t,” said Dr. Romesberg.

 

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

As Scientists Pinpoint the Genetic Reason for Lactose Intolerance, Unknowns Remain

Researchers have identified the genetic basis of lactose intolerance, the inability of most adults in the world to digest the principal sugar in milk. The finding, published today in the journal Nature Genetics, may lead to the development of a more accurate test for the condition.

Lactose intolerance can cause bloating and indigestion from consuming milk or milk products. More than 30 million Americans, mostly black or Asian, are prone to the condition.

Though lactose intolerance may sound like a disorder, it is in fact natural. In most people the gene for lactase, the enzyme that digests lactose, is switched on at birth and switched off at the age of weaning.

In most Europeans, however, the lactase gene remains active. With the domestication of cattle and goats in the Near East some 10,000 years ago, the ability to digest lactose throughout life could have conferred some nutritional advantage. Biologists speculate that a mutation that prolonged the gene’s activity was suddenly favored and spread throughout the population.

But one finding has baffled biologists: the gene for the lactase enzyme and the gene’s promoter, a neighboring region of DNA that controls the activity of the gene, show no significant difference between populations whose adults can digest lactose and those whose adults cannot

Now a team of Finnish and American biologists reports that it has identified two single-unit DNA changes that correlate strongly with the presence or absence of adult lactase activity.

The changes were found by studying the sequence of DNA units near the lactase gene in nine Finnish families. About 20 percent of Scandinavians are lactose intolerant, and Finnish scientists had collected elaborate pedigrees of the trait, allowing the precise DNA changes to be identified, said Dr. Leena Peltonen, an author of the study who works at the University of Helsinki.

A genetic test based on the finding will enable lactose intolerance to be diagnosed from the DNA in a drop of blood, Dr. Peltonen said. Now, the condition is recognized by measuring he hydrogen generated from undigested lactose by the bacteria in the gut.

But some experts do not see any particular need for a genetic test, because they do not regard lactose intolerance as a clinically serious condition. Dr. Michael D. Levitt of the Minneapolis Veterans Affairs Medical Center, whose specialty is the study of intestinal gas, said that in most people an inactive lactase gene was rarely a problem unless they drank large amounts of milk.

Many people who believe they have problems digesting lactose actually have irritable bowel syndrome, Dr. Levitt said.

Dr. Levitt, who invented the hydrogen test for lactose intolerance, said concern about the condition was ”mostly an American phenomenon, and the rest of the world is not much interested in it.” He says the concern about lactose has arisen because ”there is a tremendous amount of irritable bowel syndrome, and people would like to find a cause for it.”

Dr. Stephen James, an official of the National Institute of Diabetes and Digestive and Kidney Diseases, agrees that doctors and patients sometimes get diverted into a hunt for minute traces of lactose in the diet when the real problem is irritable bowel syndrome, a poorly understood condition for which there is no test except ruling out everything else.

The authors of the new report say the two DNA units that switch off the lactase gene are in the 9th and 13th introns in a neighboring gene whose role strangely has nothing to do with lactose metabolism. Introns are the spacer regions of DNA that separate the information-coding parts of a gene. Because the cell cuts out and discards the introns when a gene is activated, these disposable pieces of DNA have long been ignored. Now it seems they play unexpected roles in gene control.

In the default human condition, in which the lactase gene is programmed to turn off after weaning, people have C in the 9th intron position of both their maternal and paternal DNA and G in both the 13th intron positions. But changing the C to a T and the G to an A in either or both sets of a person’s DNA keeps the gene from switching off in the cells that line the intestine. (The four letters of the DNA alphabet are A, T, C and G, and one full set of DNA is inherited from each parent.)

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

Lactose Tolerance in East Africa Points to Recent Evolution

A surprisingly recent instance of human evolution has been detected among the peoples of East Africa. It is the ability to digest milk in adulthood, conferred by genetic changes that occurred as recently as 3,000 years ago, a team of geneticists has found.

The finding is a striking example of a cultural practice — the raising of dairy cattle — feeding back into the human genome. It also seems to be one of the first instances of convergent human evolution to be documented at the genetic level. Convergent evolution refers to two or more populations acquiring the same trait independently.

Throughout most of human history, the ability to digest lactose, the principal sugar of milk, has been switched off after weaning because the lactase enzyme that breaks the sugar apart is no longer needed. But when cattle were first domesticated 9,000 years ago and people later started to consume their milk as well as their meat, natural selection would have favored anyone with a mutation that kept the lactase gene switched on.

Such a mutation is known to have arisen among an early cattle-raising people, the Funnel Beaker culture, which flourished 5,000 to 6,000 years ago in north-central Europe. People with a persistently active lactase gene have no problem digesting milk and are said to be lactose tolerant.

Almost all Dutch people and 99 percent of Swedes are lactose tolerant, but the mutation becomes progressively less common in Europeans who live at increasing distances from the ancient Funnel Beaker region.

Geneticists wondered if the lactose tolerance mutation in Europeans, identified in 2002, had arisen among pastoral peoples elsewhere. But it seemed to be largely absent from Africa, even though pastoral peoples there generally have some degree of tolerance.

A research team led by Dr. Sarah Tishkoff of the University of Maryland has now solved much of the puzzle. After testing for lactose tolerance and genetic makeup among 43 ethnic groups in East Africa, she and her colleagues have found three new mutations, all independent of one another and of the European mutation, that keep the lactase gene permanently switched on.

The principal mutation, found among Nilo-Saharan-speaking ethnic groups of Kenya and Tanzania, arose 2,700 to 6,800 years ago, according to genetic estimates, Dr. Tishkoff’s group reports today in the journal Nature Genetics. This fits well with archaeological evidence suggesting that pastoral peoples from the north reached northern Kenya about 4,500 years ago and southern Kenya and Tanzania 3,300 years ago.

Two other mutations were found, among the Beja people of northeastern Sudan and tribes of the same language family, Afro-Asiatic, in northern Kenya.

Genetic evidence shows that the mutations conferred an enormous selective advantage on their owners, enabling them to leave almost 10 times as many descendants as people without such mutations. The mutations have created “one of the strongest genetic signatures of natural selection yet reported in humans,” the researchers write.

The survival advantage was so powerful perhaps because those with the mutations not only gained extra energy from lactose but also, in drought conditions, would have benefited from the water in milk. People who were lactose intolerant could have risked losing water from diarrhea, Dr. Tishkoff said.

Diane Gifford-Gonzalez, an archaeologist at the University of California, Santa Cruz, said the new findings were “very exciting” because they “showed the speed with which a genetic mutation can be favored under conditions of strong natural selection, demonstrating the possible rate of evolutionary change in humans.”

The genetic data fitted in well, she said, with archaeological and linguistic evidence about the spread of pastoralism in Africa. The first clear evidence of cattle in Africa is from a site 8,000 years old in northwestern Sudan. Cattle there were domesticated independently from two other domestications, in the Near East and the Indus Valley of India.

Nilo-Saharan speakers in Sudan and their Cushitic-speaking neighbors in the Red Sea hills probably domesticated cattle at the same time, because each has an independent vocabulary for cattle items, said Dr. Christopher Ehret, an expert on African languages and history at the University of California, Los Angeles. Descendants of each group moved south and would have met again in Kenya, Dr. Ehret said.

Dr. Tishkoff detected lactose tolerance among Cushitic speakers and Nilo-Saharan groups in Kenya. Cushitic is a branch of Afro-Asiatic, the language family that includes Arabic, Hebrew and ancient Egyptian.

Dr. Jonathan Pritchard, a statistical geneticist at the University of Chicago and a co-author of the new article, said there were many signals of natural selection in the human genome but it was usually hard to know what was being selected for. In this case Dr. Tishkoff clearly defined the driving force, he said.

The mutations Dr. Tishkoff detected are not in the lactase gene itself but a nearby region of the DNA that controls the activation of the gene. The finding that different ethnic groups in East Africa have different mutations is one instance of their varied evolutionary history and their exposure to many different selective pressures, Dr. Tishkoff said.

“There is a lot of genetic variation between groups in Africa, reflecting the different environments in which they live, from deserts to tropics, and their exposure to very different selective forces,” she said.

People in different regions of the world have evolved independently since dispersing from the ancestral human population in northeast Africa 50,000 years ago, a process that has led to the emergence of different races. But much of this differentiation at the level of DNA may have led to the same physical result.

As Dr. Tishkoff has found in the case of lactose tolerance, evolution may use the different mutations available to it in each population to reach the same goal when each is subjected to the same selective pressure. “I think it’s reasonable to assume this will be a more general paradigm,” Dr. Pritchard said.

 

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

Should Scientists Toy With the Secret to Life?

Scientists quickly condemned the Chinese researcher who altered the DNA of at least two embryos to create the world’s first genetically edited babies, defying a broad consensus against hereditary tinkering.

But as The Times reported last week, the global scientific community is divided over what to do next. Should researchers agree to a moratorium on any human genome editing that can be passed down to future generations? Or should they simply tighten existing criteria?

It’s good that the National Academies of Sciences, Engineering and Medicine are planning a global forum to address these questions. But it will be crucial for biologists to seek substantial input from policymakers, ethicists, social scientists and others.

Crispr, the gene editing technique that the Chinese scientist, He Jiankui, used, has enabled scientists to alter human DNA with far greater ease than ever before. It has the potential to remake life as we know it — by preventing devastating diseases, among many other possibilities — and decisions about its future use should be driven by as inclusive and global a dialogue as possible.

Fortunately, there are several ways to broaden the conversation.

Diversify the deciders. Science is a noble endeavor, but it is not entirely pure. Patents and profits and the race against competitors influence individual researchers as well as entire scientific programs. (The Crispr patent, which is currently the subject of a fierce legal battle, is expected to be worth $1 billion at least.) Those influences are not necessarily corrupting, but money and ego have a way of skewing priorities. Dr. He, for example, is said to have gone rogue partly out of a desire to be the first to create “Crispr babies.”

As gene-editing technology advances toward the clinic, scientists will need to do more than listen to the concerns of bioethicists, legal scholars and social scientists. They will have to let these other voices help set priorities — decide what questions and issues need to be resolved — before theory becomes practice. That may mean allowing questions over societal risks and benefits to trump ones about scientific feasibility.

As several scholars have suggested, a “global observatory” — an international consortium of experts from many different fields in many different countries — would go a long way toward making this shift.

Engage the public. Obvious though this may sound, it’s not a given. “There’s a lot of skepticism about the value of public involvement in science and technology decisions,” says Simon Burall, a senior associate with Involve, a British nonprofit dedicated to increasing public engagement in science. That’s too bad. There’s plenty of evidence that having citizens weigh in on proposed policies makes them better and more sustainable. There are also far too many examples of the converse: Leaving the public out of the conversation invites suspicion and mistrust that can be difficult to overcome. It’s easy to dismiss concerns over new technology as the product of ignorance. It’s also a mistake.

Surveys show that most people already support genome editing, as long as it’s directed at intractable diseases and not at the creation of genetically enhanced “designer babies.” Scientists and policymakers stand a better chance of preserving that good will, especially in the face of the He baby scandal, if they give the concerns that do arise a fair hearing. Social media offers an unprecedented platform for doing just that. Crispr’s proponents should start by using that platform to clarify the following:

Scientists are nowhere near being able to make “designer babies.” They have barely figured out the genetic determinants of height; there’s no telling how long it will take them to understand more complex traits, like intelligence, beauty and athleticism. What they are close to doing is using tools like Crispr to repair faulty genes that cause serious diseases. Clinical trials are already underway for hemophilia and sickle cell disease. And these trials involve editing DNA in adult study participants, not in sperm, eggs or embryos; so the results, good or bad, can’t be passed on to offspring.

The bluntest of these tools — legal prohibition — is already being used in the United States, where doctors and scientists are barred from editing human embryos. While such stringent policies may help avoid the muddiness that led to the He scandal, they have a clear downside: They also block the use of less questionable technology. For some desperate families, mitochondrial gene transfer offers the only hope for preventing horrific diseases. But because federal regulators have grouped it with other forms of embryo editing, it’s prohibited in the United States.

There are better, subtler ways to move forward. Lawmakers, regulatory agencies, patent holders, ethics review boards, funding foundations and professional journals all hold sway over how a technology is developed and used. By working together to limit what is funded, permitted or published, they might create a dynamic and flexible process for safeguarding the public while still allowing promising work to progress. It may be impossible to prevent truly rogue actors, but it is possible to slow them down without stopping everyone else.

 

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

F.D.A. Panel Recommends New Depression Treatment

In a move that may clear the way for the first new treatment in years for depression, an expert panel recommended on Tuesday that federal regulators approve a nasal spray that delivers the active ingredients of ketamine, a popular club drug in the 1980s and 1990s.

The new drug, called Esketamine and developed by Johnson & Johnson, is aimed at people with severe depression, particularly those with suicidal thinking. The panel, with 17 voting members, including psychiatrists and consumer representatives, was nearly unanimous in deciding that the drug’s benefits outweighed its risks. The Food and Drug Administration typically follows the recommendations of its expert panels.

In recent years, scores of clinics have opened around the country, offering to administer intravenous ketamine for depression, on a schedule similar to that of electroshock therapy: as a series of treatments, over a period of days or weeks, and sometimes including follow-up or “booster” visits months later. These treatments, at an average cost of $3,000, are officially “off-label,” and usually are not covered by insurance. Their effectiveness is not well studied, although people who have received the course of treatment have reported rapid, if not always lasting, relief.

If approved, Esketamine would be covered by most insurers.

The interest in ketamine as a potential treatment dates back to 2006, when researchers at the National Institute of Mental Health, led by Dr. Carlos A. Zarate, reported that 18 people who received the drugs intravenously reported that their despair lifted within hours. The drugs currently on the market for depression typically take two weeks or more to provide any noticeable relief, if they do so at all.

The discovery of ketamine’s effects on depression was serendipitous; the underlying biology of the disorder remains unknown. Some researchers have since turned away from investigating serotonin — the brain transmitter on which most popular antidepressants work — to instead study the effect of ketamine on brain chemistry, to see if the drug provides any clues to the biology of depression.

The federal agency has until March 4 to decide whether to approve the drug.

Brook Johnson, 38, a piano teacher in Westminster, Md., has been waiting on approval for months. Ms. Johnson, who is married and has a 9-year-old daughter, doesn’t know if Esketamine will help her, but said that existing antidepressants have failed. She said she had been in and out of psychiatric hospitals six times and has attempted suicide twice.

“It was back and forth, and then I’d relapse and they’d put me back in,” Ms. Johnson said in an interview last month. “None of the medicines ever seemed to work. At best, they would either numb me out completely, and you just feel nothing and you can’t think.”

“I need alternative treatment as soon as possible,” she said.

 

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

The Patient Had Bone Cancer. The Diagnosis Arrived 240 Million Years Too Late.

Certainly the patient never knew where the hip pain came from, or why its left leg stopped working. The diagnosis arrived only 240 million years later, when a femur turned up in an ancient lake bed in Germany, one side marred by a malignant bone tumor.

Cancer seldom appears in the fossil record, and its history among vertebrates is poorly understood. On Thursday, a team of researchers writing in JAMA Oncology have described the femur as the oldest known case of cancer in an amniote, the group that includes reptiles, birds and mammals.

Modern cancers are often diagnosed through soft-tissue examinations or biopsies, but that is a difficult prospect for cancer-hunters working with cold, hard fossils. Instead, it takes luck.

“When it comes to our understanding of cancer in the past, we’re really just at the beginning,” said Michaela Binder, a bioarchaeologist at the Austrian Archaeological Institute who’s researched cancer in ancient humans. “It’s not like people say, ‘Oh, I want to go study cancer in ancient turtles or in fossil mammoths,’ because we have so little evidence.”

The discovery of the femur was a stroke of luck. Originally collected by Rainer Schoch of the Stuttgart State Museum of Natural History, it belonged to a wide-bodied, long-tailed animal called Pappochelys, a shell-less relative of modern turtles.

The femur and its jagged growth caught the attention of Yara Haridy, a former medical student and paleontologist at the Natural History Museum, Berlin.

While many paleontologists look for the cleanest — or at least most representative — remains, Ms. Haridy said, the marks left by illness and injury also can shed light on the lives of ancient animals. The study of such fossils is called paleopathology, and it combines aspects of modern forensic and medical practices.

“I basically go through an elimination process, which is kind of how diagnostics in humans work,” Ms. Haridy said. “You go from the most general possibility to more specific and really strange diagnoses.”

Ms. Haridy and her colleagues brought the femur to Dr. Patrick Asbach, a radiologist at the Charité, a university hospital in Berlin. Examining micro-CT scans of the bone, the researchers began running through a checklist of possible causes.

“If you looked externally, you could easily think this was an incorrectly healed bone,” Ms. Haridy said. “I thought initially this animal had a broken femoral head or some sort of really bad shin splints.”

A drawing of the skeleton of Pappochelys and a scan of its cancerous leg bone.CreditRainer Schoch/Museum für Naturkunde Berlin

Image
A drawing of the skeleton of Pappochelys and a scan of its cancerous leg bone.CreditRainer Schoch/Museum für Naturkunde Berlin

Healed injuries are the most common type of fossil pathology, yet the micro-CT scans showed that underneath the growth, the bone was unbroken.

So Ms. Haridy considered other possibilities. A congenital abnormality would have been present on both sides of the femur, not just one. And while friction and excessive pressure can cause bone growth, the femur would have been protected by muscles.

That left the possibility of disease. But most diseases eat away at bone instead of building it up, or lead to infections that warp and wear away the underlying surface.

Benign tumors can sometimes grow on bones, but they tend to be formed from cartilage and look quite different: “They either make a bunch of cartilage or start to actually reabsorb bone,” Ms. Haridy said.

The team identified the swelling as an osteosarcoma, a type of bone cancer also found in humans. According to the National Organization for Rare Disorders, an estimated 750 to 1,000 cases are diagnosed in the United States every year.

The find is an important data point when it comes to learning more about cancer in the vertebrate family tree, Dr. Binder said.

The lack of evidence for prehistoric cancer has sometimes led researchers to speculate that the disease is a modern phenomenon related to unhealthy living, pollutant-filled environments or people getting much older than they used to in the past.

Other specialists have suggested the possible presence of a tumor-suppressor gene in vertebrates, the failure of which allows benign tumors to metastasize. In the absence of fossil evidence, however, there has been no proof.

Adding to the uncertainty, some animal lineages seem less susceptible to cancer than others: Crocodiles and a few other reptiles, along with sharks and naked mole rats, are rarely troubled by the disease, while tumors in invertebrates don’t much resemble those of vertebrates.

Still, there are other recent finds that suggest cancer’s antiquity. In 2001, a team of Russian paleontologists identified a possible cranial osteosarcoma in an Early Triassic amphibian, while a benign jaw tumor from a 255-million-year-old mammal forerunner was reported in 2016.

“What makes this really cool is that now we understand that cancer is basically a deeply rooted switch that can be turned on or off,” Ms. Haridy said. “It’s not something that happened recently in our evolution. It’s not something that happened early in human history, or even in mammal history.”

 

 

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

Searching for the Genetic Underpinnings of Morning Persons and Night Owls

Early to bed and early to rise is a maxim that’s easy to follow for some people, and devilishly hard for others.

Now, in a study published Tuesday in Nature Communications, researchers curious about the genetic underpinnings of chronotype — whether you are a morning person, a night owl or somewhere in between — looked at about 700,000 people’s genomes. They identified 351 variations that may be connected to when people go to bed. While these variants are just the beginning of exploring the differences in chronotypes, the study goes on to suggest tantalizing links between chronotype and mental health.

The researchers drew on data from 23andMe, the genetic testing company, and the UK Biobank, which tracks hundreds of thousands of volunteer subjects in Britain, about 85,000 of whom wear activity monitors that record their movements.

Those data were key, said Michael Weedon, a bioinformaticist at University of Exeter in England and an author of the new paper; earlier studies had relied only on people’s subjective opinions of whether they were morning people. Using the activity monitors, however, the team was able to confirm that self-reported morning people did go to sleep earlier — and people with the most morning-linked gene variants went to bed 25 minutes earlier than people with the fewest. Morning people did not sleep longer or better than night people; all that differed was the time that they went to sleep.

The genes flagged in the study play a wide variety of roles in the body.

Many seem to play a role in brain tissues, and others are already known to be central to the body’s circadian rhythm. A few were active mainly in the retina, and the people who possessed an uncommon version of one of these genes had an increased chance of being night owls, said Samuel Jones, a researcher at the University of Exeter and the study’s lead author. That could imply a potential a connection between how the eye responds to sunlight and when a person sleeps.

Another gene was involved in the body’s processing of caffeine and nicotine, two of our species’ favorite stimulants. Continued study of these and the other genes could provide leads for future work on the biology of sleep timing.

“The most interesting ones are the ones where we don’t know what it is,” said Dr. Weedon.

When the researchers crunched the numbers on chronotype’s connection to mental health, they also found that self-identified morning people reported a higher level of general well-being. People in this group also were less likely to report having depression or schizophrenia, in line with epidemiological studies suggesting that evening people struggle with mental health.

The researchers wonder whether having a lifestyle that aligns with one’s chronotype may be more important in mental and physical health than whether you are merely a morning or night person. In future work, they are hoping to see whether morning people who are required to stay up late for their jobs or other commitments — perhaps similar to night owls who must rise early for 9-to-5- jobs — show higher levels of mental disorders than their well-aligned counterparts.

“Perhaps evening people are constantly fighting their natural clock, which might have unintended consequences farther down the line,” said Dr. Jones.

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

Which Allergens Are in Your Food? You Can’t Always Tell From the Labels

When you’re shopping for someone who has a food allergy, a trip to the grocery store is like a police investigation. Each product must be scrutinized. Labels are examined, each ingredient studied.

My 5-year-old son, Alexander, is allergic to almonds and hazelnuts, so my wife and I spend a lot of time trying to decipher food labels. If you miss something, even one word, you risk an allergic reaction.

Although federal law requires manufacturers to include allergen warnings on prepackaged foods, it’s not always clear which products contain allergens and which do not. The regulation doesn’t cover all types of foods, nor instances in which trace amounts of allergens may be present.

This has created a confusing and risky marketplace for my family and millions of others — roughly 8 percent of children have a food allergy. I set out to better understand allergen labeling and the problems consumers face. Here’s what I learned.

Congress passed the Food Allergen Labeling and Consumer Protection Act in 2004, a rule book for manufacturers. Companies must place special warnings on prepackaged foods if they were made using certain allergens: milk, eggs, fish, shellfish, peanuts, wheat, soybeans and tree nuts.

If I grab a box of cookies from the store shelf, I might find a special warning printed near the ingredients list — “contains almonds” — because almonds are part of the tree nut family. If I don’t see one, I can be assured that the product wasn’t made using almonds.

Sesame is the ninth most prevalent food allergy among adults in the United States. But the food was left off the list of major food allergens in the labeling law passed by Congress.

Manufacturers do not have to print a “contains sesame” message. It may even be hidden under “natural flavors” or “spices” on the ingredients label.

“I can’t even trust what’s written on the label anymore,” said Madeline L. Whitney, 18, a freshman at the University of Notre Dame who is allergic to sesame.

When Ms. Whitney sat down to take the exam, she started experiencing signs of an anaphylactic reaction. She readied her EpiPen.

“All of the sudden my tongue is just totally swollen and my throat is closing,” said Ms. Whitney. The reaction was so severe that she had to be injected with two doses of epinephrine before recovering at the university’s health clinic.

Stories like Ms. Whitney’s are driving a push by advocacy groups to mandate sesame labeling. The Food and Drug Administration is considering whether to add sesame to the list of major allergens.

“Sesame should be included as one of the top allergens that needs to be disclosed on labels,” said Lisa G. Gable, chief executive of Food Allergy Research & Education, a nonprofit organization based in McLean, Va.

Sesame labeling is already mandated in Canada, the European Union and Australia.

Here’s where it gets even more complicated. Even if my box of cookies doesn’t include one of the mandated warning labels, the cookies may still contain an allergen.

Let’s say, back at the manufacturer, my cookies were put on the same conveyor belt used for almond cookies. Small bits of almond might have made it into my seemingly almond-free cookies.

This is called cross contact. And there’s no surefire way I can know it happened — the federal government does not require manufacturers to include labeling for possible cross contact of allergens.

As a result, food manufacturers developed their own unregulated labeling practices to alert consumers to potential cross contact. Here’s a sampling from a recent trip to the grocery store:

  • Cookies: “May contain peanuts and tree nuts.”

  • Chocolate bar: “Manufactured on the same equipment that processes almonds.”

  • Bread: “Made in a bakery that may also use tree nuts.”

These short descriptions, often called “precautionary allergen labeling,” may alert consumers to some risks, but because the labels are unregulated, their meanings differ from company to company.

A 2017 study, published in The Journal of Allergy and Clinical Immunology: In Practice showed that consumers make “risk assessments” based on the words used in this kind of labeling.

“We’re making consumers decide, based on the wording of that precautionary allergen label, what seems safe for themselves or their child, and I think that’s a huge issue,” said Dr. Ruchi S. Gupta, a professor of pediatrics at Northwestern Medicine in Chicago and an author of the study.

My child hasn’t had a reaction from cross contact in prepackaged food, fortunately. But other children certainly have.

“The whole world of food labeling is almost like a foreign language,” said Allison A. Ososkie of Vienna, Va.

Her 2-year-old son, Lincoln, is allergic to egg, milk, peanuts, tree nuts, soy and shellfish. This past spring, he had an anaphylactic reaction to crackers that may have been processed on equipment with milk products.

Anna M. Francis, an acupuncturist in Wheat Ridge, Colo., has a 6-year-old daughter, Penelope, who is allergic to egg, dairy, cashew, pistachio, cherry and blackberry. In 2015, Ms. Francis thought the snack bar she was giving her daughter was safe. She even called the company to ask about its equipment-cleaning process.

“My daughter had a bite and had an anaphylactic reaction,” said Ms. Francis. She wants the government’s regulation to include labeling for possible cross contact of allergens.

There’s something else consumers with food allergies have to worry about: incorrect packaging. Sometimes, during the manufacturing process, food made using one of the eight major allergens isn’t properly labeled.

In 2018, about one-third of F.D.A. recalls involved prepackaged foods that were erroneously labeled, according to data compiled by the agency.

Remember my box of cookies? Let’s say I put it back on the shelf and head over to the store’s bakery for freshly prepared treats instead. Sadly, foods produced in a bakery or deli and “placed in a wrapper or container in response to a consumer’s order” are not covered under federal labeling requirements. The label on my box of cookies, packaged by a bakery worker, will not have any federally regulated allergen labels on it.

The labeling on the side of my box of cookies — whether it says “contains almonds,” “may contain almonds” or nothing at all — is determined by the food manufacturer.

So what goes into making the food that ends up on a shelf? And what kind of consideration is given to people with food allergies?

At Nestlé’s American operation, the key is applying “allergen management” across the expansive and complex operation, said David C. Clifford, director of food safety at Nestlé USA. He described the company’s approach as “objective, science-based, risk-based.”

“It’s a very serious responsibility that we have to feed the public, and the responsibilities around these systems extend horizontally across the organization,” said Mr. Clifford, who added that his team conducts allergen safety training throughout the company.

The Hershey Company also runs a training program for employees, it said in a statement. The training “includes video interviews with allergic children and their families who face the challenges of allergen management on a personal level every day of their lives.”

Given everything we know about food allergen labeling, here is some advice.

When you’re scanning the shelves, if you spot precautionary labels beginning with “may contain” or “processed in the same facility as,” don’t buy them if they refer to your allergy, said Dr. Scott H. Sicherer, chief of pediatric allergy and immunology at the Icahn School of Medicine at Mount Sinai in New York.

“You shouldn’t make risk decisions based on what precautionary words are used on the label,” said Dr. Sicherer. “But rather, to be 100 perfect safe, just avoid products that have the precautionary label, if that’s a food that you’re avoiding.”

Instead of guessing what a label might mean, a few parents I spoke to take a proactive approach: calling companies to get answers, even if it is time-consuming.

“Maybe once a month I’m calling and trying to track something down,” said Julie V. Lunn, a bookkeeper and entrepreneur in Havre de Grace, Md., whose 3-year-old daughter, Alafair, is allergic to a variety of foods.

One way to simplify things is to seek out products made in allergen-free plants.

Enjoy Life Foods has one such facility, said Joel D. Warady, general manager of the company. He said employees are forbidden from bringing peanuts to work, and they must wear company-issued shoes that don’t leave the factory, in Jefferson, Ind.

MadeGood Foods, based in Ontario, swabs hands and tables to test for allergens, said Janice A. Harada, the company’s marketing manager.

Manufacturers like these cater to the allergy community, using branding to make it clear their foods are clear of allergens.

And that box of cookies I’ve been looking for? If its label says “made in a dedicated allergen-free facility,” it should be safe to give to my son.

 

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

Seeking Superpowers in the Axolotl Genome

The axolotl, sometimes called the Mexican walking fish, is a cheerful tube sock with four legs, a crown of feathery gills and a long, tapered tail fin. It can be pale pink, golden, gray or black, speckled or not, with a countenance resembling the “slightly smiling face” emoji. Unusual among amphibians for not undergoing metamorphosis, it reaches sexual maturity and spends its life as a giant tadpole baby.

According to Aztec legend, the first of these smiling salamanders was a god who transformed himself to avoid sacrifice. Today, wild axolotls face an uncertain future. Threatened by habitat degradation and imported fish, they can only be found in the canals of Lake Xochimilco, in the far south of Mexico City.

Captive axolotls, however, are thriving in labs around the world. In a paper published Thursday in Genome Research, a team of researchers has reported the most complete assembly of DNA yet for the striking amphibians. Their work paves the way for advances in human regenerative medicine.

Many animals can perform some degree of regeneration, but axolotls seem almost limitless in their capabilities. As long as you don’t cut off their heads, they can “grow back a nearly perfect replica” of just about any body part, including up to half of their brain, said Jeramiah Smith, an associate professor of biology at the University of Kentucky and an author of the paper. To understand how they evolved these healing superpowers, Dr. Smith and his colleagues looked to the axolotl’s DNA.

At 10 times the size of the human genome, the axolotl genome was no small beast to tackle. “This thing’s huge,” said Melissa Keinath, a postdoctoral fellow at the Carnegie Institution for Science in Baltimore and an author of the paper.

Building off a previous study, Dr. Keinath and her colleagues mapped more than 100,000 pieces of DNA onto chromosomes, the structures that package DNA in the nucleus of each cell. Their axolotl genome is the largest genome to be assembled at this level.

The scientists used an approach called linkage mapping, which relies on the fact that DNA sequences that are physically close together on a chromosome tend to be inherited together.

To identify axolotl-specific DNA, the researchers juxtaposed axolotls with tiger salamanders, which are close relatives. Specifically, they crossed axolotls and tiger salamanders, then back-crossed these first-generation hybrids with pure axolotls.

Tracking patterns of gene inheritance across 48 of these second-generation hybrids, the researchers were able to infer which sequences of DNA belonged to axolotls and where they physically sat along the amphibian’s 14 chromosomes (humans have a greater number of chromosomes, but the axolotl’s are much larger).

It was like “putting together 14 linear puzzles,” said Randal Voss, a professor of neuroscience at the University of Kentucky and an author of the study.

In the process of validating their results, they identified a gene mutation that causes a commonly studied heart defect in axolotls, demonstrating that their research will speed up the process of scanning the axolotl genome for mutations in the future.

Ultimately, knowing how DNA is positioned along chromosomes “allows you to start thinking about functions and how genes are regulated,” Dr. Voss said. For instance, much of the genome consists of noncoding DNA sequences that turn genes on and off. Often, these noncoding sequences occur on the same chromosome as the genes they interact with.

“Once these relationships are known, then we can ask questions about whether the same kind of controls happen in other animals, like humans,” said Jessica Whited, a professor and limb regeneration expert at Harvard Medical School who was not involved in the study.

Over all, she added, that will help scientists understand whether there are predictable ways to “render humans more like axolotls,” fantastic regenerators of the animal kingdom.