The 10,000-year bender: Why humans love a tipple

(image: Tom Gauld)

Our taste for alcohol results from an evolutionary tussle between humans and yeast – one in which the microbes have often had the upper hand

EVEN if you are teetotal, you cannot deny that humans, as a species, like to drink. We consume wine, beer, cider, spirits... in fact, the fermented product of almost anything we can turn to alcohol. Our fondness for this toxic substance, the cause of so much trouble, is something of a mystery. Maybe it is enough to say that we drink because it makes us feel good. But I think that to understand our love of alcohol you need a bigger, more evolutionary, explanation.

The story of alcohol is one of an intimate relationship between humans and yeasts, an affair that began millions of years ago and is still playing out today. We like to cast ourselves as the star of this drama, but in fact yeasts are the unsung lead character. Ours is a symbiotic connection - a mutually beneficial partnership. It is also one in which the balance of power is constantly shifting. If anything, the yeasts seems to have had the upper hand, at least since our ancestors began brewing their own grog. We cultivate yeasts, ensuring they survive and thrive, and in return we get, at best, a good night out and a hangover the next morning. Once upon a time, however, yeast and alcohol may have offered us more significant rewards.

Today the costs of our love of alcohol often outweigh any benefits. But, being a story of evolution, it doesn't end there. Already some humans have acquired genetic changes that encourage them to drink less. If this trend continues, it is possible that one day this long and tempestuous relationship will reach a kind of tenuous truce.

We are not the only species that likes a tipple. Fruit flies regularly consume fermented fruit, seemingly without any impairment to their faculties. Other animals don't hold their drink so well. Cedar waxwings have been spotted partaking of a few too many overripe winterberries and then flopping around among the branches of trees or crashing into buildings. Terrifying accounts of drunk elephants exist, although these are poorly substantiated. There are even records of creatures going out of their way to become intoxicated. These include tree shrews - the closest living relatives to the primates - which seek out nightly nips of a frothy "wine" produced by yeast in the flower buds of the bertam palm.

This kind of behaviour can be traced right back to the evolution of fruit around 130 million years ago, when flowering plants emerged during the Cretaceous era. With a new source of food available, a genus of yeasts known asSaccharomyces evolved to feed on it, and in the process these yeasts acquired a new physiological trick. Instead of using their energy to break down sugar completely, they evolved the ability to partially break it down, producing ethanol as waste when sugar supplies were abundant and oxygen scarce. The partial breakdown of valuable sugars meant that these yeasts were actually less efficient than their forebears. But it gave them a big advantage too. Ethanol kills most bacteria, and bacteria like to feed on fruit, so producing alcohol allowed yeasts to kill off the competition.

From the beginning, Saccharomyces would have fed on ripe fruits - unripe ones often being toxic - so the smell of ethanol might have become a universal sign that fruits were ready to eat. According to Robert Dudley at the University of California, Berkeley, natural selection favoured primates and other fruit-eating mammals that could use the odour of ethanol to locate edible fruit in vast forests. He believes they evolved a fondness for the smell that led them to experience positive sensations even before they consumed the alcohol itself (The Quarterly Review of Biology, vol 75, p 3). According to this theory, every time a primate sniffs booze, pleasure rings out in its brain. Incidentally, we primates may not be alone in this. Fruit flies' mouths have a sensory receptor, a kind of taste bud for alcohol. It was identified by a grad student who, in a moment of frustration, offered them beer.

Love at first sight?

Dudley suggests that our ancestors began to make alcohol to feed their sensory bias for it, in much the same way that we farm sugar cane and sugar beets to feed our evolved preference for sugar. If so, alcohol is like all the other things from which we once benefited but now overindulge in. Not everyone is convinced. Doug Levey of the National Science Foundation in Arlington, Virginia, believes primates never had an innate tendency to seek out the smell of ethanol - after all, fruit that smells of ethanol is already en route to being overripe. Instead, he argues, our ancestors only really started enjoying alcohol after they learned to make it themselves. By neurological happenstance, the liquor triggered feelings that they liked and desired more of, and so they sometimes indulged to excess (Integrative & Comparative Biology, vol 44, p 284). If Levey is right, our taste for alcohol is more like our taste for caffeine or cocaine than for sugar.

Alcohol does produce pleasurable feelings - this much no one debates - through its ability to bind to GABA receptors in the brain. Normally, these receptors reduce the activity of the neurons on which they are found, but when alcohol binds to them it releases that pent-up activity and, in doing so, relaxes both our bodies and our inhibitions. Thanks to this, countless babies have been conceived, countless friendships formed and rapprochements achieved. But ethanol also makes us uncoordinated, groggy, reckless and aggressive. It is the fuel behind many accidents, fights and even wars.

Overall, then, alcohol consumption may not have been advantageous to our ancient fruit-gathering ancestors but, interestingly, it seems to have offered real benefits once we began to farm. At the dawn of agriculture, around 10,000 years ago, people in small settlements began to ferment foods and drinks. This would have allowed them to preserve surplus grain, in essence by favouring yeasts in place of food-spoiling bacteria. It would even have made grain more nourishing because yeasts produce other nutrients, including B vitamins, during fermentation. Alcohol consumption might also have helped smooth social interactions, which would have become more complex as communities grew. Perhaps most importantly, fermentation offered a way to sterilise liquids, since ethanol kills not only bacteria - including the one that causes cholera - but also other pathogens. Indeed, animals may self-medicate with it. For example, fruit flies infested with parasitic wasps consume more alcohol, which usually kills the wasp without being fatal to the flies. In the unsanitary conditions faced by early settled communities, fermented drinks were both nutritious and potable - not entirely healthy, but better than unfermented alternatives.

As for how we learned to make alcohol, most anthropologists believe that the first farmers stumbled across the trick by accident, when stored wheat and barley became contaminated with Saccharomyces yeasts. There is another, more intriguing, possibility. Anthropologist Solomon Katz at the University of Pennsylvania in Philadelphia has argued that fermentation came first, giving our ancestors a strong incentive to cultivate grain to make grog. As it happens, the oldest vessel for storing alcohol found so far, 7000 years old, is contemporaneous with or may even predate the earliest evidence of farming in China, where it was unearthed (PNAS, vol 101, p 17593).

Either way, once alcohol had been manufactured, its producers realised that it could be made again and again simply by taking a sample from one fermenting liquid and using it to kick-start the process in a new batch. It must have seemed like a magical transformation to ancient brewers, but today we know that humanity's first vats were colonised by Saccharomyces cerevisae. We also have its precise genetic code: it was one of the first organisms to have its genome sequenced. However, we still know very little about basic matters such as where it came from.

An evolving partnership

Brewer's yeast has changed many times as agriculture spread and different human cultures emerged (Comptes Rendus Biologies, vol 334, p 229). New forms, as distinctive as species, emerged in association with beer and wine production in different regions. Some of these yeasts changed further to give a wide variety of bread yeasts. In a monk's cave in Germany, the cold-tolerant yeast used to make lager evolved as a hybrid of S. cerevisae and a species that hails from Patagonia. Mysteriously, this occurred more than 100 years before Europeans reached the New World (PNAS, vol 108, p 14539).

In Britain and elsewhere, brewers also began to use an entirely different genus of yeasts, Brettanomyces, which had acquired the ability to produce alcohol independently of Saccharomyces, from which it split 200 million years ago. Brettanomyces is used in the production of several speciality beers, giving an unusual sour, tangy flavour.

Humans have undoubtedly influenced the evolutionary diversification of yeasts, but we did not consciously steer the process any more than the Galapagos Islands controlled the evolution of Darwin's finches. Fungi such as yeasts often interact symbiotically with other species. Leaf-cutter ants, for example, feed bits of leaf to the fungi in their nests, which in turn produce fruiting bodies that the baby ants eat. Ambrosia beetles carry fungi in little pouches, releasing them onto dead wood where they grow, providing food for their larvae. In these and other cases, animals are often said to have domesticated fungi, but perhaps the reverse is true. After all, the animals are forced to forage and ferry while the fungi just feed, grow and reproduce. Likewise, brewers have to work hard to ensure that their yeasts thrive. What's more, those varieties that take the most advantage of us are most likely to survive. These include lineages that have evolved to tolerate higher concentrations of alcohol, allowing them to produce more potent brews, so persuading us to work even harder to cultivate them.

The yeasts have shaped us directly, too. One key change occurred very early - a big divergence between humans and other primates in levels of the enzyme that breaks down alcohol, and where in the body it is found. In non-human primates, alcohol dehydrogenase is found throughout the body. That seems unsurprising as ethanol is a by-product of various bodily processes, so most cells encounter it. The enzyme is also everywhere in our bodies, but it is disproportionately concentrated in the liver, where the alcohol we imbibe ends up. Our ancestors' increasing consumption of alcohol became increasingly dangerous: a blood alcohol level of 0.4 per cent is considered lethal for adult humans. Those who survived binges tended to have more alcohol dehydrogenase in their liver because they could process alcohol more rapidly. Today, 10 per cent of the enzymes in the average human liver are dedicated to metabolising ethanol.

Given the longstanding relationship between humans and brewer's yeasts, it is not surprising that each has influenced the other's evolution. This process is ongoing. No symbiotic relationship is simple - the costs and benefits that each party experiences shift with time and context. Alcohol may once have been a signal of good fruit; in the early days of agriculture, it probably aided our survival. But the balance would have tipped as waterborne diseases became less of a problem and as yeasts became easier to cultivate and their products more intoxicating. People may still benefit from the occasional drink: every few years a study comes out arguing that a little bit of wine or, more rarely, beer is good for you. However, for society as a whole, alcohol now brings more costs than gains, whether measured in life expectancy or money. In 2010, alcohol was the third biggest health risk globally, killing 4.9 million people worldwide (The Lancet, vol 380, p 2071), and problem drinking has an annual economic burden of hundreds of billions of dollars.

In some places, such costs seem to have been incurred for many generations, long enough to allow people to evolve once again. This time, natural selection has favoured an adaptation that encourages individuals to consume less alcohol. The detoxification of ethanol involves two enzymes - alcohol dehydrogenase, to turn ethanol into acetaldehyde, and aldehyde dehydrogenase, which converts acetaldehyde to acetate. This enzyme partnership exists in nearly every organism, including many bacteria, but in some East Asian populations, including most Chinese and Japanese people, the gene for aldehyde dehydrogenase is broken. When people with this version of the gene consume alcohol, drunkenness occurs after fewer drinks, their faces turn red, their hearts palpitate and they feel nauseous.

The mutated gene spread in geographic and temporal lockstep with the spread of rice cultivation and rice wine production some 7000 to 10,000 years ago (BMC Evolutionary Biology, vol 10, p 15). Researchers say it may have evolved for a reason, pointing out that once it arose, it spread more quickly than it would have by chance. They argue that East Asian populations had started to feel the negative consequences of alcohol so strongly that individuals whose bodies discouraged them from drinking to excess were more likely to survive. In this light, the "drink less" gene variant might have been favoured both by natural and sexual selection, at least if ruddy-faced drunks are less likely to find mates.

Evolution does not stand still, so it is interesting to speculate that various "drink less" mutations may be spreading in human populations right now. If so, then one day our love affair with alcohol might end - though one should not underestimate the evolutionary cleverness of yeasts.

In the meantime, alcohol-producing yeasts will keep evolving, as will our understanding of humanity's intimate relationship with them. Despite the story I have told, more remains unresolved than resolved, hidden in every alcoholic drink. So, while we can still enjoy it, let's raise a glass to the yeasts. Curse them, and bless them!

Rob Dunn 

Drug Makers See Profit Potential in Rare Diseases

Rare diseases once were the neglected stepchild of drug makers, who wanted medicines they could sell to millions of patients. Today, conditions afflicting far smaller numbers are seeing booming interest from the industry.

A Sanofi drug recently became the second therapy to win approval in as many months to treat an often-deadly inherited cholesterol disorder. The injectable drug, Kynamro, now will compete with Juxtapid, a pill from Aegerion Pharmaceuticals Inc. that received a green light late last month, to treat a condition that affects just a few thousand patients in the U.S.

Pfizer Inc. and GlaxoSmithKline PLC are among companies studying treatments for Duchenne muscular dystrophy, an inherited condition affecting 1 in 3,600 infant boys. Shire PLC and BioMarin Pharmaceutical Inc. are seeking treatments for a rare metabolic disorder called Sanfilippo syndrome that affects 1 in 70,000 births.

This competition to treat rare disorders underscores how shifting commercial dynamics and progress understanding the molecular roots of diseases are driving the pharmaceutical industry in new directions.

Incentives from the U.S. Food and Drug Administration to develop so-called orphan drugs can mean quicker approval, tax benefits for the developer and seven years' protection from competition after approval. Conventional drugs typically get five. Patient groups have raised hundreds of millions of dollars to give to firms for development of orphan drugs, defined as experimental treatments for diseases with fewer than 200,000 patients at any one time.

But perhaps most persuasive: Drug companies have found that they can charge towering prices for such drugs, which often treat deadly conditions for which there are few or no options.

Big drug makers had "thought that orphan drugs were small, tiny things that didn't warrant their attention," says Angus Russell, chief executive of Shire, some of whose top-selling products treat rare enzyme disorders. The big companies watched Shire and other firms "develop drugs that have gone on to" reach sales of hundreds of millions, if not billions, of dollars, and have followed suit, he says.

That said, the often-six-figure yearly price tag for each patient raises the question of whether drug makers' costs will be sustainable as efforts intensify to control health-care spending. Competition also may temper prices. Kynamro, the cholesterol drug, will be priced lower than its rival Juxtapid. But Kynamro still will cost $176,000 a year, according to Sanofi's Genzyme unit, which developed the drug with Isis Pharmaceuticals Inc. A year's treatment of Juxtapid costs $235,000 to $295,000, depending on the stage of therapy, says Aegerion Chief Executive Marc Beer.

When Congress created the orphan-drug designation in 1983, pharmaceutical companies were working on one new such treatment a year, according to the FDA. Now the agency says that nearly 200 orphan drugs a year enter development, and about a third of the drugs it approves are for rare diseases.

Francois Nader, chief executive of NPS Pharmaceuticals Inc., which late last year received FDA approval for a therapy to treat a rare bowel condition, says that shifting science and economics have made the market viable. Drug researchers can identify ahead of time "the patients who would benefit from a particular drug, rather than using the shotgun approach we used in the past," he says.

NPS's bowel drug, Gattex, cost $250 million to develop. That compares with the $1 billion or more it might cost to bring a more widely used drug to market, in part because the clinical trials for Gattex required far fewer patients and took less time, Dr. Nader says. Gattex costs $295,000 a year.

Thanks to such high prices, almost a third of orphan drugs notch more than $1 billion in yearly sales, according to a sample reviewed by Thomson Reuters. The category has more than $50 billion in world-wide sales and has been rising more than 20% annually for the last several years.

So far, private health plans and governments have agreed to pay for the expensive drugs. The diseases are rare enough that each plan might need to pay for only one patient, and the treatments often prove lifesaving, making it difficult for insurers say no.

"In the future, there will be more pricing pressure" as costly orphan drugs proliferate, says Rhonda Greenapple, founder of Reimbursement Intelligence, a pharmaceutical market-research firm that surveys insurers. "But right now, [payers] can't do much" to limit access.

For the rare cholesterol disorder, known as homozygous familial hypercholesterolemia, newly approved Kynamro and Juxtapid "are going to fill a very important need," says Steven Jones, director of inpatient cardiology at Johns Hopkins Hospital.

Patients with the condition have defects in the genes that help the body take bad cholesterol, or LDL, out of the bloodstream. As a result, even children can see their cholesterol levels reach 400 milligrams or higher per deciliter of blood—three to four times the recommended level. The disorder can lead to heart attacks, strokes and death, often before age 30.

Christian Jacobs, a 21-year-old community-college student from West Jefferson, Ohio, was diagnosed at age 2 with an LDL cholesterol level of 957 milligrams per deciliter. He takes six drugs for his cholesterol, has stents propping open seven blocked arteries and drives two hours every other week to have a machine filter cholesterol from his blood, but his cholesterol levels remain above 500.

Mr. Jacobs says Kynamro lowered his cholesterol to 250 in a clinical trial, and his family's health plan has approved reimbursement for Juxtapid treatments to start soon. If one drug "doesn't work, there's another one available," he says. "It's not, 'You're out of luck.' "

Both drugs will carry strong warnings about the risk of liver damage from long-term use because they are associated with liver-enzyme abnormalities and the accumulation of fat in the liver that could lead to disease.

Jonathan D. Rockoff at jonathan.rockoff@wsj.com

The Drug-Dose Gender Gap

Most sleeping pills are designed to knock you out for eight hours. When the Food and Drug Administration was evaluating a new short-acting pill for people to take when they wake up in the middle of the night, agency scientists wanted to know how much of the drug would still be in users’ systems come morning.

Blood tests uncovered a gender gap: Men metabolized the drug, Intermezzo, faster than women. Ultimately the F.D.A. approved a 3.5 milligram pill for men, and a 1.75 milligram pill for women.

The active ingredient in Intermezzo, zolpidem, is used in many other sleeping aids, including Ambien. But it wasn’t until earlier this month that the F.D.A. reduced doses of Ambien for women by half.

Sleeping pills are hardly the only medications that may have unexpected, even dangerous, effects in women. Studies have shown that women respond differently than men to many drugs, from aspirin to anesthesia. Researchers are only beginning to understand the scope of the issue, but many believe that as a result, women experience a disproportionate share of adverse, often more severe, side effects.

“This is not just about Ambien — that’s just the tip of the iceberg,” said Dr. Janine Clayton, director for the Office of Research on Women’s Health at the National Institutes of Health. “There are a lot of sex differences for a lot of drugs, some of which are well known and some that are not well recognized.”

Until 1993, women of childbearing age were routinely excluded from trials of new drugs. When the F.D.A. lifted the ban that year, agency researchers noted that because landmark studies on aspirin in heart disease and stroke had not included women, the scientific community was left “with doubts about whether aspirin was, in fact, effective in women for these indications.”

Because so many drugs were tested mostly or exclusively in men, scientists may know little of their effects on women until they reach the market. AGovernment Accountability Office study found that 8 of 10 drugs removed from the market from 1997 through 2000 posed greater health risks to women.

For example, Seldane, an antihistamine, and the gastrointestinal drug Propulsid both triggered a potentially fatal heart arrhythmia more often in women than in men. Many drugs still on the market cause this arrhythmiamore often in women, including antibiotics, antipsychotics, anti-malarial drugs and cholesterol-lowering drugs, Dr. Clayton said. Women also tend to use more medications than men.

The sex differences cut both ways. Some drugs, like the high blood pressuredrug Verapamil and the antibiotic erythromycin, appear to be more effective in women. On the other hand, women tend to wake up from anesthesia faster than men and are more likely to experience side effects from anesthetic drugs, according to the Society for Women’s Health Research.

Women also react differently to alcohol, tobacco and cocaine, studies have found.

It’s not just because women tend to be smaller than men. Women metabolize drugs differently because they have a higher percentage of body fat and experience hormonal fluctuations and the monthly menstrual cycle. “Some drugs are more water-based and like to hang out in the blood, and some like to hang out in the fat tissue,” said Wesley Lindsey, assistant professor of pharmacy practice at Auburn University, who is a co-author ofa paper on sex-based differences in drug activity.

“If the drug is lipophilic” — attracted to fat cells — “it will move into those tissues and hang around for longer,” Dr. Lindsey added. “The body won’t clear it as quickly, and you’ll see effects longer.”

There are also sex differences in liver metabolism, kidney function and certain gastric enzymes. Oral contraceptives, menopause and post-menopausal hormone treatment further complicate the picture. Some studies suggest, for example, that when estrogen levels are low, women may need higher doses of drugs called angiotensin receptor blockers to lowerblood pressure, because they have higher levels of proteins that cause the blood vessels to constrict, said Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown.

Many researchers say data on these sex differences must be gathered at the very beginning of a drug’s development — even before trials on human subjects begin.

“The path to a new drug starts with the basic science — you study an animal model of the disease, and that’s where you discover a drug target,” Dr. Sandberg said. “But 90 percent of researchers are still studying male animal models of the disease.”

There have been improvements. In an interview, Dr. Robert Temple, with the Center for Drug Evaluation and Research at the F.D.A., said the agency’s new guidelines in 1993 called for studies of sex differences at the earliest stages of drug development, as well as for analysis of clinical trial data by sex.

He said early research on an irritable bowel syndrome drug, alosetron (Lotronex), suggested it would not be effective in men. As a result, only women were included in clinical trials, and it was approved only for women. (Its use is restricted now because of serious side effects.)

But some scientists say drug metabolism studies with only 10 or 15 subjects are too small to pick up sex differences. Even though more women participate in clinical trials than in the past, they are still underrepresented in trials for heart and kidney disease, according to one recent analysis, and even in cancer trials.

“The big problem is we’re not quite sure how much difference this makes,” Dr. Lindsey said. “We just don’t have a good handle on it.”

NEJM

Antibiotics as Part of the Management of Severe Acute Malnutrition

BACKGROUND

Severe acute malnutrition contributes to 1 million deaths among children annually. Adding routine antibiotic agents to nutritional therapy may increase recovery rates and decrease mortality among children with severe acute malnutrition treated in the community.

METHODS

In this randomized, double-blind, placebo-controlled trial, we randomly assigned Malawian children, 6 to 59 months of age, with severe acute malnutrition to receive amoxicillin, cefdinir, or placebo for 7 days in addition to ready-to-use therapeutic food for the outpatient treatment of uncomplicated severe acute malnutrition. The primary outcomes were the rate of nutritional recovery and the mortality rate.

CONCLUSIONS

The addition of antibiotics to therapeutic regimens for uncomplicated severe acute malnutrition was associated with a significant improvement in recovery and mortality rates. 

PepsiCo Will Halt Use of Brominated Vegetable Oil in Gatorade

James Edward Bates for The New York TimesSarah Kavanagh, a high school student in Mississippi, started a petition to get PepsiCo to stop using brominated vegetable oil.

PepsiCo announced on Friday that it would no longer use an ingredient in Gatorade after consumers complained.

The ingredient, brominated vegetable oil, which was used in citrus versions of the sports drink to prevent the flavorings from separating, was the object of a petition started on Change.org by Sarah Kavanagh, a 15-year-old from Hattiesburg, Miss., whobecame concerned about the ingredient after reading about it online. Studies have suggested there are possible side effects, including neurological disorders and altered thyroid hormones.

Brominated vegetable oil will be replaced by sucrose acetate isobutyrate, an emulsifier that is “generally recognized as safe” as a food additive by the Food and Drug Administration. The new ingredient will be added to orange, citrus cooler and lemonade Gatorade, as well Gatorade X-Factor orange, Gatorade Xtremo citrus cooler and a powdered form of the drink called “glacier freeze.”

Ms. Carter said consumers would start seeing the new ingredient over the next few months as existing supplies of Gatorade sell out and are replaced.

Health advocates applauded the company’s move. “Kudos to PepsiCo for doing the responsible thing on its own and not waiting for the F.D.A. to force it to,” said Michael Jacobson, executive director of the Center for Science in the Public Interest.

Mr. Jacobson has championed the removal of brominated vegetable oil from foods and beverages for the last several decades, but the F.D.A. has left it in a sort of limbo, citing budgetary constraints that it says keep it from going through the process needed to formally ban the chemical or declare it safe once and for all.

Brominated vegetable oil is banned as a food ingredient in Japan and the European Union. About 10 percent of drinks sold in the United States contain it, including Mountain Dew, which is also made by PepsiCo; some flavors of Powerade and Fresca from Coca-Cola; and Squirt and Sunkist Peach Soda, made by the Dr Pepper Snapple Group.

PepsiCo said it had no plans to remove the ingredient from Mountain Dew and Diet Mountain Dew, both of which generate more than $1 billion in annual sales.

Heather White, executive director at the Environmental Working Group, said of PepsiCo’s decision, “We can only hope that other companies will follow suit.” She added, “We need to overhaul how F.D.A. keeps up with the latest science on food additives to better protect public health.”

Ms. Kavanagh agreed. “I’ve been thinking about ways to take this to the next level, and I’m thinking about taking it to the F.D.A. and asking them why they aren’t doing something about it,” she said. “I’m not sure yet, but I think that’s where I’d like to go with this.”

New Mutations Found in Melanomas May Shed Light on How Cancers Grow

In a leap forward in understanding the basic science of one of the most lethal cancers, two groups of researchers have found mutations in most melanomas that are unlike any they have seen before incancer. The changes are in regions that control genes, not in the genes themselves. The mutations are exactly the type caused by exposure to ultraviolet light, indicating they might be among the first DNA changes in a cell’s path to melanoma.

For years, cancer researchers have searched for mutations in genes, but this time, they looked for — and found — mutations in a region that regulates genes. They did it by examining the entire DNA of multiple tumors, studying not just genes but also what has been called thedark matter, the 99 percent of the DNA that includes regions that control genes.

“You could think of this as one glimmer in what has been called cancer’s dark matter,” said Dr. Levi A. Garraway of the Dana-Farber Cancer Institute and the Broad Instituteof Harvard and M.I.T.

The DNA sequences of 70 malignant melanomas led to the new discovery. A small control region was mutated in 7 out of 10 of the tumors, and also, the investigators found, in liver and bladder cancers. The cancer cells had one of two tiny changes that together were more common than any mutation ever found in the genes of melanoma

Their findings indicate that those who inherit the mutations might be born with cells that have taken a first step toward cancer.

The mutations spur cells to make an enzyme, telomerase, that keeps cells immortal by preventing them from gradually losing the ends of their chromosome, the telomeres. When telomeres erode, a cell dies. But the enzyme also has other, poorly understood functions that are thought to keep cancer cells alive, said Robert Weinberg, an M.I.T. researcher who studies telomerase and cancer and was not involved with the research. “The paradigm that it does nothing but extend telomeres is a gross oversimplification,” he said.

Abundant telomerase is so important to cancers that it occurs in 90 percent of them, said Immaculata De Vivo, a Harvard Medical School researcher who studies telomerase and cancer and directs a DNA sequencing program. She, too, was not involved with the research.

The results of the two studies presented in the papers “are like a court of law — it’s the preponderance of the evidence,” she said. “We all knew telomerase was important for cancer, but now we are finding the mechanisms, the machinery.”

Scientists were surprised that the mutations in the dark matter of melanoma tumors were so commonplace. Dr. Garraway and his colleagues had the entire DNA sequences for a collection of melanomas — genes as well as the rest of the DNA, including areas that turn genes on and off.

“We said, ‘Let’s just take a look and see if there are any mutations in a regulatory region,’ ” Dr. Garraway said.

At first, they looked at the DNA sequences of 19 tumors. They were amazed to find one or the other of the two mutations in 17 of them. So the researchers decided to look at 51 additional melanomas and a handful of bladder and liver cancers. The mutations popped up again.

“It was really quite striking,” Dr. Garraway said.

Research to Resume on Modified, Deadlier Bird Flu

Experiments with a deadly flu virus, suspended last year after a fierce global debate over safety, will start up again in some laboratories, probably within the next few weeks, scientists say.

The research touched off a firestorm in 2011 when it became known that two groups, one in the Netherlands and another in the United States, had genetically altered a dangerous bird flu virus to make it more contagious in mammals. Some scientists warned that a deadly pandemic could break out if the mutant virus leaked out of the lab accidentally or if terrorists stole it or made it themselves, using articles in scientific journals for the recipe.

The outcry led scientists conducting the experiments to declare avoluntary moratorium a year ago, in part to let research organizations and governments decide what safety rules to require.

Now, flu researchers say, the moratorium should end because most countries have rules in place. A letter from 40 scientists — the same ones who called the moratorium last year — was published on Wednesday in the journals Science and Nature, saying it is time for the work to begin again in countries ready to allow it.

But the United States, which pays for much of the flu research both at home and abroad, has not yet released new guidelines. So scientists here will not be able to resume experiments yet, nor will those in other countries who depend on grant money from the United States.

During a telephone news conference on Wednesday, Ron Fouchier, a virologist who conducted some of the flu experiments at Erasmus Medical Center in the Netherlands, said the scientists were lifting the moratorium without waiting for guidelines from the United States.

“How long do you want us to wait?” Dr. Fouchier asked. “If this was the Netherlands, would the U.S. wait? Should all countries really wait for the U.S., and why?”

He said his laboratory would resume research within a few weeks. Although he receives research money from the National Institutes of Health in the United States, funding from other sources will allow him to go ahead, he said. Other researchers in the European Union will be free to pick up the research if they have funding that does not come from the United States government, he said. Laboratories in China and Canada may be ready to start up, but Japan, like the United States, is still working on new guidelines, researchers said during the teleconference.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the Department of Health and Human Services was reviewing new guidelines, and that he expected them to be approved in weeks. The guidelines will specify the laboratory conditions under which this type of research is permitted and require that experiments have a potential benefit for public health.

The work is usually done in laboratories with several layers of barriers to keep viruses from leaking out, and the workers wear protective suits and receive vaccinations to prevent infection, Dr. Fouchier said.

But some scientists still have reservations. Michael T. Osterholm, director of the Minnesota Center of Excellence for Influenza Research and Surveillance at the University of Minnesota and a member of a United States biosecurity board, said that he thought the research should go on, but that details should not be published for fear others would try to replicate it without safety precautions.

“The work they’re doing is really important,” he said, “but I don’t see it as work I want in the hands of every potential gene jockey out there.”

The experiments involve a bird flu virus called H5N1. It does not often infect people, but appears unusually deadly when it does. Of 610 known cases in people since 1997, slightly more than half have been fatal. But the real death rate is not known and could be lower than half because some mild cases may go uncounted.

So far, H5N1 has rarely spread from person to person. People who fall ill have nearly always caught it from poultry. But flu viruses mutate a lot, and the fear has been that H5N1 will somehow become more contagious in humans.

The debated experiments, by Dr. Fouchier and Dr. Yoshihiro Kawaoka, at the University of Wisconsin-Madison, involved ferrets, which react to the virus in much the way people do. Researchers can infect ferrets with H5N1 by squirting the virus into their noses or lungs, but then the animals normally do not infect one another. However, by genetically manipulating the virus, researchers created a form that became airborne and spread from ferret to ferret. Its transmissibility set off alarms.

Advocates of the research insist it can be done safely. And they say it is necessary so scientists can recognize changes in naturally occurring viruses that are dangerous and signal the need to eradicate infected animal populations. Understanding the viruses better should also help researchers develop more effective vaccines and antiviral drugs, Dr. Fouchier said.

He said other scientists could be given samples of the mutant virus for research only with the permission of Erasmus Medical Center, the National Institutes of Health and virus experts at the Mount Sinai Medical Center in Manhattan.

NEJM

SPECIAL ARTICLE

21st-Century Hazards of Smoking and Benefits of Cessation in the United States

Figure 2. Survival Probabilities for Current Smokers and for Those Who Never Smoked among Men and Women 25 to 80 Years of Age.

The overall mortality among smokers of both sexes in the United States is about three times as high as that among otherwise similar persons who never smoked, and the smokers lose, on average, at least a decade of life. The women in this cohort represent the first generation of women in the United States in which those who smoked began early in life and smoked for decades, and the risks of death for these women are about 50% greater than the risks reported in the 1980s studies.4,5 For both female and male smokers, the tripling of the relative risk of death and the reduction in survival by at least a decade are similar to the risks in four other studies: a study of male British doctors born between 1900 and 1930,17,18 the large U.K. study of women born between 1930 and 1950,19 a meta-analysis of several other U.S. cohort studies,20 and a study in Japan of people born between 1920 and 1945.21 Although the relative risks were similarly tripled across the studies, the absolute death rates (for both current smokers and those who had never smoked) were much higher in our study than in other U.S. studies,20 since the NHIS is more representative of the general U.S. population. Thus, in the NHIS, the large absolute differences in risk between current smokers and those who never smoked, as well as the gains in years of life for those who quit smoking, are likely to be true for the U.S. population as a whole. The hazards associated with smoking are substantial, even though in recent decades, most smokers in the United States have smoked cigarettes with relatively low levels of tar, as measured by machine testing, as compared with the cigarettes smoked in earlier decades.22

Figure 3. Effect of Smoking Cessation on Survival to 80 Years of Age, According to Age at the Time of Quitting.

Egypt: Polio Virus Is Found in Cairo’s Sewers

The polio virus has been found in the sewers of Cairo, and it appears to have come from Pakistan, the World Health Organization said Wednesday. Egypt has not had a case of polio since 2004. A vaccination drive is being planned for Feb. 25, and health workers are canvassing the neighborhoods where the sewage samples were taken, looking for children or adults who may have recently been paralyzed, said Sona Bari, a spokeswoman for the W.H.O.  Pakistan has said it will post teams at its international airports vaccinating all outward-bound passengers under age 5. Last month, at least nine Pakistani volunteers in an internationally supported polio vaccination drive were killed by militants across Pakistan in a campaign of intimidation that has hurt efforts to eradicate the disease there. Pakistan is one of the last three countries, with Afghanistan and Nigeria, with indigenous polio.

Drug Agency Recommends Lower Doses of Sleep Aids for Women

For two decades, millions of Americans have taken Ambien to help them sleep at night. But for years, the Food and Drug Administration has gotten complaints that people felt drowsy the morning after taking the medicine or its successors, and sometimes got into car accidents.

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About 60 million prescriptions for sleep aids were dispensed in 2011, up about 20 percent since 2006.

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On Thursday the agency said that women should be taking half as much, after laboratory studies and driving tests confirming the risks ofdrowsiness.

The new recommendation applies to drugs containing the active ingredient zolpidem, by far the most widely used sleep aid. Using lower doses means less of the drug will remain in the blood in the morning hours, and will reduce the risk that people who use it will be impaired while driving.

Sleeping pills have boomed in popularity with the increasingly frantic pace of modern American life. According to IMS, a health care information and technology company, about 60 million prescriptions were dispensed in 2011, up about 20 percent since 2006. About 40 million were for products containing zolpidem.

The agency’s announcement was focused on women because they take longer to metabolize the drug than men. An estimated 10 percent to 15 percent of women will have a level of zolpidem in their blood that could impair driving eight hours after taking the pill, while only about 3 percent of men do, said Dr. Robert Temple, an official in the agency’s Center for Drug Evaluation and Research.

Reports of aftereffects from sleeping pills have circulated for years, and some doctors questioned why the drug agency took so long to act. Mishaps with sleepy driving — and even strange acts of texting, eating or having sex in the night without any memory of it in the morning — have long been familiar to the medical community.

“In this case, the F.D.A. may be behind the eight ball,” said Daniel Carlat, an associate clinical professor of psychiatry at Tufts University, referring to residual drowsiness. “Few doctors will be surprised hearing about this. They’ll say, ‘Oh yeah, we’ve already seen this in our patients.’ ”

He added that Thursday’s announcement “will be good for public health because it will get patients to ask their doctors about the appropriate dosage.”

Agency officials acknowledged that they had received about 700 reports of driving mishaps with people on zolpidem over the years, with a spike in 2007 after a change in labeling caused more people to call in complaints. But they said it was not easy to draw a direct connection between the reports and the drug. Patients often did not remember what time they took the pill. Sometimes they had been drinking.

It was not until the drug agency reviewed driving simulation studies from controlled trials of the drug Intermezzo, which was approved in 2011 for middle-of-the-night waking, that a more complete picture of the risks emerged. The agency linked the driving simulation information with data from manufacturers on the amount of zolpidem in patients’ blood and determined that levels above about 50 nanograms per milliliter increased the risk of crashing while driving, said Dr. Ellis Unger, an official at the agency’s Center for Drug Evaluation and Research.

Dr. Unger said that all makers of new sleeping drugs would now be asked to conduct driving trials; a spokeswoman clarified that it would not be required.

“A lot of people are wondering about the elephant in the room,” Dr. Unger said. “Why did this take so long? This is science, and our thinking evolves over time.”

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Zolpidem has also been known to cause sleepwalking incidents, and Dr. Unger said there was evidence that the lower dose might ease such events, though it is weaker than the evidence about next-morning drowsiness. Dr. Carlat said one of his patients discovered that her weight gain while on the drug was from midnight trips to the kitchen that she did not even remember taking.

Dr. Daniel Kripke, professor emeritus of psychiatry at the University of California, San Diego, and a leading critic of sleeping pills, welcomed the move but said the agency was still not doing enough to investigate other possible side effects.

“It’s a very small step in the right direction,” he said. He added that sleeping medications like zolpidem might increase total sleep time by 20 minutes a night, but that most studies suggest that the use of sleeping pills impairs a person’s performance the next day.

Critics of the drug agency said the label on Intermezzo, which very clearly denotes the risks for women, indicates that the agency was aware of these problems earlier.

But Thomas Roth, director of the sleep center at Henry Ford Hospital in Detroit who has been a consultant to sleeping pill makers, said that the drug agency had always been concerned about the potential risks with driving, “but they care about it more now.” He said he believed the lower dose would still be effective for many patients.

Agency officials say all patients are unique and doses will need to be tailored. They say the drugs should be prescribed at the lowest dose required to treat a patient’s insomnia.

Dr. Daniel J. Buysse, professor of psychiatry at the University of Pittsburgh School of Medicine, says he already prescribes the lower dose when he feels it is necessary, by telling patients to cut a tablet in half along the score.

“This just tells me, maybe be a little bit more cautious,” said Dr. Buysse, who has been a consultant for drug companies including the maker of Ambien. “But I do not think it will have a big effect on what I do.”