Science Tuesday - Archaeology, Thalidomide, and The CDC

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A Host of Mummies, a Forest of Secrets
By NICHOLAS WADE, The New York Times, March 15, 2010

In the middle of a terrifying desert north of Tibet, Chinese archaeologists have excavated an extraordinary cemetery. Its inhabitants died almost 4,000 years ago, yet their bodies have been well preserved by the dry air.

The cemetery lies in what is now China’s northwest autonomous region of Xinjiang, yet the people have European features, with brown hair and long noses. Their remains, though lying in one of the world’s largest deserts, are buried in upside-down boats. And where tombstones might stand, declaring pious hope for some god’s mercy in the afterlife, their cemetery sports instead a vigorous forest of phallic symbols, signaling an intense interest in the pleasures or utility of procreation.

The long-vanished people have no name, because their origin and identity are still unknown. But many clues are now emerging about their ancestry, their way of life and even the language they spoke.



Their graveyard, known as Small River Cemetery No. 5, lies near a dried-up riverbed in the Tarim Basin, a region encircled by forbidding mountain ranges. Most of the basin is occupied by the Taklimakan Desert, a wilderness so inhospitable that later travelers along the Silk Road would edge along its northern or southern borders.

In modern times the region has been occupied by Turkish-speaking Uighurs, joined in the last 50 years by Han settlers from China. Ethnic tensions have recently arisen between the two groups, with riots in Urumqi, the capital of Xinjiang. A large number of ancient mummies, really desiccated corpses, have emerged from the sands, only to become pawns between the Uighurs and the Han.

The 200 or so mummies have a distinctively Western appearance, and the Uighurs, even though they did not arrive in the region until the 10th century, have cited them to claim that the autonomous region was always theirs. Some of the mummies, including a well-preserved woman known as the Beauty of Loulan, were analyzed by Li Jin, a well-known geneticist at Fudan University, who said in 2007 that their DNA contained markers indicating an East Asian and even South Asian origin.

The mummies in the Small River Cemetery are, so far, the oldest discovered in the Tarim Basin. Carbon tests done at Beijing University show that the oldest part dates to 3,980 years ago. A team of Chinese geneticists has analyzed the mummies’ DNA.

Despite the political tensions over the mummies’ origin, the Chinese said in a report published last month in the journal BMC Biology that the people were of mixed ancestry, having both European and some Siberian genetic markers, and probably came from outside China. The team was led by Hui Zhou of Jilin University in Changchun, with Dr. Jin as a co-author.

All the men who were analyzed had a Y chromosome that is now mostly found in Eastern Europe, Central Asia and Siberia, but rarely in China. The mitochondrial DNA, which passes down the female line, consisted of a lineage from Siberia and two that are common in Europe. Since both the Y chromosome and the mitochondrial DNA lineages are ancient, Dr. Zhou and his team conclude the European and Siberian populations probably intermarried before entering the Tarim Basin some 4,000 years ago.

The Small River Cemetery was rediscovered in 1934 by the Swedish archaeologist Folke Bergman and then forgotten for 66 years until relocated through GPS navigation by a Chinese expedition. Archaeologists began excavating it from 2003 to 2005. Their reports have been translated and summarized by Victor H. Mair, a professor of Chinese at the University of Pennsylvania and an expert in the prehistory of the Tarim Basin.

As the Chinese archaeologists dug through the five layers of burials, Dr. Mair recounted, they came across almost 200 poles, each 13 feet tall. Many had flat blades, painted black and red, like the oars from some great galley that had foundered beneath the waves of sand.

At the foot of each pole there were indeed boats, laid upside down and covered with cowhide. The bodies inside the boats were still wearing the clothes they had been buried in. They had felt caps with feathers tucked in the brim, uncannily resembling Tyrolean mountain hats. They wore large woolen capes with tassels and leather boots. A Bronze Age salesclerk from Victoria’s Secret seems to have supplied the clothes beneath — barely adequate woolen loin cloths for the men, and skirts made of string strands for the women.

Within each boat coffin were grave goods, including beautifully woven grass baskets, skillfully carved masks and bundles of ephedra, an herb that may have been used in rituals or as a medicine.

In the women’s coffins, the Chinese archaeologists encountered one or more life-size wooden phalluses laid on the body or by its side. Looking again at the shaping of the 13-foot poles that rise from the prow of each woman’s boat, the archaeologists concluded that the poles were in fact gigantic phallic symbols.

The men’s boats, on the other hand, all lay beneath the poles with bladelike tops. These were not the oars they had seemed at first sight, the Chinese archaeologists concluded, but rather symbolic vulvas that matched the opposite sex symbols above the women’s boats. “The whole of the cemetery was blanketed with blatant sexual symbolism,” Dr. Mair wrote. In his view, the “obsession with procreation” reflected the importance the community attached to fertility.

Arthur Wolf, an anthropologist at Stanford University and an expert on fertility in East Asia, said that the poles perhaps mark social status, a common theme of tombs and grave goods. “It seems that what most people want to take with them is their status, if it is anything to brag about,” he said.

Dr. Mair said the Chinese archaeologists’ interpretation of the poles as phallic symbols was “a believable analysis.” The buried people’s evident veneration of procreation could mean they were interested in both the pleasure of sex and its utility, given that it is difficult to separate the two. But they seem to have had particular respect for fertility, Dr. Mair said, because several women were buried in double-layered coffins with special grave goods.

Living in harsh surroundings, “infant mortality must have been high, so the need for procreation, particularly in light of their isolated situation, would have been great,” Dr. Mair said. Another possible risk to fertility could have arisen if the population had become in-bred. “Those women who were able to produce and rear children to adulthood would have been particularly revered,” Dr. Mair said.

Several items in the Small River Cemetery burials resemble artifacts or customs familiar in Europe, Dr. Mair noted. Boat burials were common among the Vikings. String skirts and phallic symbols have been found in Bronze Age burials of Northern Europe.

There are no known settlements near the cemetery, so the people probably lived elsewhere and reached the cemetery by boat. No woodworking tools have been found at the site, supporting the idea that the poles were carved off site.

The Tarim Basin was already quite dry when the Small River people entered it 4,000 years ago. They probably lived at the edge of survival until the lakes and rivers on which they depended finally dried up around A.D. 400. Burials with felt hats and woven baskets were common in the region until some 2,000 years ago.

The language spoken by the people of the Small River Cemetery is unknown, but Dr. Mair believes it could have been Tokharian, an ancient member of the Indo-European family of languages. Manuscripts written in Tokharian have been discovered in the Tarim Basin, where the language was spoken from about A.D. 500 to 900. Despite its presence in the east, Tokharian seems more closely related to the “centum” languages of Europe than to the “satem” languages of India and Iran. The division is based on the words for hundred in Latin (centum) and in Sanskrit (satam).

The Small River Cemetery people lived more than 2,000 years before the earliest evidence for Tokharian, but there is “a clear continuity of culture,” Dr. Mair said, in the form of people being buried with felt hats, a tradition that continued until the first few centuries A.D.

An exhibition of the Tarim Basin mummies opens March 27 at the Bowers Museum in Santa Ana, Calif. — the first time that the mummies will be seen outside Asia.

An earlier version of this article incorrectly described Xinjiang as a province rather than an autonomous region.





Answers Begin to Emerge on How Thalidomide Caused Defects
By CARL ZIMMER, The New York Times, March 15, 2010

The word “phocomelia” means seal limb. It describes an extremely rare condition in which babies are born with limbs that look like flippers.

The long bones of the arms fail to develop, but fingers sometimes sprout from the shoulders. In some cases, the legs fail to develop, too. The French anatomist Étienne Geoffroy Saint-Hilaire coined the word in 1836, and it immediately sank into scientific obscurity for 120 years. And then, 50 years ago, it suddenly became all too familiar.

Doctors began to see more and more cases. It turned out that a drug called thalidomide, which pregnant women were taking for morning sickness, was responsible. Magazines and newspapers ran shocking pictures of seal-limbed children, and the drug was banned in 1962. By then, 10,000 children, mostly in Europe, had been born with thalidomide-induced birth defects.

Despite the notoriety, phocomelia remained scientifically mysterious for the next five decades. Doctors knew all too well to avoid thalidomide, but developmental biologists could not explain how thalidomide made limbs disappear.

Only now are scientists finally starting to solve the puzzle. And by deciphering thalidomide’s effects, they are discovering surprising clues about how normal limbs develop. They hope that those fundamental insights will in turn produce a medical benefit.



Thalidomide may be dangerous to developing embryos, but it is very effective for treating diseases like leprosy and some kinds of cancer. By understanding how thalidomide causes limb deformities, scientists may be able to invent safer variations of the drug.

Neil Vargesson, a developmental biologist at the University of Aberdeen, in Scotland, said that like everyone, he was horrified at children being born with drug-caused defects. “If I can stop that,” he said, “that will be fantastic.”

When thalidomide first went on the market in 1957, in Germany, it was considered so safe that it was sold over the counter. Drug companies introduced it in 45 other countries. But within a few years, doctors in Germany and Australia noticed a rise in phocomelia and eventually linked it to thalidomide. In the United States, about 40 children were born with Thalidomide-induced defects. When its side effects came to light, it had not yet been approved by the Food and Drug Administration.

About 40 percent of babies with thalidomide-induced defects died before their first birthday. Those who survived learned to cope. Survivors who had legs, for example, learned how to use them to dress and feed themselves. “They can do things that ballerinas can only dream of,” said Martin W. Johnson, the director of the Thalidomide Trust, which was established to assist Britain’s thalidomide survivors.

Unfortunately, as the survivors enter their 50s, the strain they have put on their muscles is taking its toll. “Approximately 50 percent of our people are living with chronic pain every day,” Dr. Johnson said in an interview.

Despite the devastation, thalidomide is still in use today. In 1964, Israeli scientists discovered it could control leprosy by reducing the inflammation caused by the disease. In 1998, the F.D.A. approved it for multiple myeloma, a cancer of plasma cells in the blood. Researchers are testing thalidomide in trials for other diseases including H.I.V. and Crohn’s disease. Patients are required to take thalidomide under strict supervision. But in South America and Africa, some women taking it are still giving birth to children with phocomelia.

How thalidomide deforms limbs has continued to baffle scientists. In the 1960s, developmental biologists began to inject thalidomide into animal embryos to trigger phocomelia. From those experiments, they developed about 30 theories. Some scientists argued that thalidomide damaged nerves in developing limbs. Others said that the drug triggered cells in the developing limb to commit suicide. And some said that thalidomide slipped into the DNA of cells in a developing limb, preventing the cells from making the proteins they needed.

Unfortunately, the scientists could not put any of those ideas to rigorous tests. They had only a crude understanding of how limbs developed, because they did not know how to track the molecular changes taking place. And so they had no way of knowing how thalidomide disrupted this chemistry.

Thalidomide itself made the puzzle even harder. When a person ingests a thalidomide pill, enzymes start to break it down into simpler forms, called metabolites. Thalidomide can break down into at least 18 metabolites. Each one has a different structure, and, as a result, it may interact with cells in a different way.

The complexity of thalidomide and the obscurity of limb formation left scientists stymied. “It went very quiet,” said Dr. Vargesson. “But all of a sudden in the past few years, it’s moved forward at a massive rate.”

In 2006, he and a team of collaborators began a survey of the metabolites of thalidomide. William D. Figg of the National Cancer Institute purified them, and Dr. Vargesson and his colleagues tested them in chick embryos. As they described in a report last year, they found that only one metabolite they tested, known as CPS49, caused the chicks to fail to develop wings.

The scientists also noticed something else about CPS49: within minutes of being injected into an embryo, it started killing developing blood vessels. Dr. Vargesson and his colleagues proposed that the death of these new blood vessels stopped the limb bud from taking its final shape.

In a healthy embryo, patches of cells along its sides swell into buds that stretch out into arms and legs. The proliferation of the cells triggers genes in the limb bud, which make proteins that sculpt the limb. CPS49, Dr. Vargesson argued, starves the limb, causing many cells to die. The surviving cells do not get the proper signals and fail to develop.

This model could account for how thalidomide could have such a drastic effect on limbs without causing much damage elsewhere in the body. Limbs develop relatively late, beginning about 23 days after the start of pregnancy. An embryo exposed to thalidomide at that point would suffer damage to its limbs, Dr. Vargesson said, while the rest of it would suffer less damage because its blood vessels were already mature.

Even if Dr. Vargesson’s model turned out to be right, it was missing some key pieces. In order for thalidomide to do its damage, it must grab on to some particular kind of molecule in the embryo.

To find that target, Dr. Hiroshi Handa of the Tokyo Institute of Technology and his colleagues coated microscopic beads with thalidomide. They then immersed the beads in various proteins. As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide.

“We were very surprised,” Dr. Handa said. While scientists have identified scores of genes involved in the development of arms and legs, no one had ever suspected cereblon of playing a role. In fact, no one was sure what cereblon did.

To investigate cereblon further, Dr. Handa and his colleagues ran experiments on zebrafish embryos. The network of genes that builds zebrafish fins is almost identical to the one that builds human limbs. And, just as humans lose limbs, zebrafish lose fins when they are exposed to thalidomide.

The scientists speculated that thalidomide caused the defects by disabling cereblon proteins. They prevented zebrafish embryos from making cereblon, and, just as they predicted, the zebrafish could not grow fins.

If thalidomide could not bind to cereblon, Dr. Handa reasoned, it might lose its power. He and his colleagues tinkered with the gene for cereblon and discovered that if they altered it in two spots, it made a protein that thalidomide could no longer grab. They injected the altered cereblon into the wings of chick embryos along with thalidomide. The chicks grew relatively normal wings despite the thalidomide.

“This is a very important paper,” said Rolf Zeller of the University of Basel in Switzerland. “These findings were completely unexpected.”

He said that scientists now needed to see if thalidomide was also binding to proteins other than cereblon. “This study identifies a key piece of the 50-year-old puzzle behind the thalidomide tragedy, but it is premature to say ‘case closed,’ " Dr. Zeller said.

Now scientists have to figure out if thalidomide binding to cereblon is, in fact, the process that shuts down blood vessels. Dr. Handa, meanwhile, is investigating how cereblon controls the development of limbs.

Dr. Vargesson said the new results may point the way to new forms of thalidomide that can fight cancer or other diseases without attacking cereblon, and send phocomelia back to medical obscurity. “That,” said Dr. Vargesson, “would be the golden goal.”





Obama’s C.D.C. Director, Wielding a Big Broom
By GARDINER HARRIS, The New York Times, March 15, 2010

ATLANTA — No federal health agency changed more during the Bush administration than the Centers for Disease Control and Prevention. It got new buildings, new managers and an entirely new operating structure.

A year into the Obama administration, only the new buildings remain. Dr. Thomas R. Frieden, the agency’s director since June, has quietly scrapped nearly all the administrative changes that the previous director, Dr. Julie L. Gerberding, spent much of her six-year tenure conceiving and carrying out.

Gone are the nonscientific managers whom Dr. Gerberding sprinkled throughout the agency’s top ranks. Gone is a layer of bureaucracy, agency officials said. Gone, too, are the captain’s chairs with cup holders from a conference room so fancy that agency managers dubbed it the Crown Room.

In their place, Dr. Frieden has restored not only much of the agency’s previous organizational structure and scientific managers, but also its drab furniture. And he has brought something new: a frenetic sense of urgency.



The C.D.C. is considered one of the world’s premier public health agencies, responsible for tracking the spread of infectious disease, distributing vaccines and monitoring the causes of sickness and deaths. About three-quarters of its $10 billion annual budget is given out in grants to places like state and local health departments, which collectively lost 16,000 positions last year, according to a recent public health survey, making those grants that much more important.

Dr. Frieden, 49, a former New York City health commissioner, marches around the agency’s Atlanta campus so rapidly that staffers have to trot to keep up. He uses his BlackBerry constantly, sending a stream of brief e-mail messages that are so cryptic that recipients sometimes ask for translations. “Kmi,” for instance, means “keep me informed.”

By the end of her tenure, Dr. Gerberding had become so removed from day-to-day management that some top agency officials went weeks without seeing or hearing from her, they said. Dr. Frieden, by contrast, sometimes wanders the agency’s hallways and drops in on scientists unannounced to ask about their work, both delighting and terrifying them.

In an interview last month, in his 12th-floor office, Dr. Frieden said that when he arrived in June, there was near-universal agreement that change was needed, but nobody wanted a repeat of the disruption Dr. Gerberding’s years-long reorganization had wrought.

“Faced with that, you pull off the Band-Aid quickly,” Dr. Frieden said.

Within two months, Dr. Frieden eliminated the “coordinating centers,” a layer of management Dr. Gerberding had added between the agency’s scientists and top leadership. The Coordinating Center for Infectious Diseases, with 600 employees, became the Office of Infectious Diseases, with 12. No one was fired; the agency’s leadership was simply pared.

Now president of Merck Vaccines, Dr. Gerberding said in an e-mailed statement: “The 9/11 and anthrax attacks, SARS, and other global health threats altered the landscape of public health forever and made it necessary for C.D.C. to work faster and more synergistically to protect health than it had before. That was the intent of the reorganization. I’m sure the new ideas that Dr. Frieden is introducing are motivated by the same intent."

Agency employees and former leaders said in interviews that they were thrilled with Dr. Frieden’s changes.

“I think he’s doing a great job,” said Dr. Jeffrey P. Koplan, one of five former C.D.C. directors who had publicly criticized Dr. Gerberding’s leadership. “He is setting priorities and sticking to them.”

Part of the agency’s embrace of Dr. Frieden probably has to do with politics. Despite being in a Republican state, the disease centers’ staff, like much of the public health world, is overwhelmingly Democratic, so employees tend to prefer directors appointed by Democratic presidents. Also, Dr. Frieden began his career in 1990 as an officer in the Epidemic Intelligence Service of the C.D.C. at New York City’s health department, doing the base-level tracking of diseases that is fundamental to the agency.

Dr. Frieden said that among his priorities for the agency, the most important are improving its disease tracking and supporting state and local government health offices.

“All of public health starts with more information,” he said. “We have to analyze what we have better and disseminate it better.”

And with the poor economy and mounting deficits straining budgets, Dr. Frieden has been scrutinizing the C.D.C for savings to pay for his priorities.

Some agency officials panicked when Dr. Frieden asked each to plan for a 3 percent budget cut. The exercise found few easy cuts and fewer still that could be used to finance other programs.

“We have very little flexibility to move money around,” Dr. Frieden said.

Although he now lives in the South, Dr. Frieden is still very much a New Yorker. He returns from visits to New York with bags of bagels. He speaks longingly of New York’s neighborhoods, and, in a series of meetings on Feb. 24, repeatedly referred to his experiences as the city’s health commissioner.

One of the lessons from New York, he said, is that many of the programs that have the greatest impact on public health get the least attention. During his eight-year tenure there, for instance, smoking rates among teenagers declined while colon cancer screening efforts climbed, he said. Neither got much publicity, he said, sounding somewhat wounded.

He promised to continue focusing on basic tasks like getting those people at risk of heart attacks to take aspirin; those with high blood pressure to get treatment; and those who smoke to stop.

In New York, Dr. Frieden came under fire for, according to some critics, acting like a nanny and a scold with campaigns to ban trans fats, post calorie counts in chain restaurants, reduce salt in processed food and tax high-calorie sodas. He had a supportive boss in Mayor Michael R. Bloomberg and a receptive populace in New York, but if he were to try anything similar at the C.D.C., tough Congressional hearings could be in his future because conservative lawmakers on Capitol Hill often oppose such measures.

Dr. Frieden rarely discusses his family publicly, and he dismissed questions about how his wife and two children were coping with the move to Atlanta by saying, “Moves are always transitions, and they can be difficult.” Agency officials said that the stream of e-mail messages from him tapers off between 6 and 9 p.m., when he is with family.

His days are filled with short meetings in which he quickly makes his points and leaves at the appointed times. When the 25 minutes allotted for an interview ended, he got up, shook hands and left.

“There’s a time to make things happen,” Dr. Frieden said, “and if you miss the wave, you’re not going get stuff done.”

Comments

[fingle.livejournal.com]

I love Science Tuesday, even though I didn't get a chance to read it until Thursday!

The museum exhibit on the Small River Cemetery is coming to the Bowers? So cool! That's jus up the street from my daugher's high school! I'll be sure to attend that exhibit! Thank you for the head's up. She take the train to school most days, so I often fail to see the street banners promoting whatever is currently installed at the Bowers, a fine little cultural museum!