Microbiology: Straight from the gut

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(I first heard about gut transplants when I was interviewing Michael Zasloff of Georgetown University for a different piece. The idea that you can transplant someone’s entire intestines blew my mind. None of the Nature editors had ever heard of it, either. The implications–that you can study how bacteria colonize a gut after birth–really make this story compelling. And yes, I got to see some gruesome stuff. I’ll never quite forget the startlingly yellow poop Stuart Kaufman raved about. You can download a pdf of this article.)

The human body teems with microbes. Apoorva Mandavilli meets the surgeons who have a rare opportunity to watch an ecosystem being established as they transplant guts from one person to another.

Dirty business: gut transplants give bacteria and scientists new choices.

Stephanie is the first to admit that she never had the guts for life. She was born with familial adenomatous polyposis, a genetic disorder in which thousands of polyps form in the colon. By the age of 22, much of the organ had to be removed. Four years later, a massive benign tumour choked off the blood supply to her small intestine, so doctors cut out all but a metre of it. For the next six years, she was fed by a tube every night until the feeding left her liver badly scarred and fighting recurring infections. “I was given a month to live,” she says.

That’s when doctors referred Stephanie to Georgetown University Hospital in Washington DC. There, on 17 April 2006, surgeons cut out her stomach and what was left of her small and large intestine and replaced it with new organs from a donor who had died days earlier in Tennessee. “Oesophagus to anus, her entire gastrointestinal tract was in the garbage can,” says Tom Fishbein, who directed the surgery. “She got a brand new one.”

All organ transplants are complicated, but there are only a handful of centres in the United States that have the  expertise to transplant  a small intestine, the seven metres of coiled tissue connected up to the stomach at one end and the large intestine at the other. The technique is complicated because the gut is teeming with trillions of bacteria and other microbes, plus the bulk of the body’s lymphocytes.

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Genetic variant predicts heart disease risk

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(This article was originally published in Technology Review online on January 30, 2008.)

A newly identified risk factor for heart disease also seems to indicate which patients will benefit from popular statin therapies.

Heartsick: There have been many false leads in identifying risk genes for heart disease, so the burden of proof for those studies should be much higher than usually required, some experts say.

Testing for a genetic variation could predict the likelihood that a patient will respond well to certain statins. But some researchers say it’s too soon to use the variation to determine treatment.

Researchers from Celera reported yesterday in the Journal of the American College of Cardiology that a single substitution in the sequence of a gene called KIF6 makes people both more susceptible to heart attacks and more responsive to certain drugs that lower cholesterol. Though there is no known biological explanation linking the variation to heart disease, the study found that it increases the risk of heart attacks and strokes by 55 percent.

Celera, the company best known for sequencing the human genome, examined 35 single-nucleotide polymorphisms (SNPs) in 30,000 patients. Of those, “KIF6 is by far the most significant,” says Thomas J. White, chief scientific officer at Celera. In fact, nearly 60 percent of the study population was found to carry the KIF6 variant. (According to the study, these findings take into account other factors, such as smoking, high blood pressure, and cholesterol levels.)

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Cloned hamburger, anyone?

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(This article was #64 in Discover Magazine’s top 100 stories of 2007.)

Meat and milk from cloned cattle, pigs, and goats are safe to eat, the Food and Drug Administration has declared, setting the United States on course to become the first country to approve such products. The agency’s draft risk assessment says food from clones can safely be marketed without any labels to distinguish it.

In an article in the journal Theriogenology last January, agency scientists analyzed dozens of studies—many of them from cloning companies Viagen and Cyagra—and concluded that meat and milk from clones showed no “nutritionally or toxicologically important differences” from products now consumed.

But some advocacy groups aren’t buying it. “We’re very concerned,” says Charles Margulis, spokesman for the Washington-based Center for Food Safety. “We don’t think there’s really enough science to show that clones are safe.”

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Controversy over cervical cancer vaccine

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(This article was #26 in Discover Magazine’s top 100 stories of 2007.)

This past year, several countries and at least 24 states in the United States introduced laws to mandate vaccination against cervical cancer for preteen girls. Although the vaccine was initially hailed as a breakthrough, urgent proposals to make it mandatory quickly triggered a backlash. “In the long term,” says Susan Wood, a former director of the FDA Office of Women’s Health, “the rush to get this mandated immediately has done more harm to the issue.”

The FDA approved Merck’s Gardasil vaccine in 2006, after clinical trials showed that it protects against four strains of human papillomavirus (HPV), which together cause about 70 percent of cervical cancers and 90 percent of genital warts. HPV is the most common sexually transmitted virus among Americans (and cervical cancer is the second most common cancer in women worldwide). Because the vaccine doesn’t reverse existing exposure, the CDC recommends it be administered before the age of sexual activity—specifically to girls ages 11 to 12. As for women who already have HPV, two separate studies published in May in the New England Journal of Medicine reported that the vaccine’s effectiveness in preventing cervical lesions dropped to 20 percent or less.

Some conservative groups oppose targeting preteens, arguing that because the virus is sexually transmitted, the vaccine will encourage promiscuity. Meanwhile, bioethicists who are skeptical about compulsory vaccination laws note that all other mandated vaccines protect against diseases easily transmitted in schools. “In my opinion, there’s not a compelling ethical reason [to mandate],” says Richard Zimmerman, professor of family medicine at the University of Pittsburgh. “The ethics is the opposite: to strongly recommend, but not to mandate.”

New vaccine blocks bird flu

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(This article was #12 in Discover Magazine’s top 100 stories of 2007.)

Although avian flu made few headlines in 2007, the virus continued to claim lives in Asia, particularly in Indonesia. The good news is that this year the FDA approved the first bird flu vaccine and announced plans to stockpile it for emergency use during a crisis.

The H5N1 strain of bird flu first appeared in Hong Kong in 1997 and since then has infected more than 330 people, killing more than 200. In 2007, the virus—which normally infects birds and occasionally jumps from birds to humans—affected seven countries, prompting experts to warn that it could gain the ability to jump from person to person and trigger a pandemic.

In April, the FDA approved a two-shot vaccine made by Sanofi Pasteur. In a clinical trial, this vaccine protected 45 percent of the adults who received the highest dose against infection from H5N1. The government said its goal was to stockpile enough doses of the Sanofi vaccine to protect 20 million people as a stopgap measure until a more potent vaccine is available.

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FDA says cold medicine is not for children under 6

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(This article was #18 in Discover Magazine’s top 100 stories of 2007.)

In October, Food and Drug Administration (FDA) advisers recommended against the use of most nonprescription cold and cough medicines for children under age 6, citing the lack of evidence of safety or efficacy in this age group. Prior to the announcement, most manufacturers had already voluntarily restricted sales of medicines formulated for children less than 2 years old.

The FDA review of the medications began after a report by the Centers for Disease Control in January found that, between 2004 and 2005, more than 1,500 children under the age of 2 had wound up in emergency rooms after taking over-the-counter cough and cold medicines. In another development that prompted the review, Baltimore city officials filed a citizen petition with the FDA in March, noting that the remedies do not help children under 6 years of age and may in fact harm them.

There are roughly 800 products on the market containing antihistamines, decongestants, anticough agents, and other chemicals intended to treat colds and coughs in children. Like many pediatric medicines, they have been tested only in adults and are simply packaged to deliver smaller doses to children.

In September, the FDA also required that, by November 2007, drug companies stop making unapproved prescription drugs containing the narcotic cough suppressant hydrocodone for use by children younger than 6. Manufacture of all other unapproved hydrocodone products must halt by December 31.

Male circumcision: A new defense against HIV

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(This article was #15 in Discover Magazine’s top 100 stories of 2007.)

Male circumcision cuts the risk of HIV transmission in men by about 60 percent and should be scaled up in countries hardest hit by the epidemic, the World Health Organization (WHO) announced in March, citing compelling evidence from three large trials in Kenya, Uganda, and South Africa.

Since the 1980s, dozens of smaller studies have suggested that countries with high rates of circumcision, like the Muslim nations of western Africa, have lower rates of AIDS, whereas southern* Africa, where circumcision is rare, has been ravaged by the epidemic. There, a 2006 study suggests, circumcision could prevent about 6 million HIV infections and 3 million deaths over 20 years. Still, the WHO held back its recommendation until 2007, citing the need for randomized clinical trials.

“Circumcision was ignored for ages,” says Daniel Halperin, an AIDS researcher at the Harvard School of Public Health, who laid out the case for circumcision in The Lancet as far back as 1999. “What I mainly criticize the WHO for is that, even with dozens and dozens of powerful studies, they refused to even talk about it.”

Circumcision is thought to prevent infection because the underside of the foreskin is rich in immune cells that are particularly vulnerable to HIV. Small tears in the foreskin during intercourse can also allow the virus to slip into the body.

Circumcision could reduce the odds of an infected man’s transmitting the virus to a female partner by 30 percent or more. For all its benefits, though, the WHO cautions that it should not replace standard methods of prevention like the use of condoms.

Rx for the FDA

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(This article was #5 in Discover Magazine’s top 100 stories of 2007.)

For the Food and Drug Administration, the agency charged with ensuring drug safety, 2007 brought a slew of charges undermining its credibility. The most widely reported involved a study by Cleveland Clinic cardiologist Steven Nissen showing that the diabetes drug Avandia, FDA-approved in 1999, raised the risk of heart attack by 30 to 40 percent. The agency was also called to testify before Congress about its inaction regarding side effects of the antibiotic Ketek and a widely used class of anemia drugs. In addition, a study published in the Archives of Internal Medicine in September found that reports of serious side effects and deaths caused by FDA-approved medicines nearly tripled between 1998 and 2005, to about 90,000.

The accumulation of evidence apparently forced a reckoning in Congress and the White House. On September 27, President Bush signed into law an amendment giving the agency unprecedented new powers to conduct and demand safety studies on approved drugs, police drug advertisements, and require companies to register data from their clinical trials in a publicly available database. The new law also boosts the agency’s budget, an increase approved in time to avert the layoffs of some 2,000 FDA employees, including many researchers.

“This has been a tough year,” acknowledges Janet Woodcock, deputy commissioner of the FDA and acting director of the agency’s Center for Drug Evaluation and Research. “[But] I do think this is an inflection point about the communication on drug safety. We have the opportunity to set up new systems.”

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Risky business

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(This Opinion column ran on Nature’s news site on August 21, 2007. You can download a pdf of the post.)

It’s not the technology of gene therapy but the regulation of clinical trials that we should be most afraid of, says Apoorva Mandavilli.

Almost exactly seven years after the first death in a gene-therapy trial, another unexpected death hit the field late last month – followed quickly by panic, outrage and some calls for an end to gene therapy altogether.

But to blame and ban all gene therapy because of this would be rash and misguided. And it might risk missing the point. What we should be most outraged and scared by is the way this trial took place — and the similar mis-steps that seem to accompany a vast number of clinical trials, gene therapy or no gene therapy.

On 2 July Jolee Mohr, a 36-year-old woman in Chicago, received an injection she thought would treat her painful — although not debilitating — arthritis. She died on 24 July of multiple organ failure, which was also the cause of death of 18-year-old Jesse Gelsinger in September 1999. In each case, the US Food and Drug Administration responded by suspending the trial and any others that used a similar approach.

But tragic and avoidable as both deaths were, I think we should be more worried about a broken system for clinical trials than of a risky treatment.

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Unreasonable doubt

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(This Opinion column ran on Nature’s website June 15, 2007. You can see the original post here.)

A ‘vaccine court’ case on autism could have disastrous consequences if people confuse its verdict with scientific consensus.

Why are there so many more cases of autism now than there were 30 years ago? It’s a question the best scientific minds have been unable to answer. But I’m afraid a US court now looking at that question may settle it on the basis of emotion rather than science.

The parents of thousands of autistic children think that the routine measles-mumps-rubella (MMR) vaccine and the mercury-based vaccine preservative called thimerosal damaged their healthy children’s brains and made them autistic — and they’re now suing the US government for damages. On Monday, three ‘special masters’ of the US Court of Federal Claims began hearing testimony in the first of nearly 5,000 such cases, some of which have been pending for years.

I sympathize with these parents and can understand their need to find a reason for their children’s suffering. But I trust in science, and I can’t ignore the fact that so many peer-reviewed studies — and every scientific panel entrusted with evaluating those studies — has come to the same conclusion: neither the MMR vaccine nor thimerosal is associated with autism.

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