Nature Outlook: Leukaemia

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The leukaemia Outlook is out!

I spent much of April and May working on this special magazine supplement on leukemia for Nature. I came up with the article list, commissioned and edited the articles, worked with the art department on the photos, graphics and cover, and oversaw the production. And I wrote the editorial introducing the contents (below.) You can see the supplement on Nature’s website here.

leukemia

Of all of the cancers that can wage war on the body, leukaemia — the general term for cancers of the blood — has a reputation for being among the least malevolent.

Most solid cancers are riddled with dozens of mutations, making it impossible to know which mutation set a cell on the wrong path, or which one to target. Leukaemia seems simpler: one type of the disease, chronic myeloid leukaemia (CML), can be traced to a single gene fusion (page S4). Scientists were able to develop a drug, imatinib, that exploits the errant gene, increasing the five-year survival for CML to more than 95%. Most children with acute lymphoblastic leukaemia (ALL) also survive

As we show in this Outlook, however, these headline statistics belie the reality for many patients.

The music of the night

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(This article appeared in the Winter 2008-2009 issue of NYU Physician.)

To cure sleep apnea, an ancient instrument may be best medicine of all.

Puff-cheeked and red-faced, with beads of sweat across his forehead, Kazim Yildiz, 42, is steadily vibrating his lips, much like a baby blowing bubbles. He is playing a didgeridoo, believed to be the world’s oldest wind instrument. Traditionally crafted from a branch of a eucalyptus tree, the cylindrical wooden tube is indigenous to Australia, where it’s been used in traditional Aboriginal ceremonies for thousands of years.

Now, modern medicine has found a new use for this ancient artifact. With practice, the didgeridoo produces an eerie, reverberating bellow. But to those afflicted with sleep apnea—a potentially serious sleep disorder in which breathing repeatedly stops and starts—the sound is music to their ears.

“In people with sleep apnea, the airway intermittently collapses during sleep,” explains Dennis Hwang, M.D., a researcher in the Division of Pulmonary and Sleep Medicine. “We believe that learning to play the instrument strengthens the muscles of the upper airway and reduces the airway collapsibility during sleep.”

Yildiz, an information technology expert at Merrill Lynch, is part of a 10-person study being conducted at NYU to determine whether playing the didgeridoo regularly can help to cure their disorder. Sleep apnea (Greek for “without breath”) affects as many as one in five middle-age adults, who literally stop breathing for moments while they are asleep. These stoppages cause the brain to wake up, which allows breathing to resume, but the pattern may leave him sleepy and irritable during the day. Loud snoring is a common symptom of sleep apnea, although not everyone who snores has the disorder.

Two Alzheimer’s drugs show promise

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(This story was #18 in Discover magazine’s top 100 stories of 2008.)

Two unconventional treatments for Alzheimer’s disease show promising early results. Both Rember (methylthioninium chloride) and Dimebon (dimebolin hydrochloride) appear to slow the mental decline associated with the illness.

No effective medicines exist for Alzheimer’s, which is estimated to afflict more than 4 million people in the United States alone. The disease is characterized by a decline in cognition and function and usually strikes after age 60. Most Alzheimer’s treatments have targeted amyloid, the main protein component of the associated plaques that form in the brain; Rember is the first to target the tangled, abnormal fibers of a protein called tau. At an Alzheimer’s conference in Chicago, the drug, made by TauRx Therapeutics, was reported to slow the progress of mild to moderate Alzheimer’s disease by 81 percent over the course of a year. In a phase 2 trial of 321 people with mild to moderate disease, those on the drug stayed at about the same cognitive level for up to 19 months, while those on the placebo got worse. A final trial is expected to begin in 2009.

The second drug, Dimebon, is an allergy drug used in Russia 20 years ago. A Lancet article in July reported that over 26 weeks of treatment, Dimebon significantly improved memory, thinking, and overall functioning in 68 Alzheimer’s patients, compared with a 66-member control group. Although researchers don’t know exactly how Dimebon does this, it may work by protecting mitochondria—the powerhouses of cells—from injury, says Rachelle Doody, the study’s lead author and a neurology professor at Baylor College of Medicine in Houston. A phase 3 trial for the drug began recruiting participants in June.

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.

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 imagesthe 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.

Don’t rush your vaccines

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(This Opinion column ran in Nature’s news site on May 17, 2007. You can read the original post here.)

The ethical debate about a vaccine for a sexually transmitted disease has been premature, says Apoorva Mandavilli; we don’t even know how well it works.

Here’s a good lesson: before you start pushing for a controversial vaccine to be made compulsory, HPV vaccinebest wait for the research — and I mean all the research — to come up with results.

For more than a year, we’ve been hearing that there is a vaccine that is 100% safe and effective in protecting young girls and women from the deadly viruses that cause cervical cancer.

Merck’s Gardasil, a vaccine against human papilloma virus (HPV), has been hailed as perhaps the biggest boon for women since the contraceptive pill. Across the world, including many American states, politicians and activists have proposed laws to make Gardasil mandatory for girls in their early teens or younger. Australia has already started a national programme of free vaccines for young girls.

All that sounds a bit premature — and rightly so. As we find out more about this vaccine, including new studies in last week’s New England Journal of Medicine1,2, it’s clear we simply don’t know enough about it to be giving it to young girls en masse.

The sunshine cure

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I wrote this feature for Nature Medicine after receiving a poorly-written email extolling vitamin D’s benefits. The writer was so impassioned, though, that I was intrigued. This ran in the April 2007 issue. You can view a pdf version of the article here.

Could ten minutes of sunlight a day be all that’s needed to fight multiple sclerosis, cancer and tuberculosis? Apoorva Mandavilli discovers the growing interest in vitamin D’s many virtues.

sunshine2Long before antibiotics turned tuberculosis (TB) into a curable disease, a Danish scientist  found an unusual way to treat it. In 1895 Niels Ryberg Finsen, then just 35, discovered that light from an electric arc lamp cured most people with TB of the skin. Over the following six years, he successfully treated 804 patients.

Nobody understood how the treatment worked, and the condition, lupus vulgaris, was relatively rare. But TB was such a fearsome scourge at the time that Finsen’s discovery won him the 1903 Nobel Prize in Physiology or Medicine. It also began the trend of sending those sick with TB to recover in sanatoriums housed in sunny locales.

It’s only now, more than a century later, that scientists are beginning to understand why Finsen’s method worked.

“It had to be through vitamin D,” says Barry Bloom, dean of the Harvard School of Public Health.

Last year, Bloom and his colleagues published evidence suggesting that vitamin D, made in response to sunlight, stimulates the production of a compound in the body called cathelicidin, which can kill various viruses and bacteria, including the TB microbe (Science 311, 1770– 1773; 2006).

It’s not often that you hear scientists of Bloom’s caliber extolling the virtues of a vitamin; that’s more commonly associated with over-anxious parents or ardent fans of alternative medicine.

Vitamin D may be best known for its role in harnessing calcium from the diet to build strong bones. But Bloom’s report is one of several in the past few years published in top journals— including the New England Journal of Medicine, Journal of the American Medical Association and Nature Immunology—that suggest a far meatier role for the vitamin in the body’s defense against diseases such as tuberculosis, multiple sclerosis (MS) and cancer.

“I think there’s an emerging mainstream acceptance of vitamin D as an immune- regulating factor,” says Eugene Butcher, professor of pathology at Stanford University. “The only people who are going to be skeptical of it are people who haven’t bothered to read the literature in the last five years.”

Premature medication

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(This Opinion column ran on Nature’s news site on December 22, 2006. You can see the original post here.)

Handing out experimental drugs to desperate patients is not a good idea, says Apoorva Mandavilli.

At first glance it seems only kind and right to let people with serious illnesses take whatever medicines they want. Some have campaigned so hard for this that the US Food and Drug Administration agreed on 11 December to let patients buy experimental drugs direct from the manufacturer when there are no other options available.

But this could have some terrible consequences.

Yes, the humanitarian argument for giving access is compelling. And yes, on an individual basis, it seems cruel to deny a medicine to someone who is suffering. But if the drug hasn’t been properly tested, how do we know it won’t aggravate the illness or, worse still, prove fatal to the people who take it? It may even actively discourage companies from investing in proper trials for those drugs where the only customers are desperate patients.

Troubled times force old pharma to learn new tricks

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(This article appeared in the April 2003 issue of Nature Medicine. You can download a pdf of this article.)

A combination of the floundering economy, a stringent regulatory environment and the dwindling number of drugs in the pharmaceutical pipeline are forcing translational researchers to rethink the way they structure pharma-academic partnerships, heard attendees at the Days of Molecular Medicine conference in March.

“Pharma is in the middle of a major paradigm shift,” said Jeff Leiden, chief scientific officer at Abbott Laboratories. After the golden age of drug development in the 1980s and 1990s, pharmaceutical companies expected their good fortune to continue. Rapid developments in biomedical research only strengthened that expectation, Leiden said. But, “things have certainly changed in the last three years.”

The number of new drug approvals has steadily decreased in the last few years. Researchers also filed fewer applications for patents and inventions in 2002 than in 2001. At the same time, pharmaceutical companies face the daunting costs of bringing a drug to market, pricing pressures and stringent requirements from regulatory agencies; the average size of a clinical trial has nearly tripled in the last 20 years.

Leiden says the existing model, which is a series of hand-offs from academia to biotech companies to large pharma, will soon be obsolete. Instead, he says, his company is actively recruiting both ‘scientist-physicians’—traditional M.D/Ph.Ds who can perform research—and ‘physician-scientists,’ who understand clinical trials and the regulatory hurdles in translational research. Companies like Abbott are also negotiating with universities to train students in both scientific and management principles. “I think you’re going to see a lot of those kinds of programs,” Leiden said.

Some universities are al
ready one step ahead. The
 University of California in
 San Diego—which organized 
the conference along with 
the Salk Institute and Nature
Medicine—is developing a
new inter-institutional pro
gram called the College of
Life Sciences (COILS). COILS 
is designed to bridge the 
chasms in translational re
search and will include the
 university’s Institute for
Molecular Medicine as the
 preclinical arm, the Clinical Investigation Institute for 
early-phase clinical trials and 
the Academy of Clinician
 Scholars to deliver therapies. The university will also offer joint training in science, public health and business.

In the UK, the Medical Research Council (MRC) has in the past two years reorganized its approach to translational research and has begun novel partnerships. For instance, it transferred several MRC employees to a new company, established with Amersham, that provides imaging facilities to the pharmaceutical industry.

The MRC’s new policies reward all staff involved in generating a new patent, a “real important part to encourage young people,” according to MRC chief executive George Radda. The MRC also owns all intellectual property that emerges from research done by its employees at academic institutions, allowing industry to negotiate licenses with a single organization, Radda said.

Researchers who form links with private companies need to be vigilant about potential conflicts-of-interest. Speakers bemoaned the lack of infrastructure to support the training of savvy translational researchers who can navigate such murky waters. M.D./Ph.Ds who exit the university system are better trained in basic research and are pressured to stay in those areas rather than venture into translational research, suggested students who attended the meeting.

Critical to training new physician-scientists is the role of mentors who can help young researchers find their footing. Lloyd “Holly” Smith, associate dean of the University of California in San Francisco, is one such “mentor of mentors,” and was awarded the Mentorship Award at the meeting. Attendees also honored Brian Druker and Charles Sawyers, for their work with the tyrosine kinase inhibitor Gleevec, with the Translational Medicine Award and philanthropist Evelyn Lauder, for her role in raising breast cancer awareness, with the Service Award.

Another disaster waiting to happen

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This article appeared on the now-defunct BioMedNet News.

The entire framework for regulating clinical trials in the US is flawed and long overdue for reform, says a leading bioethicist. The current review process is “somewhere between inadequate and pathetic,” Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania told BioMedNet News today. “The whole system is clearly broken.”

Federally funded clinical trials are monitored by Institutional Review Boards (IRBs), which are responsible for ensuring that trials meet federal standards for safety and are located within individual institutions. But the system, devised in the 1980s, is simply not up to tackling the volume of clinical research that now exists, Caplan says.

IRBs are “overworked, underappreciated and undersupported,” agreed John M. Falletta, a professor of pediatrics and chairman of the IRB at Duke University. Duke, for example, has 4 IRBs (with a 5th rapid-response group), each with some 20 members.

But the IRBs meet once a month, their members contribute less than 20 hours a month and, together, are responsible for reviewing the university’s 2,500 trials.