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November 22, 2010
A Man From Whom Viruses Can’t Hide
By CARL ZIMMER
Dr. W. Ian Lipkin was spending the afternoon prowling his empire of viruses. The Center for
Infection and Immunity, which he directs, occupies three floors of the Mailman School of
Public Health at Columbia University. Rather than wait for the elevator, Dr. Lipkin ran up
and down the back stairs to move from floor to floor, leaning into the doorways of labs and
glass-walled offices to get updates from a platoon of scientists.
Gustavo Palacios was sequencing the genes from a new strain of Ebola virus found in a bat
in Spain — a worrisome development, since the fatal virus has almost never been found
outside Africa.
Nick Bexfield of the University of Cambridge had flown from England with a new hepatitis
virus that has just broken out in British dogs.
Some researchers were examining New York flu, others African colds. The blood of patients
with mysterious, nameless fevers was waiting to be analyzed. There was dried African bush
meat seized by customs inspectors at Kennedy Airport. Horse viruses, clam viruses: all told,
members of Dr. Lipkin’s team were working on 139 different virus projects. It was, in other
words, a fairly typical day.
“We get 10,000 samples a year easily,” Dr. Lipkin said. “We’ve discovered at least 400 new
viruses since I came to Columbia in 2002, and the process is accelerating.”
Over the past 20 years, Dr. Lipkin has built a reputation as a master virus hunter. He has
developed ways to quickly identify familiar viruses and ways to search for new ones.
“If scientists are lucky, they’ll identify one novel virus in their whole life,” said Dr. Anthony
S. Fauci, director of the National Institute of Allergy and Infectious Diseases. “Lipkin really
stands out from the crowd.”
The emergence of H.I.V. in the 1980s first drove Dr. Lipkin to search for viruses. At the
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Dr. W. Ian Lipkin, Virus-Hunting Master - NYTimes.com
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time, he was a neurology resident at the University of California, San Francisco, and was
watching many patients fall ill with AIDS. It took years for scientists to discover the virus
responsible for the disease. Dr. Lipkin worried that in years to come, new viruses would
claim more lives because of this lag. “I saw all this, and I said, ‘We have to find new and
better ways to do this,’ ” Dr. Lipkin said.
One reason that viruses can be so hard to find is that they’re so small — typically a few
millionths of an inch across. Even the most powerful microscopes may not be able to reveal
viruses if they’re lurking in a hiding place in the body. Sometimes scientists can detect
viruses by rearing vast numbers of them in laboratories. It’s also possible to detect them by
looking for antibodies in infected people. But these methods can be slow and unreliable. Dr.
Lipkin thought it might be better to find viruses in a different way. He would go fishing for
their genes.
“It had never been done before, and it was an obvious thing to do,” he said.
Dr. Lipkin’s first quarry was the cause of a bizarre disorder caused borna disease. Borna
disease had first been discovered in horses in the late 1800s; it attacks their brains and
causes them to flail uncontrollably. When scientists injected filtered brain extracts into
healthy animals, they could develop the disease as well. Doctors worried that it might cross
over into humans and have equally devastating effects. But no one had ever found a
pathogen in an animal sick with the disease.
If a virus was responsible for borna disease, Dr. Lipkin reasoned, he might be able to find its
genes in an infected brain. He and his colleagues infected rats with the disease and then
extracted genetic material from them. They first identified the pieces of DNA that came
from the rats themselves. After they painstakingly subtracted the host genes, they were left
with a small amount of genetic material present only in the sick rats.
To see if these genes came from the cause of borna disease, Dr. Lipkin transplanted them
into bacteria. The bacteria used them to make proteins. If these were proteins from the
source of borna disease, then infected animals might have made antibodies precisely
tailored to grab onto them. In 1990, Dr. Lipkin and his colleagues reported that when they
mixed borna antibodies with the proteins, they embraced each other tightly. This discovery
allowed Dr. Lipkin and his colleagues to isolate the virus, which came to be known as the
borna virus.
As Dr. Lipkin earned his reputation as a virus hunter, other researchers began to bring
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Dr. W. Ian Lipkin, Virus-Hunting Master - NYTimes.com
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difficult cases to him. In 1999, for example, doctors noticed a cluster of cases of encephalitis
around New York City. They shipped blood from their patients to Dr. Lipkin, who was then
at the University of California, Irvine. Analyzing the genetic material, he and his colleagues
concluded that the encephalitis had been caused by West Nile virus. It was the first time the
virus had been identified in the Western Hemisphere. Since Dr. Lipkin made the discovery,
West Nile virus has spread across the continental United States.
Dr. Lipkin’s success with West Nile virus led to an invitation to come to Columbia in 2002
and set up the Center for Infection and Immunity. He and his colleagues began developing
faster, more sensitive methods to find viruses. At the time, the most sophisticated
technologies for identifying viruses could only compare their genetic material to one known
virus at a time. Dr. Lipkin and his colleagues developed a more powerful system, known as
MassTag PCR.
The researchers prepare a cocktail of genetic material from 20 or more kinds of viruses.
When they mix the DNA from a sample into this cocktail, the viral segments will bind to any
matching DNA. Dr. Lipkin and his colleagues can then fish out these matching segments
and shoot them through a mass spectrometer to determine their mass. From these clues, the
scientists can often determine what kind of virus they’re dealing with.
MassTag PCR is relatively cheap and fast, but it can miss viruses that are scarce or especially
exotic. It failed, for example, to reveal the cause of three puzzling deaths in Australia. In
2006, three women received liver and kidney transplants from the same donor. For a month
after the transplant, they were in good health, but then they all suddenly developed intense
fevers and died. Dr. Lipkin and his colleagues analyzed samples from their bodies, but they
couldn’t find any culprits with MassTag PCR.
At the time, Dr. Lipkin and his colleagues were adapting new genome sequencing machines
to virus hunting. They decided to turn the machines on this mystery.
They gathered 100,000 genetic fragments from the three women and deciphered their
sequences. Most of the sequences belonged to the patients themselves. But 14 out of the
100,000 sequences belonged to a new virus infecting all the women, which has been called
the Dandenong virus after the hospital where the transplants took place.
When Dr. Lipkin started finding viruses, the process was agonizingly slow. It took him three
years to isolate the borna virus. Now it’s possible to identify new viruses in a matter of days.
Dr. Lipkin and his colleagues are now working with the Department of Defense on even
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Dr. W. Ian Lipkin, Virus-Hunting Master - NYTimes.com
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faster methods. In one recent exercise, researchers at the center were shipped two samples
of genetic material. Each was a mixture of host DNA and the genes of a rare, dangerous
virus. The researchers identified both viruses in six hours.
Viruses don’t have to cause such horrific symptoms to have a major effect on people’s
health. A number of studies indicate children are at higher risk of schizophrenia and autism
if their mothers were infected by viruses during their pregnancy.
“We think there may be a huge range of viruses involved,” said Mady Hornig, an
epidemiologist at the Center for Infection and Immunity.
Dr. Hornig, Dr. Lipkin and their colleagues are investigating the ways in which viruses alter
the brains of fetuses. They’ve found that mice suffer similar changes in their behavior if
their mothers are exposed to viral proteins. In a paper published last month in the journal
mBio, the scientists report how these changes happen. In response to the viral protein, the
mouse’s immune system produces molecules that alter certain stem cells in the fetal brain.
“The stem cells are not maturing into neurons,” Dr. Hornig said.
Now the Columbia scientists are exploring whether this same cause and effect is at work in
humans. They are collaborating with researchers in Norway to track the health of more than
100,000 Norwegian children. As some of the children develop autism and other
psychological disorders, the scientists will be able to look at blood samples taken from their
mothers during pregnancy to see if viruses or other factors played a role. “We can go back
and say, ‘What was going on in the first, second, third trimester?’ ” Dr. Lipkin said.
Most babies born to infected women will not suffer any harmful effects from viruses, Dr.
Lipkin said. Exactly why some babies do is the result of a complex interplay of genetic and
environmental influences. Still, Dr. Lipkin thinks it’s wise for pregnant women to take
precautions to avoid viral infections. “Our work suggests it is prudent for pregnant women
to have influenza vaccines,” he said.
Yet Dr. Lipkin does not think that viruses should be blamed for all our ills. In fact, he and
his colleagues spend much of their time engaged in what he calls “de-discovery,” exposing
false links made between viruses and diseases. “It’s important for the credibility of the
field,” he said.
A decade ago, for example, a British physician, Dr. Andrew Wakefield, claimed that vaccines
against measles, mumps and rubella were linked to autism. One possibility he raised was
that the live measles in the vaccines created inflammation in the intestines, allowing toxins
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Dr. W. Ian Lipkin, Virus-Hunting Master - NYTimes.com
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or even viruses to move to the brain. One piece of evidence Dr. Wakefield and his colleagues
offered was the finding that autistic children with intestinal disorders had high levels of
measles viruses in their intestines.
Many researchers have ruled out the vaccine-autism link by looking at the epidemiology of
the disease. Dr. Lipkin decided to test the claim in a different way, by looking for the viruses
themselves. Teaming up with some of Dr. Wakefield’s original collaborators, he found no
difference in the levels of measles viruses in the intestines of autistic and normal children
with gastrointestinal disorders.
Dr. Lipkin is now preparing to dive into a new controversy. In October 2009, a team of
scientists claimed to find a virus known as XMRV in people with chronic fatigue syndrome.
A pitched debate has arisen over the findings. A number of other groups have since failed to
find the same link. To make matters more confusing, a team of researchers from the Food
and Drug Administration, the National Institutes of Health and Harvard Medical School
reported in August that they found related viruses in people with chronic fatigue, but not
XMRV itself. “I think we have to keep an open mind on this,” Dr. Lipkin said.
In September, Dr. Fauci asked Dr. Lipkin to organize a large-scale investigation. Earlier this
month, Dr. Lipkin brought together scientists from three labs that have gotten contradictory
results to begin working together on a new search for the link.
“There isn’t anybody any better at this than Ian Lipkin,” said Dr. Fauci. “If he can’t find it, it
probably doesn’t exist.”
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