Spring 2008
NIAID Discovery News
A Microbe Hunter On Call to the World
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| Ian Lipkin, M.D., right, oversees a laboratory pipetting procedure with colleague Gustavo Palacios, Ph.D., at the Columbia University Mailman School of Public Health. (Credit: Tanya Braganti) |
Ian Lipkin, M.D., finds needles in haystacks throughout the world of infectious diseases. Using precision tools that he and his collaborators continue to develop and perfect, he scouts, tracks, bags, and tags viruses and bacteria.
He is on call on at least five continents.
Dr. Lipkin, a Columbia University professor and research director, is among the notable infectious diseases investigators in a remarkable generation of discovery. In 1999, he led the study that identified West Nile virus as the cause of an encephalitis outbreak in New York, and in 2003 he developed a rapid diagnostic test for severe acute respiratory syndrome (SARS) and took 10,000 of the kits with him as an invited adviser to the Chinese government.
Last year, Dr. Lipkin identified a new virus that killed three organ transplant recipients in Australia, determined its source, and resolved a worrisome medical mystery.
“He is a modern microbe hunter,” says colleague Larry Sturman, M.D., Ph.D., director of the Wadsworth Center of the New York State Department of Health. “He is someone who is interested in discovering the causes of global diseases, and he has collaborations all over the world.”
New Tools ID Microbes Faster
Scientists have identified about 100 new infectious diseases since 1990, according to a recent study published in Nature. To do so they have frequently used cutting-edge technological advances in areas such as genomics and proteomics. The advances have been spurred along by fresh approaches from people such as Dr. Lipkin.
“He is extremely creative,” says Anthony S. Fauci, M.D., director of NIAID, which funds some of his work. Dr. Lipkin has been involved with NIAID’s Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases for the past six years. “Not only has he pioneered high-throughput technology, he also has discovered numerous new microbes, and trains others to do the same.”
High-throughput technology enables scientists to perform hundreds or thousands of tests involving genes or proteins and receive results in a matter of minutes, hours, or days – rather than weeks, months, or years through other methods.
At Columbia, where he is John Snow Professor of Epidemiology and director of the Center for Infection and Immunity in the Mailman School of Public Health, virtually every colleague that Dr. Lipkin encounters is interested in sharing a portion of their work in order to tap into his.
For example, his work with SARS resulted in a grant that has enabled him to bring about 30 people from throughout the world to Columbia for training. “They often arrive with materials from their home institutions, we work them up, and write papers,” Dr. Lipkin says. “This is how we have discovered 30 new agents in the past year alone. We can’t write them up fast enough. It’s a staggeringly productive series of collaborations.”
And at every turn, Dr. Lipkin is thinking how to apply those technologies throughout the world, in laboratories and in the field.
“Our objective is to teach people to fish instead of fishing for them,” he says, adding that his group at Columbia has established a network of more than 10 sites across the world where researchers regularly share ideas and results – in China, Africa, Australia, South America, and North America.
Right Places, Right Times
Dr. Lipkin’s first big career break came in 1981 when he started work at the University of California, San Francisco (UCSF). He recalls early employment experiences that taught him various professional skills – and introduced him to three Nobel Prize winners.
While listening to a talk on kuru by 1976 Nobel winner Carleton Gajdusek, M.D., Dr. Lipkin says he “became very much intrigued with the notion that we needed to develop better ways of disease discovery and diagnosis.”
At the time he was completing his medical residency in neurology at UCSF, Stan Prusiner, M.D., was defining prions, the novel agent thought to be responsible for kuru and other spongiform encephalopathies, and HIV was just starting to emerge. While working in a San Francisco clinic, Dr. Lipkin saw the effects of HIV firsthand.
“I was fascinated by the concept that an infectious disease could have such a profound effect on the central nervous system,” says Dr. Lipkin. This was his second key moment of recognizing the mission of global public health – something very important to him. Dr. Lipkin’s first glimpse came during medical school while working at an Indian Health Service clinic in Oklahoma. “That is where I was introduced to how health disparities can affect infectious diseases,” Dr. Lipkin recalls.
He left UCSF in 1984 for The Scripps Research Institute and a neurovirology fellowship under the guidance of Michael Oldstone, M.D. Dr. Oldstone recently recalled that his bright new fellow had no experience in a research laboratory when he arrived. “Enormous energy, intelligent, and a charm about him,” says Dr. Oldstone. “But up to that time his work was primarily all clinical.”
Dr. Oldstone and his colleagues taught Dr. Lipkin techniques in viral immunobiology. “He became very proficient,” says Dr. Oldstone, and those techniques became the basis for Dr. Lipkin’s first unique scientific discovery.
The Borna Identity
In 1985 Dr. Lipkin recalls reading a study in Science about an unknown agent that caused encephalitis in horses but was linked to bipolar disorder and depression in humans. He dug in and spent the next few years exploring that connection on his own time, aside from his responsibilities with Dr. Oldstone.
In 1989 he identified the agent, Borna virus, by a labor-intensive method known as subtractive cDNA cloning. This was the first time purely molecular methods had been used to identify an infectious agent.
The study, he says, was the precursor to his current research, though what took three years then would probably take one week today, he estimates.
The Borna studies opened another door for Dr. Lipkin – the research caught the attention of Joshua Lederberg, Ph.D., who shared a Nobel Prize in 1958 and became a mentor and friend. Dr. Lipkin delivered a eulogy at Dr. Lederberg’s funeral in February 2008.
In 1991 Dr. Lederberg helped Dr. Lipkin earn a Pew Scholar award, which provided him four years of unrestricted research funding, a huge coup for a young scientist.
The funding allowed Dr. Lipkin to expand his Borna virus studies in a new setting, the University of California, Irvine. Also while at Irvine, Dr. Lipkin took notice of the 70 percent undiagnosed case rate in encephalitis studies.
To help improve diagnostic testing for encephalitis, Dr. Lipkin decided to compare the many viruses that caused encephalitis. His work merged two different types of polymerase chain reaction (PCR), taking DNA replication technology that was still new and adapting it for novel uses. “It was tedious,” he says, “but it allowed you to do things not possible with traditional PCR.”
It also established his expertise with undiagnosed encephalitis cases.
West Nile Virus and SARS
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| Dr. Lipkin, center, at the Chinese Academy of Military Medicine during the 2003 SARS outbreak. To the left is molecular biologist Ruifu Tang; at the far left is Chen Zhu, current Chinese Minister of Health. On the right is an interpreter. (Credit: Ian Lipkin) |
In 1999, a new infectious disease in New York, which looked similar to St. Louis encephalitis, had physicians and scientists stymied. Experts arranged an encephalitis conference, which Dr. Lipkin attended. The more he heard about the mystery in New York, the more he wanted to be in the hunt. A colleague helped secure an invitation from the state of New York to collaborate on a study, and soon Dr. Lipkin was back in California using his PCR technique to test patient samples sent from the Wadsworth Center. “The ability to work with human tissue has always been a focus of ours,” says Dr. Lipkin. “It is a more direct approach with purer results.”
Within 48 hours he said he knew the cause was not St. Louis encephalitis virus. As 1999 closed, Dr. Lipkin published two papers on the New York studies, both progressively narrowing the diagnosis to West Nile virus – the first cases identified in the United States.
That discovery prompted Columbia to recruit Dr. Lipkin in 2002 to start its public health program on global emerging infectious diseases.
Today, Dr. Lipkin says he feels like a fortunate conductor leading a symphony orchestra of about 35 scientists. He seldom does bench work in the lab anymore – that’s for today’s young, energetic soloists that he mentors. Columbia also has provided him with several additional research paths, including an intriguing birth cohort study in Norway and collaborations in China. The birth cohort study is tracking health information on some 100,000 children and their parents, hoping to retrospectively identify new factors that trigger illnesses.
The relationship with China began shortly after Dr. Lipkin arrived at Columbia when SARS emerged. The Chinese government sought Dr. Lipkin for assistance after hearing about his work from two Chinese students at Columbia. He immediately boarded a plane for Beijing and developed a presentation while en route. “It was politically sensitive and scientifically important,” he says, recalling awkward, televised meetings where Chinese military leaders were expecting results.
“I was being asked to illustrate the power of science, that it could restore safety to the general population. It was humbling.”
Unwinding…Sort of
The Wadsworth Center’s Dr. Sturman fondly describes the entertainer side of Dr. Lipkin while sharing memories from a New Year’s Day celebration at the Lipkin residence in Manhattan. “He is a family man who seems to enjoy hosting guests,” says Dr. Sturman. “And that day we really saw him in action – he was managing everything: the kitchen, the food, the wine, and the guests.”
Apparently – in the kitchen or in the lab – the high energy and enthusiasm that Dr. Oldstone and many other colleagues have described still drive Dr. Lipkin.
“The speed with which he does research is truly remarkable,” says Dr. Sturman. “He and his laptop cannot be separated. He is always working, writing something, or rearranging slides for his talks.”
Dr. Lipkin says it is not feasible for him to take a real vacation, so he doesn’t. He has a cabin on a nearby lake where he goes as often as possible “to get my brain back in shape” while hiking or kayaking. He also enjoys museums: “Even an hour or two at the Met or Modern is restorative,” he says, referring to the Metropolitan Museum of Art and the Museum of Modern Art.
But even during relaxed conversation his mind is at work trying to make relevant connections to work. While discussing the future of his diagnostic testing, Dr. Lipkin suddenly moves the conversation back to 1983 and his work in San Francisco.
He talks about two HIV patients he examined, each with an inflamed nervous system, and how he successfully treated them and ultimately identified AIDS-associated inflammatory neuropathy.
How is that relevant to his current and future work? Dr. Lipkin mentions Austin, Minn. That is where, according to news reports from earlier this year, about a dozen employees in a pig slaughterhouse were sickened by a mystery illness. Inhaling airborne particles of pig brain is a possible cause, and the patient symptoms are similar enough to those of Dr. Lipkin’s 1983 patients to have caught his attention.
“Most commonly we think about infectious diseases as being acute,” says Dr. Lipkin. “Everyone understands pneumonia, diarrhea, and skin infections. But this is just the tip of the iceberg.” Infections, he says, can cause a whole range of diseases through induction of abnormal cell growth, autoimmunity, immunosuppression, or interference with normal development. “The same agent may have different effects in different individuals,” Dr. Lipkin says.
Sometimes an infectious agent may be gone by the time symptoms develop, he says, adding that some studies suggest that some forms of mental illness may be related to exposures in the womb. “We are coming to view some infectious diseases as an unfortunate intersection of genes, environment, and timing,” says Dr. Lipkin.
Then he describes his “tree of life” approach to understanding disease. Using the various techniques he has helped develop, and including factors like climate change, vector distribution, and population trends, Dr. Lipkin hopes to at least offer “an infectious hypothesis” for any ailment. The low-hanging fruit, he says, are things like encephalitis and diarrhea where an infectious agent is expected with the disease. Higher up the tree are, for example, things like cancer.
“Imagine if we had had these tools in the 1970s,” he says. “We might have been able to predict something like HIV.”
—Ken Pekoc
References
A New Arenavirus in a Cluster of Fatal Transplant-Associated Diseases (Non-government, PDF)
T Briese et al. Identification of a Kunjin/West Nile-like flavivirus in brains of patients with New York encephalitis. The Lancet 354 (9186): 1262-62 (1999).
X-Y Jia et al. Genetic analysis of West Nile New York 1999 encephalitis virus. The Lancet 354 (9194): 1971-72 (1999).
China Science and Technology Newsletter 333, June 10, 2003. (Non-government)
T Briese et al. Genomic organization of Borna disease virus. Proceedings of the National Academy of Sciences 91(10): 4362-66 (1994).
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