The “Virus Hunter” Who Advanced Public Health, One Tool at a Time

Ian Lipkin, an experimental pathologist at Columbia University, is today most famous for discovering more than 2,000 viruses, which earned him the moniker “virus hunter,” over a decades-long career in pathogen discovery. However, Lipkin's original trajectory was on a path of anthropology and theater. “I never had any anticipation and never any plan to go into medicine, let alone to go into science. It’s just something that crept up on me,” he said. A chance intro to organic chemistry—what he thought would be his first and last basic science course—steered him onto a course in public health and research.

The Extremes of Medicine: From AIDS to a Neurology Niche

After graduating college, Lipkin started a primary care program to complete medical training at Rush University, which exposed him to the extremes of medicine and public health. At the Institute of Neurology, he saw the use of the first computed tomography instruments and plasmapheresis used as a therapy for neuroimmune disease. He also practiced in resource-limited settings while working at a clinic at the Indian Health Service, and later worked with veterans at a rural clinic in Boise, Idaho, as part of a residency position in internal medicine at the University of Washington.

These eye-opening experiences were instrumental in Lipkin setting out to combine anthropology and medicine to improve understanding about working in resource-constrained areas of the world. However, since his background at the time was in primary care, he couldn’t find a landing place for his idea, so he started another residency position in neurology at the University of California, San Francisco (UCSF) in 1981.

“I drove in with my moving van on Gay Pride Day,” he recalled. “It was an amazing thing at that point, because there was this extraordinary sense of freedom and opportunity for people who came from all over the world, who were suddenly able to express who they were.”

“Sadly, within a couple of months of arriving in San Francisco, we started seeing the first cases of AIDS,” he said. Today, AIDS is known to be caused by HIV, but in 1981, doctors couldn’t explain what was causing the rare cancers and opportunistic infections that they began seeing in patients. Many of the people initially affected were from the gay community, and stigma surrounding the conditions delayed progress on identifying the causative agent and potential therapies.

Determined to help, Lipkin worked throughout the epidemic, studying how the immune response suppressed T cell proliferation.¹ He observed neuropathies appearing in some AIDS patients, and, reflecting on his experience in London, he tried plasmapheresis as a treatment, which improved one patient’s symptoms.² This therapy was later recommended for the treatment of HIV-induced neuropathies because it alleviated symptoms without worsening T cell responses.^3,4

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From Finding the Root of Neurological Disorders to Identifying Viral Culprits

While at UCSF, Lipkin was invited to attend a course on neurobiology of human diseases at Cold Spring Harbor Laboratory. At the time, researchers in the field were tracking down the infectious culprit that caused the disorders like Creutzfeldt-Jakob disease (CJD) and other neurological conditions associated with encephalopathy and amyloid plaques in the brain.⁵ CJD and other similar disorders would later be identified as caused by prions.

“I got really excited about this,” Lipkin recalled. “I said, ‘Wow, this is the kind of thing I want to do.’” He looked for a lab where he could learn basic science and bench skills.

“I found one person who thought I was somebody else,” Lipkin said. When he called the office of Michael Oldstone, a virologist at the Research Institute of Scripps (today Scripps Research), the secretary misheard his name as “Howard Lipton,” whom Oldstone knew, and transferred the call. The happy mishap led to Lipkin joining the lab.

If there is one thing that I learned from him, [it] is to have big dreams and try to solve important problems.

—Gustavo Palacios, Icahn School of Medicine at Mount Sinai

In Oldstone’s group, Lipkin’s interest in infectious origins of neuropathies and neurological damage drove him to study Borna disease, which causes central nervous system damage in animals and was suspected to cause bipolar disorder in humans. Lipkin showed that Borna disease altered neurotransmitter activity in rats.⁶ Then, he used subtractive cloning, a method that involves comparing gene expression between cell populations to identify unique transcripts, to demonstrate that the responsible agent was a virus.⁷ It was the first use of purely genetic methods to identify an infectious disease. Lipkin continued his work on Bornavirus when he moved to the University of California, Irvine in 1990 after receiving a grant from The Pew Charitable Trusts.

“He’s a very brilliant scientist,” said Avindra Nath, today a neurologist at the National Institute of Neurological Disorders and Stroke, adding, “He is a force of nature.” In the early 2000s, Nath studied how HIV led to neurological disorders at Johns Hopkins University. He met Lipkin through the latter’s Bornavirus work because of their overlapping interest in infection-driven neuropathies. “Nothing drives [Lipkin] better than a scientific question,” Nath said.

In 1999, multiple people in a New York neighborhood died after experiencing encephalitis, prompting an investigation. Given his expertise, Lipkin got involved on the project to uncover the virus behind the series of unexplained deaths. “People said it was St. Louis Encephalitis Virus, but no one had been able to find the virus or culture the virus,” Lipkin said. Using subtractive cloning, Lipkin identified West Nile Virus from the brain samples.^8,9 “That really completely changed the course, as the previous discovery had [done], of my life,” he said.

Developing New Technologies to Find SARS and Identify Mystery Diseases

In 2001, Lipkin started his lab at Columbia University to continue his pathogen discovery work. Two years later, China faced an outbreak of severe acute respiratory syndrome (SARS). Given Lipkin’s expertise in pathogen discovery, Chen Zhou, then the vice president of the Chinese Academy of Science, and Xu Guanhua, the minister of the Ministry of Science and Technology, invited him to the country to help them tackle the issue.

Lipkin developed a real-time PCR test to detect the virus in multiple biological samples.¹⁰ When he flew to China, he brought 10,000 test kits along with his own personal protection equipment. Lipkin helped develop containment and contact-tracing strategies to help mitigate the spread of the virus.

“[Lipkin] liked the challenges of solving things that are important,” said Gustavo Palacios, today a virologist at the Icahn School of Medicine at Mount Sinai who at the time was a postdoctoral researcher in Lipkin’s group. For example, he explained that, in the early 2000s, there were not good diagnostics for surveying multiple pathogens in a sample. “We were only looking for the more prevalent ones,” Palacios said, adding that this approach likely missed identifying many pathogens, even the known ones.

This led to Lipkin’s group advancing multiplex PCR by developing MassTag PCR, in which molecular tags with different molecular weights were added to genes as primers for PCR.¹¹ After amplification, the tags were removed and studied by mass spectrometry to determine the microbial species present. This technique helped them identify rhinovirus type C, a previously unknown subtype of the common cold that was causing disease in New York in 2004.¹² Subsequently, the group used microarrays to further improve disease identification.¹³ “He is a machine of pushing multiple approaches at the same time,” Palacios said.

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Palacios added that Lipkin was always ready to embrace new methods. In 2007, three people in Australia received organs from a deceased donor. Four to six weeks later, all died after experiencing similar illnesses with fever and encephalopathy. When initial tests didn’t reveal a diagnosis, Lipkin’s group was recruited to figure out the culprit.

Palacios, who was processing the samples, tried the MassTag PCR and microarray assays, but realized that whatever the pathogen was, it was too distinct from their probes to be detected. Palacios suspected that high-throughput sequencing could provide answers. Through Lipkin’s industry contacts, the team was able to submit a sample.

Since they didn’t have a bioinformatics core facility at the time, Palacios recalled waiting all night to receive the sequencing reads. “I remember that I was so excited that I was manually getting those reads, and then BLASTing them to try to figure out, one by one, what they were,” he said. The longshot paid off, and the team identified a novel Arenavirus using next-generation sequencing for the first time in pathogen detection.¹⁴

“It basically snowballed from there,” Lipkin said. “We were just able to do more and more of this sort of sequencing.” People began submitting samples for sequencing from all over the world. Lipkin and his team identified a novel virus causing disease in South Africa, discovered a new virus in bats in Bangladesh that was similar to human-infecting species and a SARS-like coronavirus in bats in Nigeria, and found a novel reovirus that was infecting salmon in Norway and the United Kingdom.^15-18

Digging into the Causes of Autism and Chronic Fatigue

Alongside his pathogen discovery work at the turn of the 21^st century, Lipkin became interested in gene-environment-timing interactions influencing autism spectrum disorder (ASD), in part because a relative had the condition. When he moved to Columbia University he was introduced to Camilla Stoltenberg, an epidemiologist at the Norwegian Institute of Public Health. She described a newly organized study, the Norwegian Mother and Child Cohort, that could provide a source of unbiased samples to explore ASD risks.

Lipkin jumped at the opportunity to explore environmental interactions associated with autism. This led to the creation of the Autism Birth Cohort. While the study is ongoing, data has pointed to a strong relationship between fever during pregnancy and autism risk.¹⁹

If there is one thing that I learned from him, [it] is to have big dreams and try to solve important problems.

—Gustavo Palacios, Icahn School of Medicine at Mount Sinai

At the same time, Lipkin began applying the techniques he developed studying Bornavirus to cases of undiagnosed encephalitis and central nervous system infections.^20,21 This led him to the field of the poorly understood condition of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

Nath, who was also studying these disorders, explained that one of the difficult elements of studying ME/CFS and unexplained encephalitis has been that the symptoms are subjective and, until recently, many doctors dismissed these patients or attributed the symptoms to psychological causes. “Nobody knows what’s wrong with [these patients],” he said. “[Doctors] keep treating them with all kinds of things, and sometimes they get better, and oftentimes, they don’t. They even get worse.”

Nath and Lipkin began their ME/CFS studies independently with their own cohorts, but shared samples and advice with one another. “What is remarkable about it is that I think both of us, independently, came to the same conclusion,” Nath said. “There is a unique immune dysfunction in these patients, and it could very well be driven by the infectious process that they never got rid of completely.”

Lipkin described the challenge in advancing the understanding of these disorders. “You not only need to be able to detect the agents itself, but you need to be able to detect footprints, and those footprints are immune responses.” His group identified that patients with ME/CFS display sustained levels of cytokines, often following an infection, and provided evidence that these patients may also have dysfunctional peroxisomes.^22,23

In 2015, Lipkin developed a new sequencing-based platform to improve viral detection using probes against human-infecting virus sequences, called VirCapSeq.²⁴ A few years later, the team developed a second platform to identify bacterial pathogens, BacCapSeq, and detect the presence of antimicrobial resistance genes.²⁵ His group is currently exploring applying these technologies to screen for infectious agents that could be responsible for triggering these neurological conditions.

In a similar vein of research, Lipkin has been working with patients experiencing Gulf War Illness. Although distinct from ME/CFS, Lipkin explained that there are similarities in these two poorly understood disorders.

Sharing Science with Students and the Public Alike

Reflecting on the many groups and unique cultures he has interacted with, Lipkin said, “I have the ability, I think as a result of the early training, to communicate with people who don’t have necessarily the same cultural background that I do.”

Palacios emphasized Lipkin’s role as a mentor in his life. “If there is one thing that I learned from him, [it] is to have big dreams and try to solve important problems,” he said. As a non-native English speaker, Palacios recalled how appreciative he was when Lipkin went through edits together on their manuscript. “He wants the prose to be well-written, and he loves to teach you [how] to do that, which was phenomenal for me.”

Nath also lauded Lipkin’s incredible interpersonal skills and noted that he is adept at bringing people together to tackle problems. According to Nath, Lipkin creates a welcoming atmosphere where discussion and scientific brainstorming thrives, even opening his home to colleagues. “That personal touch makes a huge difference because you can open up,” Nath said. “You can get to know a person personally.”

In 2010, Lipkin was thrilled when Scott Burns approached him to advise on a movie about a virus that causes a pandemic. “All of these things began to come back, sort of full circle: filmmaking, theater, anthropology, clinical medicine,” Lipkin said.

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A decade later, when the COVID-19 pandemic hit, these actors whom he met and helped train to act like scientists returned the favor and helped him create videos to communicate safety measures and encourage people to get vaccinated. He drew on his medical and cultural anthropology background again to develop safety protocols for movie producers, the Democratic National Convention, and even Amazon warehouses.

“[Lipkin] loves beauty,” Palacios said about what he considers integral to Lipkin’s scientific approach. “He loves simplicity. He loves these arts. He is a renaissance man, if you want. That’s why he’s so prolific in so many different aspects.”

From Identifying Problems to Addressing Outstanding Public Health Issues

Reflecting on his education and career journey, Lipkin described his many experiences in medicine and public health as a crucible. “All of these influences outlining, or defining I should say, vulnerabilities that we have in medicine and public health drove me in different directions.”

“What I’ve done the first 40 years or so of my career has really been trying to find ways in which you can define a problem and identify whatever it is it needs to be rectified,” said Lipkin. “I would like to spend the years that I have remaining in finding ways to help address them,” he added.

Currently, his group is trying to turn his pathogen sequencing technologies into fully-automated, user-friendly tools for laboratories, clinics, and hospitals. “The idea is that we want to take these things, integrate them in one simple system,” he said.

His goal is to be able to package this complete diagnostic tool to facilitate disease identification around the world. In the meantime, Lipkin, as the director for the Global Alliance for Preventing Pandemics, is helping improve infrastructure for disease discovery, diagnosis, and response in low-resource settings. “We’re training people now from something like 30 different countries in how to do what we do,” he said.

Another arena he has become interested in is in communicating the importance of science, from advocating for vaccination to research funding. He said this is especially important for basic science research, where the benefit is not immediately obvious to the general public. “One of the failings I think of US science, science probably elsewhere too, is that [scientists] tend to be cloistered. They have their own balloon. They only talk to other scientists, which means that it’s very difficult for us to find support right now,” Lipkin said, referring to recent funding freezes and terminations in the research sector.

While concerned about the fate of his own work, Lipkin is especially worried about the scientific pipeline affecting young researchers. “They’re going to lose hope,” he said. Lipkin explained that rallying people outside of science, including people impacted by the diseases that he and others study to encourage, to call on their representatives to support science is imperative. “If we don’t get that support,” he said, “everything is going to come to a halt.”