Article 6: David Ho

Overcoming translational science barriers:

“Don’t accept dogma, dogma are not necessarily the truth. . .  Learn to challenge dogma. I'm of Chinese heritage. In that culture, one doesn't challenge authority very often. While that may be good in controlling a pandemic when you want obedience, it's not a great science practice.”  - Dr. David Ho

Narratives of Discovery

 - All non-referenced quotes are the words of Dr. Ho

Discovery scientists achieve not only translational accomplishments but transformative ones. They shift the paradigms of what philosopher of science Thomas Kuhn called normal science toward new ones. To get there, they invariably have to overcome barriers that would have stopped less gifted investigators. Sociologist Max Weber’s enduring (though unfortunately gendered) 1919 essay “Science as a vocation” proposed that the scientist is the one who “has achieved something that will endure,” who has had “this strange intoxication [of] the ‘personal experience’ of science. . . [W]ithout this, you have no calling for science and you should do something else. For nothing is worthy of man as man unless he can pursue it with passionate devotion.”[1]

Virologist David Ho has made seminal contributions to the bioscientific and clinical knowledge of the HIV/AIDS and SARS-CoV-2 viruses, discovering effective means to treat and prevent the infections they cause. Like a spiraling hawk, he has achieved the altitude necessary to take in both the substance and the meanings of these two deadly scourges of our age. Committed to HIV research since caring for doomed patients with AIDS during the 1980s as a medical resident at UCLA and infectious disease fellow at MGH, he was named Founding Director of the Aaron Diamond AIDS Research Center (ADARC) in 1989. He generated a cascade of milestone discoveries regarding HIV viral load, protease inhibitors, and the effectiveness of triple therapy that converted AIDS from a death sentence into a manageable chronic illness. His team reveals that they are now working on a cure.

The next stage of Dr. Ho’s and his Center’s path begins on December 12, 2019, when a cluster of persons in Wuhan, China experience severe shortness of breath and fever. By January 7, Chinese health officials report the genetic sequence of a novel coronavirus and identify it as the causative agent of the Wuhan outbreak. Person-to-person spread is quickly documented. Both WHO and CDC inaugurate high-level institutional responses. The first US case is reported in Washington State on January 20, 2020. Through February, the White House Novel Coronavirus Task Force initiates travel restrictions, testing for the virus, and warns that “disruptions to everyday life may be severe.” The virus is officially named SARS-CoV-2 on February 11, 2020.[2]

The Aaron Diamond Center relocated to Columbia University’s Northern Manhattan health sciences campus in January 2020. By February 2020, the Center incorporated research in SARS CoV-2 and potential future pandemics into its mission. Dr. Ho described the moment:

“It was a dramatic decision for us. It was clear to me and my colleagues that when Wuhan locked down, it had to be a major problem that we're confronting. . .It was only a matter of time when the outbreak would catch up to the rest of the world. We also knew that there were very few virologists compared to the number of people working on HIV or flu. Today, if you look at who’s doing SARS-2 work, it’s HIV virologists and flu virologists.”

In effect, Dr. Ho realized that the depth of the Center’s virological research expertise conferred on it a scientific and even civic or ethical obligation to contribute to SARS-2 research.

On March 11, 2020, WHO declares COVID-19 a pandemic. By mid-March, New York hospitals are inundated with COVID patients. They cancel elective surgery, transform operating rooms into intensive care units, and set up in-patient beds in hospital lobbies. Personal protective equipment is rationed. Physicians are repurposed out of their fields to work in the ICUs. Visitors are banned from hospitals, and patients die alone—some while sitting in chairs in the Emergency Rooms waiting for attention. Doctors hold smart phones in front of dying patients for families’ final good-byes. Morgues cannot handle the corpses that pile up in refrigerated trucks outside of hospitals. Schools close, mask mandates are enforced, businesses shutter. Stores run out of food, water, and toilet paper. Customers are urged to swab down every purchase with Clorox. At 7 pm every evening, windows open to the clamor of spoons banging on pots and pans as ordinary people, locked down, give thanks to the essential workers, including health care professionals, who risk their lives to keep theirs going.

This was the tortured setting in which ADARC faculty and staff began to generate original and defining research in basic science, pre-clinical and clinical research, implementation, and public health dimensions of the new virus. Composed of virologists, cellular physicists, biochemists, cell biologists, immunologists, epidemiologists, and public health professionals (including fluency in at least nine European and Asian languages), the Center’s full-time faculty collaborate with investigators in the US and worldwide.

Dr. Ho gives a sense of the pace this work had reached by late 2020:

“When the alpha and beta variants emerged from the UK and South Africa . . . a group of close to 10 people worked nonstop from mid-December 2020 to mid-January, and in the course of four weeks, we put out characterization of those two variants result[ing] in a Nature paper.[3] The report of detection of Omicron was made here in the US on the day before Thanksgiving, and my group characterized it over the ensuing two weeks. We submitted that paper two days after we finished the work.”[4]

The work of the Center paralleled the work of the pandemic itself. It did not respect ordinary boundaries of time or space. Risk was calculated and matched against necessity. A Biosafety Level 3 (BSL3) was constructed in the Center’s new space at Columbia to protect staff from serious or lethal disease from inhaled material. The work closely followed—and increasingly predicted—the actions of the virus, combining and interweaving research activities from all five translation science spectra. Early, members of the team collaborated with cardiologists, pulmonologists, dermatologists, and endocrinologists to catalogue the extra-pulmonary manifestations of this novel disease.[5] To discover mechanisms of multi-organ involvement, they constructed experimental platforms of human pluripotent stem cells and organoids to study SARS-2 tropism in human tissues and to hypothesize pathophysiological  mechanisms.[6] They used the same organoids to test for SARS-2 antibody affinity in tissues and to identify virus inhibitors with high-throughput screening of drugs.[7]

Concurrently, they harvested potent SARS-2-neutralizing antibodies from pooled sera from hospitalized patients with COVID-19. Epitope-mapping allowed the team to identify viral regions of high immunogenicity as a guide to developing potential therapeutic interventions.[8] Simultaneously, they documented antibody and vaccine resistance of emerging variants,  dimming the hopes that vaccine power would match the mutational powers of the virus.3 Public health applications have emerged from the Center’s collaboration with the National Basketball Association that generates data on day-to-day viral load and infectivity among healthy adults.[9]

ADARC researchers hope that the conserved domains they identified on the virus will be sites for development of effective vaccines and antibodies. Societally, they have to hope in the increasing vaccination and boosting to halt infection and reinfection. But the chronic alarm sounded in the ADARC’s December 2021 Nature paper rings still in the air:

"It is not too far-fetched to think that this SARS-CoV-2 is now only a mutation or two away from being pan-resistant to current antibodies, either monoclonal or polyclonal. We must devise strategies that anticipate the evolutional direction of the virus and develop agents that target better conserved viral elements." [4]

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Achieving translational research accomplishments

The global urgency of the race to understand and control SARS-CoV-2 generated new forms of science-making in the lab that broke the molds of Kuhn’s normal science, both in its social practices and in its existential comprehension of its mission. These new forms may outlive this particular pandemic.

The development of tools: In looking back over his work in the 1990s on viral load in AIDS, David seemed almost stunned to remember how paltry his tools were: “Back then we didn't have the PCR technique. And so we used traditional virologic methods to quantify virus by limiting dilution of plasma.” Can contemporary investigators imagine life without all the genomic, imaging, calculating, and in silico tools that power bioscience investigation today?

In 1926, Einstein said to Heisenberg that “It’s the theory which determines what we observe,” leading Heisenberg in 1927 to publish his uncertainty principles.[10] As we know, tools fundamentally drive a laboratory’s powers of discovery, shaping or deforming the fundamental intellectual work we do. Today’s response to Einstein might be, “It’s the tools which determine what questions we ask,” with implications regarding what questions are not asked and where and by whom science can be done in today’s socio-economic realities.  

Undeniably, such contemporary tools as ADARC’s human stem cell and organoid platforms, cryo-EM, and big-data-science’s AI algorithms have made possible the speed and  precision of SARS-2 research. Consequential findings have also emerged from social/population sciences and qualitative research tools that document lived experiences of infected patients and distribution of disease according to class, race, and culture.[11]

The transformation of the team: David recognizes that "the pandemic has been one of our most productive periods of research. It's a record in terms of number of papers and prominent papers. It was born out of necessity [as] we not only could see but we could feel the impact of the pandemic. We live it along with everybody else. I need to give credit to my colleagues. My team largely moved into the [Columbia] dorm. . . . The hospital provided the meals to them. They worked anywhere between 12 and 16 hours a day. From February of 2020 through much of that year . . . they saw their families only occasionally." [I, 15:48]  

One of David’s former graduate student and post doc and now Associate Professor of Medical Sciences at Columbia Yaoxing Huang remembers, “As I look back,  I always think that in response to the pandemic, it’s a passion. . . I feel like the passion is required but not sufficient. You need to be able to carry out the work. . . Readiness is the other critical component.” When I asked Dr. Huang where his own passion came from, he says, “Dr. Ho stayed with the lab the whole time. On the weekend he’s at the same post. I was inspired by the boss.”

Sho Iketani, a PhD candidate in ADARC for 18 months, describes how David "gauged the lab asking if we wanted to get involved [in SARS-CoV-2 research]. . . It takes a team to make things happen. . .  You know the value of having people that are able to believe in the vison that you’re giving them. . . You see that kind of leadership, and hopefully I’ll be able to convey that in the future as well.”

Iketani added that, beyond the conduct of this particular lab, pandemic-inspired science may be fundamentally shifting practices of the science culture altogether. Resource and reagent sharing has become widespread. Preprints have become a common form of knowledge/data sharing. Different labs help to confirm one another’s findings. Papers can have up six or more first authors and multiple senior authors, thereby shifting possessiveness of credit for team members. These may be signs that collaborative trust builds not only among members of one lab but may gradually characterize science more widely. Such changes would require accommodations in the organization of science", Iketani noted "in funding formulae, in recognition of credit of authorship, in levels of competition among labs working in similar areas and could irreversibly alter the climate and rewards of the science itself.

Overcoming translational science barriers.

David’s reflections illuminate potential barriers to progress in translational science—the grip of dogma and the challenge of living up to science’s ethical mission:

The grip of dogma: In the early days of HIV/AIDS research, David suffered persistent criticism from colleagues and superiors when he challenged the extant dogma that HIV/AIDS was either an indolent infection or not an infectious disease at all. He had an instinct that there was far more virus present in patients with AIDS than was contemporarily thought:

"Fundamentally it was perhaps an instinct on my part that maybe the old notion was not correct. We had a suspicion in the late eighties that led to the study that indicated that there is a lot more virus than the field believed, and then as technology got better, we did better studies to understand the dynamics."[12]

Skepticism protects against blindness:

"I have since taught my students and postdocs, don’t accept dogma, dogma are not necessarily the truth. . . Learn to challenge dogma. I'm of Chinese heritage. In that culture, one doesn't challenge authority very often. While that may be good in controlling a pandemic when you want obedience, it's not a great science practice".  

David’s personal experience suggests that translational science may have an obligation to promote this skepticism and instinct in trainees and colleagues in a climate that may not always reward independent thinking and creativity in science.

The ethical mission of science

David recognizes his unique high-altitude perspective on these two scourges:

"The question is, you know, how far up do we have to go to get the full picture? I suspect we still have long ways to go. How does Omicron evade antibodies? What makes it so contagious? By climbing high enough, we are, I think asking, at least in my view, the big questions in the field. We think we have learned a lot, and we're now learning about what we don't know, and therefore posing questions for the next set of work."

Posing questions is what David does. When he received the Time Magazine Man of the Year Award for his break-through work in HIV/AIDS in 1996, science journalist Christine Gorman wrote, “During the past 15 years, he has demonstrated an uncanny ability to ask questions that seem obvious only in retrospect and to probe key issues others have overlooked.”[13] Philosophers of science following Alfred North Whitehead and Susanne Langer have insisted that formulating the question is the important stage of cognitive thought and that producing the answer is mere technique.[14] It may be the case that the scientist’s work of art is not the conclusion but the hypothesis.

David’s questions have yielded surprising dividends:

"We have never witnessed viral evolution in this manner—so close up. One variant after another, and how the human antibody responses change and try to catch up. . . It's giving us a picture of what may have transpired decades or centuries ago with other viruses. . . We didn't have the tools to know that [then, but] we can infer from the present situation back . . . And we don't know what will happen, but it's also teaching us about what we might anticipate going forward."

What, though, is the human race being asked to bear? David’s position as a major theorist of two global pandemics and as an immigrant scientist in the United States himself endows him with a second-sight regarding the global implications of his scientific work. He said in an interview with film-maker/journalist Bill Moyers in 1993 that “I always thought of myself as an immigrant, a foreigner to some extent. . . An Asian face is automatically non-American, [but] we are Americans; we’re just of a different heritage.”[15] His having grappled with the question of his own nationality might power his capacity to embrace the global mission of his work:

"We are not just scientists, we're human beings as well. In the first pandemic I dealt with, we witnessed so much inequity. The drugs that we helped develop in 1996 that transformed the disease were not available to Sub-Saharan Africa for many years later. It took Gates and WHO and many other organizations to come together to deliver the lifesaving medications to the African population. It took, you know, 15 years to do that."

The same is true now of SARS-2, complicated by the same social factors of prejudice and fear that slowed our progress in HIV/AIDS:

"I think we're seeing that once again with SARS-2. Even though there are large numbers of anti-vaxxers here and in Europe, at least two-third to three-quarters of the population has been vaccinated. But in some African countries, less than 5% are."

If only, he thinks, scientists were seen as credible and in service to the population. "We deal with issues as scientists who are trying to speak the truth. I think there's a pandemic of misinformation that is spreading equally fast. It's such a tragedy that the misinformation allows so many people to hang on to false beliefs [that] result in severe harm. As scientists, we're obligated to speak up, but it seems that our voices are sometimes overshadowed by those who espouse falsehoods."

I asked David—in his stature not as a virologist but as an eminent scientist—about the global scope of what science is learning about pandemics:

"For the scientists looking at pathogens, there's so many in other animal species. The human population is still growing. The climate is changing. We are surely going to encounter other species more and more as we invade their territory. And cross-species transmission is going to come. There's no doubt that the climate is going to get worse and worse and cause more harm. I think the pandemic situation is exactly going to parallel that."

Translational science itself is achieving the requisite altitude to acknowledge the complexities of its interrelated spectra from basic science research to population health applications. As bioscience has become a systems science, and as systems sciences have implicated forces beyond the reductive biological ones, translational science achieves the power and the potential to assess global and cosmic dimensions of its quest for knowledge. David Ho’s integrated research on his double pandemics provides a model of Weber’s “science as a vocation” and perhaps even the beginnings of a Kuhnian paradigm shift. Less a matter of morals and more a matter of effectiveness, his model helps us to perceive the fundamental challenges to life on the planet and equity in protecting its lives.