Stark, High, and Urgent

By Harvey V. Fineberg

In 1964, the physicist Harvey Brooks famously differentiated between science for policy and policy for science. In an analogous way we can see pandemics as accelerant for scientific innovation and science as solution to pandemics. Without the pandemic, certain advances in science would occur more slowly or not at all. Without science, our ability to track and suppress a pandemic, reduce its impact, and preserve lives and health would be drastically curtailed. A pandemic reveals both lessons from science and lessons for science.

The COVID-19 pandemic is a global conflagration, as was the world war that preceded Vannevar Bush’s 1945 report, Science, the Endless Frontier. Bush begins his report’s letter of transmittal with reference to the role of the war in advancing science: “What can be done,” he was asked in preparing his report, “to make known to the world as soon as possible the contributions which have been made during our war effort to scientific knowledge.” Bush concludes the letter with reference to the manifold benefits of science to society: “Scientific progress is one essential key to our security as a nation, to our better health, to more jobs, to a higher standard of living, and to our cultural progress.” Without diminishing the horrors of war or the devastation of a pandemic, we can nevertheless recognize ways they may spur scientific advances and provide insight into the key role that science can play in policymaking.

Outcome-oriented science

Pandemics summon a wide array of sciences, from artificial intelligence to zoonotic disease. The fabric of science that covers a pandemic weaves together basic biological sciences, translational biosciences, clinical sciences, epidemiological and other public health sciences, policy and regulatory sciences, behavioral and social sciences, and ecological sciences. Spanning molecules and populations, pandemic science extends from the laboratory to the natural habitat of wild animals; it also courses through clinics, hospitals, communities, nursing homes, schools, and factories.

Without diminishing the horrors of war or the devastation of a pandemic, we can nevertheless recognize ways they may spur scientific advances and provide insight into the key role that science can play in policymaking.

We can learn much from pandemic-induced science and from science as applied to the pandemic. Science in a pandemic thrives on individual creativity, attracts many participants, and can benefit from focused, sometimes elaborate collaboration. The urgency and stress of a pandemic highlight the value of pre-established research protocols and clinic- and community-based networks to rapidly produce needed scientific knowledge. And the advances in science in obtaining new knowledge, in organizational innovation for the conduct of science, and in modes of providing scientifically informed advice have salience for finding solutions to other pressing problems and meeting social needs, the “one essential key” that Vannevar Bush described.

In the context of a pandemic, the traditional division between basic and applied science is not as helpful as thinking of science as a spectrum spanning curiosity-driven science, problem-solving science, and product-targeted science—in short, what we might call outcome-oriented science. This span extends across the lines demarcated by the political scientist Donald Stokes in Pasteur’s Quadrant, differentiating pure basic research (exemplified by Niels Bohr), pure applied research (exemplified by Thomas Edison), and use-inspired research (exemplified by Louis Pasteur). Science in a pandemic illustrates the continuities and interdependencies that reveal truths of nature. Science can clarify a murky reality, while also illuminating gaps in knowledge and skills, creating solutions, and delivering improvements in people’s lives.

Prequels and sequels

Science relevant to a pandemic begins long before the pandemic appears. Indeed, none of the critical breakthroughs in COVID-19 prevention, diagnosis, or treatment would have been possible without the foundation and accumulation of critical scientific knowledge and experimentation. The Science Philanthropy Alliance has compiled a series of summaries called “Prequels” that illustrate the role of prior science in enabling detection, assessment, and response to the COVID-19 pandemic. These include genetic and genomic sequencing, viral imaging and modeling, epidemiology of disease transmission, vaccinology, and more. While the endless frontier ahead of science remains to be explored, it is possible to trace back the many pathways that led to where science has progressed thus far.

The science that bears on a pandemic is linked to numerous matters of metascience, including public attention and political support, priority setting, funding, organization, public-private and intercorporate cooperation, international relations, and equity. While these issues always hover around science, pandemics expose and intensify them. The stakes in a pandemic for science—as for society—are stark, high, and urgent.

Pandemics therefore compel attention. The eighteenth-century writer Samuel Johnson observed that when a man knows he is soon to be hanged, “it concentrates his mind wonderfully.” A pandemic exerts a similar effect simultaneously on many people, as it affects every sector and segment of society, mobilizing massive public and private resources. In a pandemic, everyone who can help, and that includes many scientists, stands ready to help.

The stakes in a pandemic for science—as for society—are stark, high, and urgent.

A pandemic interrupts many experiments and delays progress in laboratories abruptly rendered off-limits as indoor work-spaces. The disruption caused by a pandemic also creates space for innovation. Scientists engage in creative new ways to conduct their work, adopt safer protocols to prevent spread of infection, redirect their laboratories, generate new collaborations, and pursue novel experiments to solve specific problems. All this and more came in response to the COVID-19 pandemic.

The creation of multiple vaccines to protect against SARS-CoV-2 infection is a dramatic illustration of scientific innovation, capitalizing on previous research, ample public investment, private-public partnership, and cooperation across industry. For reference, most of the influenza vaccine produced in the United States relies on egg-based viral cultures, a technology that has been in use for more than 70 years. Although messenger RNA vaccines, such as those developed by Moderna and Pfizer-BioNTech, had been recently contemplated for use against several viruses, no mRNA vaccine prior to COVID-19 had been tested in large-scale, phase 3 clinical trials. Before COVID-19, the fastest any new vaccine had gone from viral samples to approval by the US Food and Drug Administration (FDA) was four years, for a mumps vaccine in 1967.

A revealing article by the microbiologist and immunologist Arturo Casadevall in the Journal of Clinical Investigation elegantly portrays the multiple lines of research that contributed to mRNA vaccines against SARS-CoV-2. These include decades of study in molecular biology, microbiology and virology, immunology, lipid chemistry, and pharmacology. Prominent along the way was the discovery by Katalin Karikó and Drew Weissman that a modified mRNA nucleoside prevented a premature inflammatory response to mRNA. This finding, one that was essential to the development of mRNA vaccines, garnered these scientists the 2021 Lasker-DeBakey Clinical Medicine Research Award.

Speed and focus

The full-bore commitment to develop, produce, and distribute an effective and safe vaccine as part of “Operation Warp Speed” will stand as one of the US government’s outstanding achievements in the early phase of the COVID-19 pandemic. In this effort, a pharmaceutical giant such as Pfizer could partner with the German biotechnology firm, BioNTech, and deploy its own resources to develop a vaccine, benefiting from government support of previous research and relying mainly on a governmental guarantee of purchase should the vaccine prove successful. Meanwhile, a smaller contender, Moderna, could receive federal funding in the development phase. There was no guarantee of the operation’s success—as the experience of Merck and other companies demonstrates. And there was certainly no assurance of the rapidity and favorable benefit-to-risk ratio that the mRNA vaccines provided. Other useful COVID-19 vaccines rely on a variety of technologies, including viral vectors (such as Johnson & Johnson-Janssen and Oxford-AstraZeneca), subunit protein (Novavax), and inactivated whole virus (Sinopharm and Sinovac).

Producing such an array of vaccine types against a single organism, available about a year after the organism was isolated, is a remarkable scientific achievement. And yet, vaccines themselves do not save lives. Immunization saves lives. The last stage of vaccine acceptance and use is therefore as critical as any previous step of discovery, design, development, testing, regulatory authorization, manufacture, or logistics of distribution. The science bearing on vaccines and immunization extends from basic biology to behavioral science. We expect and require extensive randomized controlled trials testing the efficacy and safety of vaccines. We should similarly design, fund, conduct, and learn from studies comparing different communication, messaging, and social marketing strategies on the acceptance of COVID-19 vaccines among groups defined in various ways, including by race, ethnicity, age, region, political affiliation, social group, or religion. Downplaying, and underfunding, the social sciences is self-defeating in a pandemic that is fundamentally a social and public health—as well as biological and medical—challenge. These soft sciences can pierce our hardest problems. Underfunding the social sciences, as with chronic underfunding of the public health infrastructure, undermines society’s capacity to respond to a pandemic as surely as shortchanging any biological or biomedical sciences.

New collaboration and organization

In a matter of months, the COVID-19 pandemic transformed the way science is done, sparking innumerable innovations, novel partnerships, new funding, and new forms of organization. Scientists previously working independently began to collaborate. Companies working on other organisms or diseases turned their attention to coronaviruses and COVID-19. Universities and publications began to compile, use, and release data and to model projections on the course of the pandemic. Laboratories with extensive capacity for genomic testing, normally utilized for research, redirected their instruments to detect and diagnose infection.

Underfunding the social sciences, as with chronic underfunding of the public health infrastructure, undermines society’s capacity to respond to a pandemic as surely as shortchanging any biological or biomedical sciences.

One notable example of innovation in the strategy for sponsoring and conducting science is the Rapid Acceleration of Diagnostics (RADx) initiative at the US National Institutes of Health (NIH).

After an early, flawed diagnostic test for SARS-CoV-2 was withdrawn by the Centers for Disease Control and Prevention, the United States did not have enough diagnostic tests to produce accurate, timely, and useful results. US Senators Lamar Alexander of Tennessee (now retired) and Roy Blunt of Missouri recognized that fast, reliable, and affordable testing would be critical to managing the pandemic and reopening schools and businesses. They turned to leaders in NIH to gain a better understanding of what needed to be done to secure the number and variety of tests America required.

As a result of what they learned, the senators directed $1.5 billion to NIH as part of the Paycheck Protection Program and Health Care Enhancement Act (2020) to speed up development, commercialization, and implementation of testing for SARS-CoV-2 through what became the RADx program.

Rather than establishing a traditional, investigator-initiated, peer-reviewed grants program, RADx adopted a venture capital model—soliciting ideas from every corner of relevant science; relying on a “shark tank” approach to place early bets; organizing and committing to ongoing support and nurturing of the candidate technologies; and assisting with overcoming regulatory hurdles, supply limitations, and other constraints. Hundreds of experts in fields ranging from clinical chemistry to business development were brought into the mix. Like the basic science antecedents of vaccine development, this organizational design benefited from approaches pioneered years earlier by the Consortia for Improving Medicine with Innovation and Technology (CIMIT) and further enhanced by CIMIT as the coordinating center for the Point-of-Care Technologies Research Network, which NIH enlisted to provide day-to-day management of the RADx program.

In its first 18 months, RADx supported more than 100 companies and successfully launched 32 FDA-authorized tests, including the first over-the-counter test for use at home and tests that yield results in minutes rather than days. The program has resulted in more than 800 million tests for COVID-19 on the market. The array of new technologies supported by RADx includes handheld polymerase chain reaction (more commonly known as PCR) devices, loop-mediated amplification tests, paper-based diagnostics, rapid lateral flow assay antigen tests, smartphone readers, next-generation sequencing, and artificial intelligence-assisted diagnostics. The federal government recently intensified its commitment to produce more high-quality, home-based tests, and NIH and FDA pledged close working relations to facilitate review and authorization of new, more accurate, and convenient tests.

The lessons of this success are far-reaching, specifically for COVID-19 diagnostics and broadly for the way that NIH conducts its work. RADx exemplifies outcomes-oriented science, reaching as it does from basic research through product development, licensure, market availability, and use. RADx shows how NIH can live up to its name as the National Institutes of Health, rather than the National Institutes of Biomedical Research. By spanning insight to innovation, engaging the public and private sectors, and working with universities, research institutes, and companies, the selection funnel process fostered by RADx accelerates the transition from discovery to product. RADx holds lessons for the proposed $6.5 billion Advanced Research Projects Agency for Health and offers a model for future science aimed at any definable and desired health outcome.

Separating fact from fiction

Science has played a key role in differentiating what might work in treating patients or managing COVID-19 from what actually works. Hydroxychloroquine might have worked; but it failed to show effectiveness in a randomized controlled trial. Though steroids might not have been helpful in advanced stages of the disease, they proved to reduce mortality among patients hospitalized with COVID-19 in a well-designed trial. A promising antiviral pill reportedly cuts the incidence of hospitalization and death by 89%, and monoclonal antibodies are recommended for treatment in the early stage of COVID-19 infection. A clear lesson for clinical and public health sciences in a pandemic is the value of having established study templates, ready protocols, and existing networks prepared to rapidly evaluate posited advances in prevention and care.

RADx shows how NIH can live up to its name as the National Institutes of Health, rather than the National Institutes of Biomedical Research.

Just as the need to provide credible information in real time challenged scientists as individuals, it also prompted innovations in mechanisms to advise policymakers. At the request of the White House Office of Science and Technology Policy and the Department of Health and Human Services, the National Academies of Sciences, Engineering, and Medicine established a standing committee to advise these federal agencies on matters of science that arose during the pandemic. Since the Civil War era, the National Academies have provided independent, science-based guidance to federal agencies and the public. However, this advice is not always quickly forthcoming, focused, and relevant to immediate decisions. The Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats created a new, highly responsive form of written assessment called rapid expert consultations. In the first five weeks of its existence, in March and April 2020, the standing committee provided federal agencies with 11 rapid expert consultations on such topics as bio-aerosol spread of the virus, the effectiveness of cloth masks, and conditions calling for adoption of crisis standards of care. These are a tiny fraction of the total body of reports and other scientific guidance emanating from the National Academies in response to the pandemic.

A pandemic, as with any urgent and threatening situation, exposes differences as well as convergence in scientific understanding and guidance. The airwaves, news columns, podcasts, blogs, social media, and academic journals are filled with opinion as well as evidence on matters of science and the pandemic. It is challenging for experts, much less the lay public, to distinguish responsible and well-grounded information from the irresponsible and misleading. Certainly, we have learned that strength of conviction is not a reliable guide to scientifically sound opinion or scientifically informed advice. The intense vitriol directed at Anthony Fauci—an exemplary scientist, physician, health leader, public servant, and policy advisor—demonstrates the deeply politicized anger of some segments of American society. Just as pandemics cannot be separated from their larger social context, neither can the processes and communication of science. In the end, support for science and its place in society depends on public understanding of science, its workings, and its role.

The scientific process

At the Accademia Gallery in Florence stands Michelangelo’s magnificent sculpture of David, naked, gazing steadily to his left, in ready repose with sling and stone. In the same museum, one can find four unfinished sculptures, intended for the tomb of Pope Julius II, that reveal much of Michelangelo’s artistic genius and concept. He did not sculpt in the round. Rather, he proceeded from front to back, revealing the figure along the way. The partially finished figures appear to be emerging from a pool, yet permanently immersed in the stone that holds them. As sculptor, Michelangelo conceived his craft as chipping away the negative space of stone and thus revealing the figure that was always embedded within.

Support for science and its place in society depends on public understanding of science, its workings, and its role.

Truths of nature are like Michelangelo’s figures embedded in stone. Although these truths may be hard to discern, a fundamental tenet of science is that the truths of nature are constant and not capricious. As Albert Einstein reportedly observed, “God may be subtle, but He is not devious.” The role of science, like the sculptor’s chisel, is to continually chip away at the covering, so that what remains is an ever-closer approximation to the complete figure of nature’s truths, an ever-deeper exploration of Vannevar Bush’s endless frontier.

The brilliance and durability of science rest on its inherent capacity to change in the face of new evidence, to attain a more accurate and complete understanding of the world. This is the essence of the process of science, as practiced during a pandemic or in any context. It is the hallmark of science dating from long before Bush penned his prescient report, and it will remain so for the indefinite future.

Science—a global enterprise

A pandemic, like climate change or any similarly global, disruptive, and daunting threat, teaches that enlightened science policy would incorporate both global cooperation and national competitiveness, and would recognize when the balance favors cooperation. Because a pandemic, by definition, is widespread, scientific insights and advances to contain and conquer it can come from anywhere. In some instances, as with the Pfizer-BioNTech vaccine, international collaboration manifestly pays off. Overcoming technical obstacles to equitable access to preventives and treatments is a matter for global science and engineering as well as financing, organization, legal arrangements, and political will. Some critical and contentious questions, such as investigating the origin of the pandemic, can only be carried out with global cooperation. And in the future, agreement on the terms for such inquiry should be established before a pandemic occurs.

The role of science, like the sculptor’s chisel, is to continually chip away at the covering, so that what remains is an ever-closer approximation to the complete figure of nature’s truths.

But if overcoming a pandemic and understanding emerging infections require international cooperation, it is not always easy to achieve or to sustain in a fractious world. In every country, science is promoted as the key to national competitiveness and future prosperity, a meritorious argument that is persuasive to national leaders and legislators. Those who favor international cooperation in science need to confront such genuine concerns as national security, the protection of intellectual property, and scientific integrity. While difficult to accomplish, the effort is worthwhile.

The revelations of this worldwide pandemic—that all must be protected before anyone is truly safe—are lessons that scientists and policymakers can apply to other global catastrophes. Science, in a pandemic and beyond, can build durable bridges between nations as an expression of our common humanity, in recognition of our vulnerability to pathogens and other threats to life, and as a reflection of our shared aspirations for a healthy planet.