Is Covid-19 Teaching That Personalized, Genomic Medicine Is A Mistake?

Recent advances in healthcare have been driven by the individual and his or her genome. But the lesson of the pandemic appears to be that as a first line of defense, low-tech public approaches to fighting the virus work better and are more important because they help reduce the number of victims.

In the long run, it is unlikely that personalized or genomic medicine will be dismissed because it is intellectually exciting to researchers and highly profitable as a source of both philanthropic financial contributions and medical practice. But as in so many areas where technology and experience intersect, it is probable that merging the two approaches will be the optimal strategy. JL

Amy Marcus reports in the Wall Street Journal:

The key strategies for containing the pandemic, hand washing, quarantines and contact tracing, have been successfully deployed (for) more than a century. Vaccines are a public-health standby. All are low tech and available to the population. At a time of pandemic, focus on common rather than individual solutions has taken precedence. The most serious threats come not from people’s genes but from their environment and behavior. The world in which a person is situated plays the primary role in determining health outcomes. "Much of our health is beyond the control of individuals.”

The medical world is known for its fractious debates. One of the longest running is between those who believe that more lives will be saved by a “one-size-fits-all” approach, based on public health strategies, and those who see greater promise in treatments and care tailored to each individual’s genetic code.

“If we are to advance health care in the United States, where is the dollar best spent? Is it spent on hypergranular individual solutions or is it best spent on large-scale public health ventures?” says Jeffrey Henderson, associate professor of medicine and microbiology at Washington University School of Medicine, summing up the debate.

For decades, those on the side of individual solutions have held sway. The National Institutes of Health, the major driver of biomedical research in the U.S., put a large share of its funding, prestige and attention behind the idea that focusing on people’s genes was the best way to predict, prevent and treat disease. The NIH’s signature national health project of recent years, the All of Us Research Program, has called for sequencing the genetic codes of more than a million Americans in the hope that personalized medicine will improve individual health outcomes.

The Covid-19 pandemic has now highlighted a rival perspective in the debate. The key strategies for containing the pandemic—hand washing, better hygiene, quarantines, social distancing and contact tracing—have been successfully deployed in previous outbreaks going back more than a century. Vaccines, which take longer to deploy, are also a public-health standby.

All of these approaches are low tech, available relatively quickly and applicable to the general population. At a time of pandemic, focus on common rather than individual solutions has taken precedence.

So it makes sense that the first national initiative launched to try to treat today’s severely ill patients is the National Covid-19 Convalescent Plasma Project. The project originated with a small nucleus of people who, it turns out, have been prominent critics of personalized medicine over the years, including Arturo Casadevall of Johns Hopkins University, Michael Joyner of the Mayo Clinic and Nigel Paneth of Michigan State University.

The idea of using antibody-rich plasma from recovered patients to try to neutralize a virus in those who are ill was first used more than 100 years ago. The project is designed to buy time and save lives until a vaccine can be developed and deployed or more targeted therapies can be identified and tested. It also offers a real-world test case for ideas that had largely been confined to academic journals and debates between scientists.

“There is a legitimate concern that old-fashioned, low tech, public health measures get undersold in the context of precision medicine,” says Nathaniel Comfort, a professor of the history of science at Johns Hopkins University. “A perturbation as large as this one can shift the narrative.”

The scientists behind the convalescent plasma project first coalesced as a group in 2015, after Dr. Joyner wrote an op-ed in the New York Times arguing that “precision medicine is unlikely to make most of us healthier.” For diseases that cause the greatest societal health burden, such as diabetes, heart disease and many cancers, he noted that precision medicine hasn’t fared well compared with population-wide programs such as encouraging people not to smoke.

Most common diseases, Dr. Joyner wrote, are the result of small effects from hundreds or more gene variants, making it difficult to assess an individual’s risk. He pointed to Type 2 diabetes as an example: Age, sex, weight and some blood tests are as good as DNA (and sometimes better) at predicting the disease. And in either case, he added, the doctor’s advice to someone at high risk is the same: more exercise and a healthier diet.

Nigel Paneth, an epidemiologist and pediatrician at Michigan State University, reached out to Dr. Joyner after reading the article. “I had been thinking along the same lines,” he said. A small group of like-minded scientists met in Boston in 2016 to discuss how to get their ideas out.

“Each of us introduced someone else,” says Ana Soto, a professor of immunology at Tufts University, one of the hosts of the meeting. Soon there were around 30 people participating regularly in an online study group—a growing circle of friends and colleagues who analyzed papers and started jointly writing their own.

They approached the issue from different perspectives, reflecting their specialties, but their main critique was based on a shared view of the common good. As scientists, they professed admiration for the technological achievement of sequencing the billions of DNA letters that make up the human genetic code and the new frontiers of science opened up by the project. They recognized that for some rare genetic conditions, precision medicine was a boon. But in their view, prioritizing the discovery of disease at the individual level shifted focus away from efforts more likely to improve and save large numbers of lives. Despite significant public investment, precision medicine hasn’t delivered widespread public benefits.

The one-size-fits-all camp believes that it has been a mistake to focus on the genome as the main driver of health. The most serious threats, they argue, come not from people’s genes but from their environment and behavior. The wider world in which a person is situated plays the primary role in determining health outcomes.

“The notion that we can improve health by focusing on the individual is false,” says Sandro Galea, a professor and dean at Boston University School of Public Health, a participant in the group. “So much of our health is beyond the control of individuals.”

It is not always easy to quantify the disparities in support for the two different approaches. In a 2015 paper in the New England Journal of Medicine about public health in the era of precision medicine, Dr. Galea and a colleague said that U.S. investment in public health departments and public health infrastructure trailed other well-off countries. They cited NIH data showing that funding for projects that had the words “public” or “population” in their title had dropped by 90% over the previous 10 years.

Public health infrastructure relies on funding from various federal, state and local agencies and is often subject to budget cuts. There is significant philanthropic investment in vaccines but less in other areas of public health, Dr. Galea said. Precision medicine, on the other hand, has galvanized the enthusiasm and resources not only of the government but of private institutions and companies that see ways to profit.

In 2018, members of the group put together a special issue of the journal Perspectives in Biology and Medicine, hoping to spark debate. The cover carried the banner: “The Precision Medicine Bubble.” But their ideas largely remained outside the national spotlight—until the Covid-19 pandemic arrived.

Dr. Casadevall of Johns Hopkins University, one of the early members of the study group, wrote a commentary in The Wall Street Journal in late February proposing convalescent plasma from recovered patients as a potential stop-gap solution that could be rolled out relatively quickly. He cited a report published in 1934 about the use of convalescent plasma during a measles outbreak, arguing for the same strategy now. “One of the problems is that science tends to ignore its own history,” Dr. Casadevall said in an interview. “There are a lot of gems hidden in the old literature that can be looked at through a modern lens.”

Dr. Casadevall sent his article to the study group, but this time it wasn’t just for discussion. He wanted help to test the idea in the real world. Drs. Joyner and Paneth signed on immediately. Others in the study group also volunteered. “We already had a common bond,” said Dr. Casadevall. “We knew each other’s thinking.”

Francis Collins, who led the Human Genome Project and is the director of the NIH, said that it is true that precision medicine “has been more complicated than many people guessed it would be. The genetic architecture of common diseases is turning out to be more elaborate than we might have guessed.”

But some critics of precision medicine, he said, set up “a false dichotomy that you have to have either precision medicine or population health.” In his view, “It is not a conflict.” Understanding details about individuals informs understanding of populations, he said.

“We need to better understand an individual’s susceptibility to Covid,” Dr. Collins said. A gene variant might make it harder or easier for the virus to get into cells. If a vaccine is developed but large supplies aren’t immediately available, better understanding of individual vulnerability to the disease could be the basis for prioritizing distribution. NIH is also involved, he said, in efforts to develop a vaccine and to study a proposed manufactured intravenous immunoglobulin product containing antibodies from the serum of recovered Covid-19 patients.

Even now, while the acute phase of the pandemic still unfolds, there is the beginning of a reckoning about how science should change to address future infectious diseases, whether it is another wave of Covid-19 or a different virus. In the long-running debate, it is doubtful that either side will totally prevail.

‘We know we still need to prove convalescent therapy works.’

Every evening at 9, the members of the convalescent plasma project team hold a call to assess where things stand and to discuss next steps. One of their main criticisms of precision medicine has always been that it promises more than it delivers. They recognize that they could encounter the same problem with convalescent plasma. Historically, convalescent plasma has been used for emergencies, to treat patients in the middle of epidemics who have no other treatments and will otherwise die. “We know we still need to prove convalescent therapy works,” says Dr. Casadevall.

Formal clinical trials are now under way. And in keeping with the group’s interest in prevention, not only treatment, a trial at Johns Hopkins will test if a preventive dose of convalescent plasma reduces the chances that someone exposed to the disease will get the infection or have a serious complication.

The group is scrambling to find funding for the project. They have received some money from the U.S. Department of Health & Human Services to help support data collection and trials. Bloomberg Philanthropies, Johns Hopkins and the state of Maryland came up with $4 million to support their work. And a clinical trial now under way of people hospitalized with Covid-19 respiratory symptoms is being funded by private philanthropy and money from its institutional sponsors, NYU Langone Health, Montefiore Health System and Albert Einstein College of Medicine.

‘If we develop the infrastructure now, then if we have to do this again, we can.’

Dr. Joyner of the Mayo Clinic said that they will need more resources to develop a public infrastructure that can remain, even after vaccines and therapeutics against Covid-19 are developed. Convalescent plasma might still be required to treat a different novel infection in the future. There needs to be a system in place so that scientists and the health system can pivot. “If we develop the infrastructure now, then if we have to do this again, we can,” he said.

But after years of high-profile criticism of the precision medicine movement, Dr. Joyner said he wasn’t interested in entering any debates at the moment. “I am really focused on the plasma project,” he wrote in an email. “My thoughts are well known, but now is not the time in my opinion to go down this road. The time for reassessment is when the dust settles on this crisis.”

In his classes, Prof. Comfort, the historian of science, tells his students that the tension between one-size-fits-all approaches and precision medicine has lasted for decades because each side makes crucial points and illuminates different aspects of our wide-ranging health problems. “The questions keep returning in new guises,” he said.

After the pandemic, he said, it might be time to think about the debate in a different way. “The precision medicine and one-size-fits-all approaches have always been framed as opposites, as antagonists,” he said. “It doesn’t have to be that way. The problem that stands before us now is how do we change that?”