It is likely to be remembered as the high point of Donald Trump’s tumultuous first presidency. On May 15, 2020, joined by cabinet members, public health experts, and military officials, he announced Operation Warp Speed, a “momentous medical initiative” to develop, manufacture, and distribute a successful coronavirus vaccine by year’s end, if not sooner. The event had all the trappings of a campaign rally. “Your vision,” gushed Health and Human Services Secretary Alex Azar, “will be one of the great scientific and humanitarian accomplishments in human history.” Only four of those flanking Trump in the Rose Garden that day—the physicians Anthony Fauci, Deborah Birx, Francis Collins, and Moncef Slaoui—wore masks, although 86,000 Covid-related deaths had already been reported in the United States. (“You guys, take your masks off, you hear me?” the president warned the others before stepping onstage.) This was Trump’s show, and no one dared to challenge his improbable timeline, not even Fauci, who had warned Congress three days before that “there’s no guarantee a vaccine is actually going to be effective.”
There was reason for concern. Vaccines are difficult and time-consuming to make in the best of circumstances, which was hardly the case in the spring of 2020. And yet, while the world seemed paralyzed by Covid-19 and Americans were badly divided over masking rules and school closings, Operation Warp Speed helped tame the worst pandemic since the Great Influenza of 1918. In the process, an obscure scientific acronym entered the popular vocabulary: RNA.
Why was it not better known? The answer, according to the Nobel Prize–winning chemist Thomas Cech in The Catalyst, a superb and timely history of research into RNA (ribonucleic acid), lies in the discovery of the double helix structure of DNA (deoxyribonucleic acid) by Francis Crick and James Watson in 1953. From that point forward, DNA research dominated the rapidly emerging field of genetics, relegating RNA to the role of “biochemical backup singer, slaving away in the shadow of the diva.”
Life depends on proteins, strings of amino acids that guide the critical functions of our cells. “Some proteins form structures such as muscle fibers, skin, and hair,” Cech explains. Others break down our food, clear waste, protect the shape of cells, aid chemical reactions, and fight off invading germs. When Crick and Watson showed how DNA encodes information for making these proteins and passes it from one generation to the next, questions naturally arose about how this information gets from the cell’s nucleus, where DNA is found, to the cell’s cytoplasm, where protein synthesis occurs.
It turned out that the information is carried by RNA. Over time scientists discovered several types of this workhorse molecule: messenger RNA (mRNA), which copies and transmits DNA’s genetic instructions for creating proteins; transfer RNA (tRNA), which translates these instructions until they are fully decoded; and ribosomal RNA (rRNA), which forms the ribosomes, or structural machinery, where protein synthesis occurs. Think of DNA as an archive and RNA as a scanner, notes the National Institutes of Health’s Human Genome Research Institute: “The DNA stores all the necessary information for an organism, and the RNA replicates and distributes pieces of this information as needed.”
In the 1950s and 1960s researchers developed the means to synthesize RNA in vitro—outside a living organism—which allowed it to be studied and manipulated in a laboratory. That offered the promise of creating innovative vaccines and therapies on a larger scale at a lower cost. But a major obstacle remained: synthetic mRNA must be shielded from the body’s formidable immune defenses as it travels to the cells. Otherwise it will be chopped to pieces by RNA-destroying enzymes before it reaches its destination.
The solution, still a work in progress, made the current Covid vaccines feasible. Researchers designed a delivery system that encases mRNA in fat bubbles known as lipid nanoparticles (LNPs) to prevent its degradation. Some compare LNPs to the capsule that takes astronauts into space.
Coronaviruses take their name from the spike proteins that crown their surface. Known for causing mild respiratory infections akin to the common cold in mammals and birds, they attracted little attention until 2002, when a variant causing more serious disease, severe acute respiratory syndrome (SARS), appeared in China, followed a decade later by Middle East respiratory syndrome (MERS) in Saudi Arabia. Both viruses are believed to have originated in bats, and both appeared to have an intermediate host—civets for SARS, camels for MERS. More than eight thousand SARS cases were confirmed worldwide, with a fatality rate of 9.5 percent. MERS infected fewer victims but killed a staggering number of them—nearly 35 percent.
Though vaccines were developed for SARS and MERS, none made it to market. One reason was that vigorous public health measures—contact tracing, mask wearing, quarantines—brought both outbreaks to an end. Another was that the vaccines didn’t seem promising enough to warrant serious investment, and why spend large sums on small-scale diseases that might never return?
It’s a fair question. Vaccination remains the most powerful means of preventing the spread of infectious disease, aside from clean water. The most successful vaccines work so well that they have turned deadly illnesses into distant memories. A four-dose regimen of the inactivated polio vaccine offers close to 100 percent protection, while a two-dose regimen of the measles, mumps, and rubella (MMR) vaccine is 97 percent effective against measles and 88 percent effective against mumps. By contrast, the annual flu vaccine rarely reaches 50 percent efficacy because the viral strains are constantly mutating, and HIV presents even greater difficulties because the virus destroys the immune cells that a vaccine is designed to stimulate. In 1984 the US Department of Health and Human Services announced a campaign to develop a successful AIDS vaccine within two years; the world is still waiting.
It’s true, moreover, that vaccines add little to a drug company’s ledger. In 2002, when SARS emerged, they constituted less than 2 percent of pharmaceutical sales worldwide, paling in comparison with the statins and antidepressants that are consumed by millions of people every day. And they’re extremely expensive to produce. The average vaccine today costs $888.6 million in research and development alone. Fewer than 10 percent make it to market, and those that do have taken eight to fifteen years to be approved for use.
Between 1957 and 2004 the number of companies producing childhood vaccines for the American market dropped from twenty-six to four, with just two, Merck and Wyeth, headquartered in the United States. The wave of mergers sweeping Big Pharma in those years clearly had an effect. But so, too, did dwindling profits, injury lawsuits, and a growing antivaccine movement. “Pharmaceutical companies are businesses, not public health agencies,” wrote the infectious disease specialist Paul Offit in 2005. They’re under no obligation to manufacture unprofitable goods. The best way forward, he and others believed, was some form of public–private partnership that encouraged vaccine production by sharing the financial risks.
Had there been no Covid-19 pandemic, vaccines based on mRNA might have taken years to reach the public. Big Pharma saw them as a modest advance in a largely unprofitable field, and federal officials were more worried about bioterrorism, a legacy of September 11, than about unanticipated naturally occurring health emergencies. In 2019, perhaps unknown to Trump, the Department of Health and Human Services ran an eerily prescient exercise, code-named Crimson Contagion, in which government agencies were tasked with containing an influenza of “high transmissibility and clinical severity” originating in China with the capacity to cause 110 million illnesses, 7.7 million hospitalizations, and 586,000 deaths in the United States. The results were hardly reassuring. The nation’s Strategic National Stockpile, a favorite target of Republican budget hawks, lacked both the medicines and the protective equipment to contain the virus, the exercise suggested, and US companies lacked the capacity to replenish the supply. Five months later came word of a mysterious respiratory virus circulating in Wuhan, China.
The Beijing government is not known for sharing bad news. It took months for details of the SARS outbreak to emerge in 2002; before that, in 1997, there was H5N1, a virulent avian flu that killed dozens of bird handlers in the following years and forced neighboring countries to slaughter millions of chickens and ducks. H5N1 proved to be one of the most lethal viruses known to humankind, with a fatality rate approaching 60 percent, but it showed almost no ability to jump from person to person, which prevented it from becoming an epidemic. In January the US recorded its first (and thus far only) confirmed death from H5N1—an elderly Louisiana resident with underlying conditions who had been directly exposed to flocks of wild birds. Although the federal government recently partnered with several drug companies to produce an mRNA-based bird flu vaccine for humans in case H5N1 mutates into a more contagious form, it’s still in the development stage.
How and where the Covid-19 pandemic began remains a mystery. The CIA now asserts, with admittedly “low confidence,” that the virus likely emerged from an accidental leak at a government facility in Wuhan, not from naturally infected animals in a local market. What is known is that emergency room doctors in Wuhan began exchanging messages in December 2019 about a puzzling cluster of pneumonia cases and that days passed before Chinese authorities reported the outbreak to the World Health Organization. In Shanghai, meanwhile, a distinguished Chinese virologist, Yong-Zhen Zhang, sequenced the genome of the circulating virus, SARS-CoV-2, and sent it to a collaborator in Australia, who posted it online. Furious at the leak, Chinese officials chose to spin Zhang’s sequence as an example of the nation’s scientific prowess and transparency while simultaneously punishing him as a warning to others.
President Trump, consumed by his Senate impeachment trial, didn’t receive a full briefing on the Wuhan outbreak until January 28, 2020, when his top public health and national security advisers warned him of a brewing catastrophe. “Don’t think SARS 2003,” one of them had been told by a Chinese expert. “Think influenza pandemic 1918.”
On March 2, Trump, Fauci, Vice President Mike Pence, and other officials met with drug company executives in preparation for Operation Warp Speed. A video of the event shows the president fully engaged and occasionally confused. Will the current influenza vaccine work against SARS-CoV-2? he asks. Probably not, Fauci replies. Can a Covid vaccine be ready in a few months? Hard to know, says Fauci, who gently explains the difference between a vaccine in clinical trials and one authorized for public use. There’s a surreal quality to the meeting: Trump was imploring representatives from an industry he routinely bashed for price gouging to fast-track a product he was widely believed to distrust.
What is often overlooked, however, is that Trump had shed some of his antivaccine views before the pandemic began, making it simpler for him to pursue Operation Warp Speed. He had long been influenced by the disgraced British physician Andrew Wakefield, whose false claims in 1998 linking autism to the MMR vaccine helped launch the modern antivaccine movement. During a GOP presidential debate in 2015, Trump told the unlikely story of a “beautiful child” he knew who was vaccinated “just the other day…got very, very sick, and now is autistic.” Antivaxxers flocked to his campaign; Trump returned the favor by inviting Wakefield to one of his inaugural balls.
But with the 2016 election behind him, Trump dialed down his doubts. The first sign appeared when Robert F. Kennedy Jr., a leading vaccine conspiracist, announced that the new president had asked him to chair a commission on “vaccine safety and scientific integrity.” Trump remained mum; the idea was likely quashed by nervous advisers. As president, he reluctantly got a flu shot and then endorsed a childhood vaccination campaign against measles. “This is really going around,” he told reporters. “They have to get the shot.”
The March 2 meeting offered a glimpse as well into the future of immunology. Two of the companies represented that day—Pfizer and Moderna—were already at work on mRNA vaccines and therapies for other diseases. Pfizer, founded in 1849, led the world in pharmaceutical sales, at just over $50 billion annually. But it wasn’t until 2009, following its acquisition of its rival Wyeth, whose portfolio included Prevnar 13, the hugely successful pneumococcal shot primarily for infants, that Pfizer became a force in vaccines. In 2018 it signed a $425 million agreement with a German start-up, BioNTech, to collaborate on an mRNA flu vaccine, and in March 2020 it reconnected with BioNTech to partner on a Covid vaccine.
Massachusetts-based Moderna was created in 2010 to design mRNA-based therapies for diseases that defied conventional treatment, such as cancer and autoimmune disorders. But it changed course, as did BioNTech, after discovering that mRNA technology worked better with vaccines than with treatments requiring frequent use over an extended period. Moderna didn’t have a drug giant as a partner—or, for that matter, a single product approved by the FDA. What it did have was the attention of venture capitalists and government scientists intrigued by its potential.
As Cech makes clear, the path to a successful Covid vaccine in 2020 was less about breaking new ground than about “assembling the puzzle pieces” that already existed. Researchers had
deciphered the genetic code, so anyone could read Yong-Zhen Zhang’s SARS-CoV-2 sequence and understand how to make the Spike protein. They had shown that they could in fact use mRNA to make enough protein to elicit an immune response, central to vaccine development. They had developed a powerhouse technique for copying DNA into gobs of mRNA.
And they had figured out how to safely encase the brew in protective lipid nanoparticles as it traveled to the cells.
Each step made things simpler, faster, and safer. There was no need, as with earlier vaccines, to grow, attenuate, and purify large amounts of virus—in this case SARS-CoV-2—in a laboratory, because the vaccine no longer contains it. Instead, synthetic mRNA instructs the cells to create a harmless fragment of SARS-CoV-2 that will trigger the immune system to recognize and destroy the virus when it appears. Put simply, the body becomes the factory.
First dubbed MP2 after the Manhattan Project, which developed the atomic bomb, Operation Warp Speed took its name from the faster-than-light propulsion system in Star Trek, a favorite among scientists working on the vaccine. Some worried, however, that the name sent the wrong message by appearing to prioritize a rushed product over a fully tested one. “It’s a terrible name,” warned Peter Hotez, a leading virologist, “and it’s going to cause some damage.”
It didn’t cause much, as best one can tell, but it did become part of the litany of ills associated with the Trump administration’s handling of the pandemic, from the CDC’s badly botched testing procedures, to the president’s endorsement of bleach and the malaria drug hydroxychloroquine as cures, to the mixed public health messages that left people confused—first about the efficacy of masking and later about whether the vaccines prevented Covid entirely or simply mitigated its most dangerous symptoms.
Trump naturally viewed the vaccines as a political lifeline, but only if one or more could win FDA approval before the 2020 presidential election. Operation Warp Speed fast-tracked the process by getting the vaccine makers to test and manufacture their products simultaneously, something they wouldn’t have dared to do on their own. If the vaccine failed, the company lost nothing, because Operation Warp Speed footed the bill. If it succeeded, the company got to market a subsidized product—and to keep the profits for itself.
Only Pfizer turned down federal funding. “I wanted to liberate our scientists from any bureaucracy,” its CEO, Albert Bourla, explained. Pfizer could afford to be fussy. The genetic technology for its mRNA vaccine had come from BioNTech, which received a $445 million grant from the German government, and the Trump administration had agreed to buy 100 million doses if the vaccine proved successful, not to mention the separate deals that Pfizer had signed with other countries. In a world of seven billion unvaccinated people needing multiple shots, the financial prospects were dazzling.
As were the resources. Trump invoked the rarely used Defense Production Act of 1950 to assure that the vaccine makers and their suppliers got access to the raw materials they required. Then he invoked the even more obscure PREP Act of 2005, which provides close to ironclad immunity for companies manufacturing “epidemic and pandemic products” during a “public health emergency.” That stopped potential injury lawsuits in their tracks. The final step left the intellectual property rights largely in the hands of the vaccine makers, despite the assistance of government scientists and the enormous federal subsidies—more than $30 billion. There simply wasn’t time to haggle over the contracts, the White House explained.
How well would an mRNA vaccine have to work against SARS-CoV-2 to win regulatory approval? The FDA chose 50 percent efficacy in the belief that a higher figure might be unobtainable, while a lower one would discourage people from getting vaccinated. Fauci hoped for 70–75 percent effectiveness, but Moncef Slaoui, the former drug company executive who directed Operation Warp Speed, shot for the stars. “I wouldn’t be surprised if it’s in the 90 percent [range],” he predicted.
Slaoui’s hunch was right. The Moderna and Pfizer-BioNTech vaccines were found to be about 95 percent effective against the original SARS-CoV-2 virus in randomized, double-blind trials that compared the experimental shots with a placebo. There were some minor differences. Pfizer’s two shots were spaced twenty-one days apart, Moderna’s twenty-eight. Pfizer’s shot contained thirty micrograms of vaccine, Moderna’s one hundred. (There wasn’t enough time to determine the lowest dose required for adequate protection.) Pfizer’s vaccine needed special freezers set at subarctic temperatures for cold-chain storage, while Moderna’s required only simple refrigeration.
Both mRNA vaccines won emergency use authorization from the FDA a mere seven months after Trump made his Rose Garden announcement, but too late to assist his failed reelection bid. Still, whatever one may think of Trump’s handling of the pandemic, wrote Fauci in his memoir On Call: A Doctor’s Journey in Public Service (2024), “Operation Warp Speed was a transformational program, a public-private partnership about which [his] administration should be justly proud.”
Its success dramatically recast the importance of RNA. Patent applications for products related to mRNA diagnosis and therapy have quadrupled in recent years. The 2023 Nobel Prize in Physiology or Medicine was awarded for breakthroughs in mRNA vaccines, and the 2024 prize honored the discovery of tiny RNA molecules involved in gene regulation. “There are more than 400 RNA-based drugs in some stage of development, beyond the ones that are already in use,” Cech notes. “And in 2022 alone, more than $1 billion in private equity funds was invested in biotechnology start-ups to explore new frontiers in RNA research.”
The Catalyst was published before Trump’s stunning nomination, and the Senate’s razor-thin confirmation, of Kennedy as secretary of health and human services, the department that oversees the NIH, the CDC, and the FDA, among other agencies. Reports surfaced recently that Kennedy had petitioned the FDA to withdraw its approval of all existing Covid-19 vaccines in 2021, at the height of the pandemic. And he has advocated spending larger proportions of HHS’s enormous budget on “alternative and holistic approaches to health,” which could dramatically affect the federal government’s medical research priorities.
Still, it is almost a given, as Cech makes clear, that RNA will power the next generation of pharmaceuticals, which will move beyond infectious diseases to those caused by a “missing or mutated protein,” such as muscular dystrophy, and numerous cancers caused by “normal cellular processes gone awry.” The key to this progress is CRISPR technology, a revolutionary gene-editing system that “derives its unprecedented power from RNA,” he writes—specifically the customized “guide RNA” that allows scientists to “precisely direct CRISPR’s scissors to cut any genetic sequence.”
Much like his former postdoctoral student Jennifer Doudna, a corecipient of the 2020 Nobel Prize in Chemistry for her work on CRISPR, Cech is concerned about the guardrails accompanying RNA’s seemingly unlimited potential. Will this growing focus on “disease-driven research” overshadow the more traditional “curiosity-driven” research so vital to scientific advancement? Is it possible to agree upon “what’s allowable” regarding RNA-guided gene editing? It’s one thing to compensate for harmful mutations and quite another to create offspring who are taller and faster, with light-colored eyes and other “enhancements” that could turn the process into “a dangerous tool for eugenics.”
Wondrous gains are rarely devoid of ethical concerns. The challenge, says Cech, is to find a balance between risk and reward that the public, or much of it, can accept—one that will encourage responsible long-term research in a field whose surface we’ve barely scratched. “The twenty-first century is already standing out as the age of RNA,” he adds, “and this century still has a long way to go.”
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