Almost from the moment the new Asian respiratory disease was first identified last month, scientists -- and many ordinary citizens in chat rooms on the Internet -- wondered whether it might have been the work of terrorists. Now medical and military experts say the answer is almost certainly no.

''As a scientist, you never say never,'' said Dr. Steven M. Block, a biologist and germ-weapons expert at Stanford University. ''But every indicator I'm aware of points to a natural outbreak.''

While the cause of severe acute respiratory syndrome, or SARS, has not been pinned down, the leading suspect is a virus from the coronavirus family, and the experts say there are several reasons to think its origins are natural: its birthplace in a region of China long known as an incubator for new kinds of influenza, its relatively low lethality and the individual biology of coronaviruses.

But, they add, that biology makes it menacing in a different way.

Coronaviruses have a singular talent for recombination -- for absorbing bits of stray genetic material. One day, virologists warn, that tendency might suddenly turn a benign coronavirus into a deadly one.

''It has the highest frequency of recombination that we know of for any positive-strand RNA virus,'' said Dr. Susan C. Baker, a virologist at Loyola University in Chicago. ''With high-frequency recombination, you always have potential for a new virus to emerge.'' Now, she added, ''it looks like it's happening.''

Known coronaviruses, in addition to causing the common cold, are suspected of causing diarrheal and other intestinal illnesses in humans. Though bothersome, the ailments are rarely fatal. But coronaviruses have caused major illnesses among cats, dogs, chickens, pigs and cattle.

Experts say the new human coronavirus, if it causes SARS, probably arose when it managed to incorporate similar but foreign RNA, which, like DNA, can make up the genome or genetic code of microorganisms. Such alien RNA would make it a kind of natural hybrid.

Human coronaviruses, said [Dr. Mark Randall Denison (born 1956)], an expert at Vanderbilt University, are like the mild-mannered next-door neighbor with a proclivity for doing the unexpected. ''It's always the quiet ones you worry about,'' he said.

Federal experts echo the university experts. ''I see no reason to believe this is anything other than the emergence of a natural disease,'' said [Dr. Peter B. Jahrling (born 1946)], a virologist at the Army's Medical Research Institute of Infectious Diseases.

Coronaviruses, he added, ''are ubiquitous and are relatively promiscuous'' in their ability to infect different species. Infection of a single host with two different coronaviruses can easily lead to recombination and the emergence of new forms, he said, and ''that's probably what happened here.''

Guangdong Province in southern China, where the illness is believed to have emerged late last year, has dense concentrations of domestic waterfowl in close proximity to pigs and people. Experts say those are ideal conditions for transferring diseases among different species and for the emergence of a new strain of flu virtually every year. ''It's no surprise that other viruses can take advantage of similar mechanisms,'' said Dr. Block of Stanford.

Dr. Richard H. Ebright, a microbiologist at Rutgers University who studies germ weapons, agreed that the Chinese origin of SARS argued against its being a weapon. ''If it had first been detected in New York or Washington, or Kuwait City or Tel Aviv,'' he said, ''then I'd think there'd be strong reason for concern.''

A military expert who disagrees is Dr. Ken Alibek, a former top Soviet germ warfare official now at George Mason University. In his book ''Biohazard'' (Random House, 1999), Dr. Alibek said China had developed biological weapons and had once suffered an accident at a secret germ plant, setting off two epidemics.

SARS, Dr. Alibek said in an interview, might have originated from a similar accident. ''It's a very unusual outbreak,'' Dr. Alibek said. ''It's hard to say whether it's deliberate or natural.'' He added that he knew of no Chinese germ-weapons plants in Guangdong.

Several biologists cited the low lethality of SARS -- it kills somewhere from 3 to 5 percent of its victims -- as evidence of its natural origin. Dr. Block of Stanford noted that the germs and viruses that cause diseases like anthrax and smallpox typically have mortality rates of 25 to 95 percent.

''It's bad,'' Dr. Ebright of Rutgers said of SARS. ''But 3 percent is not the Andromeda strain.''

The experts agreed that pinpointing the disease's place of origin in Guangdong could help settle any doubts about whether SARS is deliberate or natural. In China, a team of scientists from the World Health Organization is trying to discover how the illness started and spread.

Mapping the genes of the suspect coronavirus will also shed light on its origin, biologists said. Genes from a highly dissimilar organism would point to human genetic engineering. ''If they put in genes from Ebola,'' said Dr. Block, referring to a dangerous germ from Africa, ''that would be a dead giveaway.''

The Centers for Disease Control and Prevention in Atlanta, which is leading the American inquiry of SARS, said last week that the mapping, known as sequencing, should be completed by the end of this week or the beginning of the next one.

''The sequencing information will show us right away where it came from,'' said Dr. Baker of Loyola. ''I think it's highly unlikely that anybody could have created this virus.''

Gilead's antiviral remdesivir is being tested in multiple late-stage studies in China and the US to treat COVID-19.

In the coming weeks, the world will get a sense of whether Gilead Sciences’ remdesivir, an antiviral developed for Ebola, is useful against the novel coronavirus. With the coronavirus pandemic spiraling—during the week of March 23, worldwide infections crossed 500,000 and deaths shot towards 25,000—initial results emerging from several late-stage studies will be under the microscope.

But infectious disease experts on the front lines warn that the data are unlikely to clearly answer the question of whether remdesivir works in COVID-19, the respiratory illness caused by the SARS-CoV-2 virus. Those first tests are in the sickest, hardest-to-treat, patients. Moreover, antivirals don’t have a great track record at taking down coronaviruses, which can be a little more sophisticated than your average RNA virus.

Still, some industry watchers hope the studies signal enough success to convince the US Food and Drug Administration to approve Gilead’s experimental drug.

When a new infectious disease threatens the world, researchers’ first move is to look for any existing therapies that might work against it. As [Sina A Bavari (born 1959)] of Edge Bioinnovation Consulting and Management puts it, when you’re really hungry, you’d rather take a lasagna out of the freezer than make one from scratch. Bavari previously spent many years as chief scientific officer at the US Army Medical Research Institute of Infectious Diseases.

As the coronavirus began to spread, one of the first compounds to be pulled from the freezer was remdesivir. Discovered by Gilead and the Army institute during the 2014 Ebola outbreak in West Africa [see Western African Ebola virus epidemic (2013 - 2016)], the RNA polymerase inhibitor seemed like a sound choice. Although it turned out not to work in Ebola—a failure many blame on how late in the progression of the disease it was given—studies in both healthy and infected people showed the drug is fairly safe.

And researchers point to solid science for why remdesivir might still work against COVID-19.

The SARS-CoV-2 genome is made up of a string of nucleotides that, during replication, are reconstructed, one by one, by the viral polymerase. The RNA-dependent RNA polymerase is a good drug target because it is “almost exclusively associated with the virus,” says University of Wisconsin–Madison virologist Andy Mehle. Polymerase inhibitors will be highly specific for infected cells, sparing healthy ones.

Enter remdesivir, which acts like a mimic for adenosine—one of the nucleotides in that string.

The virus is tricked into incorporating the active form of the drug into its genome, preventing it from making more copies of itself. The mechanism by which remdesivir does that is still unclear, but “polymerase inhibitors primarily work by causing mutations of the genome, or by blocking polymerase function,” Mehle says.

Although Gilead developed remdesivir for Ebola, which belongs to a different family of viruses than SARS-CoV-2, the “viral machinery has elements in common,” Erica Ollmann Saphire, a virus expert at the La Jolla Institute for Immunology, said in an email. Those common elements include polymerases, meaning that for any “safe, bioavailable and manufacturable molecule, the only remaining question is will it work against this other virus,” she said.

While remdesivir was being tested in people with Ebola, several academic and government groups were exploring its potential to take down other viruses, including the coronaviruses that cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). They showed in both lab experiments and animal studies that remdesivir could treat infections and prevent them altogether—what scientists call prophylaxis.

In fact, remdesivir is one of only two highly effective compounds to come out of six years of screening against coronaviruses, says [Dr. Mark Randall Denison (born 1956)], a coronavirus expert and director of the Division of Infectious Diseases at Vanderbilt University Medical Center. Denison has collaborated with labs at the University of North Carolina and elsewhere to find small molecules that keep coronaviruses from replicating—and still work if the virus mutates. The other effective compound, EIDD-2801, was discovered by Emory University chemists and recently licensed to Ridgeback Biotherapeutics.

One reason so many compounds failed is that coronaviruses are a little smarter than other RNA viruses. They’re the only ones with a polymerase that can fix errors in their genomes, meaning they can spot and ignore the mimics that drug hunters typically design. [Dr. Mark Randall Denison (born 1956)]'s lab found that remdesivir, like EIDD-2801, can bypass that proofreading function.

Those studies, combined with the Ebola safety data, provided a rationale for trying the compound against the new coronavirus.

At the moment, five Phase III studies are testing the drug against COVID-19. Two began in China in early February—one in people with severe disease, the other in those with mild to moderate disease. One is a US National Institutes of Health–led study that started in February to test the drug in anyone hospitalized with evidence of lung involvement. And two are Gilead-led studies that started in March—one in severe disease and the other in moderate disease.

The first data should come from the studies in China, followed quickly by an initial report from Gilead. With so much pressure to find a COVID-19 treatment—even a modestly effective one—the results will be closely scrutinized. But many on the front lines caution that, even though the studies were carefully designed, the answers might not be clear cut.

“I don’t think the ongoing trials will tell us a lot,” says H. Clifford Lane, clinical director at the National Institutes of Allergy and Infectious Diseases, who is overseeing ongoing studies at the NIH, including its remdesivir study. “The studies might give us some hint, but I do think it will be important to get a study launched that focuses on early disease”—before it becomes severe.

A likely scenario is that several studies “don’t reach statistical significance but show a similar result, and that might be enough to say we should probably be using this,” Lane says. “It’s really hard to know what to do.”

Libby Hohmann, associate professor of medicine and infectious diseases at Massachusetts General Hospital, is similarly cautious. “It’s going to be a challenge to review the data because the protocol allows a wide range of illness into it,” says Hohmann, who leads the hospital’s participation in NIAID’s remdesivir trial. “Unless it’s sort of a home run, it may be difficult to parse at the get go.”

One issue is that the first studies to read out are the ones focused on the most severe cases, people whose disease might have progressed past the point of help by an antiviral.

“Everything we do in infectious disease is better treated when it’s early on and the bacterial or viral burden and the damage done is lesser,” Hohmann says. Doctors are realizing that COVID-19 is a two-phase illness, she says, that starts with upper respiratory symptoms that worsen after a week to two weeks. At some point during that period, patients “fall of a cliff,” Hohmann notes. “There’s a lot of data and speculation that it’s a kind of immunological phenomenon,” where certain people’s immune or inflammatory response goes awry.

So if those first data in severe or even moderate cases are unclear, it doesn’t necessarily mean the drug doesn’t work. Rather, it could just mean it isn’t being given early enough.

But even if patients are treated early, the benefits could be minimal, Lane warns. Consider, for example, the limitations of Tamiflu (oseltamivir), a common treatment for another virus, influenza. To have any effect, the drug must be taken within 48 hours of symptoms appearing. And even then, “the overall impact on clinical outcomes is not very dramatic,” Lane says. “We don’t have a lot of success in treating RNA viruses.”

In the ideal scenario where the trials do look good, caveats still abound. Ideally, doctors would deploy the drug either prophylactically or just after exposure, but before symptoms appear. Edge Bioinnovation’s Bavari calls it “something to give before you actually go to the hospital so you don’t end up in the hospital.”

But remdesivir can only be given intravenously, so “it’s not like we’re going to be able to give it to people with the sniffles out in the real world,” Hohmann says.

Nonetheless, her team has been trying to enroll people with a better chance of responding to the drug. Among the 16 patients her clinic has signed up so far, she’s emphasized younger people and those with mild to moderate disease—the ones with shortness of breath rather than those being intubated in the emergency room. “I think we will be able to tell if we’re making a difference in those people,” Hohmann adds.

Gilead says it has no plans to turn remdesivir into a pill. “Based on our understanding of remdesivir from preclinical studies, intravenous administration allows for the most stability and appropriate levels of the drug in the blood system,” a company spokesperson tells C&EN.

Another roadblock is manufacturing. Gilead’s spokesperson notes that “there are currently limited available clinical supplies of remdesivir, but we are working to increase our available supply as rapidly as possible.” For example, the firm is beginning in-house manufacturing of the drug, which had been made only by contract manufacturers. The biotech firm has also added new manufacturing partners around the world to enhance sourcing of everything from raw materials to the finished drug.

Despite the many caveats attached to remdesivir, stock analysts who cover Gilead say it has a reasonable chance of reaching the market. “No one expects it to be a magic bullet,” says Piper Sandler analyst Tyler Van Buren. “But if it works at all in a portion of patients, especially in severe ones, that is very meaningful.” If remdesivir can reduce the need for ventilators or time on supplemental oxygen, Van Buren argues, it could alleviate burden on the healthcare system.

While the FDA approval process typically takes 6–12 months, “this is an unprecedented, once-in-a-century situation,” Van Buren says. Gilead has been submitting as much data as possible to regulatory agencies to expedite approval, he notes. “If the data does look good, there will be tremendous pressure for FDA to make a decision within days.”

If that happens, could the world end some of the more extreme social distancing measures and start getting back to business? “I think it will depend on the level of efficacy,” NIAID’s Lane says. “The goal remains to prevent the spread of infection. While an effective therapy might have some effect, I doubt it would have a major impact.”

Even in the best-case scenario, where remdesivir moves the needle for patients in a meaningful way, successful deployment will require a health care workforce capable of administering it. Because of shortages of personal protective equipment (PPE) and other supplies, Mass General’s Hohmann says, conditions are already difficult—and the worst is yet to come.

“It’s just a challenge because the clinical workforce is overworked, nervous, worried about their own health, worried about the lack of PPE, and about the tsunami of patients that’s coming,” she says. “If we had all the PPE we need, such that nobody had to worry about going into the room of a patient with known disease, life would be a lot easier around here.”