TOKYO — Intensive care beds are beginning to fill up the Sydney hospital where Harriet, a medical registrar, has been working to prepare for a surge in COVID-19 cases. “We keep saying it’s going to happen next week,” she said. “But we’re not there yet.”
Australia has had just under 6,000 confirmed cases as of April 6, and Harriet’s hospital has done what it can to be ready if that number starts to rise. They have created a COVID-19 ward and a second intensive care unit, and made plans to ratchet up the response by moving junior doctors from their rotations onto the virus response.
“It’s really hard to say if we’re going to be ready. I hope we are,” she said. “It’s sort of the eerie calm before the storm. We’re waiting for it to hit. Because what happens is, it comes in at a trickle, then suddenly it’s a roar.”
Their preparations are hindered by the fact that as yet the disease, which only emerged a few months ago, is still poorly understood. There are no drugs proven to work on the virus.
Shortages of ventilators, beds and the personal protective equipment that nurses and doctors need to stop themselves from being infected has put a colossal strain on health systems around the world. Harriet has been receiving messages from former classmates, including those in Italy where more than 15,000 people have died. There, she said, her colleagues have been forced into impossible decisions over which patients get ventilators and which are left untreated.
“The system is collapsing. It’s impossible. They can’t keep up. It’s horrifying. I read those messages to remind myself,” she said. “Right now, everybody’s holding their breath. We’re just waiting. And hoping that what we’ve done is going to be enough.”
As the pandemic’s front line advances from country to country, the experience of doctors and nurses who have worked through the first wave is a lifeline for their colleagues in countries like Australia, for whom the worst could be yet to come. In China, Italy and South Korea, the first countries to have mass outbreaks, medics had to establish protocols for treatment from scratch. Some tried out unproven remedies in a desperate attempt to find anything that would work, from flu treatments to anti-malarials and arthritis drugs.
Their findings have flowed outward through formal and informal channels, from WhatsApp groups and online forums to international medical journals, feeding into a vast global search for a treatment that works. That search is unprecedented in scale, spanning borders and scientific disciplines, and combining front-line medicine, academic research, and cutting-edge computing, all founded on a new openness and spirit of collaboration that has defied political boundaries.
“There’s still a lot we don’t know about this virus, and we’re learning more every day,” said Tom Frieden, president and CEO of Resolve to Save Lives, an epidemic prevention initiative at the global health organization Vital Strategies. “There’s an important difference between a good response to this crisis and a great one. A great one will actively use data to adjust in real time…. Data is one of our strongest defenses against this virus. We need to learn as much as possible as quickly as possible, and we can only do that if we work together.”
‘This is the one’
On March 20, around 80 scientists and doctors from the U.S. and China dialed into a videoconference to talk about their collective experiences in tackling the COVID-19 pandemic. By that point, China had started telling the world its efforts had brought the disease under control, but the U.S. was climbing a steep curve, adding tens of thousands of confirmed cases per day. The Americans, mainly from Johns Hopkins University in Maryland, wanted to understand from their counterparts what they could do to try to stem the outbreak. Before they signed off, the Chinese doctors prayed for their American colleagues. Shmuel Shoham was on the call.
At the start of 2020, Shoham was researching infectious diseases in transplant patients at Johns Hopkins, dividing his time between consultations and working on the slow-moving, multiyear academic studies that form the basis of developing treatments in peacetime medicine. Like everyone in the infectious disease field, he said, he knew that one day there would be global pandemic, but it was an abstract. It may happen in his lifetime, it may not.
“In medicine, you’re always thinking about preparing for the future,” he said. “And now, all of a sudden, this is the future. This is the one.”
“In medicine, you’re always thinking about preparing for the future. And now, all of a sudden, this is the future. This is the one.”
Shmuel Shoham, Associate Professor of Medicine at Johns Hopkins University School of Medicine
By March, with the COVID-19 pandemic overloading hospitals in New York and spreading fast in other American cities, Shoham had handed his caseload over to colleagues and was working full-time on the disease.
A small trial in China had shown that giving patients “convalescent plasma” — blood plasma from people who had recovered from the virus — might help to prevent those in the early stages of the disease from developing more severe symptoms. Known as “passive immunization,” the approach has been used for more than a century and still forms part of the treatment for rabies and hepatitis. Shoham and his colleagues reached out to other specialists in their networks across the U.S. and around the world to launch a series of trials. “It’s all grassroots,” he said. “You [use] every personal connection you have.”
The U.S. Food and Drug Administration quickly approved trials of convalescent plasma for patients suffering from the novel coronavirus. Chinese researchers are also expanding their studies, and have shipped plasma to Italy to be trialed there.
“Material is coming across — published, anecdotal, in Chinese — needing to be translated on Google Translate, or sent to a native Chinese speaker,” Shoham said. “The scientific exchange process, which historically has been very slow and very methodical … now, in the last two to three months, has been sort of warp-speed.”
Throughout the medical world, barriers are coming down. More than 100 scientific publishers have made all of their coronavirus-related papers free to access, giving researchers a vast database of information. So-called preprint servers — repositories of studies yet to go through peer review — have been flooded with data coming out of China, South Korea and Italy.
“Given the scale and given the importance of this pandemic, I think everyone is more than willing to share their data and share their resources and share their technologies,” said Junaid Nabi, a public health researcher at Brigham and Women’s Hospital and Harvard Medical School. “The first thing that everyone is thinking about is the benefit to the patients. … I think this has definitely induced a lot more unity.”
In doctors’ forums, medics from Iran, Turkey, Germany and Spain are giving advice to their colleagues on other continents, from how to intubate a patient to their own experiences with experimental treatments.
“Information has been surprisingly easy to access,” said Edsel Maurice Salvana, an infectious disease specialist currently running the COVID-19 testing laboratories at the Philippines’ National Institutes of Health. “[The] WHO is always there, but most scientific journals have given open access to most COVID articles, and many scientists are posting their studies that are still for peer-review to give earlier access to data.”
Despite all of the available information, however, the burden of decision making is still left to beleaguered doctors and nurses in the field, who have to judge the wisdom and balance the ethics of using unproven treatments to tackle a poorly-understood disease.
In Northern Italy, Nicola Forni, an infectious disease specialist who has been working in the worst of the epidemic since late February, told the Nikkei Asian Review that doctors have been treating patients with anti-malarials, including hydroxychloroquine, as well as antiretrovirals and drugs used to treat rheumatoid arthritis, after reading small studies coming out of China. Doctors have to make tough calls on treatment based on ever-changing circumstances and information. “We are obliged to adapt every day. Every day we have to come up with new protocols,” Forni said.
This is happening against the backdrop of a system that has come close to collapse. Doctors are having to make emotionally devastating decisions about who is given access to lifesaving ventilators. “I’ve never been to war,” Forni said. “But it was like a war experience. We were overwhelmed.”
The task ahead for doctors is complicated by a glut of speculation and misinformation, distributed both on social media and through mainstream channels that are desperate to be the first with news of a cure. Small, unverified or clinically insignificant trials have been amplified, or patients have tried to self-medicate.
Salvana told Nikkei that he was aware of at least one person who died in the Philippines from self-administering hydroxychloroquine. U.S. President Donald Trump later called chloroquine and hydroxychloroquine “game changers” at a news conference. The comment was picked up worldwide, despite drawing widespread criticism from public health officials.
“The bottom line is that we need a proper, randomized controlled trial,” Salvana said.
‘The pieces were all there’
The first researchers to sequence the DNA of the coronavirus, a team from Fudan University in Shanghai, shared the genome on GenBank, a free online database, on Jan. 11. Other groups followed, and there are now more than 250 sequences listed on the server. On Jan. 24, Nevan Krogan, director at the Quantitative Biosciences Institute at the University of California, San Francisco, assigned a small team to start looking at the genome.
Founded in 2016, Krogan’s lab specializes in using quantitative and computational techniques to understand the fundamental biological mechanisms that underpin diseases and pharmaceuticals. Krogan’s colleagues began to create a map of the virus which they could compare to the human genome and identify the proteins that it relies on to replicate and infect cells. “It’s essentially a blueprint of how the virus comes in and hijacks and rewires the host in the course of infection,” Krogan said.
Just over a month after they began working on it, California began to report community transmission of COVID-19.
“I went into the lab and I realized that everything is going to get shut down, the university is going to shut down. So I assembled all my team and said, ‘We’re going to stop everything we’re doing and work on this around the clock, 24/7,'” Krogan said.
The lab’s 25 staff were joined by others in 21 other laboratories at UCSF in a hastily-established coronavirus research group. In two weeks, they had built the map, something which would normally have taken years. The last pieces of data fell into place hours before the university was officially closed.
From the map, the researchers were able to identify 332 human proteins that interact with the virus. Then they began searching through public databases of pharmaceuticals to identify compounds that target those proteins. They found 69 — 27 of which have already been approved by the FDA. Some are proven antivirals, but others are drugs used to treat other pathogens.
“On the surface that doesn’t make sense. Anti-malarial, anti-parasite, antibacterial, we’re trying to get a virus. But our map is maybe providing some molecular level understanding of why these drugs could potentially be working,” Krogan said.
Testing has begun in labs at Mount Sinai Hospital in New York and the Pasteur Institute in Paris. Pharmaceutical companies, including Roche, are poised to move promising drugs to clinical trials.
“It’s been amazing. Getting the sequence in January and testing drugs in March, that just doesn’t happen for a virus nobody knew about at Christmas,” Krogan said. “It shows you how fast things can move. … The pieces were all there. This kind of crisis has forced people to work together to get something done as quickly as possible.”
Krogan’s lab is one of several in the public and private sector that are using data, machine learning and other quantitative methods to accelerate the search for a possible treatment for COVID-19. This approach has developed rapidly over the past few years, as the technology has improved and new techniques for cheaply sequencing and editing genomes have increased the amount of data available to researchers.
“You have genetics which has become exponentially cheaper over time, you have computational resources which have become exponentially cheaper over time, and you have tools, you have deep learning and you have the data,” said Peter Fedichev, CEO of Singapore-based Gero, which is using AI to try to identify drugs that could slow the process of aging. “Here you are, 2020, these things become possible.”
As the COVID-19 pandemic worsened, Gero repurposed its algorithms to search for compounds that could stop the virus from replicating in human cells, in a similar approach to UCSF. They identified a number of candidates, including two drugs used to treat parasite infections — Niclosamide and Nitazoxanide — as well as the cancer drug Afatinib and an antipsychotic, Reserpine. The company is now looking for partners to run trials.
“The first and most important part of this [response] is identifying a candidate, and if we look at one positive aspect of this whole thing, it’s that we’re beginning to see the practical integration of machine learning, artificial intelligence and drug development,” said Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development in Boston.
The ability to quickly sift through the tens of thousands of drugs that have already gone through clinical trials, and whose side effects and toxicity is already understood, has given the global response to the pandemic a head start. However, Kaitin warns, there is still a lot of work to be done. Researchers are not just looking for one miracle drug, but for multiple options that work for patients in different stages of the disease, and for patients with different underlying conditions. Even though many drugs are being tested, the failure rate will be high.
“The likelihood of a compound actually working for any disease is very small. Our studies have shown that it’s only about 10% of compounds that are studied actually reach the market,” he said.
The World Health Organization is currently recruiting patients for an enormous global trial — called “Solidarity” — of four possible treatments: remdesivir, an unproven drug developed to treat Ebola; the anti-malarials chloroquine and hydroxychloroquine; the anti-retrovirals lopinavir and ritonavir, which are marketed together as the HIV treatment Kaletra; and a combination of lopinavir, ritonavir and another drug, interferon-beta.
The drugs were chosen based on their likelihood of working against COVID-19, on their safety data, and on the available supplies — all already in common use for other conditions and manufactured at scale.
Independently, chloroquine was one of the drugs identified as a potential treatment by Nevan Krogan’s team.
In Japan, the government is backing a clinical study of the flu drug Avigan, developed by a unit of Fujifilm, which showed some promise when used on patients in China. Avigan, which was also proposed as a possible treatment for Ebola in 2015, has regulatory approval in Japan for use only in narrowly-defined circumstances — such as a devastating flu pandemic — due to concerns about its side effects.
At least a dozen potential vaccines are also at various stages of testing.
Kaitan warned against holding out too much hope that one of these trials will deliver a solution in the near term.
“I think in a time of desperation like we’re in now, people are desperate for not just a drug, but hope that if they get the disease that there will be some way of treatment,” he said. Media speculation and poor communication from the leadership in some countries has “led to almost a crazed belief that there’s something out there,” but randomized clinical trials take a long time, and there is no way to speed them up.
“That means that we should not expect to see a drug on the market for a year or more. Which sounds horrible given the predicted fatality rate of this virus. But that’s the reality.”
That grim reality puts the burden back on public health measures and social distancing. In early April, Singapore, which had seemed to have successfully limited the spread of the virus, announced a “circuit breaker,” compelling businesses to close to prevent a wider outbreak. The Japanese government announced a state of emergency for Tokyo and six other prefectures onApril 7,in response to a spike in new cases.
The lack of treatment also increases the need for personal protective equipment for those working on the front line. In almost every country dealing with the disease, medical staff lack the PPE they need. Medical message boards are full of professionals asking for advice on how to stay safe while dealing with patients, and even how they can make and maintain their own equipment.
These shortages have led to an enormous toll on medical staff. In Italy, nearly 10% of all the confirmed cases of COVID-19 are health care workers. In some U.S. states, the percentage is even higher. Worldwide, hundreds have already died. Each infection and each death further undermines the global capacity to fight the pandemic.
“I feel a profound sadness and loss every time another doctor dies. At least three fatalities have been my professors who I have worked with as colleagues,” Edsel Salvana said in an email sent during the last few days of his own self-quarantine, imposed after two of his own patients tested positive for the disease. “It is so easy to break down in grief, but we have a lot to do. When this is all over, I’ll have a long cry. For now, I save my tears for the battle ahead.”