A future app may help you avoid getting the flu by informing you of your local risk on a given day.
Applied mathematician Sara del Valle works at the U.S.'s foremost nuclear weapons lab: Los Alamos. Once colloquially called Atomic City, it's a hidden place 45 minutes into the mountains northwest of Santa Fe. Here, engineers developed the first atomic bomb.
Like AccuWeather, an app for disease prediction could help people alter their behavior to live better lives.
Today, Los Alamos still a small science town, though no longer a secret, nor in the business of building new bombs. Instead, it's tasked with, among other things, keeping the stockpile of nuclear weapons safe and stable: not exploding when they're not supposed to (yes, please) and exploding if someone presses that red button (please, no).
Del Valle, though, doesn't work on any of that. Los Alamos is also interested in other kinds of booms—like the explosion of a contagious disease that could take down a city. Predicting (and, ideally, preventing) such epidemics is del Valle's passion. She hopes to develop an app that's like AccuWeather for germs: It would tell you your chance of getting the flu, or dengue or Zika, in your city on a given day. And like AccuWeather, it could help people alter their behavior to live better lives, whether that means staying home on a snowy morning or washing their hands on a sickness-heavy commute.
Sara del Valle of Los Alamos is working to predict and prevent epidemics using data and machine learning.
Since the beginning of del Valle's career, she's been driven by one thing: using data and predictions to help people behave practically around pathogens. As a kid, she'd always been good at math, but when she found out she could use it to capture the tentacular spread of disease, and not just manipulate abstractions, she was hooked.
When she made her way to Los Alamos, she started looking at what people were doing during outbreaks. Using social media like Twitter, Google search data, and Wikipedia, the team started to sift for trends. Were people talking about hygiene, like hand-washing? Or about being sick? Were they Googling information about mosquitoes? Searching Wikipedia for symptoms? And how did those things correlate with the spread of disease?
It was a new, faster way to think about how pathogens propagate in the real world. Usually, there's a 10- to 14-day lag in the U.S. between when doctors tap numbers into spreadsheets and when that information becomes public. By then, the world has moved on, and so has the disease—to other villages, other victims.
"We found there was a correlation between actual flu incidents in a community and the number of searches online and the number of tweets online," says del Valle. That was when she first let herself dream about a real-time forecast, not a 10-days-later backcast. Del Valle's group—computer scientists, mathematicians, statisticians, economists, public health professionals, epidemiologists, satellite analysis experts—has continued to work on the problem ever since their first Twitter parsing, in 2011.
They've had their share of outbreaks to track. Looking back at the 2009 swine flu pandemic, they saw people buying face masks and paying attention to the cleanliness of their hands. "People were talking about whether or not they needed to cancel their vacation," she says, and also whether pork products—which have nothing to do with swine flu—were safe to buy.
At the latest meeting with all the prediction groups, del Valle's flu models took first and second place.
They watched internet conversations during the measles outbreak in California. "There's a lot of online discussion about anti-vax sentiment, and people trying to convince people to vaccinate children and vice versa," she says.
Today, they work on predicting the spread of Zika, Chikungunya, and dengue fever, as well as the plain old flu. And according to the CDC, that latter effort is going well.
Since 2015, the CDC has run the Epidemic Prediction Initiative, a competition in which teams like de Valle's submit weekly predictions of how raging the flu will be in particular locations, along with other ailments occasionally. Michael Johannson is co-founder and leader of the program, which began with the Dengue Forecasting Project. Its goal, he says, was to predict when dengue cases would blow up, when previously an area just had a low-level baseline of sick people. "You'll get this massive epidemic where all of a sudden, instead of 3,000 to 4,000 cases, you have 20,000 cases," he says. "They kind of come out of nowhere."
But the "kind of" is key: The outbreaks surely come out of somewhere and, if scientists applied research and data the right way, they could forecast the upswing and perhaps dodge a bomb before it hit big-time. Questions about how big, when, and where are also key to the flu.
A big part of these projects is the CDC giving the right researchers access to the right information, and the structure to both forecast useful public-health outcomes and to compare how well the models are doing. The extra information has been great for the Los Alamos effort. "We don't have to call departments and beg for data," says del Valle.
When data isn't available, "proxies"—things like symptom searches, tweets about empty offices, satellite images showing a green, wet, mosquito-friendly landscape—are helpful: You don't have to rely on anyone's health department.
At the latest meeting with all the prediction groups, del Valle's flu models took first and second place. But del Valle wants more than weekly numbers on a government website; she wants that weather-app-inspired fortune-teller, incorporating the many diseases you could get today, standing right where you are. "That's our dream," she says.
This plot shows the the correlations between the online data stream, from Wikipedia, and various infectious diseases in different countries. The results of del Valle's predictive models are shown in brown, while the actual number of cases or illness rates are shown in blue.
(Courtesy del Valle)
The goal isn't to turn you into a germophobic agoraphobe. It's to make you more aware when you do go out. "If you know it's going to rain today, you're more likely to bring an umbrella," del Valle says. "When you go on vacation, you always look at the weather and make sure you bring the appropriate clothing. If you do the same thing for diseases, you think, 'There's Zika spreading in Sao Paulo, so maybe I should bring even more mosquito repellent and bring more long sleeves and pants.'"
They're not there yet (don't hold your breath, but do stop touching your mouth). She estimates it's at least a decade away, but advances in machine learning could accelerate that hypothetical timeline. "We're doing baby steps," says del Valle, starting with the flu in the U.S., dengue in Brazil, and other efforts in Colombia, Ecuador, and Canada. "Going from there to forecasting all diseases around the globe is a long way," she says.
But even AccuWeather started small: One man began predicting weather for a utility company, then helping ski resorts optimize their snowmaking. His influence snowballed, and now private forecasting apps, including AccuWeather's, populate phones across the planet. The company's progression hasn't been without controversy—privacy incursions, inaccuracy of long-term forecasts, fights with the government—but it has continued, for better and for worse.
Disease apps, perhaps spun out of a small, unlikely team at a nuclear-weapons lab, could grow and breed in a similar way. And both the controversies and public-health benefits that may someday spin out of them lie in the future, impossible to predict with certainty.
Dr. David Fajgenbaum looking through a microscope at his lab.
They're running a publicly accessible database called the CORONA Project (COvid19 Registry of Off-label & New Agents) that to date tracks 400 different COVID-19 treatments that have been tried somewhere in the world, along with the frequency of their use, and the outcomes.
"There's so many drugs being used all over the place, in different ways, with different outcomes," says Fajgenbaum. "We're trying to add some order to the madness."
20,000 people have accessed the registry—other physicians and researchers, those in the pharmaceutical industry, and even curious lay people—and the data are now being shared with the U.S. Food and Drug Administration in the hopes of launching large-scale trials that would lead to approving a constellation of treatment options for COVID-19 faster than any new drugs could come online.
"What David's group has done with the CORONA Project is on a scale that I don't think has ever been seen before," says Heather Stone, a health science policy analyst at the FDA who specializes in drug repurposing. She was not involved in establishing the project, but is now working with its data. "To collect and collate that information and make it openly accessible is a massive feat, and a huge benefit to the medical community," she says.
On a Personal Mission
In the science and medical world, Fajgenbaum lives a dual existence: he is both researcher and subject, physician and patient. In July 2010, when he was a healthy and physically fit 25-year-old finishing medical school, he began living through what would become a recurring, unprovoked, and overzealous immune response that repeatedly almost killed him.
His lymph nodes were inflamed; his liver, kidneys, and bone marrow were faltering; and he was dead tired all the time. At first his doctors mistook his mysterious illness for lymphoma, but his inflamed lymph nodes were merely a red herring. A month after his initial hospitalization, pathologists at Mayo Clinic finally diagnosed him with idiopathic multicentric Castleman disease—a particularly ruthless form of a class of lymph node disorders that doesn't just attack one part of the body, but many, and has no known cause. It's a rare diagnosis within an already rare set of disorders. Only about 1,500 Americans a year receive the same diagnosis.
Without many options for treatment, Fajgenbaum underwent recurring rounds of chemotherapy. Each time, the treatment would offer temporary respite from Castleman symptoms, but bring the full spate of chemotherapy side effects. And it wasn't a sustainable treatment for the long haul. Regularly dousing a person's cells in unmitigated toxicity was about as elegant a solution to Fajgenbaum's disease as bulldozing a house in response to a toaster fire. The fire might go out (though not necessarily), but the house would be destroyed.
A swirl of exasperation and doggedness finally propelled Fajgenbaum to take on a crucial question himself: Among all of the already FDA-approved drugs on the market, was there something out there, labeled for another use, that could beat back Castleman disease and that he could tolerate long-term? After months of research, he discovered the answer: sirolimus, a drug normally prescribed to patients receiving a kidney transplant, could be used to suppress his overactive immune system with few known side effects to boot.
Fajgenbaum became hellbent on devoting his practice and research to making similar breakthroughs for others. He founded the Castleman Disease Collaborative Network, to coordinate the research of others studying this bewildering disease, and directs a laboratory consumed with studying cytokine storms—out-of-control immune responses characterized by the body's release of cytokines, proteins that the immune system secretes and uses to communicate with and direct other cells.
In the spring of 2020, when cytokine storms emerged as a hallmark of the most severe and deadly cases of COVID-19, Fajgenbaum's ears perked up. Although SARS-CoV-2 itself was novel, Fajgenbaum already had almost a decade of experience battling the most severe biological forces it brought. Only this time, he thought, it might actually be easier to pinpoint a treatment—unlike Castleman disease, which has no known cause, at least here a virus was clearly the instigator.
"Because [a drug] looks promising, we need to do a well-designed, large randomized controlled trial to really investigate whether this drug works or not ... We don't use that to say, 'You should take it.'"
Thinking Beyond COVID
The week of March 13, when the World Health Organization declared COVID-19 a pandemic, Fajgenbaum found himself hoping that someone would make the same connection and apply the research to COVID. "Then like a minute later I was like, 'Why am I hoping that someone, somewhere, either follows our footsteps, or has a similar background to us? Maybe we just need to do it," he says. And the CORONA Project was born—first as a 10-day exercise, and later as the robust, interactive tool it now is.
All of the 400 treatments in the CORONA database are examples of repurposed drugs, or off-label uses: physicians are prescribing drugs to treat COVID that have been approved for a different disease. There are no bonafide COVID treatments, only inferences. The goal for people like Fajgenbaum and Stone is to identify potential treatments for further study and eventual official approval, so that physicians can treat the disease with a playbook in hand. When it works, drug repurposing opens up a way to move quickly: A range of treatments could be available to patients within just a few years of a totally new virus entering our reality compared with the 12 - 19 years new drug development takes.
"Companies for many decades have explored the use of their products for not just a single indication but often for many indications," says Stone. "'Supplemental approvals' are all essentially examples of drug repurposing, we just didn't call it that. The challenge, I think, is to explore those opportunities more comprehensively and systematically to really try to understand the full breadth of potential activity of any drug or molecule."
The left column shows the path of a repurposed drug, and on the right is the path of a newly discovered and developed drug.
Cures Within Reach
In Fajgenbaum's primary work, promising drugs stand out easily. For a disease like Castleman, where improvement almost never occurs on its own, any improvement that follows a treatment can pretty clearly be attributed to that treatment. But Fajgenbaum says tracking COVID outcomes is less straightforward since "the vast majority of people will get better, whether they take steroids or they take Skittles." That's why the intent of the database is to identify promising treatments only to generate hypotheses and fruitful clinical trials, not to offer full-throated treatment recommendations. Within the registry, Fajgenbaum considers a drug promising if it's being used in humans, not just in lab animals, and a significant proportion of cases report patient improvement.
"It's that sort of combination of rock-solid randomized controlled trial data, plus anecdotal retrospective data, that we combine to say, 'Wow, this drug looks more promising than another,'" says Fajgenbaum. "Because it looks promising, we need to do a well-designed, large randomized controlled trial to really investigate whether this drug works or not ... We don't use that to say, 'You should take it.'"
Experts say that the search for repurposed drugs to treat COVID could have implications for rare diseases in general. Rare diseases, of which Castleman is one, affect 400 million people around the world. 95% of them don't have a tailor-made, FDA-approved drug treatment. Developing one is a lengthy and often prohibitively expensive process. If only a dozen people will benefit from and buy a drug, it's not often worth it to pharmaceutical companies to spend millions of dollars making them. On occasion when they do, however, that overhead shows up in the price tag: the top 10 most expensive drugs in the world are all for rare diseases, often making them inaccessible to patients. Identifying new clinical uses for drugs that already exist is critical for opening a trap door out of a cycle that prioritizes profits over health outcomes.
"COVID is an interesting case where it's demonstrated that when the scientific and medical community really focuses all of its efforts and talents on a single problem, a solution can be identified and in a much faster time period than has ever historically been the case," says Stone. "I certainly wish it hadn't taken a pandemic to do that, but I think it does have lessons for the future in terms of our ability to accomplish things that we might have previously not thought were possible"—for example, mainstreaming the idea of drug repurposing as a treatment tool, even long after the pandemic subsides.
A Confounding Virus
The FDA declined to comment on what drugs it was fast-tracking for trials, but Fajgenbaum says that based on the CORONA Project's data, which includes data from smaller trials that have already taken place, he feels there are three drugs that seem the most clearly and broadly promising for large-scale studies. Among them are dexamethasone, which is a steroid with anti-inflammatory effects, and baricitinib, a rheumatoid arthritis drug, both of which have enabled the sickest COVID-19 patients to bounce back by suppressing their immune systems. The third most clearly promising drug is heparin, a blood thinner, which a recent trial showed to be most helpful when administered at a full dose, more so than at a small, preventative dose. (On the flipside, Fajgenbaum says "it's a little sad" that in the database you can see hydroxychloroquine is still the most-prescribed drug being tried as a COVID treatment around the world, despite over the summer being debunked widely as an effective treatment, and continuously since then.)
One of the confounding attributes of SARS-CoV-2 is its ability to cause such a huge spectrum of outcomes. It's unlikely a silver bullet treatment will emerge under that reality, so the database also helps surface drugs that seem most promising for a specific population. Fluvoxamine, a selective serotonin reuptake inhibitor used to treat obsessive compulsive disorder, showed promise in the recovery of outpatients—those who were sick, but not severely enough to be hospitalized. Tocilizumab, which was actually developed for Castleman disease, the disease Fajgenbaum is managing, was initially written off as a COVID treatment because it failed to benefit large portions of hospitalized patients, but now seems to be effective if used on intensive care unit patients within 24 hours of admission—these are some of the sickest patients with the highest risk of dying.
Other than fluvoxamine, most of the drugs labeled as promising do skew toward targeting hospitalized patients, more than outpatients. One reason, Fajgenbaum says, is that "if you're in a hospital it's very easy to give you a drug and to track you, and there are very objective measurements as to whether you die, you progress to a ventilator, etc." Tracking outpatients is far more difficult, especially when folks have been routinely asked to stay home, quarantine, and free up hospital resources if they're experiencing only mild symptoms.
But the other reason for the skew is because COVID is very unlike most other diseases in terms of the human immune response the virus triggers. For example, if oncology treatments show some benefit to people with the highest risk of dying, then they usually work extremely well if administered in the earlier stages of a cancer diagnosis. Across many diseases, this dialing backward is a standard approach to identifying promising treatments. With COVID, all of that reasoning has proven moot.
As we've seen over the last year, COVID cases often start as asymptomatic, and remain that way for days, indicating the body is mounting an incredibly weak immune response initially. Then, between days five and 14, as if trying to make up for lost time, the immune system overcompensates by launching a major inflammatory response, which in the sickest patient can lead to the type of cytokine storms that helped Fajgenbaum realize his years of Castleman research might be useful during this public health crisis. Because of this phased response, you can't apply the same treatment logic to all cases.
"In COVID, drugs that work late tend to not work if given early, and drugs that work early tend to not work if given late," says Fajgenbaum. "Generally this … is not a commonplace thing for a virus."
"There are drugs that are literally sitting in every single hospital pharmacy in the country that, if a study shows it's effective, can be deployed that evening to patients on a massive scale."
This see-sawing necessitates tracking a constellation of drugs that might work for different stages of the disease as a patient moves from the weak immune response stage into the overzealous immune response.
"COVID is difficult, compared to other diseases, because there are so many different levels of disease severity, and recovery at different rates," says Stone, the FDA researcher. "That makes it hard to see the patterns or signals and it makes it very important to collect very, very large numbers of cases in order to really reliably identify signals."
This particular moment in the pandemic feels like a massive tipping point, or the instant a tiny pinprick of light finally appeared at the end of the tunnel: several vaccines are already here, with more on the way imminently. In the U.S., more than 65 million doses of the vaccine have been administered, and positive COVID cases are finally falling back to levels not seen since October. On the hopeful surface, it might seem a strange moment to be preparing to launch trials that will validate treatments for a virus it seems the U.S. may finally be beating back. But at best, Americans are still months away from reaching herd immunity through vaccination, and new circulating variants may threaten to upend our fragile progress.
"In the meantime, there are drugs that are literally sitting in every single hospital pharmacy in the country that, if a study shows it's effective, can be deployed that evening to patients on a massive scale. It wouldn't have to be newly produced, it wouldn't have to be shipped, it's literally there already," says Fajgenbaum. "The idea that you can save a lot of lives by finding things that are just already there I think is really compelling, given how many people are going to die over these next few months."
Even after that, not everyone can or will be vaccinated, and, as the Wall Street Journal recently reported, "The pathogen will circulate for years, or even decades, leaving society to coexist with Covid-19 much as it does with other endemic diseases like flu, measles, and HIV." Neither vaccines, personal behavior, or treatments alone is a panacea against the virus, but together they might be.
"It's important to explore all avenues in this public health emergency, and drug repurposing can continue to play a role as the pandemic continues and evolves," says Stone. "I think COVID variants in particular are a big concern at the moment, and therefore continuing to investigate new therapeutics, even as the vaccines roll out, will continue to be a priority."
