Scientists Are Building an “AccuWeather” for Germs to Predict Your Risk of Getting the Flu
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.
Everyone Should Hear My COVID Vaccine Experience
On December 18th, 2020, I received my first dose of the Pfizer mRNA vaccine against SARS-CoV-2. On January 9th, 2021, I received my second. I am now a CDC-card-carrying, fully vaccinated person.
The build-up to the first dose was momentous. I was scheduled for the first dose of the morning. Our vaccine clinic was abuzz with excitement and hope, and some media folks were there to capture the moment. A couple of fellow emergency physicians were in the same cohort of recipients as I; we exchanged virtual high-fives and took a picture of socially distanced hugs. It was, after all, the closest thing we'd had to a celebration in months.
I walked in the vaccine administration room with anticipation – it was tough to believe this moment was truly, finally here. I got a little video of my getting the shot, took my obligate vaccine selfie, waited in the observation area for 15 minutes to ensure I didn't have a reaction, and then proudly joined 1000s of fellow healthcare workers across the country in posting #ThisIsMyShot on social media. "Here we go, America!"
The first shot, though, didn't actually do all that much for me. It hurt less than a flu shot (which, by the way, doesn't hurt much). I had virtually no side effects. I also knew that it did not yet protect me. The Pfizer (and Moderna) data show very clearly that although the immune response starts to grow 10-12 days after the first shot, one doesn't reach full protection against COVID-19 until much later.
So when, two days after my first shot, I headed back to work in the emergency department, I kept wondering "Will this be the day that I get sick? Wouldn't that be ironic!" Although I never go without an N95 during patient care, it just takes one slip – scratching one's eyes, eating lunch in a break room that an infected colleague had just been in – to get ill. Ten months into this pandemic, it is so easy to get fatigued, to make a small error just one time.
Indeed, I had a few colleagues fall ill in between their first and second shots; one was hospitalized. This was not surprising, but still sad, given how close they had come to escaping infection.
Scientifically speaking, one doesn't need to feel bad to develop an immune response. Emotionally, though, I welcomed the symptoms as proof positive that I would be protected.
This time period felt a little like we had our learner's permit for driving: we were on our way to being safe, but not quite there yet.
I also watched, with dismay, our failures as a nation at timely distribution of the vaccine. On December 18th, despite the logistical snafus that many of us had started to highlight, it was still somewhat believable that we would at least distribute (if not actually administer) 20 million doses by the New Year. But by December 31, my worst fears about the feds' lack of planning had been realized. Only 14 million doses had gone to states, and fewer than 3 million had been administered. Within the public health and medical community, we began to debate how to handle the shortages and slow vaccination rates: should we change prioritization schemes? Get rid of the second dose, in contradiction to what our FDA had approved?
Let me be clear: I really, really, really wanted my second dose. It is what is supported by the data. After living this long at risk, it felt frankly unfair that I might not get fully protected. I waited with trepidation, afraid that policies would shift before I got it in my arm.
At last, my date for my second shot arrived.
This shot was a little less momentous on the outside. The vaccine clinic was much more crowded, as we were now administering first doses to more people, as well as providing the second dose to many. There were no high fives, no media, and I took no selfies. I finished my observation period without trouble (as did everyone else vaccinated the same day, as is typical for these vaccines). I walked out the door planning to spend a nice afternoon outdoors with my kids.
Within 15 minutes, though, the very common side effects – reported by 80% of people my age after the second dose – began to appear. First I got a headache (like 52% of people my age), then body aches (37%), fatigue (59%), and chills (35%). I felt "foggy", like I was fighting something. Like 45% of trial participants who had received the actual vaccine, I took acetaminophen and ibuprofen to stave off the symptoms. There is some minimal evidence from other vaccines that pre-treatment with these anti-inflammatories may reduce antibodies, but given that half of trial participants took these medications, there's no reason to make yourself suffer if you develop side effects. Forty-eight hours later, just in time for my next shift, the side effects magically cleared. Scientifically speaking, one doesn't need to feel bad to develop an immune response. Emotionally, though, I welcomed the symptoms as proof positive that I would be protected.
My reaction was truly typical. Although the media hype focuses on major negative reactions, they are – statistically speaking – tremendously rare: fewer than 11/million people who received the Pfizer vaccine, and 3/million who received the Moderna vaccine, developed anaphylaxis; of these, all were treated, and all are fine. Compare this with the fact that approximately 1200/million Americans have died of this virus. I'll choose the minor, temporary, utterly treatable side effects any day.
Now, more than 14 days after my second dose, the data says that my chance of getting really sick is, truly, infinitesimally low. I don't have to worry that each shift will put me into the hospital. I feel emotionally lighter, and a little bit like I have a secret super-power.
But I also know that we are not yet home free.
I may have my personal equivalent of Harry Potter's invisibility cloak – but we don't yet know whether it protects those around me, at all. As Dr. Fauci himself has written, while community spread is high, there is still a chance that I could be a carrier of infection to others. So I still wear my N95 at work, I still mask in public, and I still shower as soon as I get home from a shift and put my scrubs right in the washing machine to protect my husband and children. I also won't see my parents indoors until they, too, have been vaccinated.
At the end of the day, these vaccines are both amazing and life-changing, and not. My colleagues are getting sick less often, now that many of us are a week or more out from our second dose. I can do things (albeit still masked) that would simply not have been safe a month ago. These are small miracles, for which I am thankful. But like so many things in life, they would be better if shared with others. Only when my community is mostly vaccinated, will I breathe easy again.
My deepest hope is that we all have – and take - the chance to get our shots, soon. Because although the symbolism and effect of the vaccine is high, the experience itself was … not that big a deal.
New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
Rob Waddell dreaded getting a kidney transplant. He suffers from a genetic condition called polycystic kidney disease that causes the uncontrolled growth of cysts that gradually choke off kidney function. The inherited defect has haunted his family for generations, killing his great grandmother, grandmother, and numerous cousins, aunts and uncles.
But he saw how difficult it was for his mother and sister, who also suffer from this condition, to live with the side effects of the drugs they needed to take to prevent organ rejection, which can cause diabetes, high blood pressure and cancer, and even kidney failure because of their toxicity. Many of his relatives followed the same course, says Waddell: "They were all on dialysis, then a transplant and ended up usually dying from cancers caused by the medications."
When the Louisville native and father of four hit 40, his kidneys barely functioned and the only alternative was either a transplant or the slow death of dialysis. But in 2009, when Waddell heard about an experimental procedure that could eliminate the need for taking antirejection drugs, he jumped at the chance to be their first patient. Devised by scientists at the University of Louisville and Northwestern University, the innovative approach entails mixing stem cells from the live kidney donor with that of the recipient to create a hybrid immune system, known as a chimera, that would trick the immune system and prevent it from attacking the implanted kidney.
The procedure itself was done at Northwestern Memorial Hospital in Chicago, using a live kidney donated by a neighbor of Waddell's, who camped out in Chicago during his recovery. Prior to surgery, Waddell underwent a conditioning treatment that consisted of low dose radiation and chemotherapy to weaken his own immune system and make room for the infusion of stem cells.
"The low intensity chemo and radiation conditioning regimen create just enough space for the donor stem cells to gain a foothold in the bone marrow and the donor's immune system takes over," says Dr. Joseph Levanthal, the transplant surgeon who performed the operation and director of kidney and pancreas transplantation at Northwestern University Feinberg School of Medicine. "That way the recipient develops an immune system that doesn't see the donor organ as foreign."
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis."
A week later, Waddell had the kidney transplant. The following day, he was infused with a complex cellular cocktail that included blood-forming stem cells derived from his donor's bone marrow mixed what are called tolerance inducing facilitator cells (FCs); these cells help the foreign stem cells get established in the recipient's bone marrow.
Over the course of the following year, he was slowly weaned off of antirejection medications—a precaution in case the procedure didn't work—and remarkably, hasn't needed them since. "I felt better than I had in decades because my kidneys [had been] degrading," recalls Waddell, now 54 and a CPA for a global beverage company. And what's even better is that this new approach offers hope for one of his sons who has also inherited the disorder.
Kidney transplants are the most frequent organ transplants in the world and more than 23,000 of these procedures were done in the United States in 2019, according to the United Network for Organ Sharing. Of this, about 7,000 operations are done annually using live organ donors; the remainder use organs from people who are deceased. Right now, this revolutionary new approach—as well as a similar strategy formulated by Stanford University scientists--is in the final phase of clinical trials. Ultimately, this research may pave the way towards realizing the holy grail of organ transplantation: preventing organ rejection by creating a tolerant state in which the recipient's immune system is compatible with the donor, which would eliminate the need for a lifetime of medications.
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis," says Dr. Suzanne Ildstad, a transplant surgeon and director of the Institute for Cellular Therapeutics at the University of Louisville, whose discovery of facilitator cells were the basis for this therapeutic platform. Ildstad, who has spent more than two decades searching for a better way, says, "This is something I have worked for my entire life."
The Louisville group uses a combination of chemo and radiation to replace the recipient's immune and blood forming cells with that of the donor. In contrast, the Stanford protocol involves harvesting the donor's blood stem cells and T-cells, which are the foot soldiers of the immune system that fight off infections and would normally orchestrate the rejection of the transplanted organ. Their transplant recipients undergo a milder form of "conditioning" that only radiates discrete parts of the body and selectively targets the recipient's T-cells, creating room for both sets of T-cells, a strategy these researchers believe has a better safety profile and less of a chance of rejection.
"We try to achieve immune tolerance by a true chimerism," says Dr. Samuel Strober, a professor of medicine for immunology and rheumatology at Stanford University and a leader of this research team. "The recipients immune system cells are maintained but mixed in the blood with that of the donor."
Studies suggest both approaches work. In a 2018 clinical trial conducted by Talaris Therapeutics, a Louisville-based biotech founded by Ildstad, 26 of 37 (70%) of the live donor kidney transplant recipients no longer need immunosuppressants. Last fall, Talaris began the final phase of clinical tests that will eventually encompass more than 120 such patients.
The Stanford group's cell-based immunotherapy, which is called MDR-101 and is sponsored by the South San Francisco biotech, Medeor Therapeutics, has had similar results in patients who received organs from live donors who were either well matched, such as one from siblings, meaning they were immunologically identical, or partially matched; Talaris uses unrelated donors where there is only a partial match.
In their 2020 clinical trial of 51 patients, 29 were fully matched and 22 were a partial match; 22 of the fully matched recipients didn't need antirejection drugs and ten of the partial matches were able to stop taking some of these medications without rejection. "With our fully matched, roughly 80% have been completely off drugs up to 14 years later," says Strober, "and reducing the number of drugs from three to one [in the partial matches] means you have far fewer side effects. The goal is to get them off of all drugs."
But these protocols are limited to a small number of patients—living donor kidney recipients. As a consequence, both teams are experimenting with ways to broaden their approach so they can use cadaver organs from deceased donors, with human tests planned in the coming year. Here's how that would work: after the other organs are removed from a deceased donor, stem cells are harvested from the donor's vertebrae in the spinal column and then frozen for storage.
"We do the transplant and give the patient a chance to recover and maintain them on drugs," says Ildstad. "Then we do the tolerance conditioning at a later stage."
If this strategy is successful, it would be a genuine game changer, and open the door to using these protocols for transplanting other cadaver organs, including the heart, lungs and liver. While the overall procedure is complex and costly, in the long run it's less expensive than repeated transplant surgeries, the cost of medications and hospitalizations for complications caused by the drugs, or thrice weekly dialysis treatments, says Ildstad.
And she adds, you can't put a price tag on the vast improvement in quality of life.