Medical Breakthroughs Set to be Fast-Tracked by Innovative New Health Agency
In 2007, Matthew Might's son, Bertrand, was born with a life-threatening disease that was so rare, doctors couldn't diagnose it. Might, a computer scientist and biologist, eventually realized, "Oh my gosh, he's the only patient in the world with this disease right now." To find effective treatments, new methodologies would need to be developed. But there was no process or playbook for doing that.
Might took it upon himself, along with a team of specialists, to try to find a cure. "What Bertrand really taught me was the visceral sense of urgency when there's suffering, and how to act on that," he said.
He calls it "the agency of urgency"—and patients with more common diseases, such as cancer and Alzheimer's, often feel that same need to take matters into their own hands, as they find their hopes for new treatments running up against bureaucratic systems designed to advance in small, steady steps, not leaps and bounds. "We all hope for a cure," said Florence "Pippy" Rogers, a 65-year-old volunteer with Georgia's chapter of the Alzheimer's Association. She lost her mother to the disease and, these days, worries about herself and her four siblings. "We need to keep accelerating research."
We have a fresh example of what can be achieved by fast-tracking discoveries in healthcare: Covid-19 vaccines.
President Biden has pushed for cancer moonshots since the disease took the life of his son, Beau, in 2015. His administration has now requested $6.5 billion to start a new agency in 2022, called the Advanced Research Projects Agency for Health, or ARPA-H, within the National Institutes of Health. It's based on DARPA, the Department of Defense agency known for hatching world-changing technologies such as drones, GPS and ARPANET, which became the internet.
We have a fresh example of what can be achieved by fast-tracking discoveries in healthcare: Covid-19 vaccines. "Operation Warp Speed was using ARPA-like principles," said Might. "It showed that in a moment of crisis, institutions like NIH can think in an ARPA-like way. So now the question is, why don't we do that all the time?"
But applying the DARPA model to health involves several challenging decisions. I asked experts what could be the hardest question facing advocates of ARPA-H: which health problems it should seek to address. "All the wonderful choices lead to the problem of which ones to choose and prioritize," said Sudip Parikh, CEO of the American Association for the Advancement of Science and executive publisher of the Science family of journals. "There is no objectively right answer."
The Agency of Urgency
ARPA-H will borrow at least three critical ingredients from DARPA: goal-oriented project managers, many from industry; aggressive public-private partnerships; and collaboration among fields that don't always interact. The DARPA concept has been applied to other purposes, including energy and homeland security, with promising results. "We're learning that 'ARPA-ism' is a franchisable model," said Might, a former principal investigator on DARPA projects.
The federal government already pours billions of dollars into advancing research on life-threatening diseases, with much of it channeled through the National Institutes of Health. But the purpose of ARPA-H "isn't just the usual suspects that NIH would fund," said David Walt, a Harvard biochemist, an innovator in gene sequencing and former chair of DARPA's Defense Science Research Council. Whereas some NIH-funded studies aim to gradually improve our understanding of diseases, ARPA-H projects will give full focus to real-world applications; they'll use essential findings from NIH research as starting points, drawing from them to rapidly engineer new technologies that could save lives.
And, ultimately, billions in healthcare costs, if ARPA-H lives up to its predecessor's track record; DARPA's breakthroughs have been economic game-changers, while its fail-fast approach—quickly pulling the plug on projects that aren't panning out—helps to avoid sunken costs. ARPA-H could fuel activities similar to the human genome project, which used existing research to map the base pairs that make up DNA, opening new doors for the biotech industry, sparking economic growth and creating hundreds of thousands of new jobs.
Despite a nearly $4 trillion health economy, "we aren't innovating when it comes to technological capabilities for health," said Liz Feld, president of the Suzanne Wright Foundation for pancreatic cancer.
Individual Diseases Ripe for Innovation
Although the need for innovation is clear, which diseases ARPA-H should tackle is less apparent. One important consideration when choosing health priorities could be "how many people suffer from a disease," said Nancy Kass, a professor of bioethics and public health at Johns Hopkins.
That perspective could justify cancer as a top objective. Cancer and heart disease have long been the two major killers in the U.S. Leonidas Platanias, professor of oncology at Northwestern and director of its cancer center, noted that we've already made significant progress on heart disease. "Anti-cholesterol drugs really have a wide impact," he said. "I don't want to compare one disease to another, but I think cancer may be the most challenging. We need even bigger breakthroughs." He wondered whether ARPA-H should be linked to the part of NIH dedicated to cancer, the National Cancer Institute, "to take maximum advantage of what happens" there.
Previous cancer moonshots have laid a foundation for success. And this sort of disease-by-disease approach makes sense in a way. "We know that concentrating on some diseases has led to treatments," said Parikh. "Think of spinal muscular atrophy or cystic fibrosis. Now, imagine if immune therapies were discovered ten years earlier."
But many advocates think ARPA-H should choose projects that don't revolve around any one disease. "It absolutely has to be disease agnostic," said Feld, president of the pancreatic cancer foundation. "We cannot reach ARPA-H's potential if it's subject to the advocacy of individual patient groups who think their disease is worse than the guy's disease next to them. That's not the way the DARPA model works." Platanias agreed that ARPA-H should "pick the highest concepts and developments that have the best chance" of success.
Finding Connections Between Diseases
Kass, the Hopkins bioethicist, believes that ARPA-H should walk a balance, with some projects focusing on specific diseases and others aspiring to solutions with broader applications, spanning multiple diseases. Being impartial, some have noted, might involve looking at the total "life years" saved by a health innovation; the more diseases addressed by a given breakthrough, the more years of healthy living it may confer. The social and economic value should increase as well.
For multiple payoffs, ARPA-H could concentrate on rare diseases, which can yield important insights for many other diseases, said Might. Every case of cancer and Alzheimer's is, in a way, its own rare disease. Cancer is a genetic disease, like his son Bertrand's rare disorder, and mutations vary widely across cancer patients. "It's safe to say that no two people have ever actually had the same cancer," said Might. In theory, solutions for rare diseases could help us understand how to individualize treatments for more common diseases.
Many experts I talked with support another priority for ARPA-H with implications for multiple diseases: therapies that slow down the aging process. "Aging is the greatest risk factor for every major disease that NIH is studying," said Matt Kaeberlein, a bio-gerontologist at the University of Washington. Yet, "half of one percent of the NIH budget goes to researching the biology of aging. An ARPA-H sized budget would push the field forward at a pace that's hard to imagine."
Might agreed. "It could take ARPA-H to get past the weird stigmas around aging-related research. It could have a tremendous impact on the field."
For example, ARPA-H could try to use mRNA technology to express proteins that affect biological aging, said Kaeberlein. It's an engineering project well-suited to the DARPA model. So is harnessing machine learning to identify biomarkers that assess how fast people are aging. Biological aging clocks, if validated, could quickly reveal whether proposed therapies for aging are working or not. "I think there's huge value in that," said Kaeberlein.
By delivering breakthroughs in computation, ARPA-H could improve diagnostics for many different diseases. That could include improving biowearables for continuously monitoring blood pressure—a hypothetical mentioned in the White House's concept paper on ARPA-H—and advanced imaging technologies. "The high cost of medical imaging is a leading reason why our healthcare costs are the highest in the world," said Feld. "There's no detection test for ALS. No brain detection for Alzheimer's. Innovations in detection technology would save on cost and human suffering."
Some biotech companies may be skeptical about the financial rewards of accelerating such technologies. But ARPA-H could fund public-private partnerships to "de-risk" biotech's involvement—an incentive that harkens back to the advance purchase contracts that companies got during Covid. (Some groups have suggested that ARPA-H could provide advance purchase agreements.)
Parikh is less bullish on creating diagnostics through ARPA-H. Like DARPA, Biden's health agency will enjoy some independence from federal oversight; it may even be located hundreds of miles from DC. That freedom affords some breathing room for innovation, but it could also make it tougher to ensure that algorithms fully consider diverse populations. "That part I really would like the government more involved in," Parikh said.
Might thinks ARPA-H should also explore innovations in clinical trials, which many patients and medical communities view as grindingly slow and requiring too many participants. "We can approve drugs for very tiny patient populations, even at the level of the individual," he said, while emphasizing the need for safety. But Platanias thinks the FDA has become much more flexible in recent years. In the cancer field, at least, "You now see faster approvals for more drugs. Having [more] shortcuts on clinical trial approvals is not necessarily a good idea."
With so many options on the table, ARPA-H needs to show the public a clear framework for measuring the value of potential projects. Kass warned that well-resourced advocates could skew the agency's priorities. They've affected health outcomes before, she noted; fundraising may partly explain larger increases in life expectancy for cystic fibrosis than sickle cell anemia. Engaging diverse communities is a must for ARPA-H. So are partnerships to get the agency's outputs to people who need them. "Research is half the equation," said Kass. "If we don't ensure implementation and access, who cares." The White House concept paper on ARPA-H made a similar point.
As Congress works on authorizing ARPA-H this year, Might is doing what he can to ensure better access to innovation on a patient-by-patient basis. Last year, his son, Bertrand, passed away suddenly from his disorder. He was 12. But Might's sense of urgency has persisted, as he directs the Precision Medicine Institute at the University of Alabama-Birmingham. That urgency "can be carried into an agency like ARPA-H," he said. "It guides what I do as I apply for funding, because I'm trying to build the infrastructure that other parents need. So they don't have to build it from scratch like I did."
Two-and-a-half year-old Huckleberry, a blue merle Australian shepherd, pulls hard at her leash; her yelps can be heard by skiers and boarders high above on the chairlift that carries them over the ski patrol hut to the top of the mountain. Huckleberry is an avalanche rescue dog — or avy dog, for short. She lives and works with her owner and handler, a ski patroller at Breckenridge Ski Resort in Colorado. As she watches the trainer play a game of hide-and-seek with six-month-old Lume, a golden retriever and avy dog-in-training, Huckleberry continues to strain on her leash; she loves the game. Hide-and-seek is one of the key training methods for teaching avy dogs the rescue skills they need to find someone caught in an avalanche — skier, snowmobiler, hiker, climber.
Lume’s owner waves a T-shirt in front of the puppy. While another patroller holds him back, Lume’s owner runs away and hides. About a minute later — after a lot of barking — Lume is released and commanded to “search.” He springs free, running around the hut to find his owner who reacts with a great amount of excitement and fanfare. Lume’s scent training will continue for the rest of the ski season (Breckenridge plans operating through May or as long as weather permits) and through the off-season. “We make this game progressively harder by not allowing the dog watch the victim run away,” explains Dave Leffler, Breckenridge's ski patroller and head of the avy dog program, who has owned, trained and raised many of them. Eventually, the trainers “dig an open hole in the snow to duck out of sight and gradually turn the hole into a cave where the dog has to dig to get the victim,” explains Leffler.
By the time he is three, Lume, like Huckleberry, will be a fully trained avy pup and will join seven other avy dogs on Breckenridge ski patrol team. Some of the team members, both human and canine, are also certified to work with Colorado Rapid Avalanche Deployment, a coordinated response team that works with the Summit County Sheriff’s office for avalanche emergencies outside of the ski slopes’ boundaries.
There have been 19 avalanche deaths in the U.S. this season, according to avalanche.org, which tracks slides; eight in Colorado. During the entirety of last season there were 17. Avalanche season runs from November through June, but avalanches can occur year-round.
High tech and high stakes
Complementing avy dogs’ ability to smell people buried in a slide, avalanche detection, rescue and recovery is becoming increasingly high tech. There are transceivers, signal locators, ground scanners and drones, which are considered “games changers” by many in avalanche rescue and recovery
For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
A drone can provide thermal imaging of objects caught in a slide; what looks like a rock from far away might be a human with a heat signature. Transceivers, also known as beacons, send a signal from an avalanche victim to a companion. Signal locators, like RECCO reflectors which are often sewn directly into gear, can echo back a radar signal sent by a detector; most ski resorts have RECCO detector units.
Research suggests that Ground Penetrating Radar (GPR), an electromagnetic tool used by geophysicists to pull images from inside the ground, could be used to locate an avalanche victim. A new study from the Department of Energy’s Sandia National Laboratories suggests that a computer program developed to pinpoint the source of a chemical or biological terrorist attack could also be used to find someone submerged in an avalanche. The search algorithm allows for small robots (described as cockroach-sized) to “swarm” a search area. Researchers say that this distributed optimization algorithm can help find avalanche victims four times faster than current search mechanisms. For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
An avy dog in training is picking up scent
Sarah McLear
While rescue gear has been evolving, predicting when a slab will fall remains an emerging science — kind of where weather forecasting science was in the 1980s. Avalanche forecasting still relies on documenting avalanches by going out and looking,” says Ethan Greene, director of the Colorado Avalanche Information Center (CAIC). “So if there's a big snowstorm, and as you might remember, most avalanches happened during snowstorms, we could have 10,000 avalanches that release and we document 50,” says Greene. “Avalanche forecasting is essentially pattern recognition,” he adds--and understanding the layering structure of snow.
However, determining where the hazards lie can be tricky. While a dense layer of snow over a softer, weaker layer may be a recipe for an avalanche, there’s so much variability in snowpack that no one formula can predict the trigger. Further, observing and measuring snow at a single point may not be representative of all nearby slopes. Finally, there’s not enough historical data to help avalanche scientists create better prediction models.
That, however, may be changing.
Last year, an international group of researchers created computer simulations of snow cover using 16 years of meteorological data to forecast avalanche hazards, publishing their research in Cold Regions Science and Technology. They believe their models, which categorize different kinds of avalanches, can support forecasting and determine whether the avalanche is natural (caused by temperature changes, wind, additional snowfall) or artificial (triggered by a human or animal).
With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides.
With data from two sites in British Columbia and one in Switzerland, researchers built computer simulations of five different avalanche types. “In terms of real time avalanche forecasting, this has potential to fill in a lot of data gaps, where we don't have field observations of what the snow looks like,” says Simon Horton, a postdoctoral fellow with the Simon Fraser University Centre for Natural Hazards Research and a forecaster with Avalanche Canada, who participated in the study. While complex models that simulate snowpack layers have been around for a few decades, they weren’t easy to apply until recently. “It's been difficult to find out how to apply that to actual decision-making and improving safety,” says Horton. If you can derive avalanche problem types from simulated snowpack properties, he says, you’ll learn “a lot about how you want to manage that risk.”
The five categories include “new snow,” which is unstable and slides down the slope, “wet snow,” when rain or heat makes it liquidly, as well as “wind-drifted snow,” “persistent weak layers” and “old snow.” “That's when there's some type of deeply buried weak layer in the snow that releases without any real change in the weather,” Horton explains. “These ones tend to cause the most accidents.” One step by a person on that structurally weak layer of snow will cause a slide. Horton is hopeful that computer simulations of avalanche types can be used by scientists in different snow climates to help predict hazard levels.
Greene is doubtful. “If you have six slopes that are lined up next to each other, and you're going to try to predict which one avalanches and the exact dimensions and what time, that's going to be really hard to do. And I think it's going to be a long time before we're able to do that,” says Greene.
What both researchers do agree on, though, is that what avalanche prediction really needs is better imagery through satellite detection. “Just being able to count the number of avalanches that are out there will have a huge impact on what we do,” Greene says. “[Satellites] will change what we do, dramatically.” In a 2022 paper, scientists at the University of Aberdeen in England used satellites to study two deadly Himalayan avalanches. The imaging helped them determine that sediment from a 2016 ice avalanche plus subsequent snow avalanches contributed to the 2021 avalanche that caused a flash flood, killing over 200 people. The researchers say that understanding the avalanches characteristics through satellite imagery can inform them how one such event increases the magnitude of another in the same area.
Avy dogs trainers hide in dug-out holes in the snow, teaching the dogs to find buried victims
Sarah McLear
Lifesaving combo: human tech and Mother Nature’s gear
Even as avalanche forecasting evolves, dogs with their built-in rescue mechanisms will remain invaluable. With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides. (Humans in comparison, have a meager 12 million.) A new study published in the Journal of Neuroscience revealed that in dogs smell and vision are connected in the brain, which has not been found in other animals. “They can detect the smell of their owner's fingerprints on a glass slide six weeks after they touched it,” says Nicholas Dodman, professor emeritus at Cummings School of Veterinary Medicine at Tufts University. “And they can track from a boat where a box filled with meat was buried in the water, 100 feet below,” says Dodman, who is also co-founder and president of the Center for Canine Behavior Studies.
Another recent study from Queens College in Belfast, United Kingdom, further confirms that dogs can smell when humans are stressed. They can also detect the smell of a person’s breath and the smell of the skin cells of a deceased person.
The emerging avalanche-predicting human-made tech and the incredible nature-made tech of dogs’ olfactory talents is the lifesaving “equipment” that Leffler believes in. Even when human-made technology develops further, it will be most efficient when used together with the millions of dogs’ smell receptors, Leffler believes. “It is a combination of technology and the avalanche dog that will always be effective in finding an avalanche victim.”
Living with someone changes your microbiome, new research shows
Some roommate frustration can be expected, whether it’s a sink piled high with crusty dishes or crumbs where a clean tabletop should be. Now, research suggests a less familiar issue: person-to-person transmission of shared bacterial strains in our gut and oral microbiomes. For the first time, the lab of Nicola Segata, a professor of genetics and computational biology at the University of Trento, located in Italy, has shown that bacteria of the microbiome are transmitted between many individuals, not just infants and their mothers, in ways that can’t be explained by their shared diet or geography.
It’s a finding with wide-ranging implications, yet frustratingly few predictable outcomes. Our microbiomes are an ever-growing and changing collection of helpful and harmful bacteria that we begin to accumulate the moment we’re born, but experts are still struggling to unravel why and how bacteria from one person’s gut or mouth become established in another person’s microbiome, as opposed to simply passing through.
“If we are looking at the overall species composition of the microbiome, then there is an effect of age of course, and many other factors,” Segata says. “But if we are looking at where our strains are coming from, 99 percent of them are only present in other people’s guts. They need to come from other guts.”
If we could better understand this process, we might be able to control and use it; perhaps hospital patients could avoid infections from other patients when their microbiome is depleted by antibiotics and their immune system is weakened, for example. But scientists are just beginning to link human microbiomes with various ailments. Growing evidence shows that our microbiomes steer our long-term health, impacting conditions like obesity, irritable bowel syndrome, type 2 diabetes, and cancer.
Previous work from Segata’s lab and others illuminated the ways bacteria are passed from mothers to infants during the first few months of life during vaginal birth, breastfeeding and other close contact. And scientists have long known that people in close proximity tend to share bacteria. But the factors related to that overlap, such as genetics and diet, were unclear, especially outside the mother-baby dyad.
“If we look at strain sharing between a mother and an infant at five years of age, for example, we cannot really tell which was due to transmission at birth and which is due to continued transmission because of contact,” Segata says. Experts hypothesized that they could be caused by bacterial similarities in the environment itself, genetics, or bacteria from shared foods that colonized the guts of people in close contact.
Strain sharing was highest in mother-child pairs, with 96 percent of them sharing strains, and only slightly lower in members of shared households, at 95 percent.
In Italy, researchers led by Mireia Valles-Colomer, including Segata, hoped to unravel this mystery. They compared data from 9,715 stool and saliva samples in 31 genomic datasets with existing metadata. Scientists zoomed in on variations in each bacterial strain down to the individual level. They examined not only mother-child pairs, but people living in the same household, adult twins, and people living in the same village in a level of detail that wasn’t possible before, due to its high cost and difficulties in retrieving data about interactions between individuals, Segata explained.
“This paper is, with high granularity, quantifying the percent sharing that you expect between different types of social interactions, controlling for things like genetics and diet,” Gibbons says. Strain sharing was highest in mother-child pairs, with 96 percent of them sharing strains, and only slightly lower in members of shared households, at 95 percent. And at least half of the mother-infant pairs shared 30 percent of their strains; the median was 12 percent among people in shared households. Yet, there was no sharing among eight percent of adult twins who lived separately, and 16 percent of people within villages who resided in different households. The results were published in Nature.
It’s not a regional phenomenon. Although the types of bacterial strains varied depending on whether people lived in western and eastern nations — datasets were drawn from 20 countries on five continents — the patterns of sharing were much the same. To establish these links, scientists focused on individual variations in shared bacterial strains, differences that create unique bacterial “fingerprints” in each person, while controlling for variables like diet, demonstrating that the bacteria had been transmitted between people and were not the result of environmental similarities.
The impact of this bacterial sharing isn’t clear, but shouldn’t be viewed with trepidation, according to Sean Gibbons, a microbiome scientist at the nonprofit Institute for Systems Biology.
“The vast majority of these bugs are actually either benign or beneficial to our health, and the fact that we're swapping and sharing them and that we can take someone else's strain and supplement or better diversify our own little garden is not necessarily a bad thing,” he says.
"There are hundreds of billions of dollars of investment capital moving into these microbiome therapeutic companies; bugs as drugs, so to speak,” says Sean Gibbons, a microbiome scientist at the Institute for Systems Biology.
Everyday habits like exercising and eating vegetables promote a healthy, balanced gut microbiome, which is linked to better metabolic and immune function, and fewer illnesses. While many people’s microbiomes contain bacteria like C. diff or E. coli, these bacteria don’t cause diseases in most cases because they’re present in low levels. But a microbiome that’s been wiped out by, say, antibiotics, may no longer keep these bacteria in check, allowing them to proliferate and make us sick.
“A big challenge in the microbiome field is being able to rationally predict whether, if you're exposed to a particular bug, it will stick in the context of your specific microbiome,” Gibbons says.
Gibbons predicts that explorations of microbe-based therapeutics will be “exploding” in the coming decades. “There are hundreds of billions of dollars of investment capital moving into these microbiome therapeutic companies; bugs as drugs, so to speak,” he says. Rather than taking a mass-marketed probiotic, a precise understanding of an individual’s microbiome could help target the introduction of just the right bacteria at just the right time to prevent or treat a particular illness.
Because the current study did not differentiate between different types of contact or relationships among household members sharing bacterial strains or determine the direction of transmission, Segata says his current project is examining children in daycare settings and tracking their microbiomes over time to understand the role genetics and everyday interactions play in the level of transmission that occurs.
This relatively newfound ability to trace bacterial variants to minute levels has unlocked the chance for scientists to untangle when and how bacteria leap from one microbiome to another. As researchers come to better understand the factors that permit a strain to establish itself within a microbiome, they could uncover new strategies to control these microbes, harnessing the makeup of each microbiome to help people to resist life-altering medical conditions.