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."
Even before the pandemic created a need for more telehealth options, depression was a hot area of research for app developers. Given the high prevalence of depression and its connection to suicidality — especially among today’s teenagers and young adults who grew up with mobile devices, use them often, and experience these conditions with alarming frequency — apps for depression could be not only useful but lifesaving.
“For people who are not depressed, but have been depressed in the past, the apps can be helpful for maintaining positive thinking and behaviors,” said Andrea K. Wittenborn, PhD, director of the Couple and Family Therapy Doctoral Program and a professor in human development and family studies at Michigan State University. “For people who are mildly to severely depressed, apps can be a useful complement to working with a mental health professional.”
Health and fitness apps, in general, number in the hundreds of thousands. These are driving a market expected to reach $102.45 billion by next year. The mobile mental health app market is a small part of this but still sizable at $500 million, with revenues generated through user health insurance, employers, and direct payments from individuals.
Apps can provide data that health professionals cannot gather on their own. People’s constant interaction with smartphones and wearable devices yields data on many health conditions for millions of patients in their natural environments and while they go about their usual activities. Compared with the in-office measurements of weight and blood pressure and the brevity of doctor-patient interactions, the thousands of data points gathered unobtrusively over an extended time period provide a far better and more detailed picture of the person and their health.
At their most advanced level, apps for mental health, including depression, passively gather data on how the user touches and interacts with the mobile device through changes in digital biomarkers that relate to depressive symptoms and other conditions.
Building on three decades of research since early “apps” were used for delivering treatment manuals to health professionals, today’s more than 20,000 mental health apps have a wide range of functionalities and business models. Many of these apps can be useful for depression.
Some apps primarily provide a virtual connection to a group of mental health professionals employed or contracted by the app. Others have options for meditation, sleeping or, in the case of industry leaders Calm and Headspace, overall well-being. On the cutting edge are apps that detect changes in a person’s use of mobile devices and their interactions with them.
Apps such as AbleTo, Happify Health, and Woebot Health focus on cognitive behavioral therapy, a type of counseling with proven potential to change a person’s behaviors and feelings. “CBT has been demonstrated in innumerable studies over the last several decades to be effective in the treatment of behavioral health conditions such as depression and anxiety disorders,” said Dr. Reena Pande, chief medical officer at AbleTo. “CBT is intended to be delivered as a structured intervention incorporating key elements, including behavioral activation and adaptive thinking strategies.”
These CBT skills help break the negative self-talk (rumination) common in patients with depression. They are taught and reinforced by some self-guided apps, using either artificial intelligence or programmed interactions with users. Apps can address loneliness and isolation through connections with others, even when a symptomatic person doesn’t feel like leaving the house.
At their most advanced level, apps for mental health, including depression, passively gather data on how the user touches and interacts with the mobile device through changes in “digital biomarkers” that can be associated with onset or worsening of depressive symptoms and other cognitive conditions. In one study, Mindstrong Health gathered a year’s worth of data on how people use their smartphones, such as scrolling through articles, typing and clicking. Mindstrong, whose founders include former leaders of the National Institutes of Health, modeled the timing and order of these actions to make assessments that correlated closely with gold-standard tests of cognitive function.
National organizations of mental health professionals have been following the expanding number of available apps over the years with keen interest. App Advisor is an initiative of the American Psychiatric Association that helps psychiatrists and other mental health professionals navigate the issues raised by mobile health technology. App Advisor does not rate or recommend particular apps but rather provides guidance about why apps should be assessed and how health professionals can do this.
A website that does review mental health apps is One Mind Psyber Guide, an independent nonprofit that partners with several national organizations. One Mind users can select among numerous search terms for the condition and therapeutic approach of interest. Apps are rated on a five-point scale, with reviews written by professionals in the field.
Do mental health apps related to depression have the kind of safety and effectiveness data required for medications and other medical interventions? Not always — and not often. Yet the overall results have shown early promise, Wittenborn noted.
“Studies that have attempted to detect depression from smartphone and wearable sensors [during a single session] have ranged in accuracy from about 86 to 89 percent,” Wittenborn said. “Studies that tried to predict changes in depression over time have been less accurate, with accuracy ranging from 59 to 85 percent.”
The Food and Drug Administration encourages the development of apps and has approved a few of them—mostly ones used by health professionals—but it is generally “hands off,” according to the American Psychiatric Association. The FDA has published a list of examples of software (including programming of apps) that it does not plan to regulate because they pose low risk to the public. First on the list is software that helps patients with diagnosed psychiatric conditions, including depression, maintain their behavioral coping skills by providing a “Skill of the Day” technique or message.
On its App Advisor site, the American Psychiatric Association says mental health apps can be dangerous or cause harm in multiple ways, such as by providing false information, overstating the app’s therapeutic value, selling personal data without clearly notifying users, and collecting data that isn’t relevant to mental health.
Although there is currently reason for caution, patients may eventually come to expect mental health professionals to recommend apps, especially as their rating systems, features and capabilities expand. Through such apps, patients might experience more and higher quality interactions with their mental health professionals. “Apps will continue to be refined and become more effective through future research,” said Wittenborn. “They will become more integrated into practice over time.”
Podcast: Has the First 150-Year-Old Already Been Born
Steven Austad is a pioneer in the field of aging, with over 200 scientific papers and book chapters on pretty much every aspect of biological aging that you could think of. He’s also a strong believer in the potential for anti-aging therapies, and he puts his money where his mouth is. In 2001, he bet a billion dollars that the first person to reach 150-years-old had already been born. I had a chance to talk with Steven for today’s podcast and asked if he still thinks the bet was a good idea, since the oldest person so far (that we know of), Jeanne Calment, died back in 1997. A few days after our conversation, the oldest person in the world, Kane Tanaka, died at 119.
Steven is the Protective Life Endowed Chair in Health Aging Research, a Distinguished Professor and Chair of the Department of Biology at the University of Alabama Birmingham. He's also Senior Scientific Director of the American Federation for Aging Research, which is managing a groundbreaking longevity research trial that started this year. Steven is also a great science communicator with five books, including one that comes out later this year, Methuselah’s Zoo, and he publishes prolifically in national media outlets.
See the rest of his bio linked below in the show notes.
Listen to the Episode
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Steven Austad is featured in the latest episode of Making Sense of Science. He's a distinguished professor of biology at the University of Alabama Birmingham and has a new book due to be published in August, Methuselah's Zoo.
Photo by Steve Wood
Show notes:
2:36 - Steven explains why a particular opossum convinced him to dedicate his career to studying longevity.
6:48 - Steven's billion dollar bet that someone alive today will make it to 150-years-old.
9:15 - The most likely people to make it to 150 (Hint: not men).
10:38 - I ask Steven about Elon Musk’s comments this month that if people lived a really long time, “we’d be stuck with old ideas and society wouldn’t advance.” Steve isn’t so fond of that take.
13:34 - Why women are winning maybe the most important battle of sexes: staying alive. This is an area that Steven has led research on (see show notes).
18:20 - Why women, on average, actually have more morbidities earlier than men, even though they live longer.
23:10 - How the pandemic could affect sex differences in longevity.
24:55 - How often should people work out and get other physical activity to maximize longevity and health span?
29:09 - Steven gave me the latest update on the TAME trial on metformin, and how he and others longevity experts designed this groundbreaking research on longevity not in their offices, not on a zoom call, but in a castle in the Spanish countryside.
32:10 - Which anti-aging therapies are the most promising at this point for future research.
39:32 - The drug cocktail approach to address multiple hallmarks of aging.
41:00 - How to read health news like a scientist.
45:38 - Should we try a Manhattan project for aging?
48:47 - Can Jeff Bezos and Larry Ellison help us live to 150?
Show links:
Steven Austad's bio
Pre-order Steven's new book, Methuselah's Zoo - https://www.amazon.com/dp/B09M2QGRJR/ref=dp-kindle-redirect?_encoding=UTF8&btkr=1
Steven's journal article on Sex Differences in Lifespan - https://pubmed.ncbi.nlm.nih.gov/27304504/
Elon Musk's comments on super longevity "asphyxiating" society - https://www.cnbc.com/2022/04/11/elon-musk-on-avoid...
Steven's article on how to read news articles about health like a pro - https://www.nextavenue.org/how-to-read-health-news...
AFAR's research on Targeting Aging with Metformin (TAME) - https://www.afar.org/tame-trial