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."
The Friday Five: Scientists treated this girl's disease before she was born
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- Kids treated for diseases before they're born
- How to lift weights in half the time
- Electric shocks help people regain the ability to walk
- Meditation just as good as medication?
- These foods could pump up your motivation
Tapping into the Power of the Placebo Effect
When Wayne Jonas was in medical school 40 years ago, doctors would write out a prescription for placebos, spelling it out backwards in capital letters, O-B-E-C-A-L-P. The pharmacist would fill the prescription with a sugar pill, recalls Jonas, now director of integrative health programs at the Samueli Foundation. It fulfilled the patient's desire for the doctor to do something when perhaps no drug could help, and the sugar pills did no harm.
Today, that deception is seen as unethical. But time and time again, studies have shown that placebos can have real benefits. Now, researchers are trying to untangle the mysteries of placebo effect in an effort to better treat patients.
The use of placebos took off in the post-WWII period, when randomized controlled clinical trials became the gold standard for medical research. One group in a study would be treated with a placebo, a supposedly inert pill or procedure that would not affect normal healing and recovery, while another group in the study would receive an "active" component, most commonly a pill under investigation. Presumably, the group receiving the active treatment would have a better response and the difference from the placebo group would represent the efficacy of the drug being tested. That was the basis for drug approval by the U.S. Food and Drug Administration.
"Placebo responses were marginalized," says Ted Kaptchuk, director of the Program in Placebo Studies & Therapeutic Encounters at Harvard Medical School. "Doctors were taught they have to overcome it when they were thinking about using an effective drug."
But that began to change around the turn of the 21st century. The National Institutes of Health held a series of meetings to set a research agenda and fund studies to answer some basic questions, led by Jonas who was in charge of the office of alternative medicine at the time. "People spontaneously get better all the time," says Kaptchuk. The crucial question was, is the placebo effect real? Is it more than just spontaneous healing?
Brain mechanisms
A turning point came in 2001 in a paper in Science that showed physical evidence of the placebo effect. It used positron emission tomography (PET) scans to measure release patterns of dopamine — a chemical messenger involved in how we feel pleasure — in the brains of patients with Parkinson's disease. Surprisingly, the placebo activated the same patterns that were activated by Parkinson's drugs, such as levodopa. It proved the placebo effect was real; now the search was on to better understand and control it.
A key part of the effect can be the beliefs, expectations, context, and "rituals" of the encounter between doctor and patient. Belief by the doctor and patient that the treatment would work, and the formalized practices of administering the treatment can all contribute to a positive outcome.
Conditioning can be another important component in generating a response, as Pavlov demonstrated more than a century ago in his experiments with dogs. They were trained with a bell prior to feeding such that they would begin to salivate in anticipation at the sound of a bell even with no food present.
Translating that to humans, studies with pain medications and sleeping aids showed that patients who had a positive response with a certain dose of those medications could have the same response if the doses was reduced and a dummy pill substituted, even to the point where there was no longer any active ingredient.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders.
Those types of studies troubled Kaptchuk because they often relied on deception; patients weren't told they were receiving a placebo, or at best there was a possibility that they might be randomized to receive a placebo. He believed the placebo effect could work even if patients were told upfront that they were going to receive a placebo. More than a dozen so call "open-label placebo" studies across numerous medical conditions, by Kaptchuk and others, have shown that you don't have to lie to patients for a placebo to work.
Jonas likes to tell the story of a patient who used methotrexate, a potent immunosuppressant, to control her rheumatoid arthritis. She was planning a long trip and didn't want to be bothered with the injections and monitoring required in using the drug, So she began to drink a powerful herbal extract of anise, a licorice flavor that she hated, prior to each injection. She reduced the amount of methotrexate over a period of months and finally stopped, but continued to drink the anise. That process had conditioned her body "to alter her immune function and her autoimmunity" as if she were taking the drug, much like Pavlov's dogs had been trained. She has not taken methotrexate for more than a year.
An intriguing paper published in May 2021 found that mild, non-invasive electric stimulation to the brain could not only boost the placebo effect on pain but also reduce the "nocebo" effect — when patients report a negative effect to a sham treatment. While the work is very preliminary, it may open the door to directly manipulating these responses.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders, areas where drugs often are of little help. Still, placebos aren't a cure and only a portion of patients experience a placebo effect.
Nocebo
If medicine were a soap opera, the nocebo would be the evil twin of the placebo. It's what happens when patients have adverse side effects because of the expectation that they will. It's commonly seem when patients claims to experience pain or gastric distress that can occur with a drug even when they've received a placebo. The side effects were either imagined or caused by something else.
"Up to 97% of reported pharmaceutical side effects are not caused by the drug itself but rather by nocebo effects and symptom misattribution," according to one 2019 paper.
One way to reduce a nocebo response is to simply not tell patients that specific side effects might occur. An example is a liver biopsy, in which a large-gauge needle is used to extract a tissue sample for examination. Those told ahead of time that they might experience some pain were more likely to report pain and greater pain than those who weren't offered this information.
Interestingly, a nocebo response plays out in the hippocampus, a part of the brain that is never activated in a placebo response. "I think what we are dealing with with nocebo is anxiety," says Kaptchuk, but he acknowledges that others disagree.
Distraction may be another way to minimize the nocebo effect. Pediatricians are using virtual reality (VR) to engage children and distract them during routine procedures such as blood draws and changing wound dressings, and burn patients of all ages have found relief with specially created VRs.
Treatment response
Jonas argues that what we commonly call the placebo effect is misnamed and leading us astray. "The fact is people heal and that inherent healing capacity is both powerful and influenced by mental, social, and contextual factors that are embedded in every medical encounter since the idea of treatment began," he wrote in a 2019 article in the journal Frontiers in Psychiatry. "Our understanding of healing and ability to enhance it will be accelerated if we stop using the term 'placebo response' and call it what it is—the meaning response, and its special application in medicine called the healing response."
He cites evidence that "only 15% to 20% of the healing of an individual or a population comes from health care. The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life."
To better align treatments and maximize their effectiveness, Jonas has created HOPE (Healing Oriented Practices & Environments) Note, "a patient-guided process designed to identify the patient's values and goals in their life and for healing." Essentially, it seeks to make clear to both doctor and patient what the patient's goals are in seeking treatment. In an extreme example of terminal cancer, some patients may choose to extend life despite the often brutal treatments, while others might prefer to optimize quality of life in the remaining time that they have. It builds on practices already taught in medical schools. Jonas believes doctors and patients can use tools like these to maximize the treatment response and achieve better outcomes.
Much of the medical profession has been resistant to these approaches. Part of that is simply tradition and limited data on their effectiveness, but another very real factor is the billing process for how they are reimbursed. Jonas says a new medical billing code added this year gives doctors another way to be compensated for the extra time and effort that a more holistic approach to medicine may initially require. Other moves away from fee-for-service payments to bundling and payment for outcomes, and the integrated care provided by the Veterans Affairs, Kaiser Permanente and other groups offer longer term hope for the future of approaches that might enhance the healing response.
This article was first published by Leaps.org on July 7, 2021.