Thinking outside the box: A new approach to scientific discovery

Elena Fuentes-Afflick, MD, leads a plenary discussion with Kizzmekia S. Corbett-Helaire, PhD, and David Fajgenbaum, MD, MBA, MSc, at Learn Serve Lead 2024: The AAMC Annual Meeting on Nov. 11.

Credit: Kaveh Sardari

The pace of scientific innovation can seem incremental - until it isn't.

When the COVID-19 pandemic hit Wuhan, China, in late 2019, Kizzmekia S. Corbett-Helaire, PhD, had been researching novel coronaviruses for five years as a senior research fellow at the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. She and her team had been working on a vaccine against similar coronaviruses, and immediately turned their attention to the new virus - work that ultimately resulted in the Moderna mRNA COVID vaccine, which saved millions of lives around the globe.

In 2010, David Fajgenbaum was a third-year medical student at the University of Pennsylvania Perelman School of Medicine when he was diagnosed with Castleman's disease, a rare and fatal autoimmune disease. Over the next three years, the former Georgetown University quarterback would face four relapses, and his doctors ran out of drugs to treat him. That's when Fajgenbaum set out to find his own cure, eventually finding an old drug called sirolimus, which successfully tamed his out-of-control immune system. Fajgenbaum is now an associate professor of medicine at the University of Pennsylvania and executive director of the nonprofit Every Cure, which seeks to repurpose some of the more than 4,000 existing, FDA-approved drugs to cure other diseases. Thus far, his team has identified 14 drugs that have successfully treated thousands of patients, and is harnessing the power of artificial intelligence to identify many more.

These discoveries - the mRNA vaccines for COVID-19 and repurposed drugs for known diseases - required Corbett-Helaire and Fajgenbaum to think not in terms of what small discovery can I make that will advance the science - but what big ideas do I have that can make a meaningful difference.

"The truth of the matter is that the types of questions that I have tended to ask throughout the course of my career, and specifically in my lab, are the questions that are outside of the box," Corbett-Helaire said during a plenary titled "Scientific Discoveries for a Healthier Future: Connecting the Dots" at Learn Serve Lead 2024: The AAMC Annual Meeting on Nov. 11. "I allow the science to lead the way."

Fajgenbaum similarly didn't have "a billion dollars and 10 years" to find a cure for his own disease - he had months. As a result, he had to flip the typical way of doing scientific research: Instead of coming up with a drug or an idea and trying to find funding to test it, he gathers physicians, researchers, and patients, and asks them: "What research should be done? What research questions need to be asked?" And then he finds the best people to do those studies.

"I get this tremendous motivation from each of the patients that we're able to help," he said. "And that really motivates me. But what really, really motivates me are the patients we weren't able to help in time."

In a far-ranging conversation with Elena Fuentes-Afflick, MD, AAMC chief scientific officer, Corbett-Helaire and Fajgenbaum shared their perspectives on the importance of mentors, the funding conundrum, and the importance of teamwork - "Who wants to save the world alone?" Corbett-Helaine quipped.

The panel also discussed the importance of sharing not just positive research results - but negative ones as well - to advance scientific knowledge.

These negative results are critically important not just to inform the rest of the scientific community, but to help train AI algorithms (for future scientific research) and to help educate the public about how science works, the panelists agreed.

Several months ago, Fajgenbaum sat down with AAMCNews to share his experience as a physician-researcher, patient, and advocate; creating an innovative research approach for rare diseases; and finding hope in the midst of adversity.

This interview has been edited for brevity and clarity.

You nearly died multiple times from a rare disease but were able to discover your own treatment for it. How did you manage to do that?

Out of nowhere, I became really sick and spent months in the ICU. It turned out I had Castleman disease, which causes the immune system to attack one's organs. I nearly died four more times in three years. Thankfully, I got a lot of chemotherapy that worked well enough to save my life all of those times. But I knew I was unlikely to survive that way long term.

After one of my relapses, I began collecting blood samples on myself. Then, after graduating from medical school, I had my fourth near-fatal relapse. There were no other options left, and I couldn't afford to wait until new drugs might be developed. I knew I needed to figure out what was going wrong in my immune system and see if there was an existing drug that could be repurposed to treat it.

So I began performing experiments on my blood samples. Two datasets pointed to a key communication line in the immune system called mTOR, which seemed to be in overdrive. One drug, sirolimus, is a really good inhibitor of that communication line, so I began testing it on myself with my doctor's permission.

It's been over 10½ years that I've been in remission on sirolimus. Thankfully, many other patients are doing really well on it too.

What have been some of the significant obstacles for researchers hoping to find treatments for rare diseases like yours?

Rare-disease research is challenging for a number of reasons. One problem is clear just in its name: With a rare disease, there are fewer patients for clinical trials, and there's typically less funding and awareness. There's also less work that has been done to date, so there's less to build upon. Science is all about building upon previous work to get the answers you need.

Sometimes there's data that suggests that an existing drug might work for another disease. But because over 80% of approved drugs are already generic, there's no profit incentive for drug companies to find new uses for them.

Rare-disease researchers face major challenges. But they also have great opportunities to make a lot of progress.

You created an innovative nonprofit, the Castleman Disease Collaborative Network (CDCN), which launched a new paradigm for research into rare diseases. Can you describe the group's unusual approach?

The first [change in approach] is how we do research. A traditional rare-disease organization usually starts by raising money and then inviting researchers to apply for that money. You hope that the right researcher with the right skill set applies for the right project at the right time. But that's very unlikely.

At CDCN, rather than raising money and hoping the right people apply, we build a network of physicians, researchers, and patients, and we ask them what questions need answering. Then we use those questions to determine what studies should be done. Once we know what research should be done, we recruit the best researchers in the world to do it.

The second transformative approach is a shift regarding drugs, to repurposing them. It's incredible when drug companies can develop medications from scratch. But developing a new drug requires between 1 billion and 2 billion dollars, and it takes over 10 years to get FDA approval. So CDCN is much more focused on repurposing drugs that have already been approved by the FDA.

There are 3,000 FDA-approved drugs. We already know how those drugs work. We know how safe they are in certain populations. We know what problems they address. So we have the opportunity to really move things forward rapidly.

Finally, we bring together stakeholders from across health care. So we've got patients, doctors, and researchers in the room, sharing diverse perspectives. That is so important.

Another nonprofit you helped to create, Every Cure, recently received a $48 million award from the Advanced Research Projects Agency for Health for its AI-driven research approach. Can you talk about that?

After I finished medical school and business school, I joined the faculty at Penn to focus on discovering treatments for hyperinflammatory diseases like Castleman. Over the past nine years, the team has led the advancement of 14 repurposed treatments for those diseases.

Humans deal with about 20,000 diseases, and the majority don't have a treatment. A few years ago we started asking, "How many more diseases could be treated by drugs sitting in pharmacies?" Could we replicate more broadly what we'd done before for some diseases by repurposing medications - and could we utilize artificial intelligence to do that?

About two years ago we decided to launch Every Cure, because the AI technology had advanced so much. It's pretty cool what you can do with artificial intelligence. We can run analyses that look across all of the world's knowledge of every drug and every disease.

We come up with a single score for every one of the 3,000 approved drugs and the likelihood that it can treat another one of the 20,000 diseases. That's 60 million computations. We can do that in about one day. If my team was trying to do that by running experiments in the lab, we'd need about 1,000 years. AI won't be perfect, but it can help find the drugs that it makes sense for researchers to explore further.

Has Every Cure had any successes yet?

One that comes to mind is from this past January. We had a woman reach out to us on a Friday because her fiancé, Joseph, was going to be transferred to hospice care on Monday. He has a rare disease called POEMS syndrome.

We looked through our scores and found drugs that had worked in a similar disease, myeloma. I got in touch with his doctor over the weekend and advocated for trying three drugs used for myeloma to see if they could help. After a long conversation, he agreed. Joseph responded beautifully to them, and he did not have to be transferred to hospice. He's back home with his family now. And we can say, "Let's look into this combination of drugs to help other patients too."

What has being a patient taught you about being a researcher and a doctor?

For one, it has focused me entirely on what's going to help patients. The driving force for all my research is patient impact.

Second, it has created an incredible sense of urgency within me, not just for Castleman disease, but also for every other condition we study. I know what it's like to be on the other side of these diseases, when every day is a day when someone will pass away.

The third thing is that it's helped me to see just how important everyone's perspective is. When you're a patient, you think that doctors and researchers don't know much because they don't have the disease. And when you're a doctor or researcher, sometimes you think patients don't know much about the science. But it's abundantly clear to me that we all have important contributions to make and we all have to work together.

You've had many successes, including creating the first-ever diagnostic criteria and treatment guidelines for Castleman disease. What makes you most proud?

Undoubtedly, one of the things that I'm most proud of is the many patients that we've been able to help. It would be impossible for me to pick between Joseph and the thousands of other patients we've helped with repurposed drugs. I can't put into words the joy and the excitement when we find out that a drug that wasn't made for someone's disease helps save them anyway.

I'm also so proud of and thankful for my family. I've got two amazing children - David, who's almost 3, and Amelia, who's almost 6 - and my amazing wife, Caitlin. I work crazy hours. I'm on call all hours of the day. They support me throughout all this, even though it's not easy on them. I'll be putting Amelia to bed, and I'll get a call, and she'll say, "Oh, Daddy, is that about a patient? You're helping a patient!"

You write a lot about hope. How did you maintain hope through your extremely difficult medical journey?

There's the kind of hope where you hope for something and you wait for it to happen. And then there's the kind of hope that inspires you to act. That's my favorite type.

I said, "I'm hoping for a family with Caitlin one day." Well, in order for me to have that, I needed to get involved in Castleman research, even if the chance that it would help me was one in a million. I love the kind of hope where I want something so badly that it inspires me to act. Then that action gives me more hope, because I see that I tried something and, oh my gosh, amazingly, it worked, which then drives me to try another action.

That cycle of hope driving action and then action driving more hope has been a really essential ingredient to help me make it through any challenge.