Scientific, moral imperatives underlie including rare disorders in the ARPA-H mandate

The response to Covid-19 by the biomedical research community in the U.S. and around the globe has been spectacular in both speed and impact. It is time to respond with the same sense of urgency to every disease. Toward that end, President Biden has proposed creating a new agency, the Advanced Research Projects Agency for Health (ARPA-H), modeled on the defense-focused DARPA. He cited cancer, Alzheimer’s disease, and diabetes as motivating challenges.

DARPA’s track record in transformative innovation is unparalleled. It brought us the internet, GPS, Siri, stealth fighters, and more. In fact, in responding to the threat of pandemics as a national security matter, DARPA invested years ago in the mRNA technology so essential to devising the vaccines that, we hope, will bring Covid-19 under control.

The urgency of the pandemic forced biomedical research to take a targeted, flexible, DARPA-like philosophy, building on the strength of public-private partnerships and engaging in streamlined, “fail fast” research with a diversified portfolio of approaches.

As proposed, ARPA-H would generalize the pandemic’s lessons beyond Covid-19, creating a patient-facing engine for biomedical innovation.

To be clear, targeted efforts at accelerating applied research have always built on decades of basic research, without which there would be nothing to accelerate. That makes projects like what ARPA-H might take on powerful and necessary complements to more traditional basic research, not replacements for it. And for this new agency to achieve its goals, it must be created and managed differently than those that focus on basic research, just like DARPA.

My understanding of urgency comes from my son Bertrand, who died during the pandemic at age 12, not from Covid-19 but from an ultra-rare genetic disorder called NGLY1 deficiency. I spent most of his life trying to understand this previously undiscovered illness and fighting it, giving up my career as a professor in computer science to focus full time on the emerging field of precision medicine.

Bertrand’s life became an example to me of why the kind of acceleration promised by an ARPA-H matters: Although he was born with a life expectancy of just two to three years, a series of novel technologies, from genomic sequencing to metagenomics, continued to emerge just barely in time, one after another, to help extend and improve his life.

Bertrand’s fragile but joyful existence rode the ever-expanding wave that is the outer edge of human knowledge, right up until the day the science could no longer move fast enough. When the pandemic hit, every one of us began to feel the kind of urgency that I had known for Bertrand’s whole life.

For a moment, we all rode the wave together.

As vaccination ramps up, along with hopes for an end to the pandemic, pause for a moment to realize that everyone with a life-threatening illness is still holding out hope that some innovation will jump from bench to bedside.

I’m a veteran of the DARPA process, having spent nearly a decade of my life as the principal investigator on DARPA projects for transformative new technologies for cybersecurity. To that end, I adapted the organization’s research model, using its fail-fast, try-everything approach to jump the gap from theory to practice faster than is normally considered possible. This approach was key to developing the therapies that extended and enriched Bertrand’s life.

As I’m now pursuing a second academic life, this one focused on finding therapies for people in need, the upside of a DARPA-like approach for biomedical research is clear to me. While the National Institutes of Health excel in the essential basic research that eventually leads to major breakthroughs, a new agency within NIH could serve as the catalyst for taking these breakthroughs to patients.

Scientific and moral imperatives underlie the mandate for ARPA-H and for explicitly including rare disorders within that mandate.

The scientific imperative is clear: Treating rare disorders will be the key to treating many common ones.

Paradoxically, rare disorders are devastating even though in a biological sense they are “simple” because, by their nature, each one tends to have just a single genetic cause.

The cause or causes of common disorders, by comparison, differ from person to person, arising from a cocktail of genetics, environment, lifestyle, nutrition, and more. In fact, the field of precision medicine takes this view to its limit: Every individual with a common disorder is seen to have an ultra-rare version of the disorder that is uniquely their own.

To tackle diseases as complex as Alzheimer’s, diabetes, and cancer, it may take “simplifying” them into ultra-rare disorders that require solutions tailored to the specific needs of each individual.

To achieve its goals, ARPA-H must move to erase the line between treating rare diseases and personalized medicine, moving from curing a disease to curing a person.

Rare disorders force researchers and clinicians to peer into regions of the human genome that may otherwise go unexplored, and that research can unexpectedly spill over to aid those with extremely common conditions.

The moral imperative to include rare diseases in ARPA-H’s mission is clear from their scale: while individually uncommon, the many thousands of known rare diseases collectively affect nearly 10% of the American population — more than those who have cancer at any one moment.

From three different vantage points — as a parent of a child who lived with a rare disease, a researcher, and a public servant in both Democratic and Republican White Houses — I offer four suggestions for structuring ARPA-H to maximize the benefit to patients:

• To align incentives and focus the mission, ensure that patients and patient advocates are represented among the program managers leading the high-risk, high-reward projects.
• To avoid duplication and capitalize on the nation’s flagship hub for biomedical innovation, make ARPA-H part of the NIH rather than an independent agency. In fact, the tiny yet effective Cures Acceleration Network (or its parent, the National Center for Advancing Translational Sciences) within NIH could serve as the seed crystal from which ARPA-H is grown.
• To create the culture and independence necessary to innovate boldly, bring in program managers from outside government; give them broad autonomy in assembling their research portfolios; and use the same three- to five-year term limits to force them to move quickly to achieve their proposed visions for targeted patient-facing innovation.
• To bring new therapies to patients quickly yet safely, include regulatory science as part of ARPA-H’s mission and provide a formal conduit to the FDA. Just as with Covid-19, moving faster depends just as much on regulatory innovation as it does on biomedical innovation.

For all lives lost for failing to move as swiftly as possible, establishing ARPA-H honors their memory.

Matthew Might is director of the Hugh Kaul Precision Medicine Institute at the University of Alabama at Birmingham and a senior lecturer at Harvard Medical School.