Jonathan D. Grinstein, PhD, the North American Editor of Inside Precision Medicine, hosts a new series called Behind the Breakthroughs that features the people shaping the future of medicine. With each episode, Jonathan gives listeners access to their motivational tales and visions for this emerging, game-changing field.
Josh Denny, MD, is a leader in precision medicine whose path was profoundly shaped by his family’s experiences with cystic fibrosis. Growing up hearing stories of his grandparents’ loss of four children to the disease, Josh was inspired to pursue a career at the intersection of medicine, genetics, and technology. From his early explorations in computer science to groundbreaking work in medical informatics, he has sought to transform healthcare through personalized approaches.
In this episode of Behind the Breakthroughs, we explore Josh’s role in the All of Us Research Program, a pioneering initiative launched in 2018 that now boasts 850,000 participants and over 400,000 genomic profiles. The program’s mission is clear: to leverage big data and diverse biological samples to uncover insights into health disparities, rare diseases, and common conditions. This episode highlights the revolutionary potential of precision medicine, from life-saving genetic testing to advancements in therapies targeting diseases like cystic fibrosis and APOL1-related kidney disease.
Join us as we discuss how this visionary leader bridges personal inspiration with groundbreaking science, creating a future where healthcare is tailored to each individual’s genetic, environmental, and lifestyle factors.
Highlights of this interview have been edited for length and clarity.
IPM: What notable research has All of Us been involved in?
Denny: Researchers are examining fundamental mitochondrial aspects of DNA and various clinical conditions, while others focus on topics unrelated to genetics. Some are looking at environmental exposures.
One will be the world’s most extensive precision nutrition study. They enroll people, and these people complete diets. Some individuals even wear glasses, activating pictures through chewing. Then, AI processes the images of the food to understand and learn what we’re looking at, including calorie content and stuff like that based on images. They fill out traditional diet forms. We measure a microbiome, and there’s a smart toilet component. Then, we randomize diets. In the randomized diet stage, we can look at the traditional American diet versus other diets like low-salt and Mediterranean diets and see what happens to the outcomes of those kinds of things. It gives us a powerful way to use this as a platform to do new science on top of already having the medical record on top of having all these survey answers, being able to link into exposures in the environment by geospatial location, as well as things like your blood samples, that we can test. All sorts of studies are being done to aid our basic understanding of biology and directly make a clinical impact to improve lives, which is what we’re trying to do.
IPM: What kinds of feedback are most often heard when interacting with communities?
Denny: One of those first things, when you want to get to all communities and try to get that broad coverage, it’s crucial to have community groups help carry that message and meet people where they are in different communities because precision medicine is not a one-size-fits-all understanding and how you engage people for research isn’t one-size-fits-all either. We try to help address people’s concerns. One of the most common questions is about data privacy and security. We talk about how we protect the data by centralizing it; there is a lot of data security around it. We can protect it. We can continuously monitor it instead of having many people download it, for instance. We de-identify the data that researchers get. We monitor for certain data loss prevention things that are still to be looked for. That’s number one. Then, people want to know what’s being done with the data.
One of the things we started doing last year that was fun was our virtual participant convenings. Many different awardee sites and medical centers that work with us have done different participant gatherings, which are when I joined those, and they’ve been fun. But we started doing these large virtual ones last year, and it’s just fun getting all the questions from participants running the gamut. People want to be involved in new studies based on their conditions. That was one that I don’t think I recognized that there would be as strong a desire for that as it seems that we’re hearing, that maybe they have diabetes or they have a fibrillation that they’re interested in being available for a clinical research study, in addition to All of Us, makes complete sense, but it was neat to hear it.
They have all sorts of questions. They want to know about the science. They want to know what our discoveries are. We send out regular newsletters to participants, highlighting research articles and trying to make public-friendly documents that explain and give graphics around some of the research that’s being done on the workbench. The number one question is always about data security and privacy or when am I getting my genetic results back. For those who haven’t, we’re closing in on that gap. We’re launching a new protocol soon that will catch up with those who haven’t been able to get those results back yet.
IPM: How has the shift from President Biden to President Trump’s second term affected All of Us?
Denny: We’re well situated to tackle the new administration’s priorities and understand how environment, nutrition, lifestyle behaviors, activity levels, and genomics interact. We were always set up to do that. Science is not based on the leadership of governments. Science focuses on different things at a time. Our focus is holistic. We know that zip codes and genetic codes both have a profound influence on health. Why does a zip code influence health? It’s all the things associated with the zip code that collocate. How do we know those different elements and disentangle those components of health so that we can make our populations healthier again? We want to do that.
Basic discovery will lead to understandings that are more robust for health. Having reproducible science has always been a driver for us. That was the whole idea about having these notebooks that people can do their analyses on, specifically on exact versions of data that someone else can go back to and look at the precise analysis on the identical data set you used and say, if there is anything that maybe you should have considered in your analysis that you didn’t, they can copy that; throw in some other thing that could be a confounder and see whether or not it changes the results. That’s the real power of the future of science: making science in truly shareable ways that can be transparent, investigated, and reproduced. The data grows over time, and you can keep following people, creating another powerful tool to understand the long-term impacts of environmental exposures, genetic changes, or medications you take. Those are real questions we should answer. I think we provide the data to help answer.
IPM: What will make All of Us a success?
Denny: Our future should be long, and we’re just starting. It’s essential to think that our understanding, knowledge, and discoveries will grow over time because that’s where you get more stories like that type 2 diabetes story, where people have developed it over time. We can go back and look at that biospecimen beforehand and say, “Did some of these measurements make a difference or not?”
As people go through their lives and health journeys, we can analyze that, and it will be incredibly powerful. I’m looking for new treatments and a better understanding of screening. I’m looking for two-thirds of the genes out there. We don’t understand what they do in humans regarding the impact of disease. I’m looking to figure some of those out. With sequencing, a whole bunch of those variants come back, and we have no idea what they do. I hope we can disentangle what a variant of uncertain significance is versus one that’s pathogenic or benign and that we push toward a true understanding of pathogenicity and its impact on health. I hope that we continue to do many other things on environmental exposures. Maybe there’s another lead out there that we’ll find in an environment that we can systematically eliminate and make a difference in health. Having this kind of data will be helpful there.
In terms of the future, one of the things I’m most excited about is the potential of looking at kids. Right now, we enroll, generally 18 and up. We are shovel-ready with kids, and we’ve done small numbers of zero- to four-year-old kids. The difference there is with adequate funding to support that, we’re ready to go and do that kind of study for child health and progression to adult health in the same way that we’ve tackled with adults. That is the thing I would most like to do in the future.
I get a PubMed alert on papers written on All of Us, and it’s taking off. We’re at an inflection point. Seven papers were published today using All of Us data. There were five yesterday, and it’s just that it’s at that point that we’re finding things, even though it’s young. One of those papers is on a genetic variant in the channel of APOL1, which essentially mitigates APOL1 kidney disease risk. That’s essentially a pathway to treating that condition. There are many papers like that pointing toward things that I think you’ll start to see in some guidelines.
We have already seen some guidelines being changed around pharmacogenetics testing and an interpretation of those ClinVar variants. The most significant impact today is probably those 4,000 people who received potentially life-saving results. What research program directly benefits their patients that way? Some have had benefits from family cascade testing, where an individual learns about risk and has their other family members tested. They now know why their uncle died at a young age for an unknown cause. It was probably this fatal arrhythmia that’s in their family that was completely mitigated by having an ICD implanted. Things like that are happening now, too. I am bullish on the future, which is always ahead of us. However, even today, the impact remains real.
