Regeneron Genetics Center ONE OF THE WORLD'S LARGEST HUMAN GENOMIC RESEARCH EFFORTS

In early 2020, the RGC sequenced its 1,000,000^th exome, making it the world’s largest database of genetic sequences and corresponding de-identified electronic healthcare records.

The genomic data derived from this database teaches us about human health and how to improve it through novel treatment approaches.

Jeffrey Reid: The things that my team are doing that are focused on accelerating the discoveries that we're making on the RGC, which Enron is a broader entity, are really focused on giving people less friction between the data and the insights that they try to reach from that data.

Jeffrey Reid: Machine learning and AI are extremely exciting. They are extremely powerful. They are really good at solving some classes of problem. They are really bad at solving some classes of problem. So our AI and ML perspective is really a data perspective. These are methods that are going to learn from the data. So we need the data to be as clean, to be as harmonious, to be as well structured and composed as possible so that these methods can learn what they need to learn from them to build the models that can be informative.

Goncalo: I think a big challenge in the field is figuring out how do you deliver. Each of these processes are so complex that you could say, "I'm going to spend years figuring out the best way to clean the data. Once I've cleaned it, I'm going to spend a few more years figuring out the best way to store it". By the time you're done, it'll be time for retirement. So we need to balance that with urgency that the data is more valuable if we can have these insights sooner rather than putting them all off.

Jeffrey Reid: For the RGC, I think it is not an overstatement to say that there is no other data set in the world quite like the data set that we have. It is extremely informative about phenotypes, has a lot of electronic medical record data, it has relatively complete genomic characterization on the [inaudible 00:01:35] so we can really understand what the protein coding regions are. There aren't other data sets like that.

Jeffrey Reid: So we made a big commitment to the cloud from the very beginning at the RGC for two really important reasons. The first is it's actually cheaper and easier. More importantly, it's fundamentally enabling for our collaborators to have the data served up to them in a way that they can actually use the data where it is. So they don't have to have any particular computing resource. All they really need is an internet connection.

Jeffrey Reid: We recognize that the data that we have comes from people who want to make the world better and we want to respect their contributions of data and sample as much as possible which means being a good steward of their data.

Goncalo: We need to continually push ourselves to do something a little better and let's deliver data to as many people as we can.

Jeffrey Reid: I think that's both a lotable goal in terms of enabling our colleagues here but it's also really important to the science because you never know where that next great idea comes from. If everyone isn't enabled to ask the questions that they want to ask, then we're missing out on the possibility of getting some important answers.

Jeffrey Reid: I think by focusing on the data we can both enable ourselves for the things that we can do today and we can have a leg up on staying on the leading edge.

Aris Baras: I came to Regeneron as a physician by training, as a scientist. I came because my passion was to really help patients, and to do that through developing new drugs. Genetics became the top priority at Regeneron, in terms of how we were going to do drug discovery and development better. A collection of really able, and willing and passionate scientists at Regeneron came together and built this program, and now that's what I do.

John Overton: We were a new project for Regeneron. We literally had an empty building. We set up on the other side of campus and we kind of had this stealth thing going on. We took a lot of time very early on, taking our expertise in biology and genetics, working with the engineers, and building an automated pipeline.

Aris Baras: Building the sequencing lab was one of the core and initial areas that we wanted to focus on for the Genetics Center.

John Overton: My team sat with the engineers every day, we went step-by-step through our protocols. We designed robots that could do all of this work. We've made some really, really great advancements on the way that we prepare samples for DNA sequencing. We felt very confident that the sequencing was advancing at a very fast pace, we needed to develop the automation that could keep up with it.

Aris Baras: And that has allowed us to go from tens of thousands of sample capacity, to hundreds of thousands, to even moving to millions. So that's been a big area of innovation, advancement, and technology.

John Overton: We need huge databases to do this because we take a really agnostic approach to looking at this, in that we never know if it'll be the next person we sequence that has that genetic factor that describes the disease that we're looking for. And to really show that that's real, you may need to see that 10 times, or 20 times, or 30 times. And if it's rare, if it's on in every hundred thousand people that they have this genetic anomaly, you need to have a database that's millions of people to find that.

Aris Baras: The beauty of that also is that there's an innovation curve that they continue to bend and advance, and so what they're doing one year, they're now tenfold better the next year. It's really enabled us to seamlessly scale, as the technology of sequencing and how well it's being adopted has just taken off.

It's part of our DNA here, that we will always innovate. We will embrace failure. We will see those roadblock as opportunities to innovate around them, find solutions, break bottlenecks, whatever it takes. Genomics, at this scale and how we do it in drug discovery and development, was not routine. We had to figure it out and implement it, and we just really thoughtfully and passionately developed a plan that made sense and was rooted in science and that would get the job done. We made it much bigger and grander than we imagined, and that's where we are now, almost five years later.

Alan Shuldiner: Well, I think one of the best things about genetics is that it's a way in which we can connect the dots. Starting, essentially with the genes that encode everything about us that's human and also all of the variation that occurs across the human species. That not only includes various traits like what we look, but also our susceptibility to diseases and if we can understand the underlying genetics, we can then connect the dots to understand the mechanisms and the pathways and then ultimately find the better ways to treat and prevent disease.

Aris Baras: A lot of what we've done so far has been focusing on the best drug targets, or using genomics to advance our existing programs. Now we made big bets in genomics and now we're doubling down. We're going all in, and we can jump in with those teams, shoulder to shoulder, and think about how we can apply human genetics to help guide the development of those therapeutics.

Alan Shuldiner: One of the things I love about Regeneron is the fact that the genetic center is embedded in a high power science, pharma, and biotech company. As a result, when we come across discoveries in the genetics realm that lead to new targets, we can move very quickly to understand that target better and ultimately develop medications that target that particular pathway.

Aris Baras: One great example of a RGC discovery that is impacting Regeneron's science and pipeline is a new target that we discovered from our large scale sequencing work.

Aris Baras: This is something that an antibody could block, it's a secreted protein, and we see individuals who have this gene knocked out, and they have pretty compelling phenotypes.

Aris Baras: They're taller. They have more muscle mass. They have stronger grip strength. They have a higher metabolism. We have some hints that maybe they're even protected from diabetes, which goes hand in hand with a more lean mass, and a better metabolic picture. But, these are the types of discoveries that we're making, and will be sorting out with human genetics, hand in hand with our biology teams at Regeneron.

Aris Baras: The possibilities are really endless. We have franchises at Regeneron working on muscle diseases and metabolism and diabetes. We could plug these things right in and hopefully, quickly, get to new therapeutics that could really help patients with these diseases.

Alan Shuldiner: We do a lot of DNA sequencing for research purposes. We work very closely with physicians around the world who have access to patients with both common, and rare diseases. When we come across a new discovery of a new gene, after that mutation is validated in a clinical laboratory, the physician can actually use that information for patient care. We now have literally hundreds of examples of new diagnoses for patients with very rare Mendelian disorders, in which the physicians have been able to utilize that information to treat their patients in better way. So through human genetics, we're actually in some ways, redefining diagnosis and in so how we think about treating patients across a broad range of diseases.

[Man] At Regeneron, we provide so much to people who are sick. Innovation, it's the name of the game. It drives everything we do. It's really cool because we go from the really big thought, the really big idea, all the way to seeing the impact on a person. We have a healthy dose of optimism and just enough naivete to think anything's possible. When you think about the ethos of this company, what you'll hear over and over again is science, science, science, science leads, science dictates. But I think what keeps us all grounded is the fact that these are people that wanna help people.

As the global obesity epidemic remains unchecked, placing millions at risk for serious health disorders, scientists are working to uncover new tools to positively impact human health.

The Regeneron Genetics Center, or RGC, is identifying new therapeutic targets for treating obesity, tapping into its large-scale genomic database, cutting-edge DNA sequencing technology, and in-depth data analytics, to help match genes to specific health traits.

Now, in the largest such study to date, the RGC sequenced the protein-coding sections of DNA from over 640,000 diverse volunteers and identified 16 genes linked to body mass index or BMI.

One of these genes, which is expressed in the brain, showed the strongest association to lower BMI.

It’s called GPR75.

Those rare individuals with a broken copy of the GPR75 gene tended to weigh less and faced a much lower risk of obesity than those with a working GPR75 gene.

To test these findings Regeneron studied “knockout” mice, engineered to lack the GPR75 gene.

When fed a high-fat diet, the knockout mice gained 44% less weight than mice with the normal GPR75 gene.

Knowing that people with a broken GPR75 gene may be protected against obesity, Regeneron is exploring multiple pathways toward a therapy that mimics this rare genetic superpower.

The advanced capabilities that helped single out GPR75 as a target in obesity illustrate the RGC’s real-world impact: leveraging genomic successes to rapidly translate science to medicine.

When we start a study, like the one we carried out, it's all unknown in terms of where we're going to be in a year's time. We don't know. We know what we're searching for. We don't know if and when we're going to find it. And so the analogy that I can think of is, as an explorer about to embark on a new expedition, there's a mission, there's something to be found. It's just a matter of if and when that's going to happen. We knew that we could put the right team together, and we had the right technology to try to embark on that expedition, but we didn't know, is it going to succeed or not?

The chances of success are always lower if you concentrate on just a handful of diseases. If you want to ensure that the team and these experiments are successful, the better strategy is really to concentrate on many different diseases.

What's different about this expedition is that we had to leave behind traditional way of looking at genetic data. Instead, we'd looked at genetic data at a resolution and at a scale that had never been done before. It's the difference between setting course to a group of known islands, where you pretty much know what you're going to find, as opposed to what we did, which is to set course into uncharted seas, where the goal is to find potentially new islands that have never been discovered. And so that's what we found. When we find a gene like GPR75 that has these rare variants that are really strongly protective against obesity, it vindicates the expedition.

We've all come across the observation that people differ in their ability to maintain weight. Some people tend to gain weight rapidly, and that has a lot to do with the environment, the diet, the level of physical activity, but it also has, science shows, a very strong genetic and biological component. It is really important to study the genetics of obesity because genetic studies can highlight new biological pathways, and some of these pathways may be therapeutically modifiable to benefit patients who cannot maintain a healthy weight with lifestyle intervention.

I've been working for many years on the genetic basis of obesity, but to be honest with you, I didn't really know what to expect because this study was unique for its design and its size.

We came in with an open mind, with curiosity. Nobody had ever done a study of this size and with this particular study design using exome sequencing, so we had to come up with innovative ways of analyzing the data, develop new tools, ways to visualize it. It's something like trying to race a car while you're trying to build it at the same time, so it was a very exciting, sometimes hectic, but very fun process, and fun project and study to be in.

As a medical doctor who is focusing on research, the ability to influence patients with my science, in this case, human genetics, it's a thing that is really close to my heart and it's really important in what I do every day.

We're really hooked on this idea of genetics to therapeutics. It really provides us unbelievable insights and starting points to revolutionize and rewrite the rules of drug discovery and development. We're really excited about this finding, the discovery of GPR75, and mutations that are protective for obesity. We really believe this is an actionable finding. And once you start to realize that there's actually millions and tens of millions of variants out there across our genome, and it's only going to grow the more and more we study this, we're able to mine that now and find those really important changes, those variants that have a big impact on your health and disease.

People should think about the RGC as really an engine for discovery and help translating new targets and genetics to therapeutics. So we work around the world with many different medical centers doing genetics on hundreds of thousands, millions of people of all diverse backgrounds and all diseases. We have infrastructure here, automation, robotics, the latest and greatest technologies in genetics, and we're plugged into a world-class ecosystem of R&D, going from biology to therapeutics, clinical trials, really marching forward game-changing therapeutics to new medicines. And that is just an incredibly exciting quest to be on, to look for these protective genetics, and further, to be able to drive them forward and not just have it be a scientific discovery, but for those things to actually quickly translate into new medicines that hopefully can confer those amazing protective genetic benefits, those genetic superpowers to the very few, the one in a thousand, the one in a million that hit the genetic lottery. And now we try to take those new medicines that mimic those genetics, and we try to help the masses, right? The hundreds of thousands, the millions that may be suffering with heart disease, with obesity. We're even searching for these protective genetics in cancer. So, it's an incredibly exciting thing to be involved in.

With a rapidly growing roster of breakthrough genetic superpower discoveries the Regeneron Genetics Center’s “team-science” approach to discovering life-changing genetics-based medicines continues.  

Did you know, a type of chronic liver disease called nonalcoholic steatohepatitis, or NASH, poses a high risk for progression to liver failure and is one of the top causes of liver transplants? 

NASH prevalence has risen over time, as have contributing factors like obesity and type 2 diabetes, with no medicines approved to treat it.

To accelerate transformative drug discovery for people with NASH, RGC tapped into its vast, global genomic database and first discovered links to a gene called HSD17B13.

After studying thousands of genomes, RGC found that individuals with mutated, nonfunctional copies of this gene are better protected from developing nonalcoholic forms of liver disease.

In an even larger study, a gene called CIDEB took centerstage where RGC identified very rare mutations that are highly protective against nonalcoholic forms of liver disease. 

To mimic the protective superpower of these genetic mutations, Regeneron, with its partner Alnylam, is applying RNA interference technology to develop potential therapies that aim to silence non-mutated or working forms of the target genes in people with NASH. 

By providing fresh insights into the genetics of liver disease, RGC is feeding Regeneron’s pipeline with multiple potential therapeutic options in difficult to treat diseases like NASH.

Genetics to therapeutics, moving at the speed of science.