A transatlantic collaboration is uncovering the role of key genetic variants in common diseases like type 2 diabetes and obesity

Like many research endeavors, the Novo Nordisk Foundation Center for Genomic Mechanisms of Disease at the Broad Institute of MIT and Harvard (NNFC) grew out of a conversation between scientists. Kasper Lage, a Danish-born researcher at Broad, and Niels-Henrik von Holstein-Rathlou, then senior vice president, biomedicine and health sciences, at the Novo Nordisk Foundation (NNF), began chatting in 2019 about the state of the research ecosystem in Denmark and recent scientific advances at Broad. That conversation laid the foundation for a bridge between Broad and Denmark—the vision for the NNFC. 

Since its launch in 2021, the NNFC has facilitated collaborations between Denmark-based experts and Broad researchers who are using cell and computational models to investigate the function of genetic variants linked to metabolic diseases. The overall goal is to translate genetic findings into biological mechanisms underlying disease that could be targeted with new medicines.

Twenty-one NNFC early-career and senior scientists from Denmark have already visited the Broad for up to five months at a time, launching collaborations and learning new methods that they are now applying to their datasets. Broad scientists have also traveled to Copenhagen to attend scientific symposia with their Danish NNFC colleagues and to learn computational tools and glean insights into metabolic research. Indeed, the third annual NNFC symposium took place in Copenhagen last month, where more than 60 Broad scientists and 70 Denmark-based researchers from Aarhus University, the University of Copenhagen, and the University of Southern Denmark met to discuss the status of the collaborative research programs and the future vision for the center.

We spoke with Lage about the NNFC’s roots, what it has accomplished so far, and what’s in the works. 

How did the idea for the NNFC come about?

It was the right energy at the right time. The NNF was interested in doing something; the Broad was interested in doing something; and there was a major scientific need. 

Back in 2018, Eric Lander, Aviv Regev, Melina Claussnitzer, and Jesse Engreitz, among others, launched the Variant to Function (V2F) initiative aimed at leveraging the genetic data Broad had been accumulating for years into a mechanistic understanding of disease. Eric, Melina, Ben Neale, and other Broadies played leadership roles in the International Common Disease Alliance (ICDA), co-authoring a white paper that mapped out next steps for the human genetics community toward new treatments for common complex diseases. The V2F initiative and the conversation catalyzed by ICDA led us to the realization that Broad needed an entity for this purpose—serving the ultimate goal of laying the foundation for rationally-designed medicines. Simultaneously, and somewhat serendipitously, I grew curious about advances in biomedicine in my home country. I'd been so Boston- and U.S.-centric for 10 years that I was out of the loop. So I started talking to Niels-Henrik. 

To this day, I don't know who said it first, but we noted that the NNF had been sponsoring thematic research centers in Denmark for over a decade. The Broad has thematic research centers like the Klarman Cell Observatory and the Merkin Institute for Transformative Technologies in Healthcare; shouldn't there be an NNF center at the Broad that does something exciting in the genomics space? What if it could connect the Danish life sciences ecosystem to the next generation of genomics, biomedicine, and computational biology, by creating a bridge that leverages Denmark's deep history of universal healthcare and excellence in basic metabolic research and the Broad’s genomics and technology expertise? From that point on, it was a tremendous co-creation process between many people at the Broad and the NNF.

What stands out to you as an important scientific step forward that the NNFC has made?

It’s not one step; it’s the path that we’ve created. There are too many variables—too many genetic variants, cell types, genetic backgrounds, etc.—to just map all the pathways, regulatory effects, and genomic mechanisms relevant to disease through sheer brute force. But between all of the involved investigators, the NNFC has created a viable experimental and computational strategy to map deep and integrated multimodal datasets on metabolically relevant cells and tissues and describe their programs under many different conditions. Not only is this a data universe that could—in the future—describe many of the cellular programs of these cell types, but it could serve as the basis for developing generative AI models that can predict the mechanisms of hundreds of thousands of genetic risk variants in metabolic diseases like type 2 diabetes and obesity. 

Our vision is to transform our understanding of cardiometabolic disease-causing biology anchored in genetics, lay the foundation for a new generation of rationally designed medicines, and hopefully use these insights to enable much better patient stratification and genomic medicine in these diseases.

To do that, the NNFC’s strategy is to produce deep and integrated datasets in cell models for a subset of genetic variants, enhancers, regulatory regions, differentiation time points, and genetic backgrounds, and then to train computational models to predict the rest. It requires thinking strategically about which datasets to generate. Are they of high enough quality that you can actually make accurate predictions from them? Are they consistent enough between all the different metabolic developments and cell models that exist? What role should ultra-rare coding variants play in this vision?

For the first couple of years of the NNFC, we were building the team, getting people to talk to each other, defining the research vision, and only starting to produce the data. Now we’re fully operational and generating a lot of data. 

What has been the most exciting part of the NNFC’s journey so far?

It’s very easy to say, ‘We’re going to create a partnership between the Danish research ecosystem and the Broad and leverage real synergies between their expertises.’ The reality is much more difficult. But we’ve done it: We have created space for Denmark-based and Broad researchers to exchange ideas and transfer technology across institutions. We have scientific planning committees that work together to determine which datasets we should produce. Then, we generate datasets together, and every researcher at the Broad and at Danish partner institutions has access to that data, which is shared in a joint NNFC data repository. 

We have had tremendous traffic from researchers in Denmark coming to the Broad for training, which allows those researchers to bring Broad technology back to Denmark to sequence samples there. The Danes have built enormous resources like cell models and tissue repositories from Danish patients—unparalleled in the United States—but it would be very difficult to bring those materials to the Broad. Instead, Danish researchers can bring Broad cutting-edge technology home. The prospective discoveries made possible by this exchange will benefit Broad and Danish scientists, Danish society, of course, but also patients around the globe. 

On a more personal level, it has been deeply meaningful to connect two places so important to me—Denmark and the Broad—in this way. I say this a lot, but if you’re part of the NNFC, you’re in the bridge-building business. Researchers on both sides are busy, so the effort needed to maintain this architecture is enormous. We are very fortunate to have the center's leadership and operations team working on this tirelessly. It is a great achievement that, using transformative science as the pillars and collaboration as the pavement, we have managed to create this unique transatlantic bridge.

Looking ahead, what do you anticipate being the biggest challenge facing the NNFC?

We don't yet know if the data we're producing will enable us to make the types of generalizable models that can lead to rationally-designed medicines. That being said, it looks promising. For example, we’re closer to being able to reliably predict if a genetic variant maps to a certain enhancer in a specific gene on a cellular program. But there is a lot of space to be covered from variants all the way to disease-relevant mechanisms. The data that we're currently producing may not fully enable us to predict and train models that can answer the questions that exist in that vast space. 

A potential stall in our ability to make variant-to-mechanism predictions would not mean failure; it would mean we need to reassess our datasets. There could be a gap in the data—we may need other data types that we didn’t know we needed. But it could also be that we need more of the same data—that the density of the datasets that we've produced to that point is insufficient. 

Scientifically speaking, what intrigues you about the future of the NNFC?

The potential for achieving the NNFC’s mission. There could be a future where we take any genomic variant, bring it to the center's data universe, and either look up what that variant is doing and get a crystal clear answer—for example, it’s executing on this cellular program under these circumstances in this genetic background—or, we can predict it using our models. We're making a lot of headway by producing models that generalize and can do some of those things that I just mentioned. I’m also very excited to keep thinking about how we use these insights to help patients. But that whole path is dependent upon the wonderful people we have working here. 

While it is logistically challenging to build and maintain a transatlantic collaboration like this, we’ve made great strides in just these few short years. I believe very strongly in this vision, and it wouldn’t be possible without the organism—and leadership team—of the NNFC. Every person here is a vital organ in that organism, functioning independently in their individual roles at their home institutions as well as providing valuable contributions to the NNFC. It’s quite beautiful, and I can’t wait to see where we are in the next few years as this partnership between the Broad community and our Danish counterparts continues to thrive.