A Conversation with Dr. Nigel Mouncey, Director of the Joint Genome Institute: The next frontier of genomic breakthroughs

Aaron Steger

Nigel Mouncey, PhD is the Director of the Joint Genome Institute (JGI), a U.S. Department of Energy Office of Science National User Facility located at Lawrence Berkeley National Laboratory in Berkeley, California. Previously, Dr. Mouncey held increasing leadership roles at Dow AgroSciences, most recently as the Director of R&D for Bioengineering and Bioprocessing. Before that, he led research groups at DSM Nutritional Products and Roche Vitamins. We sat down with Dr. Mouncey to discuss the most exciting ongoing developments in genomic research and how data will continue to shape life science R&D.

Q: I understand that your dad was a microbiologist, and you often joke that he passed down that trait to you. Tell us about your early experiences with science and how that put you on your current path.

Yeah, so Dad was a microbiologist, and I know haemoglobin (British spelling) was a fairly early word in my vocabulary. I went on to do a microbiology degree, and I actually elected to take a crop biology course. People thought I was crazy. It was like degree suicide taking this course, but I wanted to understand biology more broadly, and it was during this time when I started to think about plant/microbe interactions.

Once I finished my PhD in the UK, I wanted to come to the United States. Primarily the driver was because I’m a Deadhead. I said, “Great! If I move to the United States, I’ll get to see all these Grateful Dead concerts.” It was the summer of ‘95 when I was finishing up my PhD, and that’s the year Jerry died, and the Grateful Dead ceased to be. Unfortunate timing.

So, I started to apply for a few assistant professorships back in the UK, but I saw an ad in the back of Nature for a position at what was then Roche Vitamins in New Jersey to do metabolic engineering on Bacillus. I thought, “That looks really interesting,” and the rest is history.

Q: Tell us about your work in industry, and what led you to transition from industry to the JGI?

At Roche, we developed a pipeline to rapidly make precise DNA changes in Bacillus and could crank out 20 or so engineered strains a day. Today, it’s really interesting to see how people are automating these things, but we were still able to do it pretty quickly back then.

Later on at DSM, I had the chance to work in their “Innovation Center,” where we came up with all these new ideas for bio-based routes for different products across different industries. It’s been really pleasing to see how that has spearheaded a lot of where DSM’s bio-based products have come from now.

Then at Dow AgroSciences, I led Bioengineering and Bioprocessing R&D where we worked closely with manufacturing to not only support existing commercial products but also to develop and bring new products into large-scale commercial production and to the market. I was very fortunate to have a successful industry career, but eventually I felt I was getting further and further away from the science, and I really missed that. Now at the JGI, I’ve gotten to move back towards more fundamental research.

Q: Tell us about the current state of the JGI.

Originally, the JGI was founded to be one of the centers for the Human Genome Project. Now, the JGI is the only institution dedicated to characterizing genomes of plants, algae, fungi, other non-biomedical microbes and environmental microbiomes to elucidate their role in the DOE mission space of understanding the processes of carbon cycling, biogeochemistry, developing sustainable high-value biofuels and bioproducts from lignocellulose. Our strategy, fueled by submissions for our DNA sequencing, DNA synthesis, and data analysis resources from the worldwide research community, is moving much more towards functional genomics and away from just cataloging. That has morphed into us providing a much broader range of genomics capabilities, so we also do transcriptomics, metabolomics, synthetic biology and a lot of epigenomics now. We’re actually doing more experimental work as well as taking on massive-scale, complex science projects initiated by our users. Our strong in-house research gives us the ability to stay at the forefront of the those complex projects and allows us to blaze trails into new scientific frontiers such as viral ecogenomics and exploring new lineages of life.

Q: What do you see as some of the most exciting applications of the work being done at JGI right now?

In our plant program, we’ve been able to identify traits to improve yield in response to different soil types or temperatures that might be present in different growth areas. We’re excited to identify traits that can have significant impacts on yield to actually make sure that growers plant or breed the right crops.

A former industry colleague asked “What would you do differently now if you were still in industry?” I said, “We would collect and analyze more data, and use that to drive decisions in a more intelligent manner.”

From a synthetic biology standpoint, we’ve been very interested in a piece of synthetic biology that hasn’t received as much attention as DNA constructs: the host organism. People are developing lots of really nice circuits, but if we want to look at 10 or 100 or 1,000 pathways, that’s going to be a tremendous amount of work to refactor all those pathways individually, and so we’ve said, “Can you look at the hosts, and can we actually domesticate a broader set of hosts that can be used for expression?” We’ve been pretty successful in this regard, and we’re very excited about how this technology can be utilized more widely.

On the virology front, M13 is a very well-known model virus of the inovirus family. It’s used in many applications. Prior to our work, only 56 inovirus genomes were reported. Our study expanded this to approximately 10,500 genomes, so again, there’s massive expansion of biological diversity that we’ve been able to enable and facilitate. We found many interesting biological features within these genomes.

Q: Wow, that’s a significant increase in the number of inovirus genomes. Do you have any other examples of this “data explosion” in biology and the challenges it has created?

So for example, we celebrated, in December 2018, our sequencing of our first petabase of data. It’s 10^15 base pairs of DNA sequence. It took us 20 years to do that. We will celebrate the next petabase in probably about another two years as sequencing technology has exploded.

The biggest challenge is not only the amount of data we are generating ourselves, but also data that we need to incorporate from other institutions as well to serve as comparative datasets. And how do we best manage all of that data, how do we store that data, how do we process that data, and how do we make it all freely available to our users. So those are the biggest challenges.

Q: What’s one area that you’re really focusing on in terms of unlocking the potential of all this data?

We’re really trying to establish much more standardization. I mentioned microbiomes – we were fortunate enough to receive additional funding from the Department of Energy to stand up our new National Microbiome Data Collaborative (NMDC). We’re working to develop and employ standardized ontologies that will allow for much more comparative types of analyses, and also to standardize the data pipelines, as well as the infrastructure to make data available.

It’s all about having standardized datasets so that different people can analyze each other’s data, actually compare it, and make accurate decisions to move research forward.

Q: I understand that in 2018, you started a Data Science and Informatics department. What kind of impact has that had on your research efforts?

When I came into the organization, obviously we had tons and tons of data, but we needed to have a more enterprise-wide approach to how we manage all of this data, and it was clear that that was best going to be served by forming a new department. Data Science and Informatics brings together systems engineers and analysis and informatics people under one umbrella, to have them really think strategically about what our needs are across the organization.

We keep thinking about how to bring together our data systems, and bring commonality to them as well. They all have their own features, and user communities, but as we’re starting to have more users today that transcend the microbe and the plant worlds, we need to harmonize these systems more. We need to have this integration with different disciplines to really afford us a much broader picture of what is going on in biology.

It’s all about having standardized datasets so that different people can analyze each other’s data, actually compare it, and make accurate decisions to move research forward.

Q: I can see how this approach to data might arise from your past experiences at Dow, DSM, and Roche. What’s the most important thing that you learned in industry that you’ve now taken and applied to the JGI?

When I came in, it was quite apparent that JGI was a collection of silos – cylinders of excellence, as they say. And in order to be more impactful and more efficient, we had to work together across the organization, and so we’ve been breaking down a lot of the walls over the last couple of years in order to make that happen.

Our strategic plan is entitled Beyond Base Pairs: Integrative Genome Science. We’re very deliberately bringing scientific disciplines together. Earlier, I mentioned bringing together the microbes and the plant worlds: data underpins all of that, so bringing the data folks in with the biologists allows us to seamlessly trace from genes to enzymes to molecules to function. We recently moved with our colleagues from the DOE Systems Biology Knowledgebase (KBase) to a new building on the Berkeley Lab campus, adjacent UC Berkeley, so we’re now all under one roof, and that really is going to further allow us to enable our strategy by bringing together all these different disciplines and work together on the biological challenges that we’re facing.

Q: Beyond JGI, how have you approached breaking down external silos and collaborating with outside partners? How has your recent move to the Berkeley Lab campus facilitated this?

Being here on the Berkeley Lab campus affords us new opportunities to interact with our colleagues across Berkeley Lab and formulate new types of collaborations in new spaces that we hadn’t been working in in the past. One example is a new bio-materials initiative we started here. We have a couple of projects here in JGI already that we’re working with the Molecular Foundry, which is a nanoscience research center here at Berkeley Lab. Now we can actually go and have those meetings over lunch or tea with colleagues from the Foundry to discuss project progress, other opportunities, and any issues that are arising. It just makes it so much easier. The new building is more energy efficient and also has a much more open and modular lab space, which will allow us to much more easily adapt to technology changes going forward.

Q: What breakthroughs in scientific technology do you think will most strongly impact the JGI’s cross-disciplinary work?

One of the things that I’m really excited about are cell-free capabilities. We have a project with a collaborator to develop new cell-free systems to prototype metabolism. I think these could be very, very powerful systems that take care of a lot of the issues surrounding how we get stuff into cells, cultivation, tolerance to products, you name it!

I think the other area is now being able to do in situ work, use different types of fluorescent labels, substrates, molecules or being able to tag cells and actually study them in situ. Obviously the big thing for us is around the interaction of microbes with plants, so being able to use fluorescently-tagged microbes and not just a single one, but to actually look at communities of microbes, will be incredibly powerful for us. We’ll get a better understanding of them, not only in terms of a snapshot in time, but in terms of the dynamics as plants recruit organisms and as plant growth happens. You have different populations that are playing different roles, and we’ll be able to measure that in ways that we’ve never been able to before.

Q: And how have you seen breakthroughs in data and computer technology change the nature of scientific discovery at the JGI?

Today, it’s much more about scale and speed. We can do things at a much larger scale and faster pace than when I was really a lab scientist. Things that took 5 years in the late 90s are now taking months to accomplish.

The scientists of today, whether you’re working with data or whether you’re working in the lab, have the opportunity to generate and analyze so much more data than they’ve had in the past. Tying together all of that data and interpreting the results is most of the work.

In fact, one of the biggest things that we see with our users is that a lot of them underestimate the sheer volume of data that they’ll get back. And so we end up being collaborators most times on projects to help them navigate through datasets that we generated for them.

Today, it’s much more about scale and speed. We can do things at a much larger scale and faster pace than when I was really a lab scientist. Things that took 5 years in the late 90s are now taking months to accomplish.

Q: What are your thoughts on inspiring the next generation to get excited about genome research?

We had a terrific project with a high school down in Florida to look at Everglades samples, and students were super excited to get out in the field, collect the samples, and process them. We did the sequencing, we sent them back, they did the analysis.

The paper for this work was just published (on January 20th), and the students are absolutely thrilled with that fact. These are high school students, and they’re getting a paper. Not many high school students already have a publication reference to bolster their college applications!

Q: Lastly, we’ve heard you’re a big craft brewing fan. Having spent such an extended period of time in the US, how does the craft beer scene here compare to the UK?

I have to say I think the US beer scene is the best in the world, because people are brewing every darn style known; even styles that have been lost to history have been recreated as best brewers can imagine them. We’re seeing a lot of these breweries now using yeasts from Scandinavia – this Kveik style of brewing has come in. There’s Sahti from Finland. Even Chicha from Peru. You can find all these styles here in the US, so that’s amazing.

And if you want to know what my favorite beer is, it’s got to be Goose Island’s Bourbon County Stout. A big beer but bloody good! So as you can see, my life is immersed in biotechnology!

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