Jacob Corn, Professor of Genome Biology at ETH Zurich, is one of the prominent specialists in molecular health science worldwide. His Genome Engineering and Measurement Lab GEML, led by Zacharias Kontarakis, provides services for the most important institutions in Europe in this field. Currently, the group is working on no less than four European projects: an insight into a booming research area.

Jacob, you have been a very successful scientist in the USA, before you came to Switzerland. What made you decide to come here?

Jacob Corn: The United States is a wonderful place to do science, but Switzerland is better in some aspects. It favours an environment in which you can do long-term, far-reaching experiments that would be frankly very hard to do in the United States. So, Switzerland takes a longer view about science and that leads to, in my mind, more innovation in some way. That’s very important for a very fast-moving field like ours. Gene editing is extremely competitive, and support to compete on the global stage is built into the Swiss system.

What about you, Zac, you are the head of the GEML. Since when?

Zacharias Kontarakis: I got recruited by Jacob to be the first Head of the GEML Hub and started in August 2019. I am interested in genome engineering technology and how to improve it. So, when I saw this opportunity and Jacob explained his vision, I thought that this would be an important step for me, to build a Hub helping groups that don’t have access to the technology and provide support for answering a lot of different research questions rather than focusing on a particular one.

You do have many clients?

Yes, we have collaborations across Europe, which is an indication that we are doing work that is recognised internationally.

How many scientists work in this field today?

Jacob: This field has really exploded. Gene editing has been around since the 1990s. The clinics have been around for decades. It shows that gene editing itself is not inherently more dangerous than taking a pill. But those technologies were very slow and expensive. The real revolution happened about ten years ago. The development of the technology called CRISPR CAS let you do the exact same things as the older technologies, but for a tiny fraction of the money and time. So instead of taking six months, it takes one week. And instead of costing 60,000 francs, it costs 100 francs. Instead of having an entire company, you can have one graduate student. Each graduate student tries a different thing, and that means that you’re really democratising science.

You currently have three Horizon Europe projects and one ERC Synergy Grant. How did you come to have so many EU projects running at the same time?

When I first arrived in Switzerland, it was important for me to be connected to both the service community and the broader European Community. I knew people in the UK and Austria who had complementary research and I talked to them and said, “There’s this thing called ERC Synergy.” And as we talked about it more and more, we got more and more excited about the type of research that we could do. So, we put together a proposal and we were fortunate enough to have the ERC Synergy funded.

What about the others, the Horizon projects?

These were actually results of other people reaching out to us — and this is an important point, that I think should potentially be a focus of discussion: for the ERC Synergy, I’m the lead PI. All of the other grants came in after Switzerland was no longer allowed to be leading. I have ideas of what I would like to do for the Horizons and Pathfinders, but I’m not allowed to apply for those. I had to wait until other groups reached out to me. It’s very nice to be part of these consortiums and we’re doing great work. But it’s a step backwards now that Swiss researchers can no longer take the lead on these kinds of projects.

Which one is the most important or promising one for you?

That’s like asking which one of your children is your favourite! They’re all special in their own way.

Which is the most important for you, Zac?

Zac: Jacob is right. I’m personally interested in each of them for different reasons.

Jacob: There’s a good balance. Some projects are very basic research. In others, we’re trying to help people get things into the clinic. The science is different, the focus is different. I find that more invigorating than just having the same project over and over.

So, you work on the whole spectrum from fundamental science to almost pharmaceutical applications. This is very rare.

Yes. On the one hand, it’s positive to have such a breadth of research going on at once. On the other hand, it could be a little bit of attention deficit disorder on my part. The fundamental research in my lab spans several disciplines. And that’s because I like thinking about different things. Some days I wake up and I want to think about how something is going to affect patients and other times I wake up and I want to focus on details of cell biology. I find it more stimulating to have that diversity. There’s a lot of really wonderful science that’s been done by people that totally focus. However, I’ve learned over the decades that if I focused on only one problem for years, I would burnout. I need to be able to switch.

For most scientists, ERC Synergy Grants are more important than any others because of its prestige. Not for you, it seems.

For me, the ERC is incredible from a scientific point of view. I don’t necessarily put it in terms of prestige. To me, it’s all just about ways to do very interesting things. The ERC Synergy Grant is great because it lets me ask questions about pure and fundamental workings of biology. But then, it’s going to be decades before that research affects somebody’s life. Whereas the Horizon projects could go in a patient’s body in four years. By the end of the project, who knows? That’s just a different level of satisfaction. I find fundamental research very personally satisfying. But it’s also incredibly fulfilling if somebody else’s life is better because of the work I’ve done. These are different forms of enjoyment.

Your ERC project DDREAMM is about DNA damage. Can you describe this?

In school, we learn that DNA is static. But your DNA is actually constantly getting broken and destroyed and damaged by things like sunlight and toxins such as smoking. That’s one of the ways you can get cancer, but your cells actually take care of most of the damage! Disease can come around when we don’t take care of it enough or when the damage overwhelms it. If you smoke too much, you get cancer because you can only deal with so much damage. There are also people who have mutations in the genes that take care of DNA damage, who have cancer all the time. They go outside in the sun and they instantly burn and get cancer. So DDREAMM is all about understanding how all of this damage gets taken care of. And especially how different cells in your body take care of this: how your skin deals with the sun and how that’s different from how other organs deal with toxins.

You are now halfway through this project. Where do you stand?

There have been some super milestones, several really important papers were submitted and published. They’ve pushed forward the scientific boundary and, very importantly, they’re very critical for the careers of the people that work on these things. So, these people will go off and have their own labs in either academia or industry and they’ve proven that they can do this type of science.

The Horizon project EDITSCD is dedicated to efficacy and safety of genome editing treating sickle cell disease. How common is this?

Technically it is classified as rare disease: in the USA, there are about 100,000 persons. But in Sub-Saharan Africa, it is so endemic that it’s hard to estimate how many people have it. It’s estimated that there are millions.

Are there other monogenic diseases that are more common?

Globally, there are about 7,000 monogenic diseases. And they affect about 350 million people across the whole world. That’s why we’re excited about gene editing, because there’s this concept called the long tail. If you think about the things that mostly kill — heart disease, cancer — this is the big peak. But then, there is the whole long tail, 350 million people, who have all of these diseases. And the promise of the gene editing technology, which is very fast and inexpensive, is that you can maybe do something about the long tail. They’re all individual diseases, but through this crowdsourcing of research technology, you can actually tackle this long tail.

What is your job within the project?

Zac: We are in involved both in selecting efficient tools to correct the disease and to make sure that they’re also safe. And for assessing safety we are using some of the methods that have been previously developed in Jacob’s lab or other labs, while also further developing and improving them.

Another Horizon project you are working on, geneTIGA, focuses on IgA nephropathy. How common is this disease?

Zac: It’s not as common as the sickle cell disease, but the coordinator of this project has both expertise and access to patients. So, we will be able to apply the tools in real samples. IgA nephropathy is also a good example for cell therapy, an approach where we are not correcting the affected cells, but reprogramming/training other cells to do the healing for us. And the process of how we do this can be applied to other diseases requiring cell therapy.

In the centre of the project stands DISCOVER-seq, the speciality of your GEML. What exactly is this?

Zac: It’s a method of listing the side effects of the different genome editing procedures.

Jacob: The key differentiator is that it asks the cells. There are other ways to find the things that could affect safety. But they mostly come in with a heavy hammer and they try to make the cell do something that it wasn’t doing. With DISCOVER-seq, cells tell us what’s wrong — and it actually works anywhere, in any cell in the human body. It works in any organism, even plants.

The project would not be possible without you?

Zac: DISCOVER-seq is very important. I think it’s part of the reasons why Jacob was approached for these projects. It’s important both for designing tools and selecting tools, but also for the profiling and the safety assessment of these tools.

In your third Horizon project called T-Fitness, DISCOVER-seq plays also a central role.

Jacob: Yes. This is one of the great things about DISCOVER-seq. Whether you’re doing bone marrow stem cells or T cells or any of these things, the results are comparable between cell types. They’re comparable between patients. And you can take real patient material. And practise with different diseases, totally different cell types.

You invented DISCOVER-seq, right?

Full credit where credit is due: it was developed by my lab. But the people in the lab are the most important part. All the postdocs and graduate students, the master students, those are the real key of any lab.

What makes such a lab successful?

I think you have to be pretty deep into gene editing itself to understand how the tools work, to understand what cells do with them. And I think you also have to have the ability to go fast and have a high tolerance for risk.