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John Doench: Advancing Functional Genomics through Collaborative Science

SLAS2019 Conference Co-Chair John Doench, Ph.D., associate director of the Genetic Perturbation Platform and institute scientist at the Broad Institute of MIT and Harvard (Cambridge, MA, USA), believes in collaborative science. That’s why he’s at the Broad, and it is why he’s dedicated to working with others at SLAS to be sure the SLAS International Conference and Exhibition delivers ideas and connections that enable scientists to make a difference.

“Getting people to buy into the idea of collaborative science is a challenge,” Doench says. “So much of how we think about science is about the individual. We talk about Nobel Prizes. We refer to studies by the last name of the first author. Once the paper is published, we refer to the results as from the PI in the lab – this lab did this, that lab did that. It’s always focused on an individual person. That’s not how you actually do most science.”

Doench believes part of the problem is that the culture doesn’t reward team science terribly well. That makes it tough to encourage scientists – especially new graduate students – to talk with others and share their ideas. He knows it is hard for scientists to defer to others who might have more expertise.

“No one is good at saying ‘I don’t know,’ but scientists are truly bad at saying it, especially in academia,” Doench says. “Admitting that you don’t know something takes a lot of maturity. Going to other people for help who might be experts in something – rather than just doing it yourself – that’s a very vulnerable experience for a lot of people, especially those who probably got As in every class they ever took. They’re not used to admitting weakness in any way, shape or form.  But that’s implicit in doing team science. It’s saying you know you have limitations and that’s why it is better to work with a lot of different people, and that doesn’t necessarily come naturally. But, it’s going to become increasingly important as we face the fact that the complexity of biology – and disease – requires more expertise than any one person or any one lab or any one group can possibly possess.”

Doench wants to be a part of helping to grow collaborative science, and feels his career to date has afforded him that opportunity.

The Road to the Broad

Doench was not drawn to science until later in his school years. He was a history major at Hamilton College, a liberal arts school in upstate New York.

“While I liked studying history, I didn’t see myself as a historian in any way – that did not seem like the right career path,” Doench recalls. “I really liked the science classes I was taking and in particular there was a microbiology class I took my sophomore year that I really loved. I loved thinking about molecules in the chemistry classes that I took. It was pretty obvious to me that staying in school and studying biology would be a good idea for me. I applied to a bunch of different graduate schools and I decided to go to MIT (Massachusetts Institute of Technology, Cambridge, MA). So, I showed up in Kendall Square in August of 2000 and I’ve never left.”

His doctoral work at MIT was with Nobel Prize winner Phillip A. Sharp, Ph.D., who Doench called “an incredible mentor” and he is grateful Sharp was willing to take in someone with limited biology experience.

“When I started graduate school I was very intimidated by how much my classmates already knew about biology, whereas I knew relatively very little and had very little biology lab experience,” Doench says. “From that standpoint, I was quite a risk. But Phil took me into his lab and there I met an intellectual soulmate – Christian Petersen – someone who had also attended a liberal arts school and also had not taken 28 of his 32 classes in biology. We joined the lab at the same time, survived and thrived in graduate school together and that got me through to getting a Ph.D. in biology.”

Doench says Phil’s mentorship style is ‘here’s some rope; go hang yourself’ and that he gives his students a lot of freedom to try things and to learn from failing.

“It’s not at all that Phil didn’t care about how we were doing,” Doench adds. “He’s an intense scientist; there’s no denying that. He loves the results of every experiment that you do. I remember having lunch with him at the Whitehead Institute cafeteria and he’d want me to bring my autorads. We’d squint at bands on a gel together. Phil loved getting into that level of detail in experiments which I really enjoyed and still do.”

Doench also credits a Hamilton College history professor with having a profound impact on him.

“The energy that Doug Ambrose brought to all his interactions is something I can’t quite reach but something I certainly strive for,” Doench says. “He was excited about what he was doing and always tried to share that excitement. I think he of anyone else I know of – with the possible exception of Bruce Springsteen – he took very seriously the idea that if someone is giving you their time and their attention, you owe it to them to give them your best. There were no lectures that weren’t fascinating; he never mailed it in ever – not once in the four years that I knew him.”

Daily Discovery at the Broad

“My daughter drew a picture of me at work, and it was just me sitting in front of a computer,” says Doench, laughing. “While not fully accurate, maybe it’s not far from the truth. I think that my day is more interconnected than most from the standpoint that I meet with an awful lot of people who are studying an awful lot of different biological problems. That’s the nature of being more focused on technology rather than on a specific biological problem per se.”

CRISPR technology and other functional genomics tools in his toolbox can be applied to a lot of different biological questions, Doench says. On any given day, his 9:00 a.m. meeting might be with someone studying diabetes and his next meeting might be with someone working on immunotherapy and the next meeting will be with someone working on psychiatric disease. It’s collaborative and he believes being able to think about so many different areas and how the technology can help to answer some of these biological questions is truly exciting.

Coaching people on how best to use the tools and techniques of functional genomics – including CRISPR – for their specific biological problem is just one aspect of Doench’s job at the Broad.

“The other hat I wear is actually doing research and development on the technology of CRISPR – primary research on how we make CRISPR technology better, how we extend its uses, how to be one of many people at the Broad and elsewhere who are trying to push the limits of CRISPR technology to discover all it might possibly do,” he says.

Doench states that CRISPR in the laboratory has already been a game changer.

“The ability to manipulate DNA and learn about the function of genes has been a renaissance in the field of functional genomics,” he says. “That’s going to continue; there will always be more improvements to make, new things you can get the CRISPR technology to do, new types of manipulations. There are a lot of people on that path and though we don’t know exactly what the future looks like, it’s clear that this technology is here to stay and is going to continue to see very wide use.

“From the standpoint of CRISPR at large, though, what’s not clear is how much of a therapeutic impact it’s going to have on patients,” Doench continues. “There are still a lot of challenges to using CRISPR therapeutically. There are some companies, of course, that are developing CRISPR-based therapeutics and I’m sure that there are going to be clinical success stories in a relatively short time horizon – hopefully within five years. Is a CRISPR-based therapy going to start to become commonplace in medicine? I don’t know. At least in the short term, there are so many challenges to solve that it’s going to be the exception rather than the rule that a CRISPR-based therapy is the way to go for a particular human disease.”

Doench shares a couple reasons for that, one being the tremendous delivery challenge. He says if you want to use CRISPR therapeutically, one way is to remove the cells that need modification, modify them ex vivo and then put them back into the patient. Doench says some cell types are amenable to this, such as stem cells in your blood.

But there are many cell types that are not, such as your brain or your stomach,” he continues. “Any vital organ – you can’t remove it for a while and then put it back in later! Another option is to deliver the necessary CRISPR components directly to the patient, where the challenges are similar to those of delivering a small molecule. Finding a small molecule that is stable in serum and goes to the right organ and doesn’t build up toxicity over time is a huge challenge. That increases exponentially when you’re talking about delivering a protein or large nucleic acid or some combination of both and actually getting that into the cell of interest. Each tissue type, each disease, each cell type is going to be its own challenge from the delivery standpoint. That’s not to say it’s an insurmountable challenge but it’s absolutely a large challenge that’s going to require a lot of attention before CRISPR becomes an off the shelf therapy for a lot of different diseases.”

Photo by Len Rubenstein Photography, courtesy of Broad Institute

CRISPR Success Stories

Doench believes that CRISPR is the defining technique of the age.

“In the Sharp lab, I worked on RNA interference and for a long time that was basically the only game in town if you wanted to perform loss of function studies,” Doench says. “A lot of the lessons we learned from RNAi we very easily were able to port over to CRISPR. This is one of the reasons – by no means the only reason – CRISPR technology was able to make such an impact so quickly and so broadly in the realm of genetic screening. We had all the tools and techniques and lessons learned from RNAi, so we weren’t starting at ground zero when it came to CRISPR. I’d say CRISPR is where the excitement most lies now, but I also think it’s very important to understand that it doesn’t solve every problem by any means.”

Doench shares a couple recent collaborations from his work at the Broad – norovirus and cancer immunotherapy – that have been especially important and meaningful to him.

“Norovirus is the cause whenever you read about a cruise ship having to dock because everyone’s vomiting,” he says. “It is a particularly nasty bug and a couple of years ago no one knew how norovirus actually got into cells; the receptor for norovirus was not known. In collaboration with Skip Virgin’s group at Washington University in St. Louis and using a mouse model of norovirus, we used CRISPR technology to knock out every gene in the mouse genome and put norovirus onto the cells. The vast majority of cells died because the norovirus was still able to successfully infect and kill the cells, whereas there were a tiny number of cells that survived. We then determined which genes had been perturbed by CRISPR in those cells and long story short, we found the mouse receptor for norovirus – something that had not been known.

“To me, what’s most striking is it was such an easy experiment to do once we had the right model system, the right assay, the right perturbation," Doench says. "That highlights the power of CRISPR technology – to be able to ask a question that had been unanswered in virology for years, for decades, and in a one-month timeframe be able to answer it. At the time we did that experiment I had never actually physically met the people in the Virgin lab. We had an e-mail, fed ex and phone call relationship. It really highlights the power of collaboration. We were expert at certain parts; they were expert at other parts. We were able to work together even though we weren’t in physical proximity.”

Doench’s second success story is in the realm of cancer immunotherapy.

“Cancer immunotherapy is an incredibly revolutionary way of treating patients,” says Doench. “In some cancers that would have been a death sentence within months, now people achieve long-term response. One of the issues of immunotherapy is that only a small fraction of patients respond. We are only starting to understand the factors that govern the patients who will respond vs. those who won’t. That begs the question, how do you take a patient who won’t respond and turn him into one who will?”

The Broad Institute and Nicholas Haining’s lab at the Dana-Farber Cancer Institute (Boston, MA), a long-time collaborator, worked together to address this challenge. They again used a mouse model and screened using CRISPR technology to find genes that when perturbed would enhance the response to immunotherapy.

“We found a whole bunch of genes that were able to do that; the one that we focused on was a gene called PTPN2,” Doench explains. “One of the reasons to focus on this gene was the phenotype was very strong but also it is an enzyme and, at least in theory, it could be drugged. One could design a small molecule to inhibit that gene so making sure that was a robust hit in our screen was one of the priorities. What’s exciting about this is that there wasn’t just one gene but a whole list of genes, so by looking at what all those genes do, you can start to understand how we might turn a patient who’s not a responder into one who is a responder by manipulating some of those pathways.”

Doench says he and Haining are pressing forward in multiple directions – both screening against more genes and screening in more models of immunotherapy. They are also taking some of the genes that were already validated and starting to think about developing small molecules that could inhibit them to see if small-molecule based inhibition of that putative target would potentially be a viable option.

“The specific cancer we were working on with PTPN2 was a model of melanoma,” Doench says. “I think one always open question is how much does a mouse model translate to humans? The answer will be different all the time. Another open question is will this only work in melanoma or are there other types of tissues where this would also be the right target, or will a different cancer require a different target? These are all very active areas of investigation – not just at the Broad but at many, many labs around the world.

“To do a successful experiment, it’s not just about having good perturbations,” he continues. “We could be putting magic fairy dust on to cells but if your assay isn’t good or your model system is irrelevant to the disease or biological problem of interest, then it doesn’t matter that CRISPR is such a powerful technology; you’re still not getting the right answers.”

SLAS2019 Experience

Collaborative science thrives within the SLAS community and Doench feels completely at home in its midst. He is enjoying his SLAS2019 role along with a great group of colleagues on the SLAS2019 Scientific Program Committee.

“I’m finding that being conference co-chair is actually a lot less work than being a session chair,” he says. “Seriously, it’s going great. When the Cellular Technologies Track got started four years ago, I was the associate track chair and then track chair the next year, so I’ve been involved with conference planning for a few years now. It’s work, no doubt, but it’s fun and I get to help select what sort of science I’m going to sit and listen to for several days! In the same way that I meet with a lot of different biologists in my office for whatever CRISPR screen they’re going to do, at SLAS I get to interact with people who are complete experts in their particular fields and I get to hear their sense of what’s hot – what are the things I don’t even know about that are going to be front page news in the coming months and years. It’s a great learning experience – you put in the time and you get a lot out of it.”

Doench also taught the SLAS Gene Editing for Drug Discovery Short Course until this year, with co-course developer Samuel A. Hasson. For SLAS2019, he has transferred teaching responsibilities to his Broad colleague, Scott T. Younger.

Doench invites curious colleagues to check out all SLAS2019 offerings on the conference website.

Recharging the Battery

“My number one priority is my wife and daughter,” Doench says of his after-work time. “My daughter is eight going on 18, but she’s still sweet most of the time. I want to squeeze as much juice from that lemon as I can while I can before she’s a complete teenager and doesn’t want to have anything to do with me.”

He indicates the family likes to travel and this summer, for the first time, his wife and daughter accompanied him to a conference in Italy. It went well and he hopes they can take similar summer trips in the future – nothing during the school year, though. His wife is a teacher so there is no skipping school. Doench also likes to run, bike, play volleyball and check out whatever new microbrew there is in Boston.

But, he truly loves his work.

"The fun part about discovery-based science is that we think we’re good about predicting the future, but we’re really not. The way we write our papers is that every experiment was this linear step and if-then statements that all came true. But that’s not how science actually happens; it’s the surprising stuff that we appreciate. That’s the part I still love."

October 22, 2018