Interview with Dr. Derrick Rossi of Moderna Therapeutics

JYI: Could you tell me a little bit about your educational background?

Derrick: I went to undergrad at the University of Toronto, so I did my Bachelor’s of Science at the University of Toronto and then I did my Master’s of Science degree, also at the University of Toronto and then things get strange. I went to the University of Paris in France, and I was in a graduate program there for about a year and a half but I ran out of money for one thing and also the lifestyle was a little bit too much, I wasn’t sleeping because I was staying awake in Paris every night. So I left Paris cutting the graduate degree short and then I went to Texas for a little while and then I ended up going into another graduate program at the University of Helsinki in Finland and there I finished my PhD. And then I did a post-doctoral fellowship at Stanford in California, and after that I took my faculty job. It was several graduate programs, first Toronto, then Paris, then Helsinki, took a while but ended up having a very successful graduate career.

JYI: What was the topic of your graduate research?

Derrick: What wasn’t the topic is more of the question. So when I went to the lab in Helsinki I had this great skill that I had learned at University in Toronto in the early 90s when gene targeting was first being developed and Toronto was one of the centers for the development of those technologies --- so I learned how to make specific mutations in the genomes of mice by homologous recombination in ES [embryonic stem] cells. So I took that skill to Helsinki and basically knocked out all the genes in the lab that they were working on. I knocked out three of the genes and then characterized the phenotypes of those mice. The genes were all involved in the pathways of cell cycle regulation, but the phenotypes were quite diverse. So one published study, for example, had pre-implantation embryonic lethality. I also made a conditional knockout out in Schwann cells and the mice developed a peripheral neuropathy. When we knocked out another gene it had an embryonic lethality at about mid-gestation that was due to a vascular defect so we studied and characterized that and published that. The heterozygous mice for that same gene developed gastrointestinal polyposis, tumors in the gut, which actually modeled a human disease called Peutz-Jeghers syndrome. So in the end I studied genes which when mutated led to pre-implantation embryonic lethality, mid-gestation embryonic lethality, peripheral neuropathy, or gastrointestinal polyposis.

What I didn’t study in grad school was stem cell biology, which is what I went on to do in my post-doctoral research at Stanford. But I had been reading literature and stem cell science was coming of age and also I had this idea that aging, which was almost a pseudo-science for a really long time, was actually turning into real science and I felt there was an intersection between aging and stem cell compartments, and so I went very specifically to work on stem cell aging in the lab at Stanford. I sort of took my hypotheses with me and I worked on that for my post-doctoral career and then carried that over into my lab and I still work on that to this day.

JYI: Why did you go abroad to study?

Derrick: The great thing about science is that you can do it anywhere, it’s kind of like “science without borders” - that’s the way I think about it, and I was pretty interested in other cultures and I actually liked traveling and so science was a perfect way to do that. You could join a great lab anywhere, so I did that. A lot of it was exploring the world as a young person, which I think was a great thing to do and if I had to do it again, I wouldn’t change it at all.

JYI: Did you always know you wanted to go into academia?

Derrick:  I knew I was certainly going to go into science -- math and science were always my forte. In high school I really got turned onto biology. I took a course that introduced basic molecular biology, how genes are transcribed, and proteins are made, etc. and I was blown away by that, I thought it was the coolest thing I’d ever heard so I knew I was going to go into biology/molecular biology at that point. When you’re in the science track and you’re thinking about science, academia makes sense because you just continue to pursue questions of interest to you. It’s a good setting to do that in. I hadn’t really thought about transitioning to biotech or pharma, although that would have been possible as well. Still, I think I prefer academia simply because you can pursue the questions that are really of interest to you, whereas if you’re in biotech or pharma it’s a different flavor of science focused on trying to develop a product for patient translation and so the things you pursue are less about answering basic question and more about how to make a product work for the best. This is a generalization of course. We do a lot of translational science in the lab, it’s actually a main focus. Nonetheless I still prefer academia because it gives you the freedom to pursue whichever questions you want.

JYI: I’ve also read that you are one of the founders of a company, could you talk about that? How did you get the idea?

Derrick: The biotech company is called Moderna Therapeutics and it’s probably one the most successful young biotech companies in Boston/Cambridge right now. It is only 4 years old, has about 170 employees, and has recently been recognized as one of the top 10 most disruptive companies in America by CNBC (http://www.cnbc.com/id/101715269). The technology at the heart of the company, which we developed in my lab, is very exciting and very powerful.

I’m a stem cell biologist and I’m mostly, almost exclusively focused on hematopoietic stem cell biology. This said, we had a side project in the lab dealing with IPS [induced pluripotent stem] cells shortly after the publication of Yamanaka’s great discovery that you could put four transcription factors into any number of somatic cell types and turn them back into induced pluripotent stem cells. So we got very excited by that, and at the time of Yamanaka’s discovery everybody was thinking about eventual therapeutic translation.

One potential problem however was that Yamanaka had used retroviruses to achieve reprogramming, and retroviruses themselves are mutagenic because they insert into the genome, and also some of the Yamanaka factors happen to be pretty potent oncogenes -- c-MYC for example. The prospect of integrating an oncogene into the genome to make a pluripotent stem cell was scary, as ultimately those cells would be turned into some other cell type to give to patients preloaded with a potential ticking time bomb of a potent proto-oncogene built right into the cell. That’s the background to why we came with the idea that we could get rid of the DNA altogether. We knew we needed to make proteins for c-Myc, Oct4, Sox2 and KLF4, but instead of using a DNA vector we envisioned that we could use an mRNA vector. Since RNA does not integrate into the genome we could avoid the potential problem of inserting proto-oncogenes into the genome. At the same time mRNA would still allow us to express the Yamanaka factors in somatic cells to generate IPS cells. That’s how the concept started.

As it turns out, you can’t really use synthesized mRNA in the cells, because as soon as you put it in the cells, the cells think they’re being infected with an RNA virus, and they respond with a robust anti-viral response. The work-around that we came up with was to modify the nucleosides. When you synthesize mRNA you would typically use the off-the-self standard ribonucleosides, but if we substituted pseudo-uridine in place of uridine, and methyl-cytosine instead of cytosine, we discovered that such modified-mRNAs do not elicit this antiviral response yet they encode the same proteins that a normal mRNA would.

As it turned out this technology worked very robustly, which was very exciting. When we published the study, it was recognized as one of the top ten medical discoveries of the year by Time Magazine in 2010. What I was most excited about was the prospect of using modified-mRNA as a therapeutic and use it to treat patients directly. For patients with genetic mutations that lead to a protein deficiency, one could imagine that instead of using a DNA vector like a virus, you could theoretically come in with modified-mRNA and achieve gene replacement for the missing or defective protein.

That was the idea of the company that I founded, and I convinced several people that it was a good idea, attracted some investors and the company was launched in 2010. As it turns out, it can be used therapeutically in vivo which we demonstrated last year in a published study. You can make therapeutic proteins for literally thousands of different proteins. The great thing is that it’s the same platform technology every time, you’re just encoding a different protein. So the therapeutic potential is massive, and that’s why the company has been so successful.

The parallel approach would be using recombinant proteins. But recombinant proteins for, say, enzyme replacement, if you’re missing an enzyme in your liver and you’re sick because of it, if you have a mutation that you got from your parents. The problem with that is that recombinant proteins take years and hundreds of millions of dollars to develop. With modified-mRNA however, you don’t need to make the proteins ex vivo, you simply synthesize a nucleic acid which costs very little, and takes only a few days to make, and then the patient’s own cells make the needed protein. All of a sudden the cost of developing protein-based drugs has gone from several years and hundreds of millions of dollars to a couple of days at a fraction of the cost. That’s a massive value proposition. I feel certain that modified mRNA therapeutics will be used to treat many dozens of diseases in the future. Ten years from now there will be several modified RNA drugs in patients, in twenty years there’ll be tens of them.

JYI: You said that the mRNA will be present in every cell in the patient’s body. How will you get it into every cell?

Derrick: Delivery is an issue for sure; you’ve put your finger on a critical issue. For many diseases you might need gene replacement only in a certain cell type in a specific tissue or organ. For example, if you have a mutation such that you are missing an important liver enzyme, then you would need to express the missing enzyme in liver cells but not necessarily in other tissues. The challenge then becomes delivering the modified-mRNA to your liver, and not necessarily to any other tissues. Here the liver is just one example but you can imagine a similar scenario for any other tissue type. Fortunately there are multiple technologies that can very specifically deliver cargo to different tissues. But certain tissues/organs will for sure be more challenging to target than others – for example the blood/brain barrier presents a challenge for delivery to the brain.

There are also diseases for which the mutated gene encodes a protein that is secreted and acts in tissues and cells other than the cells that actually produce the protein. In that case it doesn’t necessarily matter which cells receive the modified-mRNA and ultimately produce the protein since it is secreted and finds its therapeutic target after entering the circulatory system.

JYI: And this treatment is something that would be needed to be done over and over again, because it has a transient effect, is that right?

Derrick: Also a smart observation. Yes, we’re not talking about permanent cures, we’re talking about treating. Whereas you might be able to cure a disease with a DNA-based vector that integrates permanently into the genome of a cell and remains there forever. Not so with mRNA. You can imagine treating a disease by giving the patient a regular dose of modified-mRNA, somewhat like how many recombinant proteins are used -- once every two weeks or three weeks, depending on the particular disease.

You can also imagine clinical settings, in which you need a protein acutely. For example we published a paper last year in Nature Biotechnology in which we used a cardiac infarction model to model the setting in which a patient gets a heart attack.  So we induced a heart attack in mice and at the same time treated the infarct area with a modified-mRNA encoding VEGF (vascular endothelial growth factor), which promotes blood vessel growth. What happens in infarction is that blood vessels and cardiomyocytes are killed and upon repair there is considerable scarring. One of the recovery issues after infarction is poor vascularization, so we thought that if we administered VEGF that promotes neovascularization at the same time as the patient (the mouse in this case) is getting the heart attack, we might be able to improve cardiac repair after infarction. Indeed, that’s exactly what we saw: we got very effective re-vascularization, which led to significant clinical improvement after infarct in the mice that were treated. So that’s an example of a clinical setting where you only need the modified-mRNA drug once: you come into the operating room, you’ve had a massive heart attack, you get one shot of modified-mRNA for VEGF to the heart that elicits a much better recovery.

JYI: The applications of this therapy seem very diverse.

Derrick: Yes, that’s what makes the modified-mRNA platform so exciting -- there are literally thousands of applications, you just have to use your imagination to envision clinical settings in which modified-mRNA could be a transformative therapy.

JYI: What are your future career plans?

Derrick:  Well… I like my day job so think I’ll keep doing science for a while. I don’t really have any other plans beyond that other than to perhaps retire at a relatively early age, and then read books, plant a garden and travel around the world. But until that point I’ll continue our work in academic science, because that’s what I really enjoy doing.

JYI: What advice would you give to students considering careers in science and/or biotechnology?

Derrick: It’s a good choice right now, because it’s a golden age of bioscience, so it could be a good career move. If you look at the history of different fields you see often see an arc. At first discoveries are made that open a new field, and this is often followed by a sudden and sharp upswing in people entering and publishing in the field. After some time it is possible that a particular science/discipline becomes saturated, plateaus, becomes less relevant or even exhausted, such that there are less questions to ask, or little funding for support. Of course it is also possible that a given area may enjoy a renaissance if a new discovery is made that re-energizes the field. But generally I would urge students to try to be thoughtful about what field exactly they want to go into, and if possible to enter a field that’s on the ascent. It’s important for sustaining one’s career, or for eventually doing your graduate work, doing your post doc, and then getting your own lab that you can then support with funding. You want to be in a field that has a good future to it, so you have to be forward looking.  I did that when I entered the stem cell biology field -- I saw that stem cell biology was about to come onto itself, and that has indeed been borne out.

So that’s a little bit maybe of a sterile way of looking at one’s career -- you might have expected me to answer that you should just follow your passion and pursue whatever you’re most interested in. Ultimately that also has to be true. You really have to be committed to science. Science is not an easy thing to do, because most of the time, 9 times out of 10 when you pursue an academic question, you fail in answering it. You get stuck technically, or it didn’t turn out the way you thought it was going to be, or your hypothesis was proven wrong. So you have to be prepared to deal with a lot of disappointment to get your 1 out of 10 scientific successes. Therefore, you must be passionate about what you’re doing, that much is clear.

But science is a great career -- you interact with smart people all the time, you get to ask questions for which there isn’t an answer yet on the planet, and find out the answer, and that’s permanent, it goes into the logs of science, so that’s pretty cool.

JYI: What would you say are the areas of science that are on the rise right now?

Derrick: Areas of science on the rise… Regenerative medicine is certainly on the rise, and with good reason.  Gene therapy is certainly back (it emerged in the late 80s and then there was a setback in which first generation vectors led to activation of oncogenes and patients that were being treated for diseases ended up getting cancer due to the viruses they were being treated with. But next generation viruses are much safer and there are currently 1700 gene therapy trials on going, so gene therapy is certainly back, and that’s very exciting. Cas/CRISPR is also very exciting; the idea of correcting genetic mutation at the genetic level has amazing potential. First generation zinc finger nucleases are in patient clinical trails now, with TALENS and Cas/CRISPR surely to follow. Personalized medicine, the ability to deep sequence a patient’s genome cheaply and quickly is very exciting and has huge potential. For example, two patients come in with seemingly the same disease, but actually their underlying genetics of disease are entirely different, and while one patient might be responsive to a certain therapy because it targets the pathway that’s affected in that patient, the other patient might not respond at all. Targeted tumor immuno-therapy with chimeric antigen receptors, is also very exciting as it opens the possibility of targeting immune cells to cancer cells specifically. Aging research is also very exciting right now as there have been multiple studies published recently that suggest that certain aspects of aging might be reversible by targeting certain pathways or molecules. So that’s certainly a very excited area to be in.

JYI: What do you think will be the next greatest discovery in the area of science that you’re working in, in stem cell biology?

Derrick: You asked specifically in the area I work in, which is hematopoietic stem cell biology, and as you know these cells are the functional units of bone marrow transplant, with approximately 60 000 patients per year get bone marrow transplants, but there’ll be a lot more transplants if there were alternative ways of deriving hematopoietic stem cells. I’m pretty certain that within a couple of years a robust protocol for generating transplantable stem cells from iPS cells, for example, or possibly by reprogramming, or possibly via transdifferentiation from another cell type will be developed and that will I think be really impactful for the translational aspect of hematopoietic stem cell biology and transplantation medicine.

 

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