BlueRock Tx: Seth Ettenberg, CEO
“I think that's how you do your best work…get in a room where you are constantly challenged.”
Hebe, daughter of Zeus, had many tasks on Mount Olympus. The majority were of the domestic variety—drawing baths, helping Hera into her chariot and waiting on Aphrodite. Yet, Ovid writes that she was cherished by Zeus, well ahead of her more famous siblings. How did she attain such stature? The reason is simple—regenerative medicine.
Hebe (“bloom of youth”) was cupbearer to the gods and had the ability to serve ambrosia (life force) to fellow Olympians and a few lucky humans. Chalice in hand, Hebe could heal sickness, prevent aging and restore youth.
As mortals, we have always sought such remedies. Following Martin Evan’s identification of mouse embryonic stem cells in 1981 (Nobel ’07), and Shinya Yamanaka’s development of induced pluripotent stem cells (Nobel ’12), it seemed that stem cells may be the secret ingredient in ambrosia: “During disease and aging, there are cell types that just go away…what’s needed is a ‘find and replace’ solution, because replacement potentially allows you to restore function,” comments Dr. Seth Ettenberg, CEO of BlueRock Therapeutics.
In practice, harnessing stem cells to treat conditions such as neurodegeneration, stroke and heart disease, has been challenging. What’s required is a sophisticated understanding of cell development, and the ability to coax these fickle units of life into becoming specific cell types: “BlueRock has figured out how to characterize and build cells from developmental biology—and replace the exact cell type deficient in a given disease. We call it ‘authentic’ cellular replacement,” says Ettenberg.
Work from Lorenz Studer’s lab over the past 20 years laid the scientific groundwork for a high fidelity platform able to turn induced pluripotent stem cells (iPSCs) into dopaminergic neurons, cardiac myocytes or other diverse cell types. Improved, scaled and now translated at BlueRock Therapeutics LP (Bayer subsidiary), this “cell+gene platform” aims to make authentic cellular replacements for a range of conditions in neurology (Parkinson’s lead, Ph1 ongoing), cardiology and immunology.
As Hebe would likely admit, cooking up “ambrosia” is difficult—yet armed with deep scientific expertise, clinical development knowhow, and the financial and logistical support of Bayer, BlueRock aims to deliver first in class stem cell therapies. In 2016, Bayer (Leaps) and founding investor Versant Ventures established BlueRock Therapeutics with a $225 Million Series A Financing. In 2019, BlueRock and its powerful cell+gene platform was acquired outright by Bayer ($240M upfront and $360M in biobucks). The following year, BlueRock brought on experienced scientist and drug developer Seth Ettenberg as CSO (’20 – ’21): “I knew instantly I was in a group with the best cellular biologists I had been around, bar none.” For the past year, Ettenberg has taken the helm as CEO and President.
Dr. Seth Ettenberg has always wanted to pursue science and make an impact on disease. From the jump, he chose industry rather than academia, as his battleground. Following graduate and postdoctoral training at the NIH, studying the role of E3 ubiquitin ligases in cancer, he started in R&D at CuraGen. There he helped develop early-stage antibody therapies in oncology before moving to the Novartis Institutes for BioMedical Research (NIBR) as a lab head. For almost a decade, Ettenberg ran a research team at NIBR, and became head of oncology biotherapeutics in Cambridge. In 2014, Ettenberg was a founding member of the Unum Therapeutics team, where he served as Chief Scientific Officer. In this role, he built and led teams that brought several novel cellular therapies from invention to clinical testing. Though new to developing stem cell therapies for conditions like Parkinson’s, Ettenberg is embracing the novelty: “I love the challenge and the idea of coming in and doing this.”
Below is an interview with Dr. Seth Ettenberg, CEO of BlueRock Therapeutics from October 2022:
1. What first made you initially interested in science? Was there an early mentor or teacher that set you on this path?
There are two parts to this answer. The first one is very personal. When I was 11 years old, and my brother was 13, he was diagnosed with acute lymphoblastic leukemia—ALL. After about a year and a half's battle, he succumbed to that disease. That tragedy in my family's life created this passion within myself to bring a cure to my brother's disease. That's how I thought of it as a young child, and actually still think of it as an adult today. Though I can no longer help my brother, I still have that desire to do something for a single patient's life.
I think I've always had a natural curiosity, which ties into a funny story about my family that my father loves to tell. Growing up, my brother was a computer geek and was already working with an MIT professor at age 12 and coding—back then we had a TRS 80, so not what we would even call a computer today. At dinner one night, he said to my father: “I wonder what's at the end of the universe?” And my father turned to me and said: “I don't know. Seth, what do you think?” We were eating fried clams for dinner, and so I picked up a clam and said: “I don't know. But how do we get the clams in this shape?”
And I tell you that mostly as a bit of a laugh, but also because it illustrates that my curiosity was always very…practical. It was like “how do we do this?” I see something in front of me, and I want to understand it. My teachers and the professors along the way were definitely part of the story of me becoming interested in science. They made me believe in myself, and that I was capable of learning, of asking questions and finding answers. The first one was a physics professor in high school. The next one was my first research mentor in undergrad—I was helping set up his lab as an entomologist. So I was out in the field, and got to name a new species, which I wanted to name after my girlfriend at the time. He [PI] said it wasn’t appropriate, so we left out the “Jennifer” part of the species name.
I wasn't a natural student. I didn't score straight A's all through high school and college, and it wasn't until I got to grad school that I started really “kicking ass and taking names” in terms of my work. All through school I had learning disabilities and other things that I dealt with, so having professors who believed in me and gave me some confidence was really important. I went to a fairly rare University. In the States, it's called USUHS, which is Uniformed Services University of Health Sciences. It's the only military medical school in the United States and the only way to get there is to have an acceptance letter from a US medical school and then go to USUHS with that acceptance letter. If admitted there, they pay for your training in return for service in the military. I did not have this service requirement as a graduate student.
2. Briefly describe your research as a grad student and post-doc. What was the moment you decided to jump from academia (NIH) into industry (CuraGen)? What different paths did you consider, and what was the deciding factor to make the transition?
I studied ubiquitin ligases in the cancer institute at NIH. I was in a lab that was a breast cancer genetics group. So, we studied a lot of the genes that caused breast cancer and other malignancies. We could use gene screens at the time, and had identified a family of genes [ubiquitin ligases] potentially implicated in cancer. And then we got to name those genes and ascribe function to them. A high point for me was when we stumbled upon this gene family; we were working out the characteristics and had reached out to other labs that were in the same area. So in flew this professor [Yossi Yarden] from the Weizmann Institute – he was actually the head of the Weizmann - to take a look at my [lab] books. The reason he came over was that his lab was studying the same gene, and we were getting similar findings. I just remember the moment where he was flipping through my notebook, and he told me my experimental question was not “elegant.” What he meant by that, amidst the English to Hebrew translations that were going back and forth, was I needed to ask the big question. We kept detailing small things about the gene or amino acid structure, but he urged me to really find the significance of this molecule to biology.
That was really interesting and led to a whole new series of papers with his lab around the class of genes regulating all these receptor tyrosine kinases, which had important implications for cancer.
[On what drove the transition from academia to industry]
To tell you the truth, I was always focused on industry. Partly because it's just the way I am setup. By the time I went to grad school in science, I had already built three or four businesses: from a fish tank aquarium service when I was in high school to a graduate tutoring conglomerate with about 50 or 60 tutors and angel investors. Growing up, I was always building businesses.
For me it came down to what I call the “reward systems” of industry and academia, and what you personally value. There is no judgment here, it is a personal choice.
In industry you are valued on the amount of money a product could make and the impact you could have on patients’ lives. In academia, I see the value as the amount of money you could bring in grants and the impact you could have on science via publishing articles. For me, I lean towards industry: I want to impact patients’ lives and build a good business.
[Though interested in industry] In my mind at that time [after post-doc] I wanted to be a scientist that works with a team focused on making discoveries that could be useful in industry. I loved the idea that in research you could hold up this analysis, in those day films [sanger sequencing or westerns], and be the first one in the world to know the result. So I really wanted to be involved in that process but just in the industrial world. From my graduate and postdoctoral training, I felt that I learned how to discover in an academic lab—so I wanted to take that same skill set to industry.
3. You spent ~10 years at Novartis first as a Lab Head and then head of Oncology in Cambridge. What were the lessons you learned here that helped you in your subsequent roles as CSO and now CEO of BlueRock?
I went to Novartis [NIBR] when they were just moving into Cambridge and setting up. Throughout my career I have always joined things at the beginning: at the stage when people are figuring things out. At the time, Novartis really didn't have a lot of biologics, such as antibodies or protein therapeutics. Coming from CuraGen, I joined to help get that initiative started. I was able to get a role because of my past experience in biologics—it was competitive to get a lab head job at NIBR. The organization had really high standards and rigor in both their employment and talent management.
[At Novartis] It was an incredible ride, an incredible education, and I was surrounded by lots and lots of brilliance and enough resources to get things done in a meaningful way—meaning we hit obstacles, went back and did it again, which is what this business takes. The hard part of the biotech boom and bust is it takes an iterative cycle to learn enough to get something moving.
At the time, Mark Fishman used to speak to the [NIBR] campus about a “new grammar” of drug discovery—a way to do science and drug discovery by understanding what you know, and precisely impacting cell signaling with your drug. No matter how small the indication was, let the economics go temporarily to get that done. This new way of thinking felt incredibly energizing.
4. How did you get involved in Blue Rock?
I started a company after I left Novartis. My last role at NIBR was building early cell therapy [for oncology]. I was the scientific liaison that originally started to work with the team at the University of Pennsylvania, on an [CAR T] therapeutic candidate that eventually became Kymriah. This experience ties us back into the original part of my conversation with you, because one of the first patients [dosed with Kymriah] was a pediatric ALL patient--so for me, it was massively rewarding and reminded me why I went into it [biotech] in the first place.
That moment inspired both the Head of Business Development for NIBR, Chuck Wilson, and myself to go start a next generation CAR T company. I realize now there are probably 100 or 200 such companies, but we were early in that boat.
Unum was an incredible learning experience again, to be employee number one and start everything from scratch: my roles were catering all the way through scientific strategy. And we did the series A, series B, crossover and IPO and ran some clinical trials, before we delisted and were sold to another company. I was asked to stay on, but they were a small molecule company, which is not where my passion or my skill set lies.
All of this brought me to BlueRock, because the Company’s mission is larger than any other cell therapy business I've ever seen before. The founding science is incredibly inspiring. And the founding scientists that built the engine [cell+gene platform] of BlueRock are incredible.
Until meeting the founders and team at BlueRock, I felt that the field of induced pluripotent stem cells was too far reaching and that we weren't “really there yet.” My mind changed when I met the founding CEO, board members and core scientists.
There are two individuals in the company, Mark Tomishsima and Stefan Irion who are two of the core scientists at BlueRock. When I met them, I knew instantly I was in a group with the best cell biologists I had ever been around, bar none. I love surrounding myself with people that are just better at the game, and better at the play. They are incredible. I think that's how you do your best work… get in a room where you are constantly challenged. So, I was brought on as CSO initially. I'd never worked in Parkinson's or cardiac disease previously; I was always in oncology. But I love the challenge and the idea of doing this.
5. Briefly, what is BlueRock’s origin story, and how has the vision or platform changed or stayed the same since the company’s inception?
I think it’s a really important point for the stem cell field to disassociate itself with some of the previous work [injecting undifferentiated and unreliable stem cells of dubious origins].
BlueRock is premised on a really simple hypothesis, which is that during disease and aging there are cell types that just go away. At this point, you can't bring forward a small molecule or an antibody to resurrect function because these cells are already dead. They are gone. What you need to do [once cells are dead] is either use a different tissue to compensate for lost function, or you have to rebuild the tissue.
For instance, in Parkinson's disease at first diagnosis, about 80% of the dopaminergic neurons in the midbrain are already dead. Over the next several years, those remaining 20% of neurons are “falling off a cliff" or going away as well. So patients just start to lose response to the dopamine replacement drugs, which are actually really impressive and helpful to the patients initially. But once those remaining 20% of cells go away, the response is lost. At BlueRock we want to design a cellular “find and replace” solution. It’s a simple concept: we go through diseases and see where else we can “find and replace,” to restore function. Our lead program is in Parkinson's disease. Work from Lorenz Studer’s lab over last 20 years has figured out how to characterize and build cells from developmental biology, to turn into the exact cell type needed for a given function. We call this strategy “authentic cellular replacement.” And so that's what we're doing in PD: we inject these cells through two different burr holes, making six deposits, into the putamen of severe Parkinson's patients. We have now closed our phase one trial with 12 patients dosed. We are watching the data come in, as it is an open label trial. And BlueRock’s strategy is so simple but takes so much to get done: from building the device, to building the cell types, manufacturing at scale, working with regulators, defining how to deliver the therapy and what it means for patients, is all incredibly complicated. It’s thrilling, and definitely a “pinch myself” moment that we are going through this together as a company.
6. Describe BlueRock’s culture. What are the core values you try to give the organization as CEO and how do you build this culture?
For any growing team doing science, I think the right question is how do you start and then foster an inspiring culture? How do you then water or irrigate that culture to make sure it can grow and scale? We follow four key principles at BlueRock that we just started naming last year. The first one is community: how is it that you are part of a community. What are you giving of yourself, and what are you getting in return? It takes recognizing that we are all trying to do this and focus on the patient and focus on what we're doing. The next one is integrity. Why integrity, well it goes back to what Dylan said earlier around the stem cell field. We’ve all heard it before: “stem cells are the black box magic that will cure everything.” And so, we think that having integrity both in how we approach our science and how we interact with each other, and calling out our data or risks, is integral to making progress in our field.
The next one is really building a sense of urgency for patients. When we bring patients in to speak to us about their experience with Parkinson's disease, every one of them will without fail say: “help me now.” Yes, they want to bring something forward to the marketplace, and see us as a company be successful. But their focus is rightfully: “I want to get to my daughter's wedding,” or “I want to see my grandchildren grow up.” We have to help these patients now. So that's something that we say to our team: time is something we can't get back. The last part of our culture is having courage. What we're doing is incredibly difficult, and it takes a lot of resilience. The team has to have the courage to understand that most of us fail at what we're doing. We have to stay active in the face of that failure and knowledge.
7. How do BlueRock and Bayer interface? As CEO how do you effectively leverage the resources and expertise of Bayer, while maintaining the “startup” or “entrepreneurial” feel of the company?
For me, it’s an important question. I came to BlueRock post-acquisition purposely for this moment.
We have a pretty unique setup in the biotech environment. There are other wholly owned subsidiaries, but not many of them are operating in what we call an “arm's length” model. The way the operation works is that we have a Board of Directors, like every other biotech in the world, but that board is made up of about half Bayer executives and about half non Bayer—including myself, independents, as well as BlueRock’s past president/CEO. The board sets forward both a strategy and a budget, for yearly and the long term. The difference here is that you have a long-term budget, which you can actually count on—compared to saying: “well if the street and data provides, we can do this.” And so then after that the daily operations, strategy, risk and the decisions for the pipeline, BlueRock itself makes all of those. So, it operates very much like my last company [Unum], except the difference is that we can reach out for the muscle of Bayer when we file an IND or need help or guidance on issues that a big company like Bayer has experience dealing with. For instance, we filed in Canada for our first clinical trials, and this allowed us to have the trial in two different countries, at two different sites. But with Bayer’s help it was like the snap of a hand, which would have been very hard with consultants and arrangements and contracts to help us file a CTA. They let us maintain both the “knowhow” and the strategy, so it's been a great relationship. I like to call it the best of both worlds [small biotech and large pharma]. It's not always perfect but overall we and Bayer are very conscious of maintaining our relationship. So I came into BlueRock hoping to try to make sure it stays the “best of both worlds.”
8. In today’s climate what is one short piece of advice you would give to trainees considering going into biotech or becoming entrepreneurs [can be about building a team/culture, raising funding, keeping motivated, pivoting etc.?].
If you are starting your career in the science track, like I did, the most important thing as you enter industry is to build your data foundational house. Stop worrying about getting to the “C suite” or the next promotion or being the next department head. Focus solely on learning how to build datasets that make decisions.
Build datasets that make decisions--not papers, not pretty graphs. This is very different in industry than it is in academia. After looking at a dataset the next step or decision might be a $20 million investment to go to the clinic. And so we want to know that the data is both reproducible and robust. Making data-based decisions is how you build your career. Once a company knows it can rely on you to perform that role there are so many more opportunities that open up, and so many other parts of your skill set that can be tapped: whether it is building teams or collaborating, or being able to articulate very complicated science down to a simple layman's terms for investors. But you first have to get this data step right. The efficiency that happens here is very different from the academic labs that we all get trained in.
I would rather have a scientist come to my decision board and stand up and say: “I could spend the next six months and $100,000 doing the experiment you just told me. But I can tell you based on x, y or z, that we already know the outcome will be this.” Or “I'm telling you based on my gut and my experience, we don't need to do that. So don't do it.” And to me, that’s an amazing training moment. That's a scientist I want to follow now and have run my project team, or help make my next decision. This can really be just such a different skill set than what is learned in academia.
9. What is another biotech (public or private) that you think serves as a paragon of an impactful company? What are the key learnings from this case study?
I always fall back to Genzyme, inspiring leadership, visionary mission, great execution and never lost sight of the importance of culture. There are many more recent examples, but I like this one.
10. What is one book that has influenced the way you think, which you would recommend to fellow scientists or entrepreneurs?
While I was in the Oncology field I loved Emperor of All Maladies by Siddhartha Mukherjee. It is an amazing history and telling of drug discovery and some of the learnings in the field. For neuroscience, I am still reading and searching for this one, so stay tuned.
11. Any recent announcements about BlueRock you want people to be aware of?
One thing I want people to know is that we’re hiring and I encourage your readers to check the job postings section of our website. Looking to 2023 we hope to have some announcements about our Phase 1 trial in Parkinson’s Disease in the first half of the year so stay tuned!
