SR One: Simeon George

“You have to feel fired up about what you're doing.”

On a surface level, the biotechnology industry resembles any other sector. The pitter-patter of investment bankers discussing M&A events, journalists reporting on C-suite shakeups and analysts opining on data readouts is not dissimilar from other capital markets.

Yet occasionally, events remind us that the stakes in biotech are far higher—especially for those of us trained as physicians: “I came to UPenn’s shortly after Jesse Gelsinger died,” remembers Simeon George (MD MBA), CEO of SR One.

Gelsinger was a rising high school senior with OTC deficiency, a rare disease in which ammonia builds up to lethal levels in the blood. Scientists at UPenn recruited Gelsinger into one of the first gene therapy trials, which used a viral (Ad5) vector to deliver the missing OTC enzyme to his liver cells. Gelsinger developed a lethal immune reaction to the adenovirus vector—within four days of receiving the experimental therapy he was dead. “His death reinforced the gravity of the work that our sector does. When we bring these amazing new therapies to bear, we need to be humble and cautious…it really underscored the challenging nature of trying to develop new therapies,” reflects George. 

As we sat down for this interview, nearly 25 years after Gelsinger’s death, Simeon George’s firm SR One has just announced a registered direct offering in CRISPR Therapeutics. CRSP recently developed the first FDA-approved gene editing therapy to cure sickle cell disease and beta thalassemia. “This is a brand-new modality that didn't exist a decade ago, and now has a first product on the market with a rich pipeline of other applications,” comments George, who is on the CRSP board of directors.  For someone who helped treat sickle cell patients at UPenn, the moment is surreal: “Meeting some of the patients that have been on this therapy and hearing their story, is the reason I get out of bed with a smile on my face. It is so incredible just to have even the smallest level of involvement in a story like this.”

The son of physicians, George was motivated by the Gelsinger tragedy to help safely develop new therapies for patients in need. After a brief stint as a life sciences consultant at Bain and Co, George joined SR One (GSK’s former venture arm) where he has been for over 15 years. He led SR One’s investments in CRISPR Therapeutics (CRSP), Principia Biopharma (acquired by Sanofi for $3.7bn), Turning Point Therapeutics (TPTX), Progyny (PGNY), Arcellx (ACLX) and Nkarta Therapeutics (NKTX), both of which he co-founded. In 2020 George led SR One’s spinout from GSK—opening the firm to outside capital.

In our interview, George talks us through his early interest in medicine and lessons learned in nearly two decades of investing. He discusses why areas like gene-editing, cell therapy in autoimmune disease and artificial intelligence are exciting, and the importance of investing in teams: “I bet on teams that understand how to execute, and how to do all of the critical pieces of drug discovery and development.”

For those wishing to make an impact in biotech, his advice is short and sweet: “You must follow your passion. I can't stress that enough. You have to feel fired up about what you're doing.”

Below is an interview with Simeon George, MD MBA, CEO of SR One from February 2024:

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1. What was your first taste of science and medicine? Briefly, what about these initial experiences drew you in? 

Honestly, it's been the only thing that I've been passionate about since I can remember. My earliest memories have all been around medicine and science—I grew up in that kind of household. My parents were both physicians. I just loved the idea of training in this craft, using all of your skills and your experience to solve someone’s most pressing problems.

My Dad was an OBGYN and my mom also initially trained in that field. It's such an intense experience–delivering babies, dealing with malignancies, but also benign gynecologic conditions in healthy patients. I remember [growing up] feeling like my parents were in an episode of a soap opera–there was medical drama daily. I came to appreciate the problem solving part of medicine– I love this about biotech, too: the concept of figuring something out that isn't necessarily obvious. It’s such a high impact way to spend your time.

If you can help people at critical points of their life, you also directly impact their loved ones, their livelihoods and society. This is the first thought I have in my mind every morning and honestly, I wake up with a smile on my face ready to tackle whatever challenges lie ahead. How I have impact now (investing) is much different from my wife who is a pediatric ophthalmologist. I see what she experiences with patients directly, and how incredibly rewarding it is for her to use her skills and experience. In my career, the thing that I love the most is the idea of working with incredible founders and entrepreneurs. We’re trying to rewrite the medical textbooks: I genuinely believe in that and it's so inspiring to work with people who have the same ambitions. In our sector, regardless of your motivations, success is defined by helping patients and bringing new medicines into the market. It’s such an empowering way to spend your time. It is hard for sure, but it has always been my driving force.

[Did you have experiences early on that piqued your interest in biotech or drug discovery?]

The most vivid memory I have about biotech early on, was when I was at Penn for medical school. Shortly before I arrived there was this tremendously unfortunate death from a gene therapy–the patient’s name was Jesse Gelsinger. Jesse had a rare metabolic disorder and unfortunately succumbed due to an immune reaction to his AAV gene therapy treatment. A lot of the amazing work in gene therapy, cell therapy and mRNA has all come out from Penn which is amazing! But Jesse’s death was this really dark moment for the field.

I remember being on campus and everyone talking about what happened. At that moment, the gravity of the work that the biotech sector does was really apparent. When you're bringing these amazing new therapies to bear, the upside sounds incredible. But human biology is unpredictable and we need to be cautious and humble. This tragedy left an immediate impact on me, underscoring the challenging nature of trying to develop new therapies.

2. What led you towards the MD-MBA path, and what was graduate school like for you?

On my CV it looks like I did a lot of things with a “plan” in mind. The reality is that I did not have a clear plan or career objective in mind while I was in graduate school. I wanted to do something in medicine and have patient impact–but I didn't exactly know what this would look like.

I came to Penn to pursue the dual degree in part to explore various paths and in part to follow my fiancée (and then wife) who was already at Penn Med. My wife is my role model for someone who should pursue medicine. If there is anyone you would want taking care of your child or your loved one, it is my wife. She’s got this service orientation and a drive to pursue excellence in her clinical domain. She’s had [this quality] ever since I’ve known her.

For myself, while I loved medicine, I was exploring different ways that I could express my creativity. After finishing the basic sciences portion, I took a gap year and worked at an agricultural bio startup, which ultimately didn’t pan out, but it was an incredible first business experience.

The MD/MBA tract is this amazing program at Penn and while I was there, every waking moment was spent either in the clinic or learning about business. I did several internships across consulting, banking, and at SR One. I loved my clinical rotations too, as I was really drawn to putting my skills to work to have maximum patient impact. But my intuition was that I wanted to be closer to biotech in some capacity, even though it wasn’t exactly clear where that would lead me. Upon graduating from Penn, I pursued consulting because it felt like doing a “residency” in business. However, I was in consulting for less than a year when SR One reached back out because they wanted to hire an investment professional.

It all just worked out! My wife was at CHOP training as a pediatric ophthalmologist, and SR One at that time was based in Philadelphia, so it made sense personally to make the move. I honestly didn't know much about the venture career path, but I liked the team and thought it could be an interesting area to dip my toes in and see what happened!

3. What was it like making the transition to GSK/SROne?

At that time, SR One was a really interesting setup as the corporate venture arm with GSK as its sole LP. The fund was largely left to its own devices and everything from sourcing, to diligence to decision making, to board management, to investment management through to exit was done in house [at SROne]. For me, it was a great training ground. I got to work with some really high quality people who really understood pharma, since a lot of them had come from GSK R&D and BD. They understood how value is created through medicines and how everything that we do is in service of how we identify and develop these medicines. The SR One team was an understated group of people who produced a lot of high quality work with not a lot of hubris or ego around them.

A colleague of mine, who unfortunately, passed away, Ken Gossett, just had a nose for founders and companies with a vision for how they were going to develop medicines. He focused primarily on small molecules like antivirals or cancer agents but also worked with Algeta, one of the first big successes in the radio pharma world. His track record was honestly one of the best that I've seen. Just to be able to spend time with him, and observe the way that he worked was great mentorship for me.

After a few years in Philadelphia, I moved to the Bay Area which was a formative period for me as I had to really learn by doing. I got to build my network, and led my first deal. Principia is one of the early deals that I did–SR One co-led Series A. When I think back on that period post global financial crisis, there are so many lessons learned including the level of resilience that the entrepreneurs had to build and run start-ups. It was so hard to raise money at the time, the Principia round took over a year to raise a 36 million series A. A lot of foundational experiences came from those first five to six years, between learning from my team and then figuring stuff out by myself.

Over the years we developed an incredible track record at SR One, and with GSK’s support in 2020 we spun out and raised third party capital. Since that time we have now raised multiple funds investing across company creation through to public market investing.

4.  What were some of the lessons you learned on notable and successful deals like Principia? Generally, what were the key things that went right, in companies like these?

I'm a big believer in this idea of learning from good and bad experiences. Sometimes you learn more from things that don't go well than you do from the successes. If you've read the book by Daniel Kahneman, Thinking Fast and Slow, there's definitely an element of this business based on intuition and gut instincts. You have to learn to trust that. I think this intuition and judgment is what separates the highest quality investors from the rest of the pack. With Principia, honestly, the first meeting with those scientists, David Goldstein and Ken Brameld, you could just tell these are truly world class chemists. Their understanding and insight was profound. They knew just how to design these reversible covalent binders and how they were going to pursue these first sets of targets, including BTK. At that time, everyone was focused on BTK for oncology, and it was really exciting to see how with “just a chemistry tweak”, Principia could go into the autoimmune disease space. They laid out their capabilities and experiences from Roche so clearly. I vividly remember coming out of that first meeting with their team on University Ave, Palo Alto. I wanted to invest in the company right after meeting them. But of course I had to then do the work to back up that initial hunch. We did the work on markets and technical and chemistry and IP. We didn't have a CEO yet, and had to also figure out how to build the investment syndicate. There’s all this work that you have to do, but I go back to that first principle on how you have to have an intuition around the quality of the founders. During the early stages, I think that's critically important. That has been true of every deal that I've done that has been successful. And frankly, I didn’t trust my intuition on a lot of the deals that turned out to have not been successful. The deals that I should have done but missed were also instances where I didn’t trust my intuition.

The best example I can give you [of a miss] was when we were thinking about investing in Chinese biotechs, and so I spent quite a bit of time there. When I met John Oyler, I just knew he was extraordinary. I came close to investing in his company [BeiGene] but ultimately, we chose not to. My intuition was telling me that there is something special about this individual and the company he is building. I wanted to be close to him and invest, but I couldn't get over my own hang ups around all the risks associated with investing in China. We missed that. I saw [John Oyler] last year and told him I wish I had a time machine to go back and invest. He was incredibly gracious, and I hope that we find another way to work together in the future. I'm drawn to compelling founders and entrepreneurs, and I feel like I've got a pretty good sense of what that looks like. So that’s a skill set I’ve always tried to lean into, and I hope that it gives me an edge.

5.  Does today’s venture ecosystem—feel like previous cycles you have lived through? What are the similarities in terms of venture funding and creation to previous post-bubble times? 

I’ve been pretty clear on this, with myself and with my team: there's no time to moan or complain about what's happening with inflation and the stuff you can't control. There's just no point spending time to predict it. History doesn't repeat itself, but it rhymes. From the day I started at SR One through to today, the one thing that has held true is that if you have a line of sight towards a medicine, all options are open. You can raise private money, public money, venture debt, royalty…you can do partnering deals with biotechs or pharma. There are so many ways to continue to build your business, if you are singularly focused on creating a medicine that has true patient impact.

As a fund, we exist to raise and deploy capital. For us, it's all around executing on a plan to develop the medicine. This strategy worked in 2008, in the aftermath of the global financial crisis. It also worked during COVID. Everything that we need to do has to be focused on identifying the next crop of startups, founders and entrepreneurs who are building companies that will bring new products to the market. This is where we spend all of our time. The cost of capital can go up or down, the quantum of capital can be constrained and can be relaxed. However, our job is to be appropriately balanced in terms of risk and reward and focus on one question, “where is the medicine?”

The beauty of being a venture capitalist is that we have time to be able to build these companies to hit their critical milestones. So thinking about building a business that is fit for February 2024 is not going to do us any good when we're in 2030. A practical example would be when we are thinking about an early-stage company during its series A round. I'm certainly focused on and have a heightened sensitivity around what are the key deliverables for this round of financing. I also think about how much conviction we have if the company hits a portion of their deliverables. Is there an ability for this company to keep raising money to continue to be a viable startup? And the nuance of that question is understanding where [SR One] and our co-investors are going to be at that point in time. Are they aligned in supporting this fragile startup that is usually at a very nascent stage of development? It's like locking hands with the partners around the table, and trusting that as the company progresses and achieves its goals, those already involved will keep up the support.

We have more modalities than we know what to do with them at this point. The CRISPR Therapeutics approval is so incredibly formative because we got involved when it was the proverbial “two guys in a garage” with questionable IP, to where it is today: a multi-billion dollar company with one approved product and a deep pipeline across oncology, cardiovascular, auto-immune disease and regenerative medicine. CRSP also has a team that has proven it can out-execute any other company in gene editing. These were the ingredients that got us excited to invest once again, even at this later stage.

6.  Casgevy was approved in December 2023 for treatment of SSD and recently for beta thal, representing an enormous milestone for the CRISPR/gene editing field. What does this mean for you personally, and for the field?

It was such a surreal moment. As the data was being generated, we became aware of the jaw dropping concept that [Casgevy] was curing these patients. Thinking back, while I was in medical school, we had patients who were suffering from sickle cell crisis coming into the hospital. There was not much that you could do for them- oxygen and pain relief. For those who can even find a bone marrow donor, often the body rejects the graft later on.

The ability of a therapy to transform the lives of sickle cell patients is incredible to me. Meeting some of the patients that have been on this therapy and hearing their story, it's the reason I get out of bed and have a smile on my face. It is so incredible just to have the smallest level of involvement in a story like this. I wish my father was alive so I could tell him about it, because it's definitely the proudest moment in my career.

For the field, it sets the bar for what the technology needs to deliver to impact patient care across the next crop of medicines. There are so many logistical challenges around a product like this: from the supply chain, to the way it's delivered. Ultimately, the patient receives the care so if you're going to go down that path, the drug needs to be the best thing that has ever existed for them. One of the things the last few years have helped clarify in my mind is that you can't come up with a “me too” product for a new modality. The data needs to be truly differentiated.

I believe it’s beneficial to consider the landscape where revolutionary technologies like CRISPR/Cas9 can be applied to understand the genetic causes of diseases. We should focus on executing plans to develop products with positive outcomes. Although challenges remain regarding their delivery, I’m confident they are going to get solved. We have challenges around bone marrow preconditioning, which I’m confident will be solved. This is going to take time. However we have got to capitalize these companies and be there to support them in finding the answers. This approval is the tip of the iceberg for what it means for the field. It's possible! We have the regulatory prowess to get through it, and there is receptivity. Thinking back to Jesse Gelsinger, we must remember that there is always a risk-reward trade off with these approaches. However, the narrative is pretty clear on what needs to happen next for gene and gene editing therapies.

[Please discuss the recent registered direct offering. What does it give the company?]

After spinning out from GSK in 2020, and having a new fund now set up, we have wanted to continue to support CRISPR. It's been a personal ambition and a great testament for our continued support and belief in this incredible company.  We wanted to supercharge the incredible activities that are happening on the in vivo gene-editing side, as well in the cardiovascular, oncology and auto-immune CAR-T programs.  Over the next couple of years we expect to have line of sight towards more medicines to come from the CRISPR engine.

[Many challenges remain in gene editing: ex-vivo approaches, cost, access, scalability, harsh bone marrow conditioning regimens. What do you see as the major obstacles for the next-gen therapies?]

At SR One, we've been focused on looking at ways to do whole gene insertion with small and large stretches of DNA. We also need to deliver these editors in a way that has optimal editing efficiency in the right tissues. This is one of the largest bottlenecks. We need to solve this in order for the field to evolve to in vivo therapies. Preconditioning is another problem that we are now focused on solving to help increase both the patient access and commercial opportunity for Casgevy and other medicines. If we can make it easier for patients to go through bone marrow preconditioning, it could potentially unlock even more patients that would be able to benefit from this therapy. Beyond DNA editing, we've made an investment in a company ADARx that's working on RNA editing. There's also epigenome editing, base editing, amongst many editing approaches in development. Going back to first principles, focus on medicine, the optimal indications, and then just start executing. We know that the CRISPR/Cas9 system works incredibly well. You can't just pick another technology to be different, or to simply try to get around existing IP. The rationale should ideally be driven by why your approach makes sense for the disease you’re going after.

7.  There has been a shift from using CD19 or BCMA CAR-T in autoimmune diseases. Companies like Arcellx (co-founder), Kyverna, Cabaletta, Gracell (AZ), NKarta are pursuing this strategy. What gets you most excited about this area?

This is certainly an area that we're following very closely across both our existing investment portfolio and the new deals we are evaluating. Both cell therapy companies that we have co-founded (Nkarta and Arcellx) have generated exciting clinical data in the oncology setting and are now looking to potentially expand their scope into autoimmune disease.

[To harken back to the Principia story where BTK inhibitors were applied to autoimmune disease after cancer, it seems like there is a similar theme with CAR-T therapies]

Yes, you are right. I honestly feel like we should have thought of this idea sooner! The Principia example is perfect. We knew how Rituxan (anti-CD20 mAb) worked mechanistically and the impact it had on B cells. You see the great treatment effect on cancer, so it made sense that you could have profound benefits in a wider set of diseases. The same thing could be said when we think about the B-cell resetting via CAR-T therapies for autoimmune diseases. When we saw the data presented last year in 15 patients, well the pictures are worth 1000 words. There were amazing responses. Though a small study, it certainly got the field excited. Kyverna also just had incredible success with their IPO.

In part, I think it is because there is a strong mechanistic rationale for why these treatments work, in particular for CD19 B cell depletion therapies. There are questions around which indications to go after and which subset of patients to target? How severe do they need to be to go through a therapy like this? For autologous therapies, the regulatory considerations will need to be worked through carefully. I'm optimistic, but I also think these companies need to be thoughtful about the way they develop this product. We ideally want to invest behind teams that understand how to execute and navigate through these critical pieces of drug discovery and development.

8.  Alphabet’s Isomorphic labs just entered into agreements with Novartis and Eli Lily to use their AI tools, including a next-gen alpha fold, for small molecule and therapeutic discovery. What has you excited about AI in early-stage companies?

It's a good question- we're still grappling with it. We come from the mindset that medicine is the product from which value is ultimately derived. Despite this product centric approach, I think the power of computation is going to transform every industry including biotechnology. The Nimbus example is a great one; they've been using their computational capabilities from Schrodinger over the last 15 years now and have had immense success moving programs forward and creating shareholder value. Odyssey (where SR One co-led the Series A) has benefited from the computational approaches to advance their product pipeline in short order. The company has moved its lead program from the research setting to clinical testing in less than 3 years.

I'm excited to see how our start-ups now use AI and ML to tease out the signal from the noise in clinical development. As a physician, what I am most excited to see if we can new medicines forward for patients in needs by better designed clinical trials. AI might even obviate the need for a certain amount of testing, either preclinical or clinical- because of the quality of the data it can produce, its reproducibility and the separation of signal to noise across massive data sets.

We led an investment last year in Rezo based on founding technology out of Nevan Krogan’s lab at UCSF/QBI. He is truly one of the pioneers of using quantitative biological approaches across disparate data sets (including human tissue samples / genetics / proteomics) to create protein protein interaction maps of different diseases. You’re then able to see things that you wouldn't see if you're only looking at one data set. We've hired an ex-Google scientist to come and really focus on the AI aspects of this approach. It’s early days, but I’m encouraged by the level of pharma engagement around what Nevan and Rezo are doing. I am hopeful that [AI] will have a profound effect on biotech in the coming years.

9. Any advice for trainees interested in biotech or investing? Particularly, career advice you wish you had known when coming up?

You just have to follow your passion, I can't stress that enough. You have to feel super fired up about what you're doing. You have to have a learning approach and mindset, and you have to look at every situation, no matter how challenging, from the perspective of what can you learn from this. Ultimately, if you survive it, you should also think about what you can do better or differently. The mindset around what you're doing is so important! You should leverage the power of networks and be curious as well to meet people who inspire you. For me, none of this has been planned. I had no idea what I was going to do in my career. It's all about being open and being curious: working hard, talking to interesting people and following your intuition. That’s critical! As you hone in on where you want to spend your time, then I think you really need to build expertise. You really need to have a point of view and you need to be informed. That thought, and that passion should come out when you're interacting with people. When I meet someone new and they leave an impression, it means something. For those working and living in Boston or the Bay Area, take advantage of the fact that you are in the hotbed for biopharma innovation. I like the idea of being well rounded too. Have some interests outside of science and try to get a holistic view. Don't just think about drug discovery and development, but think about all the other issues that ultimately impact our sector. Start to think about the IRA, about pricing, reimbursement, access, all the different parts of the value chain. As it actually turns out, they are important for our businesses. Maintain that broad approach to understand ultimately what creates value in biotech, which is bringing transformative new medicines to patients.

The last thing I'll say: I spend time between the Bay Area and London. What is interesting to see is in Silicon Valley you’ve got young adults (and sometimes kids!) with an aspiration to transform the world. This is usually done most effectively through technology start-ups but there is no reason that we can’t inspire young adults in biotech to do exactly the same thing.

In biotech there is more of an expectation that you have to work your way up and have grey hair before taking on the establishment. I just don't think that's right. If you look at the CEOs we have backed, it has been more first time CEOs than experienced CEOs. While I love experienced CEOs, there is something about the pure hunger, ambition, desire, chip-on-your-shoulder attitude that the first-time entrepreneurs have. I think young people that are reading this should be inspired to go out and build the next crop of great biotechs bringing new medicines to patients. This is your time! It's not like the older people have figured everything out–we're all learning as we go. The onus is on the next generation to push hard now and change the world!