Mubadala Capital: Rami Hannoush

"I've always believed that people are our greatest assets in whatever venture we pursue."

An education is a privilege. It “pays the best interest” [Ben Franklin], is a “passport to the future” [Malcolm X] and is humanity’s “ultimate good” [Socrates]. For Dr. Rami Hannoush, education was also an escape.

As a child growing up in a war-torn Lebanon, books provided both emotional and physical safety: “We used to sit down and read in the hallway outside of our apartment, since this was the safest place during times of bombing” (Q#1). Armed with an innate intellectual curiosity and his father’s old college textbooks, Hannoush soon “fell in love with chemistry and biology.”

By learning the rules that governed molecules and cells, he found a bit of order and happiness amidst a turbulent reality: “I would spend hours and hours reading [science] textbooks in the attic. These were joyful times during my childhood.”

These early experiences instilled in Hannoush a desire to learn more about science, and the resilience to pursue this passion. In college, he was struck by the beauty of molecular orbitals and their power to quantitatively describe chemical reactivity. With the encouragement of his undergraduate organic chemistry professor (Dr. Hanadi Sleiman), Hannoush decided to pursue graduate research training at McGill. Under the instruction of Masad Dahma, he synthesized early RNA-DNA hairpins to block HIV replication. Though he considered starting a company focused on his thesis work, a desire to “get more experience in other disciplines” led him to a post-doc with Matt Shair at Harvard. Undaunted by combining disparate fields, Hannoush screened diversity-oriented synthesis (DOS) chemical libraries for their ability to modulate the cell biology of vesicular and ER transport. Part of a new generation of “chemical biologists” trained in both disciplines, Hannoush took his talents to Genentech as a group leader. During his 15 year tenure at the company, he built a talented research team and made seminal discoveries in stem cell biology, Wnt signaling and the design of peptide therapeutics, including multiple candidates that progressed into pre-clinical development stages.  

As a Senior Group Leader, Hannoush also helped Genentech diligence key external collaborations and M&A opportunities. He discovered that he had a passion and talent for analyzing how science connected to value: “Throughout these years and experiences, I developed a new skill set on the job” (Q#6). While contemplating a life after Genentech, Hannoush was approached by Mubadala Capital Ventures to help invest in and create new life sciences companies. He joined in September 2021 as a General Partner, and with the team has so far made investments in Auron, Juvena, Dewpoint, Interline and Neumora (Q#8). He has also helped co-found, finance and operate multiple “Newcos” currently in stealth mode.

An accomplished scientist, operator and now biotech investor, Hannoush has come a long way from studying his father’s old textbooks in the hallways of his home in Lebanon. And yet speaking with him about exciting new frontiers in science and current role at Mubadala, it is clear the intellectual curiosity, resilience and love of learning he forged during childhood remain unchanged. To quote Isaac Asimov: “An education isn't something you can finish.”

Below is an interview with Dr. Rami Hannoush, General Partner at Mubadala Capital Ventures, from October 2022:

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1. What first got you interested in medicine and science?

My interest in science traces back to childhood. I grew up in Lebanon during the Civil War, which were really turbulent times. My dad - in his own way to shield his family from everything that was going on around us - emphasized education at home. We used to sit and read in the hallway outside of our apartment, since this was the safest place during times of bombing. Living through these times taught me a lot of lessons, including resilience and also persistence, which is an attribute that I have carried with me in everything else that I've done in my life. In high school, I fell in love with chemistry and biology. I just became fascinated with how things work inside the human body, and what mechanisms were involved in disease at the molecular level. I was so curious about fundamental physiological processes.

[How much did your father influence this interest in science?]

My father was supportive of any discipline I wanted to pursue. Because of this curiosity I had, I started to read old college level books that my father had left in the attic since his college years. He was a mathematics major – coincidentally at the same undergraduate college that I ended up going to - and he had collected many science and philosophy books over the years. I would spend hours and hours reading these books in the attic. These were some of the best times I remember in my childhood. It was this passion actually, that grew over the years in high school, and really fueled my desire to go into a science major in college.

[How were your teachers in high school and university? Did they encourage you?]

I had excellent teachers, in chemistry, physics and math. My dad actually was my teacher in mathematics [in high school]. I'll tell you a story of that first year that he started teaching me in class: I couldn't bring myself to call him by his formal name of ‘Mr. Hannoush,’ because I was so used to just calling him ‘dad.’ So, what happened was one of my closest buddies, who used to sit next to me, would call ‘Mr. Hannoush’ and I just raised my hand. Then my dad would look and see that it was actually me who had the question. But funnily enough, [having him as my teacher] put more pressure, though I'd say in a positive way, to excel in other subjects besides math.  

I was fortunate to have great teachers in chemistry and physics who helped to foster this early curiosity about science. Towards the end of high school, I knew that I eventually wanted to go to industry. In particular, I was interested in working on challenging problems that would impact human health—but I didn't know specifically what I wanted to do. I really didn't have much exposure to the types of opportunities that existed. While I was an undergrad, I met my organic chemistry professor. She was an excellent teacher who was passionate about chemistry. In her classes, I immediately gravitated to how atoms interacted to form chemical bonds, and how molecular orbitals could describe this ‘phenomenon’ of chemical reactivity between elements in the periodic table. With her encouragement – during my undergraduate thesis work—I decided that I wanted to go to pursue a graduate degree. I ended up joining McGill University based on her recommendation. I was drawn to a lab to work on understanding the basis of interactions between ribonucleic acids, and how they could be assembled into structures with potential applications in medicine. When you think about it, the whole story [of my career] seems cohesive, almost like a continuum, but it was never planned.

2. What was your first exposure to research?

When I was an undergraduate, I did an honors thesis project. That was my first exposure to research outside of the lab courses. It was a lot of fun. I loved the discovery aspect of it. At the time, we were making transition metal catalysts for industrial applications and drug development. Even though it was a very focused project, I just loved the rigor of doing research. I loved the excitement about finding out what the product of a reaction was going to look like, the efficiency and how you can improve it. What resonated with me was the [scientific] process: generating information from empirical methods, deriving hypotheses from the data, and then going on to design more experiments to test those hypotheses. So [the undergrad thesis] was really where it all started. This work was a great segue—I felt comfortable in the lab as an undergraduate, so it felt very natural to go on to graduate school.

[Which lab were you in grad school at McGill and what was the high point of your PhD?]

I was with Professor Masad Damha. He is a bio organic chemist. My undergraduate organic chemistry professor - Hanadi Sleiman - ended up moving to McGill a year after I went there, and established her own lab in the department of Chemistry… small world.

Like in any other PhD, there are a lot of low points. But you have to build on these low points and continue to drive the projects forward. It takes resilience, something I learned during the times of Civil War.

One of the highest points of my PhD was when I was designing and developing a class of hybrid RNA-DNA molecules to target HIV reverse transcriptase [RT]. At the time this was a very important target to go after, and it still is today. At the time, we didn't have the wide array of inhibitor drugs that are currently available. So, this was purely based on rational design to mimic the natural substrate recognition mechanism for RT RNase H [and block its function]. So, the high point: I remember being in the lab one afternoon, and we did the key experiment to test whether the molecules that we designed would selectively inhibit the activity of HIV RT RNaseH. That afternoon, we got positive data to show that this was indeed the case! It was a great moment - for me and everyone else in the lab - because it was the first demonstration showing that we could take this class of RNA hairpins, inspired from natural substrates, and inhibit the enzymatic activity [of RT]

[Can you tell us about your years as a postdoc in Boston at HMS?]

I was in Boston for four and a half years. After I finished my PhD, my supervisor and I were contemplating forming a new company based on my thesis work. But at the time, I thought that I really needed to get more experience in other disciplines or fields outside of what I’d done in my PhD. I'd gotten this advice from a number of mentors at the time. So I decided to go to Harvard and join Matt Shair’s group. This was early in the days when they were setting up phenotypic screens to look for small molecules that would control cellular processes in a temporal manner. I was fortunate to join Matt’s Lab and started to work on creating a library of natural products using diversity oriented synthesis. This is an incredible technology that was developed by Stuart Schreiber. Matt did his training with Stuart Schreiber as well, and then became a professor in the Chemistry Department at Harvard.

A year and a half into my tenure in the Shair lab, when we had these DOS libraries, we wanted to explore their utility for perturbing or modulating cellular processes. So rather than handing off the library to the cell biologists at Harvard Medical School, I decided to learn the cell biology myself. I ended up joining Tom Kirchhausen’s lab at Harvard Medical School.

I remember my first group meeting in Tom's lab where folks were showing movies of fluorescent  objects moving around inside cells. The chemist in me was thinking: ‘wait, is there a way we could quantify the movement of these objects? How could we put some numbers besides just explaining them or describing them qualitatively?’ That was quite an incredible experience because I got really immersed in cell biology studying the trafficking of proteins, endocytosis of receptors, and also the impact of small molecule probes on the cellular processes. We ended up discovering a molecule that perturbed membrane transport from the ER to the Golgi apparatus. So, I guess I was part of the ‘first generation’ chemical biologists who got trained in both disciplines. And I found that this [fusion of disciplines] was really what I wanted to do.

Four years into my time at Harvard, a few Genentech scientists happened to be on campus. They would visit certain colleges in the US to recruit talent. So, that's how I was introduced to the company.

[Do they still do this program?]

They do, and while I was at Genentech, I actually became part of these programs to visit colleges and to recruit students. I also organized a program for Bay Area students to host them for the whole day at Genentech. Students would listen to talks from leadership about the culture of the company and the scientific approach. They would hear firsthand from scientists that they would meet with over lunch. Students would provide in advance a small summary of what their research interests were, and then I would match them to meet with scientists of similar backgrounds who work at Genentech. In the afternoon the students would go on a tour of the pilot plant at Genentech. I used to organize this event two to three times a year. Each time, we'd host a different institute from the Bay Area: Stanford, UCSF, UC Davis, Caltech, and others.

3. What was it like transitioning into industry? What was the initial experience like at Genentech?

The experience at Genentech was incredible. At the beginning, there was some adjustment in terms of figuring out how things worked at the company: which group was doing what, who was responsible for what, how this big and well-oiled machine of drug discovery and development worked, and then integrating myself into it. There were also some adjustments in terms of building teams and managing people, which are things that postdocs and graduate students don't get trained to do. You get thrown into the battle and you have to figure it out. But thanks to the company culture, which is very supportive of early career leaders – they provide all the necessary tools to put them on track. Of course, this was coupled with my own personal interests of becoming a great people leader and manager. These two things really helped me to grow my team and eventually lead an R&D group at Genentech.

I was in a unique position to be able to work at the interface of biochemistry, chemistry and biology. This was especially key in driving early drug and target discovery efforts and in building new drug modalities. I was following the science in a way that was agnostic to the type of approach or modality required to address the key biological questions, to formulate hypotheses around the path for how we were going to go about discovering drugs and doing all of this with talented teams.

4. What do you think about a recent shift towards a demand for talent with hybrid computer science/biology backgrounds? Do you see that in industry now?

I think that being grounded in computer science brings a lot of leverage and strength to address key biological problems in modern biotechnology. We can talk about the power of bioinformatics and the power of being able to tackle big data, single cell transcriptomic data, and spatial genomics data—and this is why having a background in computer science, or computational biology, is so powerful. We've been witnessing great advancements over the past decades in enabling technologies for drug discovery; from peptides to antibody-drug conjugates, to cell and gene therapies…. Now we are witnessing another major revolution in the context of artificial intelligence and machine learning-enabled drug discovery. The big question is: how do we translate this into meaningful outcomes that will have an impact on the drug discovery process, and improve the efficiency of drug development? Fields like computer science and computational biology are really critical for the future of medicines.

5. How do you think about good leadership and culture?

I've always believed that people are our greatest asset in whatever venture we pursue. Having the right leadership with the right vision, and building an inclusive culture that brings in and empowers everyone to be at their best, is something critical to the success of any project. This is true whether it is in a company like Genentech or whether it is in building your own biotechnology company. I learned this early on in my career. Going back even to my childhood: I spent 17 years in Boy Scouts - I was an Eagle Scout - which helped to foster the sense of leadership when working with others. This [helped] in terms of interpersonal communication: how to work within teams and be collaborative, and how to inspire others to give their best. The biggest difference between academia and industry is that in academia, we're typically used to working within individual labs, with little crosstalk with other groups in the same university or even the same hallway. One of the main differences I saw when I joined Genentech was that for teams to work you have to have the capability to collaborate with others and to be a good team sport.

The process of drug development takes a village. I often liken it to sports teams, like the Golden State Warriors [or Celtics!]. You build the key pieces together. The team is like your project. For that project to succeed and be competitive, everyone needs to be fully invested, but at the same time have their own defined role. There is also the element of trust that you build as a leader of the team, and some of that comes from an ability to resolve differences and talk through issues. It takes courage to do so.

6. How did you first get involved in venture investing (Mubadala)? What was hardest part about making this transition into VC?

I've always loved the business side of science, while continually being drawn to the science itself. Back at Harvard, I used to have many joyful conversations with my mentor, Matt Shair, who was involved in the formation of a number of pharmaceutical companies in the Boston area. He would share stories about these companies and his perspective on the challenges of company formation, and what it takes. So I was exposed to it from that angle. During my time in grad school [at McGill], we were considering spinning out a company. So I learned about this process early on, even though I didn't end up pursuing it.

While at Genentech, I was closely involved in the diligence on a number of key strategic collaborations that we pursued with external parties. This also gave me a better understanding of how these deals were structured and term sheet negotiations. Throughout these years and experiences, I developed a new skill set on the job [in evaluating biotechs]. But also, I was passionate about it, which helped me to learn it as well.

After spending 15 years at Genentech, I felt it was the right time to move to a new adventure that merges exciting disciplines: science and entrepreneurship. At the time, I was contemplating going out and starting my own company. I met a number of VCs, and they said, ‘Well, how about you come work with us, and we can help you in terms of starting companies. And you can help us with diligence.’ I figured this would be the best combination of both worlds where I still get to be involved with the science, but in a different capacity. [At Mubadala] I work with outstanding founders, and get to help them on their journeys to build their companies. I also get to be involved in creating new companies.

The transition [to investing] was exciting, but it did have some challenges, or adjustments. The size of teams that I used to lead at Genentech were much bigger, relative to the smaller size of teams in the VC world. It was almost like going back 15 years ago, when I was just starting to build my team at Genentech. I also felt that the pace of the VC work seemed to be – and this might sound strange - a bit slower than what I was used to at Genentech. But it's still very intellectually stimulating to be a biotech investor. I like having the opportunity to actively review science and technology advances from all disciplines and think about deal structures and building strong syndicates of investors to fuel the growth of science for the betterment of human health..

I came to [Mubadala] Ventures for the opportunity to help shape and develop the healthcare investment strategy and thesis, and  to scale the company creation effort, which gives us access to compelling valuations and meaningful ownerships in transformative companies. I'm one of those hybrid biotech investors who have both operational and investment experience. I think the ‘hybrid’ type of role has been a theme throughout my whole life. At first I was a ‘chemical biologist’ and now I am an ‘operational VC’.

7. Can you briefly describe where Mubadala Capital Ventures is as a firm—balance between venture creation and investing? Any special focus on target area or company stage?

The US healthcare ventures has been focused primarily on early-stage investments in both the biotech and the health tech sectors. The overarching investment strategy has focused on enhancing drug discovery and development and also improving the quality of patient care while driving down costs. The company building aspect is a relatively new effort that was kicked off in the past couple years. Our goal here is to partner with outstanding founders to create disruptive biotechnology and healthcare platforms with the potential to impact patient outcomes. We tend to focus on disruptive platforms, whether it is in drug discovery or in digital health.

8. Can you tell us about the first couple investments you made at Mubadala?

Dewpoint Therapeutics, which is based in Boston, is an early-stage drug discovery company that is targeting bio molecular condensates. These are membraneless organelles that are formed by liquid-liquid phase separation inside of the cell. So it really challenges the dogma of having organelles in the cell that are always bound by membranes. For the lay audience, one could think of them as liquid droplets, very similar to the droplets that form on the windshield of a car when it’s raining,  except that these droplets are forming inside every cell in our bodies.

Importantly, disrupted condensate biology has been linked to neurodegenerative disease and various types of cancer. I'd say condensate biology is a developing field of biology. What's exciting about it to me is that there is the potential to uncover new ways of targeting diseases with differentiated drugs, and novel mechanisms of actions that have been historically thought to be intractable. Today in the biotech industry, we're facing a big challenge in terms of the types of targets that we want to go after. Most of the low hanging fruit targets have already been drugged. Dewpoint’s approach, where we are looking at condensates, really opens up opportunities to discover novel ways of perturbing pathogenic mechanisms in disease. It adds another powerful dimension to the drug discovery and development process.

The second investment is in a company that I've been building, which is still in stealth mode. It has been a great journey for me, fundraising and building a strong syndicate for the company, putting together the founding team, and stepping into an operational role to run the company. We have made tremendous progress over a short period of time. Working with like-minded investors and co-founders to build a talented team, and to establish the scientific and the business strategy for the company from the ground up has been an incredible experience. One of the most important aspects in company creation is to build an inclusive culture with a strong vision and values that really foster innovation. People are the greatest assets in a company.

9. Which broad areas of science and medicine are you most excited about seeing develop in the next 5-10yrs? (Any portfolio companies you want to mention here?)

There are a number of areas in science and medicine that I'm excited about, and it's hard to name them all. We are living in the golden age of biotechnology and are witnessing substantial scientific advances in therapeutic modalities, our understanding of human genetics, artificial intelligence, and precision medicines.

But if I were to name a few areas that I think will have the biggest impact in on the biotech industry in general, I would name three broad areas. The first is cellular reprogramming technologies for human rejuvenation therapies. It's still early days, but as the science evolves, we will have a better understanding of the mechanisms of aging, and how reprogramming [stem cells] could lead to rejuvenation of tissues. It'll take a while before we get there. The biggest challenge is to figure out how to do this in a safe manner in people [as opposed to mice]. This was an effort that my group was working on while I was at Genentech, and we have just published a paper that describes some novel agents to promote the growth of alveolar stem cells in lung organoids, and also to promote the growth of human intestinal organoids. Emerging therapeutic modalities such as mRNA medicines that enable reprogramming or restoring tissue states that are often lost with ageing, could have a substantial impact on human health and longevity.

From a drug discovery and development perspective, we will start to see a lot of medicines in the future that will work in a tissue specific- and cell type specific-manner. This should enable achieving superior efficacy and improving safety profiles of medicines. To enable this precision approach, delivery technologies become really critical. For instance, in cancer, how can you spare normal stem cells, for example, that are responsible for tissue renewal, while still hitting malignant tumor cells.  Tissue specific and cell type specific delivery of therapeutics is paramount.

The third bucket is more of a technological area, which has to do with 3D organoid systems and microphysiological systems which could be enabled by advances in nanofluidics. These would recapitulate the complex physiology across different tissues like the lung, the colon, the eye, the kidney, and the liver. I think it's still early days, but these systems could have a big role in accelerating the process of drug development as they could serve as mimics of in vivo systems, and potentially replace animal studies down the road. This is an area that we'll probably see develop over the next several years or so, and it could really revolutionize the way we discover drugs to treat patients with different types of diseases.

10. What advice would you give to a startup today?

Focus on what really matters, especially in today's environment. It's really important in today's macroeconomic environment to conserve the cash runway. I say this as an investor, but also as a founder. It's critical to maintain optionality and to execute efficiently in both the scientific and business strategy of a company. Given the inflation and geopolitical issues we're witnessing today, early stage biotech founders and entrepreneurs have to face these realities. They need to adapt fast to achieve a delicate balance between advancing forward the most critical assets that the company has while still maintaining a mission focused pipeline [with optionality].

As a founder, I'd ask myself, ‘what is it that I want to focus on today? What is it that we're going to focus on over the next two to three years to create benefit for patients and value for the company? What are things that are not important today, or will not contribute to the bottom line? Or are not going to be our top winners? Where could we shift our resources to focus on what really matters? That's a tough task. For some founders, they might feel that they're giving something away when they do this [focus]. On the contrary, when you're focused on what really matters, that's going to really help to advance the company to the next milestones in a timely manner.

We could also talk about company valuations in today’s environment. There's been a significant impact on valuations of public biotech companies. We are continuing to see some major investments in the private biotech market, and these are creating real value for patients. In 2017, for example, we saw the largest drop ever in US cancer death. I'd say this is thanks to all the innovative medicines that are being discovered and developed by the biotech and pharma industry—many of which have been fueled by venture investments in early-stage life science companies. The public markets today have an impact on how we value and underwrite investments for the early-stage companies. But despite all of these challenges, I remain cautiously optimistic and encouraged by all the advances and innovations that we have been witnessing in biotechnology These could really disrupt entire the sector.

11. What are you reading in your free time?

I like to read books that are related to science or world history, in particular human civilizations and the origins of human evolution. I’m currently reading “Who we are and how we got here” by David Reich. It’s a book about using genetics to understand our ancestry, tracing our origins all the way to Neanderthals. It really changes the way we think about our past, and that different groups of people living in different continents share their DNA.

There’s another book that I just finished reading called “Phoenician secrets” by Sanford Holst. It talks about the ancient people in the Mediterranean, and the incredible civilization they built through their 3000 years of existence. I was drawn in particular to Carthage which was one of the most advanced and influential civilizations of antiquity founded in the 9th century BC on the Northwest coast of Africa. It was an important trading hub on the Mediterranean sea, and was well known for textile production. But eventually it all got destroyed due to the war with Rome. As I reflect on it, there are many similarities between the past and present especially as it relates to the Cathage. – Rome wars and the wars we have witnessed during the past century.