Tessera: Jacob Rubens
“If you can imagine a better solution than the one you're working on, you're probably focusing on the wrong solution.”
Public perception regards “gene editing” as a Microsoft Word for biology. Cut, paste, find, replace at the click of a button. The truth is that first-generation CRISPR/Cas9 systems are more akin to white-out applied to paper—individual words can be erased or written over, but adding in longer sentences or paragraphs often doesn’t work. Not too infrequently, the whiteout spills, blotting out important (off-target) prose.
Biotech companies are seeking to make drugs that have true “editorial control” over the genome through pasting sequences into a target site. The issue of versatile editing is particularly important when there is a gene (paragraph) riddled with many different disease-causing mutations (typos). Rather than correcting mutations individually for each patient (word by word), it would be simpler to just replace the whole stretch of DNA in one go—with a clean, corrected copy.
Tessera Therapeutics is advancing Gene Writing™ to make therapeutic alterations to the human genome. Incubated within Flagship Pioneering, the company most recently raised a $300M Series C financing in April 2022 to further develop their suite of gene editing and delivery technologies. Tessera is in seasoned hands—captained by veteran drug developers Mike Severino (CEO), Michael Holmes (CSO) and David Davidson (CMDO).
Jacob Rubens is the Chief Innovation Officer (CIO), founding Chief Scientific Officer, and co-founder of Tessera, and a senior principal at Flagship Pioneering. Prior to Tessera, Jake co-founded Sana biotechnology and helped launch Kaleido Biosciences. A Massachusetts native, Jake is a self-described “late bloomer” in science. He discovered a passion for research in college that led him to a PhD in Tim Lu’s lab at MIT. There he learned how to engineer gene circuits and create “smarter” cell therapies. Jake was honored in 2017 in Forbes' 30 under 30 list in science, in 2021 in Endpoints’ 20(+1) Under 40 list of the next generation of biotech leaders, and in 2021 in Business Insiders’ list of 12 young serial entrepreneurs building the next generation of biotech startups.
An engineer and tinkerer at heart, Jake’s innovation team at Tessera is taking on the big problems—improving the fidelity of their writers, optimizing indication selection, and delivering their constructs to target tissues. Making a “Microsoft Office” for living systems isn’t easy, but Jake and Tessera have the experience, financing, and tools to make this a reality for patients.
Until that day, please forgive any typos.
Below is an interview with Dr. Jacob Rubens from September 2023:
1. When did you realize you were interested in science and medicine?
I'm kind of a late bloomer as a scientist. Many of the people in our industry became passionate about science from a young age. They entered competitions in their high school or internationally. I was more of a jock in high school—more interested in excelling in sports and socializing than I was in academics. However, I come from a family where both of my parents are in analytical professions. My mom is a doctor and my dad is a lawyer. Growing up, they definitely focused more on the math grades in my report card than English or history.
There was an especially big emphasis in medicine on my mom's side of the family. Her father and uncle ran a medical practice together for over 50 years. They were old school doctors who did a lot of house visits and even had their patients visit them at home if anything was wrong. On top of that, my mom's first cousin, Elliot Sigal, was the head of R&D at Bristol Myers Squibb when I was in high school and college. It was great to hear his perspective on what a career in biotech and pharma could look like. When I began to take science courses in high school, I realized that I had a knack for biology and really enjoyed it. There was something about the principles of evolution and molecular biology that just clicked. It also helps that I learn visually. I'm the type of person who, when I want to learn something, looks first at Google Images to see if there's a nice diagram.
At my high school, there was a biotechnology investing course, which is an usual class for a public school in Massachusetts. I took it in my senior year and was drawn to biotechnology and the different types of medicines and technologies that companies were developing. I also found that outside of school, I was spending a lot of time reading about these companies and their science —I began to wonder whether this was an area that I might be interested in for the longer term.
Around the same time, I did a short internship with a family friend at an investment bank called Leerink Swan. The family friend is Jonathan Gertler, who today runs Back Bay Life Science Advisors, where he’s the founder and CEO. From that experience, I realized that I didn't want to be a traditional investor--because they are removed from the science going on at these companies. They're much more focused on how much capital companies need to reach an inflection point, which is very important but wasn’t the part of biotech that excited me.
When I got to Wash U [for undergrad], I had to decide whether I wanted to major in biology with a business minor, or vice versa. I chose biology as a major, and actually didn't end up taking many business courses at all. My interest in research began when I was a sophomore. I recall sitting in the back of a very large introductory biology class and reading Rolling Stone magazine. There was an article that featured Craig Venter and his effort to make biofuels by engineering algae. I thought this was the coolest concept ever--that there is a way to apply cell engineering to make fuels just blew my mind. It led me to wonder whether I could be involved in trying to help save the world, in some small way, through research. Fortunately, there was a group at WashU run by Bob Blankenship that was just beginning to build a team focused on engineering photosynthetic bacteria to make biofuels. I reached out to Bob, and he was willing to give me an opportunity to conduct research in his lab. I actually brought him a project proposal. It was a big leap of faith for me to put a research idea in the world and ask for feedback. Fortunately, Bob was encouraging and gave me resources to try to put my idea into practice. The concept was that we could engineer the photosynthetic antennae of photosynthetic bacteria, so that they would be responsive to light and intensity and more productive at making biofuels. While working on this project, I realized that we lacked the gene circuit tools to realize our aims. This led me to become interested in the field of synthetic biology, which is where I spent the next period of my academic career.
2. What led you to MIT/the Lu Lab?
At WashU, I started an undergraduate synthetic biology research team. We entered into a competition called IGEM, which stands for International Genetically Engineering Machines. At the time, most undergraduate research universities had an IGEM team, but WashU did not. Building the WashU IGEM team was my first great entrepreneurial experience. I had to recruit, organize, and goal-set for a multi-disciplinary research team composed of science, engineering, and medical students from across the campus. Getting resources required coordinating with different academic departments to support our team with stipends and research funding. We also received donated reagents from Sigma Aldrich, a St. Louis-based company that was really supportive of the effort. By the end of the project, we had executed on our vision and had an amazing presentation.
It [IGEM] helped me figure out that I enjoyed bringing people together, painting a big vision, and motivating the team to execute on that vision. During the process, I realized that we were early in the synthetic biology field and became interested in advancing the synthetic biology toolkit towards the long-term vision of unlocking programmable cells.
I was drawn to MIT because there was a new synthetic biology center there with Tim Lu as a new PI and Ron Weiss from Princeton. They had recruited Chris Voigt from UCSF and had a lot of involvement from across the campus. Cambridge also has entrepreneurship in the water, especially in biotech. MIT is an epicenter of folks starting companies based upon their academic work, something that I thought I might do as well.
At MIT, I worked on engineering cells to do computations and calculations based upon information in their environment. Our goal was to build intelligent cell therapies/diagnostics that could pass through someone's gut or bloodstream, take in certain information, and then make a decision, like killing a cancer cell, measuring inflammation levels, or making an anti-inflammatory compound at the site of inflammation.
I worked with terrific people, and we made real progress towards our vision. It was my first exposure to cross disciplinary thinking in a big way and, in the process, learned so much from the electrical engineers that I teamed up with—who saw the world in a different light than I did as a biologist.
3. What was a low point in the PhD training process?
Science is a humbling endeavor. During grad school, our group had some great success. We published a couple high impact papers on engineering bacteria to respond to small molecules and conduct calculations like addition, subtraction, multiplication, and division. We made progress in building what I thought at the time were going to be foundational circuit architectures for enabling intelligent cell therapies. Ultimately, however, it became clear that it would be a long-road to translate this research to real-world applications.
For example, we began to engineer a pill that could be ingested to measure the level of inflammation in the intestine. We created bacteria that could detect reactive oxygen species or other inflammatory molecules in the gut lumen. When the bacteria detected inflammatory signals, they would fluoresce. This fluorescence could be measured by a small microchip in the pill and then this information could be transmitted through a Bluetooth chip to a cell phone. As we conceived and began to develop this project, we became excited about building a company around the concept. I put together a business plan with a few of my colleagues, and we named the company EnteroSense. There's still a horrible video on the internet of me pitching it at a OneStart competition back in 2012 or 2013.
It [EnteroSense] ended up being a bad idea. Enthralled by the concept, I planned on spinning the tech out into a company and becoming an entrepreneur. However, as I reflected on what it would take to make the company successful, I was hit with two realizations. First, I had a lot to learn about biotech entrepreneurship. Second, the tech felt like a lead weight holding me back as opposed to a springboard propelling me forward in my career. I could go into detail ad nauseam about how our business plan and tech was flawed. For example, it was just recently that Tim Lu and his collaborators published a paper showing that this tech could even work. Looking back to 2013, we were quite far away from proof of concept. However, it was through this experience and the realizations coming out of it that led me to join Flagship Pioneering, which is where I've been since 2015.
[On the Flagship Internship Program]
I joined [Flagship] as an intern in 2015 and worked on few different projects. Every summer we [Flagship] bring in a group of between 25 and 30 talented PhDs, postdocs, and medical students who are interested in learning about the Flagship process. I was fortunate to be one of those people in 2015 and just fell in love with the process.
The Flagship process is asking a series of “what if” questions and trying to make really big leaps. It is the process we use to teach each other and learn and team up to build companies. I always thought of entrepreneurship as an individual sport and reading popular news or literature about it, you'd get that same impression.
However, and especially in biotech, it is such a team sport. Building a successful company, let alone making a successful drug, is composed of 1000s upon 1000s of very small decisions compounding on each other. Thus, if a team has great, collaborative people with divergent experiences, knowledge, skill sets, it will make 5% better decisions every time. That 5%, compounded to the power of 1000, makes a huge difference in the probability of success. That is one of the things that drew me to Flagship; the opportunity to maximize the probability of success by working with people who have deep domain expertise across, not only ideation and leadership, but also intellectual property, corporate legal, finance, accounting, capital formation, talent acquisition, and HR. I was just blown away by the quality of the people at Flagship.
4. What was it like being involved with Cobalt when it was ultimately purchased by Sana?
The company that today is called Sana can trace its earliest research to Cobalt Biomedicine, which we started at Flagship. It originated from an exploration that I did over my summer as a fellow. I worked with Geoffrey von Maltzahn, Jack Milwid, and Michael Mee, exploring the phenomenon of cells exchanging mitochondria. We wondered whether we could leverage that biology to make drugs. We initially had two therapeutic focuses. First, ischemic diseases, which we believed we could address by delivering healthy mitochondria. Second, mitochondrial diseases driven by mutations in mitochondrial DNA, which we could address by delivering a new mitochondrial genome.
This was also a humbling scientific experience. We learned, through a series of experiments, that mitochondrial delivery premise was going to be more challenging to realize than we initially thought. Fortunately, those experiments led us to the insight that the mechanisms by which cells naturally exchange mitochondria were quite remarkable. They [the cells] deliver a one micron or a larger organelle across a membrane, which is really good at keeping stuff out. We began to wonder what this mechanism was and whether we could leverage it to, not only deliver mitochondria, but also to deliver other payloads like DNA, RNA, or proteins.
Eventually, we focused in on fusogens, which likely first evolved in viruses for delivering their genetic payloads into cells. Fusogens can be exquisitely cell specific and efficient. So, we changed directions as a company from mitochondrial delivery to genetic delivery and began to work on the concept of fusosomes. Fusosomes are lipid vesicles that comprise a genetic payload and are decorated on their surface with a fusogen that is targeted to a specific cell receptor. We built a platform that enabled us to deliver DNA, RNA, or protein to specific cells at very high rates of efficiency and specificity. This meant we could do things like make CAR-T cells inside the body of mice as opposed to having to take T cells out of body, engineer them, and return them. We saw an exciting future for the company in solving the limitations of today's genetic medicines, especially in delivery. During the process of forming the capital for our series B fundraise and recruiting long term executive leadership for the company, we were connected with Steve Harr, Hans Bishop, and Richard Mulligan. They had just begun to crystallize what Sana would become today and convinced us that the best way forward for the company [Cobalt] was to team up with them and their vision [for Sana]. It has been really wonderful working with them and seeing what they've built since then.
5. How did the idea of gene writing for Tessera form? [Put in context with other gene editing technologies like CRISPR transposases and piggyBac]
An advantage of building companies with Flagship is that we are able to learn from prior builds and use that knowledge to inform our next direction. This has played out a couple of times during my career. In the case of Tessera, we were one of the first and largest investors in Editas. Because of this, we became aware that while the space was enabled by nucleases, like CRISPR-Cas9, this system had inherent limitations. Cas9 is just a nuclease and it evolved to simply break DNA. However, most of the opportunity in genetic medicine is in not breaking DNA, but in editing a specific base pair or series of base pairs, or to add a new gene to the genome. The first generation CRISPR-Cas9 tools lack this capability.
We were also excited by the early literature on base editing showing that, if another enzymatic function was brought along with a guided nuclease, higher efficiencies could be realized for the change trying to be made. With all of this we said, “Hmm, this is pretty cool. I wonder if nature has evolved a tool to write and rewrite genomes.” With that question, we quickly came across mobile genetic elements and were amazed by the wondrous biology of these genes. These were genes which evolved for the sole purpose of writing DNA. It turns out that they're also the most abundant genes in genomes. The diversity of these elements is also enormous. The question then changed from, “Could mobile genetic elements have a solution for writing genes,” to “Where do we start and which are the best ones?” This led to an exploration at Flagship, and in 2018, we launched Tessera in the basement of Alexandria Launch Labs. We began with a really talented core group of scientists that came from other genome engineering companies. Today, we have about 350 full time employees across a couple floors in a new building in Somerville, Massachusetts and have raised roughly $600 million to support the science.
[Seems like a very broad mandate, what did it feel like going off into such uncharted territory?]
The synthetic biology mindset has really been helpful. We realized the best way to find effective gene writing systems was to test as many of evolution’s innovations as we could. We invested very early in computational tools to identify different types of retrotransposon species. We built tools to manufacture DNA and RNA, culture cells, and read out the genome manipulation with high accuracy. Then we built machine learning tools that could inform the next round of iterations.
Doing all of this, however, was really hard, and it takes hundreds of millions of dollars to advance the science. Biology is unbelievably complex. Making drugs is unbelievably complex. Ultimately, the more fantastic people working on a problem, the higher probability of success.
[Differentiation from Piggyback and CRISPR transposase systems?]
Retrotransposons have a four-step biochemical process called Target Primed Reverse Transcription. First, the gene writer protein, or the retrotransposase, binds to an RNA template based upon specific interactions between the RNA template and the retrotransposase. Second, that ribonucleoprotein complex binds a specific sequence of DNA. Third, the [retrotransposase-RNA] complex nicks it [the DNA]. That means it breaks one of the two DNA strands and uses that free flap of DNA to anneal the RNA template based upon Watson Crick base pairing, the same way PCR reactions are primed. Finally, the reverse transcriptase component of the enzyme copies the RNA template into a new sequence of DNA, writing the DNA sequence into the genome.
6. Tell us about your role at Tessera
I was originally the founding Chief Scientific Officer (CSO) at Tessera and led the research organization until we grew to ~180 people in the company. We got to a point where I knew that the most important decisions for the company were going to be how to turn this platform into drugs. The current CSO Mike Holmes has been a wonderful addition to the team. Mike has been in the nuclease and genome engineering field for as long as anybody, and has a lot of experience engaging with regulatory authorities--he developed many genetic medicines in his time leading Sangamo’s research. Much of our strategy was worked out at that time and we've been executing well since then.
My current role as Chief Innovation Officer is actually quite different than the CSO role. In this role I still have general R&D and managerial responsibilities, but most of my time is spent trying to come up with new technologies that can displace our current platforms. This entails going back to the mine of mobile genetic elements and finding alternative mechanisms of gene writing. My team is structured more like an academic lab than an industry team, being that it's quite flat. The team members are capable of doing all the different types of science they need to develop a project as opposed to specializing in one area. Since starting this role, we've made some good insights, that we're just starting to advance now as a company.
7. What areas of science have you fascinated and why?
I'm a DNA nerd so I’ll stick to what I know and love. I think that DNA is the most powerful molecule in biology – if you make a small change in DNA you can have a large impact on an organism. In terms of the long-term mission of understanding how changes in our genome impact biology and making medicines based on this understanding, we're only at the beginning of the frontier. I have complete conviction that, fast forward 30+ years, genetic medicine, which today is a fraction of our industry, is going to be the majority of it. Patients don't want to be patients. They want to be people who had a medical procedure one day, similarly to the way that today we fix broken bones. They want cures. DNA is the one place in biology where interventions can permanently address disease. A lot of my excitement remains around genetics and genome engineering.
One area of biology that I've been quite fascinated by recently is this emerging story about the somatic genome. We've known for a long time that cancer is caused by genetic mutations, but cancer cells don't go from being normal cells to cancer cells. There are 100s, if not 1000s, of mutations in between [the transition from] the normal cell and the cancer cell. Some really great work over the past decade has started to reveal that, on average, most cells in our body have 10 distinct coding mutations that differentiate them from their next-door neighbor. This means that we shouldn't think of ourselves as one genome, but trillions of genomes where every cell has a distinct version of that genome. We're just at the beginning of understanding the implications of this for biology and for medicine. That's a really cool area that's just starting to emerge and I think will really explode over the next 5-10 years.
8. What are you reading/watching now?
I just finished watching the second season of The Bear. After watching that, I must say it is just as hard to build a restaurant as it is to build a biotech company, and maybe even harder honestly. It gave me a great appreciation for the difficulty involved in doing anything where you're going out on a limb and recruiting other people. It's stressful. It's hard. It requires amazing teamwork. I have a great appreciation for all entrepreneurs. I also realize how fortunate I am that the fruits of my labor are something that ultimately can hopefully make the world a better place. We are fortunate that the work we love and are good at may do good in the world
As far as reading, I really enjoy science fiction and magical realism. For magical realism, I enjoy how you can take one little aspect of the world and turn it on its head or like 15 degrees off kilter. That thought process oftentimes reveals assumptions we hold about the reason the world works a certain way or why things are the way they are, which I find funny, fascinating, and quite insightful. As far as a magical realism author, I enjoy reading Murakami.
In science fiction, I think the person doing the most remarkable work is a writer named Ted Chiang. He has mostly written short stories. “Story of your life,” is his best known work, and it was the inspiration for the movie, “Arrival”. Someone described his writing as soulful science fiction, and that’s an apt description. It's very human-centric science fiction as opposed to stories about futuristic societies trying to mine some mineral
9. Going back 10 years, during your PhD, what advice would you give to PhDs or other students interested in getting involved in the biotech industry?
Try a lot of things to figure out what you love to do. The people who ultimately make the largest impact love their work and, because they love their work, are on rapid growth curves. They seek feedback. They seek challenges. It's easy for them to overcome failures.
There are many different ways to make an impact in our industry. I happen to be an entrepreneur in an investment firm. There are obviously other types of VC, but there is also medicine, pharma, biotech, R&D, or consulting. These are all different paths and they're all terrific. We're all helping move forward this revolution of medicine and genetics, and many of us believe we're still at the beginning.
Boiling it down: figure out what you love and you'll be successful and make an impact in the process. Pick a place to work where there are people that you look up to, can learn from, are able to watch closely, and that can challenge you. Ideally, you’re following great science that you're convinced will make an impact because that will always be the guiding light that will keep you motivated over time.
 | A guest post by
|