Founder Spotlight #48: Richard Novak @ Unravel Biosciences

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Unravel Biosciences is a personalized therapeutics company that redefines diseases through RNA network analysis to seamlessly bridge target discovery with clinical efficacy of new drugs. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases impacting the whole body. Unravel’s platform discovered RVL001, a proprietary formulation targeting Rett Syndrome that will enter the clinic this year, and RVL002, a new small molecule with applications in CNS and metabolic diseases.

Richard Novak is a bioengineer and entrepreneur dedicated to solving unanswerable questions through technology innovation. Prior to Unravel Bio, he was a Lead Engineer at the Wyss Institute for Biologically Inspired Engineering at Harvard University where he managed fast-paced programs in drug discovery, advanced disease models, human Organ Chips, and integrated automation and sensor systems. He has over 15 years of experience in microfluidic system development and applications in the therapeutic space. He is a founder and president of the nonprofit Future Scientist and a founder and director of the sample collection platform company Rhinostics Inc. He received a BS in biology from Emory University and a PhD in Bioengineering from UC Berkeley.

Personal Spark

What prompted you to pursue a career in Life Sciences? Was there a specific moment in time or influence you can remember?

In my early childhood in the Czech Republic, my family spent most of our free time outside, picking berries and mushrooms in forests, gardening, and hiking. This continued after immigrating to the US, and I grew to love nature, and from there, biology. In high school, my father guided me to develop my own research studying turtle migration using genetic sequencing, and from there, I was hooked on a life science career trajectory. I gravitated to work specifically in advancing therapeutics after spending several months working in a remote corner of the Amazon rainforest and seeing the massive impact of parasitic infections and other under-resourced diseases, where rapid and efficient therapeutic interventions could have profound benefits.

How did you get your training to be able to build your company?

My initial response to the need for rapid interventions was to found Future Scientist with my PhD program colleagues. We felt that science and engineering education would enable communities to sustainably address challenges using locally available resources and have the most immediate impact on health. In the process, I was thrown into building a non-profit startup with all that company building entails: fundraising, team building, logistics (in this case bringing US students to Latin America through educational programs we designed), marketing, legal and accounting, and delivering a clear benefit to our stakeholders (communities and program participants). I am grateful for all the mentors and supporters who took us under their wings and provided guidance and reality checks we so badly needed to build a good company. This experience has stuck with me, not benefiting Unravel but also clearly demonstrating to me the value of mentorship and generosity with time.

I also gained a great deal of insight from NSF’s iCorps program on product-market fit, Creative Destruction Labs mentorship program, and multiple business competitions at UC Berkeley run through the Haas Business school. They provided exposure to a side of technology translation not easily achieved in a lab.

Can you tell us a little bit about your background & career thus far? What were you doing before you started running a high potential venture backed startup?

I was a member of the Advanced Technology Team at the Wyss Institute at Harvard University, which is effectively a playground for scientists. I joined the Wyss because of the incredibly wonderful opportunity to lead teams on high risk high reward therapeutics and diagnostics programs with the specific mandate to identify translation and commercialization paths and mature technologies for outlicensing. As an engineer, I focused on the technology platforms, from Organ Chips that spun out into Emulate Bio to computational and screening platforms that led to Unravel and other companies. During the COVID pandemic, I, along with many others, was drafted into supporting the many hospitals around the Wyss Institute that were running into supply chain issues and specifically swabs shortages. Together with the incredible team at the Wyss, we developed a 3D printed swab that was tested in 3 days from first design, in a month an injection molded design was in volunteers, and another month after that was available as a sterile product at a million unit scale. I partnered with Michael Springer, a Harvard professor building Harvard’s diagnostic lab for regular testing, and together we developed a highly automatable swab that enabled his lab to run tens of thousands of SARS-CoV-2 tests per week with only a handful of staff. We spun that out into Rhinostics, which took the concept and has applied it to blood and genomics testing. All of these highly translational experiences with rapid impact only reinforced my desire to continue this trajectory within Unravel.

Anything else you’d like to share about your life, academic trajectory, etc.?

In high school and college, I was that annoying kid asking questions that couldn’t be answered with existing tools. So I became a tool builder, from custom genomics tests for turtles to a portable water filtration system to study parasites in streams. It took me an embarrassingly long time to realize that I approached everything through the lens of an engineer. Once I did, I embraced it fully, heading off to UC Berkeley for my PhD in Bioengineering and developing single cell microfluidic platforms at a time when we had to convince journal reviewers of the power of Poisson statistics and the value of single cell analysis. There I became enamored with rapid prototyping. I saw its immense value in reducing an initially intractable engineering problem into manageable components that could be efficiently solved. I applied this to Future Scientist’s curriculum, building on IDEO’s Human Centered Design principles that embody rapid yet systematic prototyping for humans, not hardware. I saw the impact of quickly testing multiple potential solutions in a matter of days with materials on hand to ensure that a final product would truly meet the needs of the end-users. I came with this perspective to the Wyss Institute, where our one and only command was to make an impact on the world by taking technologies out of the lab. Which technologies are best? For which problems? How fast can we do it? I realize that these were all questions suited to a rapid prototyping approach so embedded in engineering disciplines. At the Wyss, we built a prototype water purification system that heavily relied on a $3 bucket from Amazon and shipped it to partners in Panama to road-test it with potential end-users in remote villages. We did this even before we had the pathogen-killing technology fully functional so that we could get feedback on the envisioned solution and use that to refine the technology as early in development as possible.

My team and I took the same approach developing new swab designs in the earliest days of the COVID pandemic, bringing 3D printers home for the shutdown and handing off samples in COSTCO parking lots to not lose out on the value of rapid prototyping. The shared uncertainty around the pandemic enhanced collaboration, and prototyping surprisingly became easier as the rapid progress across all areas (devices, diagnostics, therapies, prevention) became impossible to ignore. I’ve now extended this rapid prototyping approach to therapeutics development.

Company Overview

What problem is your company solving?

Neurological disorders have been among the most challenging diseases to treat because drug candidates end up being in patients despite the most thorough preclinical target validation. Basically, the drug targets are wrong. In multiple clinical trials year after year we see a target being successfully engaged by a drug, sometimes changing a biomarker readout, all the while not bringing a therapeutic effect to the patients. On the other end of the spectrum, we have drugs, such as some oncology drugs, that do provide a meaningful benefit to patients but not through the targets they were originally developed for. We set out to build therapeutics programs that provide efficacy first without requiring an initial commitment to a drug target.

How did you become motivated to tackle this particular problem?

We were working on a DARPA program with Don Ingber to enable a patient to ignore or tolerate an infection such as sepsis and enable treatment in the field, as opposed to treating infections directly with antibiotics. As our drug candidates became quite effective, we started asking questions about how this could impact cognitive function once the acute phase of infection was addressed. It became apparent that these questions were difficult to answer, so we collaborated with Michael Levin at Tufts and the Wyss Institute, who spent a couple decades developing technologies to do just that. We soon saw the bigger opportunity of screening for cognitive and behavioral therapeutic effects in addressing diseases of the central nervous system, which are among the top most debilitating and unaddressed indications globally and with few tailored resources to tackle them.

It was here that I saw the opportunity to bring the iterative design-build-test prototyping cycle of engineering into drug development. While drug repurposing has long been the mainstay of fast drug development with many success stories, the process has largely been a brute-force approach with limited new drug potential. I wanted to take Unravel beyond repurposing concepts and focus on entirely new mechanisms without brute-force screening or being limited to existing knowledge (let’s face it, we are only scratching the surface of biology!). Most importantly, seeing the massive failure of translating preclinical results to patients, my co-founder Frederic Vigneault and I aimed for a fast-track path to the clinic, using existing drugs to prove out novel targets. This runs counter to a widely held myth that each drug has one or few drug targets one can look up in a database. In reality some drugs engage hundreds of proteins and other molecules in tissues in unique ways, and these potential targets are all interconnected. We realized that these existing drugs are the key to rapidly prototyping new targets in patients as a first step in developing new, effective therapies.

As a result, at Unravel we are asking the most important, end-user- facing question first: does the drug help the patient? By making that concept the north star of our company and building out a suite of cutting edge discovery tools and innovative clinical trial designs that let us quickly test a drug target in actual patients, we are testing the idea that biotechs can be accelerated through rapid prototyping.

Quite simply, what does your company do?

Unravel is at its simplest a precision medicine platform using patient transcriptome data to redefine disease states to accelerate drug discovery and test predictions in record time in patients. Unravel discovers new, often hidden targets for neurological disorders and immediately asks “will this help actual patients?” by quickly and inexpensively testing existing drugs in custom animal models and clinical trials. In parallel, we develop highly effective new therapeutics for the validated drug targets.

Now in more depth, what are the specifics of what your company does?

Unravel leverages its proprietary BioNAV™ platform for treating complex neurological diseases impacting the whole body where traditional target-driven drug programs have often failed, combining AI drug discovery, patient stratification, rapid preclinical screening, and efficient N-of-1 clinical trials to discover effective treatments. Unlike other personalized medicine approaches, Unravel uses RNA network signatures sensitive to dynamic changes in patients to simultaneously discover personalized treatments while stratifying other patients into therapeutic response groups to rapidly scale clinical and commercial impact regardless of the root cause.

Unravel’s target-agnostic approach has resulted in the identification of an entirely new drug target for treating Rett syndrome. The target and discovery platform are being clinically de-risked using RVL001, a promising proprietary formulation of an existing drug, in N-of-1 trials to assess individual patient response through frequent RNA sequencing. Unravel has already developed a new lead small molecule, RVL002, that safely and efficiently treats Rett syndrome preclinically through the discovered drug target with potential applications in other CNS and metabolic diseases. Other target and therapeutics discovery programs include the neurodegenerative disorder X-linked dystonia Parkinsonism, Okur-Chung Neurodevelopmental Syndrome, and bipolar disorder.

Why does your solution matter for the world when you get it right?

Imagine precisely and effectively treating patients based on their current disease states, not clinical symptoms or unclear genomic data, and without forcing a long and often inconclusive diagnostic odyssey. Imagine if you could quickly prototype a treatment in patients to help them while answering the most critical drug development questions first. This is what Unravel will achieve for the 10% of the world’s population with one of 15,000 rare diseases.

Genesis

Tell us about the founding of your company — how did everything come together?

My co-founder Frederic Vigneault and I started collaborating on an internal program at the Wyss Institute that for the first time combined multiple discovery technologies into a single program aimed at developing a treatment for Rett syndrome. We had been using Xenopus laevis tadpoles as a model organism of infection, and the tadpoles have well-developed brains with complex behaviors that could be suitable for screening neurodevelopmental disorder therapies. I asked Frederic, with his extensive experience in CRISPR development with George Church, if he could CRISPR engineer tadpoles to disrupt the MeCP2 gene that is known to cause Rett. His response was “yes of course, but why tadpoles if mice are already inaccurate models?” Long story short (and many attempts to try to make the tadpole models fail), we saw a beautifully synergistic platform taking shape. Tadpole engineering allowed us to easily generate entirely new and robust disease models in a couple weeks, computational predictions of candidate drugs and targets were rapidly translating into stunning results even in mouse models, and talking with clinicians made it clear that we may have a revolutionary solution for tackling neurological disorders not just for Rett but as a rapid prototyping approach suitable for any number of indications. What was to become the Unravel platform was extremely effective in uncovering specific COVID repurposing therapies that ended up having significant clinical impact based on electronic health records (another great form of rapid prototyping!). In parallel, we used the platform to develop artificial hibernation inducers for limb and organ preservation, exceeding DARPA 5-year milestones in just 2 years. All of those successes made it clear that our platform works, and Rett syndrome is the way to prove out our approach.

Accomplishments

What are some of the notable milestones your company has achieved thus far?

We raised a pre-seed round in 2021 to get the company operational. Of course the biotech market tanked soon thereafter, but we were able to hire a top team of scientist and computational experts, discover a new drug target for Rett, new pathways for several other indications, get to pre-IND in the US by bringing in Neal Muni as our Chief Medical Officer, discover and patent RVL002, a new molecule to treat Rett syndrome, and establish several partnerships and obtain grants.

What are some of the biggest hurdles ahead? How do these create points of value inflection?

Our key path is to show in a proof of concept clinical study how our platform can lead to new drug targets that actually are therapeutically effective. We are working with TMA Precision health, a CRO partner, on a clinical trial in Colombia to accomplish this while we continue to develop the high value new drug candidate. This single step will clinically validate our computational platform and rapid prototyping approach for further partnering while de-risking the drug target and new molecule to show how Unravel generates value directly through therapeutic assets.

Pay It Forward

Throughout the journey, what have been some of your biggest takeaways thus far? What advice/words of wisdom would you share from your story for other founders?

• Get used to hearing “no” more than you ever have! The corollary of that is to learn how to benefit and learn from those responses.
• Surround yourself with people who want to find ways to achieve success. It’s too easy to come up with reasons for why something won’t work, and it rarely adds value. Instead, look for optimists who will chip in to make goals a reality or quickly find ways to pivot and keep moving forward.
• Don’t get irrationally optimistic and attached to your preferred path. Be realistic about what works and what doesn’t and pivot as soon as you know you’re not making headway. This is where surrounding yourself with seasoned mentors is key in telling the difference between optimism and idealism.

What are some of the must-haves for an early stage Life Sciences startup in your eyes? (Key critical components like team, academic papers, industry know-how, etc.)

Network, network, network. This builds a team and customers/partners, bridges any expertise gaps, and enables you to bounce ideas off of more neutral (or, ideally, critical) parties.

For folks coming out of academia, what advice would you share?

While individual academic labs can be quite distinct, from basic research focused to highly translational and entrepreneurial, none of them fully prepare an aspiring entrepreneur. However, there are many wonderful mentoring and accelerator programs that can provide a strong foundation, from NSF’s iCorps program, to Nucleate, to university-specific programs that are often partnered with business schools. YC, Petri, and other accelerators may be helpful once a startup kicks off.

Not everyone knows everything. Often founders have to learn either the science or the business side better. What advice would you give for someone picking up a new skill set such as this?

Do your best but don’t try to pick up all the skills yourself! Balance rapid uptake of what is a firehose of information and need for new skills with targeted expert support to fill the gaps. Much has been said about finding a great co-founder and legal counsel; on top of that, bring in accounting, marketing, regulatory, or technical expertise through contractors and vendors. A full time hire may not make sense early on, but at the same time one cannot afford to make mistakes in critical company-building steps. Also, I absolutely recommend bringing in interns, especially co-op students who work full time for many months. With the right support, everyone has marketable skills as well as a unique perspective that can helpfully challenge established assumptions, and motivated interns can be very cost-effective while providing specific value to startups.

What advice for managing and hiring a great team can you share?

• You spend a lot of time hiring great people to work on a project they are excited about. So let them! Get out of their way except to navigate the team toward a clear goal and provide needed resources and mentoring support.
• Hire people based on alignment of motivation, because that will get them (and you) through almost certain adversity and keep you honest in times of success.

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