Jake Becraft: Origins of Strand and the Future of RNA Therapy (Nucleate Insights #2)

Welcome to the Nucleate Insights program.

Nucleate is a student-led nonprofit agency for future biotech leaders. Among our educational initiatives is Insights, which invites life sciences trainees to engage in deep-dive discussions with company founders who transformed academic projects into thriving biotechnology companies.

In these journal club-style discussions, we uncover what helped founders fully realize and grow the commercial potential of their original academic projects.

Background

Jacob Becraft, CEO of Strand Therapeutics

Insights’ guest for this session was Jake Becraft, synthetic biologist, entrepreneur, CEO and co-founder of Strand Therapeutics, a company at the forefront of mRNA therapeutics and synthetic biology. Together with colleagues at MIT’s renowned Synthetic Biology Center, Jake led the development of the world’s first synthetic biology programming language for mRNA. In 2018, he and his colleagues published Small-molecule-based regulation of RNA-delivered circuits in mammalian cells in Nature Chemical Biology, forming the basis for Strand Therapeutics.

Jacob Becraft, Ph.D., CEO, Co-founder at Strand Therapeutics

Among many national and international recognitions, Jake earned the MIT Tech Review 35 under 35, Boston Business Journal 40 under 40, and EndPoints News 20 under 40. Beyond his work at Strand, Jake’s broader interests span synthetic biology, biologically engineered organism-machine interfaces, and the intersection of tech and biotech methodologies. He is an advocate among the life science entrepreneurial ecosystem for supporting young founders in biotech entrepreneurship. We joined Jacob to discuss the landmark Nature paper and the basis for Strand Therapeutics, summarized below.

Scientific Context

The idea of “mRNA therapeutics” catapulted itself into the public conversation in 2020. However, mRNA as a therapeutic had been a subject of great interest for scientists and clinicians long before its introduction as the molecule behind the COVID-19 vaccines. Messenger RNA (mRNA) is a cell’s solution to transcribing the code of DNA into an intelligible “message” which ribosomes can then “read” to create functional proteins. DNA resides within the protective shell of the nucleus, whereas mRNA exists in the cytoplasm of the cell where it is translated into protein then degraded thereafter. Both DNA and mRNA can be generated and delivered to patients therapeutically to produce proteins needed by the patient. The functional and regional distinctions between DNA and mRNA are central to how we think of these two molecules in the context of clinical utility. The major advantages of mRNA-based clinical applications are two-fold:

1. mRNA is a transient molecule which is degraded by a cell’s intrinsic mechanisms. This makes mRNA well-suited for applications which require only temporary protein generation such as vaccines, time-bound cellular reprogramming, or time-bound therapies.
2. mRNA is restricted in location and activity to the cell’s cytoplasm. Unlike DNA-based therapies which require specific engineering to cross the complex nuclear membrane, mRNA has only one barrier to cellular entry — the cellular membrane itself. Additionally, there is virtually no risk of genomic integration as mRNA does not enter the nucleus or get retro-transcribed to DNA.

These are balanced against several obstacles:

1. Duration — The short-lived timeline of mRNA needs to be extended to better suit applications that require prolonged (but perhaps not permanent) protein expression.
2. Control — The safety and efficacy of mRNA-based therapeutics requires a precise control over the strength and timing of protein expression to avoid the over-, under-, or mis-timed- expression of a protein.
3. Specificity — It is critically important that whatever mechanisms are used to control mRNA expression level and timing are specific to the therapeutically introduced mRNA and will not affect any other mRNA in the recipient’s body.
4. Immunogenicity — Introducing novel mRNA can trigger an immunogenic response which poses a considerable safety risk.

Together with colleagues at MIT’s Synthetic Biology Center, Dr. Jacob (Jake) Becraft recognized that these obstacles could be addressed with the implementation of small-molecule-based RNA circuits. The idea was to engineer an mRNA therapeutic which includes modified sequences (modRNA) that can interact with delivered small molecules to alter the behavior of the modRNA. For example, the group engineered a modRNA, containing sequence elements which interacts with TMP (an FDA-approved small molecule antibiotic). The modRNA expresses a protein of interest until TMP is experimentally added to the cells, at which point TMP interacts with its corresponding element in the modRNA to stop expression. Thus, the group had created an engineered “OFF” switch circuit. In a similar fashion, the team developed a small-molecule controlled “ON” switch then built on the idea to develop a “two output” switch, allowing for the regulation of two proteins in a single system. This could be used, for example, to induce the short expression of protein A, then turn it off as you turn on the expression of protein B for a longer duration. These same switches were then applied to replicons which are RNA enabled with a self-replicating function, allowing for prolonged, “switch”-controlled protein expression.

This work culminated in a 2018 publication in Nature Chemical Biology. Shortly thereafter, Strand Therapeutics took form, built around a philosophy of engineering-based problem solving in the space of mRNA therapeutic applications. Early on, Strand zeroed in on immune-oncology applications. Jake and co-founders recognized a valuable potential in developing tunable mRNA therapies to target solid-tumors. In January 2021, Strand entered a partnership with Beigene to develop the solid tumor therapies and the group now plans to begin human clinical trials of its first candidate in 2023.

Key Insights

1. Minding the Gap

The Gap: Early in Strand’s development, Jake and his team were following the immuno-oncology (I-O) space closely and thinking about how mRNA fits into the picture. A major approach to I-O is based on the delivery of specific cytokine cocktails to solid-tumors in the hopes of creating an appropriate immune response to clear the tumor. Moderna, a pioneer of mRNA-based approaches to protein delivery, was running up against challenges in duration and specificity.

“We realized: this is what everyone’s trying to do. We can actually do it.”

The Tech: Strand saw a gap between the goal — deliver cytokines to solid tumors — and the means by which people hoped to achieve this goal — durable, controllable, cell-specific cytokine expression. This was a gap which Strand’s programmable mRNA platform was built to bridge. Strand anchored onto cytokine-based solid-tumor therapy as their launching point, recognizing as Jake says, “This is what everyone’s trying to do, we can actually do it.”

The Talk: As the team started identifying their direction, Jake emphasized the importance of talking about it. He worked quickly to meet with as many people as possible early on who could serve as advisors, mentors, advocates, and partners in helping shape a company strategy. He thinks about the process of forming the early company strategy in the frame of, “What the technology can do today. What you want it to do in the near future, and what steps you need to take.” Jake cites his experiences in these early conversations as one of his motivations for paying it forward himself. Jake is an advisor to early-career scientists and entrepreneurs through his involvement with Nucleate.

2. Making the Point

Version 1: Jake is not shy to admit that the first version of Strand’s investor pitch deck was…rough. Jake describes how easy it is to forget that while you are embedded in your world and driven by an intrinsic knowledge and sense of the vision you have for your technology, investors are seeing this for the first time and need to be effectively brought into your world. Strand’s early pitch leaned heavily on data and scientific/mechanistic theory.

“Get [investors] to think ‘big if true,’ and then spend the next weeks figuring out if they believe it’s true and if you’re the right person to bring that truth forward.”

Version 100: Eventually, Jake and team got to a point where they led the pitch with a call to the company vision: realizing the full potential of mRNA as a therapeutic modality beyond vaccines. Jake urges that the goal of the first pitch to a new investor is to “get them to think ‘big if true’ and then spend the next weeks figuring out if they believe it’s true and if you’re the right person to bring that truth forward.” Staying resilient through rejection and refining your pitch as you go are critical to success.

Version Time Travel: If he could do it over again, Jake says he would have used data slide real estate in his early pitches to demonstrate that some of Strand’s future milestones are de-risked. This is something that was incorporated later in the fundraise as they acquired early response-rate data, but Jake says these pieces could have strengthened the pitch sooner.

3. Engineering the Solution

Where to Take Risk: In defining a clinical indication and business strategy, Strand leaned on a central philosophy of engineering-led problem solving. They understood that their strength is in the programmable mRNA platform. So instead of innovating on a novel biological target, they aimed for a target that was previously robustly validated. This allowed the team to leverage their strengths and focus on developing the platform tools rather than validating new biology.

A Tiered Approach: Strand is currently focused on building out the solid tumor targeting mRNA platform. By choosing a specific indication, Strand is concentrating its early limited bandwidth on a previously validated target and putting the burden of problem-solving on the manufacturing, formulation, delivery, and mRNA programming end. These solutions will serve to entice investors in the near term while proving out and stress testing the system within a constrained biological context. The next tier in Strand’s approach will see them pivoting their technology to other cell types. For example, instead of turning tumors into protein-producing factories, they will deliver their mRNA to T cells for in vivo chimeric antigen receptor (CAR-T) applications.

4. Leading the Company

Chief “Liaison” Officer: As Jake stepped into the CEO role, he shifted his frame of mind from a “scientist” phenotype to a “liaison” phenotype. Jake now sees his role as, “a liaison between capital market and capital expenditure.” He projects research ideas to the capital market, gathers feedback, then carefully uses the feedback to inform the team’s direction. Jake sees this process of navigating, negotiating, and communicating as a critical set of skills that any successful CEO should be constantly growing into.

Milestone Driven Teams: One of Jake’s early moves as “liaison” was to hire himself out of the science, to help him focus on thinking about the company strategy from a broader vantage point. To make early hiring choices the co-founders worked backwards from specific milestones to figure out which processes and areas of expertise would need to be built out first — immuno-oncology and manufacturing. Jake specifically looked for people who he saw as being better and smarter than himself which makes for a team that Jake readily trusts and does his best to provide with resources and liaising support.

5. Building the Future

Manufacturing: One of the challenges facing mRNA manufacturing is the length of the mRNA strand. The manufacturing process can result in mRNA products which are not the full-length desired product. The longer the desired strand, the harder to produce a high percentage of full-length products. Currently, Strand is relying on CDMOs to manufacture GMP-grade mRNA but they eventually plan to bring manufacturing in-house. Strand sees the manufacturing process itself as another engineering problem which they are poised to resolve and are incentivized to tailor to their particular mRNA platform.

Tissue-Specificity: Strand aims to be an industry-defining company. To them this means, in the next 10 years, mastering the ability to express mRNA across any tissue in the body with high specificity. In the next 20 years, they look to completely master the challenge of immunogenicity and extend the duration of mRNA expression.

Learn more

Thank you to all who participated in this vibrant discussion! To dig deeper into the details, check out the full recording of this Insights session.

To participate in a future session of Insights, please apply here:

Wagner, T.E., Becraft, J.R., Bodner, K. et al. Small-molecule-based regulation of RNA-delivered circuits in mammalian cells. Nat Chem Biol 14, 1043–1050 (2018). https://doi.org/10.1038/s41589-018-0146-9

Author

Jessica Roginsky is a PhD student in the lab of Dr. Susan Kaech at the Salk Institute / UCSD, where she studies immune cell interactions in the brain and its barriers.

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Ackowledgements

About Nucleate
Nucleate is a nonprofit organization dedicated to empowering the next generation of biotech leaders, with chapters spanning 10 regions and participation from over 70 academic institutions. Nucleate identifies future biotech entrepreneurs, removes barriers, and helps founders concentrate on building transformational technologies.

Nucleate’s programs are made possible thanks to our generous sponsors: (platinum) Alnylam, Genentech, Pillar; (gold) Alexandria LaunchLabs, Benchling, Emerald Cloud Labs, Morrison & Foerster; (silver) Latch Bio, Watershed; and philanthropic support from Schmidt Futures. Visit www.nucleate.xyz for our regional sponsors and more information.

About Strand Therapeutics
Strand Therapeutics is an emerging biopharmaceutical company applying synthetic biology to RNA therapeutics and developing the first platform for the creation of programmable, long-acting mRNA drugs capable of delivering precise, multi-functional, potentially curative treatments with a single dose.

Co-founded by world-leading mRNA researchers from the MIT Synthetic Biology Center, Strand’s technology potentially has broad applicability across a spectrum of diseases. The company will initially focus on the development of mRNA therapies that act through multiple immune mediated mechanisms to deliver potentially curative treatments in oncology. In solid tumors, Strand’s mRNA approach has the potential to significantly improve response rates to checkpoint inhibitor therapy. In hematological tumors, Strand’s early work may have the potential to revolutionize CAR-T therapy.

Jacob Becraft, PhD is a synthetic biologist and entrepreneur. He is the co-founder and CEO of Strand Therapeutics, and serves on its Board of Directors. Together with colleagues at MIT’s renowned Synthetic Biology Center, he led the development of the world’s first synthetic biology programming language for mRNA. Jake has been featured in Fierce Biotech, Bloomberg, the Boston Business Journal, and BioCentury, among others, for his vision and mission at Strand of applying this unique platform for real world disease applications. He has also been the recipient of prestigious national and international awards for his scientific and entrepreneurial achievements, including the Barry Goldwater Scholarship and Excellence in Education Award, the Andrew Viterbi Fellowship of MIT, Amgen Fellowship, and the Bristol-Myers Squibb 2018 Golden Ticket for recognition of Strand as an innovative startup. Beyond his work at Strand, Jake’s broader interests span synthetic biology, biologically engineered organism-machine interfaces, and the intersection of tech and biotech methodologies. He is an advocate among the life science entrepreneurial ecosystem for supporting young founders in biotech entrepreneurship. Currently, he serves on the advisory board of Starlight Ventures, an early stage venture firm, and also serves on the Executive Board of Public Health United, a non-profit focused on helping scientists better communicate their research for maximum impact. Previously, he served as a Science and Technology advisor to legislators in the Massachusetts State Legislature. Jake received his Ph.D. in Biological Engineering and Synthetic Biology from MIT and his B.S. in Chemical and Biomolecular Engineering from the University of Illinois at Urbana-Champaign, graduating Magna cum Laude with distinction. He is an author or inventor on numerous high profile publications, patents and white papers, including in top tier journals such as Nature Chemical Biology and PNAS.