• December 1, 2022

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In my previous articles, I covered the wonderful female medical doctors working in longevity medicine, female reproductive longevity and inequality, skincare, and other areas. Here, we continue on this journey and look at the stellar scientist and entrepreneur, Dr. Denitsa Milanova. I heard about Dr. Milanova a few years back when she just joined Harvard, and met her for the first time in person in May 2022 when she told me about her new exciting venture – Marble Therapeutics and her quest to use genetic engineering to target aging.

Denitsa was born in Bulgaria to a family of engineers. As a child, she excelled at analytical disciplines, and especially in math and physics. She learned at a young age that exceptional results can be achieved with hard work and perseverance. In school, she participated in science competitions routinely winning top places. For college, she moved to Florida, and then continued her graduate studies at Stanford University where she earned her master’s and doctorate degrees in mechanical engineering and completed a business degree. Her studies were focused on microfluidics and she pursued research in single-cell sequencing using microfluidic technologies with prominent scientists including Michael Snyder. For her postdoctoral training, she moved to Harvard Medical School and Wyss Institute to work with George Church and soon focused on aging research.

Milanova tells me that this is simply the perfect time to build a rejuvenation company with new tools and large amounts of human data. “We are doing great things in molecular biology,” she says. But from her perspective, scientists are too focused on accumulating experimental evidence – hugely important – but when a field is starting to mature, we need to ask larger questions beyond “what is there?” but more “how can we manipulate it?” We need to shift from “knowledge-based” to “inquiry-based” frameworks, focusing on the complexities and stabilities of aging systems, and how they evolved to be a certain way.

Milanova and her team spend a lot of time on the “why” questions. “This is the data but why does it look like that? We want to think from first principles”, she explains. Drug development is expensive and betting on the wrong targets can be detrimental to companies. Identifying the right drivers amidst a sea of passengers, and spurious events is very hard. “We are building algorithms that probe tipping points, thresholds and breakpoints, regime shifts. Going after those genetic perturbations that lead to the largest changes of aging states,” she continues.

While Marble is still more or less in stealth mode without a public website, word had gotten around over the last year through top biotechnology and longevity investors that George Church’s lab was cooking up a secretive rejuvenation startup. Now known as Marble, led by his engineer-biotechnologist protégé Dr. Milanova, the effort has garnered considerable inbound attention. Denitsa says that her team is developing methods to drive rejuvenation of skin cells with gene therapy and is working on a product that could reverse wrinkles like a genetic Botox.

The magic words in longevity biotech nowadays are platform and pipeline, where the company develops a platform for drug discovery and is using this platform to discover and develop its own therapeutic programs. And Marble is building target discovery and delivery platforms to drive its first pipeline program in the skin. To search for such powerful genes, they use computational methods taken from the study of non-linear dynamics and complex systems. The sort of things which can infer causality in other fields like ecology and finance. And they are attempting to predict the effects of changes in gene expression over time and thereby identifying key driving events and genes of aging.

The Marble team is taking an unbiased approach, agnostic to biological mechanism, and instead search the entire genome for those genes and proteins responsible for large, global shifts in the biology of cells as they transition from young to old. “The aging field has leaned too heavily on hypothesis-driven approaches which insist that specific pathways must be involved in longevity and age-associated molecular mechanisms”. These things do not necessarily tell us how a cell becomes old, or how to make it young,” Milanova points out. The precise details of Marble’s approach are being kept a secret, but Milanova has assembled an all-star team led by chairman Matt Rabinowitz (the man behind Natera) and an acclaimed scientific board that includes George Church, Michael Snyder, Carl June, Bob Langer, George Sugihara, Yoav Freund. Rabinowitz says, “Aging is the king of all maladies. It remains to be seen how much we can massage our natural mortality, but usually when people place limits on science – and biotech in particular – they are wrong. The approaches Marble is working on to better understand dynamic gene signaling networks and drive those networks with gene therapy are important, would have broad application and are guided by a strong team of scientists.”

While building Marble, Milanova sought the advice of a man who would become one of her early backers, Tony Robbins. Robbins, who has coached presidents, elite athletes, and business leaders on the psychology and mechanics of building organizations, became a mentor and advised her on building the most effective team. “I met Denitsa when she had just assembled an impressive team of experts prior to any funding into the company. People had signed solely based on the science and mission. What stood out to me was her ability to influence, in a very raw, authentic way. To sell the dream equally well to scientists, and business people”, Robbins says. “This quality is crucially important and at the core of exceptional leadership. It is truly amazing to see how much Marble has grown in a short period of time and I am excited to be part of it.”

As one example of how the company is building competitive advantage, Milanova points to the future collection of proprietary human multi-omics data to fuel rejuvenation target discovery. And the company is well positioned to execute on this goal. Not only are two of its founders – Church and Snyder – pioneers in multi-omic technologies, they have also worked for decades to develop primary human data collection initiatives. As Church explains, “Despite 20 million-fold improvement in the cost of reading human genomes, and trillion dollars per year avoidable by testing, the word is spreading slowly – in part because people feel that they are in the lucky 98% (similar to past denialism for cigarettes and seat belts.)” He continues, “We need to know our genome but for most of us, it is not actionable. It is different with aging and epigenetics (broadly defined as all -omes). We all age and likely care about aspects of aging (at least most of us).”

This focus on human data is at the core of Marble. “Our vision is that aging research will become more human data focused. That is, discovery will start with human data first, not hypotheses based on comparative longevity or mechanistic studies between species. We expect that targets best-suited for rejuvenation of specific cells and tissues may not be one-size-fits-all. And it’s hard to identify such targets if we are focused solely on highly conserved master regulators,” explains Milanova.

Marble is starting with skin rejuvenation, but they aren’t trying to be just a skin company. “Think of deep-omic profiling of skin, blood, muscle, even reproductive cells with a time stamp on it,” Milanova says. “Our vision is to have high-quality cross-sectional and longitudinal datasets and all discoveries being data-driven rather than hypothesis-driven,” she continues. “If you think about those tissues, there are some unique and untapped markets to break into, if you had the right technology,” says Milanova. And importantly, they may not have to follow human subjects over years to collect the right data. “The cross-sectional data capability is really where our data analytics could shine. We could potentially cut through the noise of human-to-human variation to find deterministic signals, and likely with hundreds of donors. Not like with GWAS where you need tens of thousands.”

Alex: Denitsa, you have a very impressive resumé with multiple graduate degrees from Stanford, postdoctoral training at one of the top labs at Harvard and consulting engagements with a variety of companies. When did you decide to go into aging research?

Denitsa: Thank you, Alex. I’d say about five years ago when I started working with George Church. Being new to the field helps with bringing in a fresh perspective. George took a chance on me when I had no background in aging research and taught me how to take risks and pursue groundbreaking science. And this is the best way to tackle big problems, starting with the basic science but also being comfortable for things to take time and even failing before succeeding.

From the beginning I had a vision to do gene therapy for skin rejuvenation, and at the time, everyone thought that was a totally crazy idea. The cost of gene therapy then was as high as $2.8 million, but we have seen huge reductions in the cost of similar modalities like mRNA to as low as $2 per dose, largely driven by the market size. Clinical products in the skin have an enormous market (Botox alone is larger than all of cell and gene therapy combined), and true rejuvenation therapies could reach markets larger even than COVID vaccines.

Alex: This is your first venture. Did you think you would be able to raise funding? Do you have any notable investors in your seed round?

Denitsa: I am a big optimist and even a little bit of a dreamer by nature, but I do get anxious about fundraising. I think some fear of failure and a certain level of anxiety actually helps me, it motivates me to deliver. Yes, we were fortunate to attract prominent investors, and even more so to have them mentor and advise. Success leaves clues and learning from experience saves years. I force myself to maintain a “no limitations” mindset, both in science and business. What keeps me highly motivated is the certainty that rejuvenation is fundamentally possible, that we have the tools, and is worth doing – it is one of the biggest problems of our time.

Alex: When are you planning to get to the preclinical proof of concept (POC) in animals and start IND-enabling studies? And if all goes well, when do you think we will be able to see Marble’s products in the clinic? I understand how speculative this is but what is your vision?

Denitsa: It is early to say, we are at the preclinical stage right now. Skin is a very interesting organ clinically and an attractive entry point for newer therapies both in terms of targets and modality. You can test human organ skin grafts in mice to validate function in live human tissue physiology. Clinical trials and endpoints are more defined too because you can have multiple treatment and control locations across the skin, and the accessibility of the skin lets you assess aging phenotypes visually and mechanically to prove effectiveness of your therapy and approach in general.

Alex: What is your long-term vision for the company and for longevity biotechnology in general?

Denitsa: Over the long term we have no shortage of ambition. Skin is the start, because that’s where we could get the right data. But I want all tissues. All ages made functionally young. We are starting with single-gene perturbations, but changes in complex cell states are typically polygenic processes. So we have a plan for moving into multi-gene targets using concepts analogous to those which have powered engineering and evolution of antibodies, enzymes, and protein-based drugs, but applied to whole-cell states. That is where I think the future is. We should be evolving cells in the lab to just be very good at being young. That’s not how our cells have evolved naturally, but it is how we can select them to be. Screening, genetic libraries and evolutionary approaches are central to the world of George Church’s lab, and that mindset has definitely rubbed off on me. We will need to intelligently explore genetic space to really ratchet up young-like cell behaviors.

Alex: And another very personal question. You do not need to answer it if it is too sensitive. I know what it takes to run a startup in the longevity space. It does not get intense from time to time – it is a life at full throttle when there is no time to stop and take a breath. How are you planning to maintain the work-life balance?

“I have no idea what that [work-life balance] is,” she smiles. “But really, this isn’t work to me. It’s not some necessary evil to be balanced. It’s a mission, it’s my life and I love what we are doing,” she continued. “Of course, I do things to keep sane. I love cryotherapy,” another smile.

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