The Humans of the Wyss (HOW) series features members of the Wyss community discussing their work, the influences that shape them as scientists, and their collaborations at the Wyss Institute and beyond.
When Denitsa Milanova was an engineering graduate student at Stanford University, she started taking business classes on the side to learn more about herself and her interests. She ended up with a business degree in entrepreneurship and a passion for translational high-risk, high-impact science. Now, at the Wyss Institute, she’s applying those skills to the MRBL Institute Project – a next-generation gene therapy platform for treating skin diseases and rejuvenating the skin. Learn more about Denitsa and her work in this month’s Humans of the Wyss.
What project are you working on?
I’m working on an Institute Project called MRBL, which essentially enables in situ genetic engineering of the skin. It’s a platform technology and has a variety of applications. We started the project looking at the hardest problem – how to solve skin aging at the molecular level. Our gene-potentiating technology could make skin cells go back to their younger state, causing a true rejuvenating effect, and we’re trying to get there by modifying the levels of the right fingerprint of genes in the skin.
This technology can also be applied to monogenetic skin diseases, which are diseases that are controlled by the malfunction of a single gene. These conditions manifest in phenotypes like blistering skin and numerous open wounds. With MRBL we are creating novel therapeutics that can correct the levels of such dysfunctional genes or even permanently correct mutations causing injured skin using a skin cell-specific, minimally invasive, adenovirus-associated (AAV)-based gene delivery system.
Beyond that, we are using the same technology to try and leverage the skin as a bioreactor for the production of neutralizing antibodies directly in the body that could help fight HIV, COVID-19 or other infectious diseases. In these instances, the skin is not being treated because it is sick or aging, but instead used as a “factory” to produce therapeutic antibodies or even foreign proteins that stimulate the immune system in a protective way.
What real-world problem does this solve?
I’d say skin aging is the biggest one. Beyond appearance, there are numerous health conditions that start later in life. Fixing the molecular dysfunctions associated with older age is the best way to cure the root cause of, delay, and even completely prevent such dysfunctions. Examples include melanomas, other skin cancers, and wounds that don’t heal.
Further, monogenetic skin diseases are very nasty and deadly conditions. Often children who suffer from these disorders spend their whole lives with most of their bodies wrapped in bandages. It’s extremely painful. Right now, there’s no cure. MRBL could provide relief, help them feel less pain, and permanently decrease the number of wounds on their skin. This would be life changing. I’m really excited about the impact on that population.
Though it’s further in the future, if we are able to apply MRBL as an immunoprophylaxis and vaccine delivery tool for COVID-19 and other viruses, that would also be very interesting. Because we deliver our therapy topically, co-formulated in polymers, we are able to bypass the need for refrigeration. This thermal stability feature of our technology opens avenues to applications in remote areas and developing countries.
What inspired you begin working on this project?
I come from a diverse technical background. I started in math, physics, and computational science in high school. I used to go to science competitions, called Olympiads. I loved it – I believe that skillset shaped the way I think and solve problems, the way I connect dots and pull knowledge from multiple disciplines. Even then, I was always drawn to applied science. In college, I started doing research in nanotechnology, and I worked with nanomaterials such as nanoparticle and carbon nanotubes. Then I transitioned to engineering at the cross-section of technology and biology, and in graduate school I focused on developing approaches for new analytical tool of biological molecules, more specifically, utilizing microfluidics, applied to single cell sequencing. My Ph.D. is in mechanical engineering and genetics. I also have some exposure to aerospace engineering – I was part of the Stanford Space Initiative and am certified for high-power rocket launching. Interestingly, I met George Church through that interest, at a space event held on Sand Hill Road in the Bay Area, and shortly after I joined his lab.
When I started working in George’s lab, I became even more passionate about aging and rejuvenation, so I knew that was the scientific problem that I wanted to tackle. Marrying the biology of aging and technology of genetic engineering was very exciting for me. At that time, I sat next to Noah Davidsohn, who co-founded Rejuvenate Bio, a Wyss startup that is focused on aging reversal in dogs. Conversations with George, Noah, and other members of the lab got me thinking about what tools for genetic manipulation are best suited for skin, those with the highest efficiency and safest profile. Thinking about the efficiencies of delivery lead me to explore research out of MIT and specifically Bob Langer’s lab, who I am now collaborating with.
Reversing aging systemically is quite complex. Current approaches involve targets that are blood circulating factors with the idea that multiple organs can get rejuvenated all at once. But there’s so much we don’t know about the aging mechanisms and anything you would apply systemically could have undesired effects, as it could be good for certain organs but bad for others. So, an easier route would be to start with a single tissue type, which led me to the skin. Focusing on aging reversal in skin instead of the whole body is much safer. Also, the results are easily visible, whereas with systemic aging reversal you have to look at more complex biomarkers to determine your success. This is especially important for the clinical development of rejuvenation therapies, since defining your endpoints in skin is easier than relying on surrogate endpoints for other organs. Overall, treating skin seemed like a more manageable challenge, but still really excited me.
What continues to excite and motivate you?
One thing that keeps me motivated is the potential to translate my work into real therapeutics that people can use and adopt. This is why the Wyss was a perfect fit for me – it’s a great place to do translational research and de-risk technologies. The marriage of technology and commercial applications is extremely exciting and thinking about the patient is always inspiring.
I’m enthusiastic about having the opportunity here to tackle real-world problems and potentially find solutions that have a great impact. What’s also really exciting is the people. Working on difficult problems is always challenging, and it’s never a one-player game. Finding the right team is important. Finding that right fit – people who have complementary skillsets and similar goals – it’s amazing. I feel very fortunate to have David Thompson and Ski Krieger on my team. They bring their extraordinary drive, expertise, and personalities to the project. Doing new science, solving important problems, and working with the smartest people is awesome. It is very stimulating and never gets boring.
What are some of the challenges you face?
On a personal level, the most difficult thing that I am facing is not having all of the dimensions of my expertise recognized. Breadth of technical knowledge fosters unique thinking which I feel is at the core of all innovation. I believe diversity in thinking and diversity in technical background are extremely valuable and important.
Separately, professionally as a scientist, I think the most difficult thing is the length of time it takes to get research done. It’s a long process, so it is important to be genuinely passionate about your work and to stay curious. Many different challenges come up along the way, from technical to financial, but you have to be persistent and push through.
How have your previous experiences shaped your approach to your work today?
While I was pursuing my Ph.D. at Stanford, I ended up getting a business degree. I was interested in learning about myself and understanding whether I preferred translational research to fundamental research. I discovered that I loved applied science more, and I learned how to think about technology translation, which has really helped me with my own work. It influences what projects excite me, and once I start, it influences how I structure the research.
I discovered that I loved applied science more, and I learned how to think about technology translation, which has really helped me with my own work. It influences what projects excite me, and once I start, it influences how I structure the research.
Living in Silicon Valley during graduate school, I met a lot of people with an entrepreneurial spirit that considerably shaped what I wanted to do and how I saw my future. Coming to Boston, I found this same mindset of pushing through challenges and thinking outside of the box, but it was paired with a stronger focus on medicine and healthcare. There is a whole ecosystem of hospitals, research institutions, and biotechnology companies. Being able to channel that way of thinking I first came across in California here in Boston has allowed me to actually develop super interesting science with very cool applications and find people with the expertise to support me in my ambitions.
What attracted you to the Wyss Institute?
When I initially met with George Church, he told me about the Wyss Institute and what it was all about. I was immediately intrigued by the fact that you could focus on both research and entrepreneurship at the same time. I liked the idea that I could be in control of my research and think about exactly what milestones I’d have to hit to successfully translate it. Given my background, I knew that working on a project that will turn into a company is different than fundamental research. You’re not just thinking about publications, but also patents and how to protect your technology legally. At the Wyss, there is an interdisciplinary team of people that act as a centralized support system to scientific development. It’s this unique environment with a defined and clear model for taking top science and commercializing it so you can have a real-world impact.
At the Wyss, there is an interdisciplinary team of people that act as a centralized support system to scientific development. It’s this unique environment with a defined and clear model for taking top science and commercializing it so you can have a real-world impact.
MRBL is an Institute Project. How has that helped you towards your translation goals?
Of course, the obvious answer is that you have more resources and can scale experimental work faster, which is true. But I would say the other benefits are also really important. Being an Institute Project has forced us to think about how to best package the technology. As an Institute Project, you have a lot of people working with you, questioning what you want to do, how you want to do it, and why you want to do it. Since our technology has so many potential applications, answering these questions has helped us to prioritize the most important and immediate ones. Thinking about indications, pipeline, and how to sequentially reduce technical and biological risks while at the same time optimize for building the highest value is critical. We also have access to external feedback from people with a variety of backgrounds, which is extremely helpful. Generally, hearing what all these experts have to say has refined our thinking in ways that will help us as we move towards translating our technology. Asking questions is very important. Asking the right people questions is even more important. Our team has focused on reaching out to visionary leaders, both in industry and venture capital, who support risky, outside-of-the-box science.
Thinking about indications, pipeline, and how to sequentially reduce technical and biological risks while at the same time optimize for building the highest value is critical. Hearing what all these experts have to say has refined our thinking in ways that will help us as we move towards translating our technology.
If you had to choose an entirely different career path, what would it be?
It would probably be something related to design or art. I’m very visual and like drawing. Before going into engineering, I even considered studying architecture.
What does it feel like to be working on cutting-edge technology that has the potential to have a real and significant impact on people’s lives and society?
I feel very grateful. I think people, including myself, often focus on the future and what comes next because they are ambitious and constantly want to do more and do better. In some ways, that’s a good thing, because it contributes to success. At the same time, I think it’s important to appreciate what we have in the moment.
I was not born in the United States. I did not go to high school in this country. So, the fact that I came here, got my degrees here, and now work at Harvard with someone like George in an up-and-coming field that I really enjoy is amazing. I feel fortunate to have met George at the right time and found out about the Wyss. I love what I do. The possibility that my work could have a big real-world impact makes it even better. I’m incredibly thankful and appreciative.