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Alex Plesa on Reversing Aging

The Humans of the Wyss (HOW) series features members of the Wyss community discussing their work, the influences that shape them as professionals, and their collaborations at the Wyss Institute and beyond. 

Alex Plesa on Reversing Aging
Alex Plesa, Postdoctoral Fellow. Credit: Wyss Institute at Harvard University

Most people believe that declining health as we age is an unfortunate, inevitable fact of life – but not Alex Plesa. He thinks the reason we think we can’t change it is because we don’t understand it. After being exposed to the field of aging research and watching elderly members of his family seem to wither away over time, he’s leading the Ichor Project at the Wyss, trying to figure out why cells become more dysfunctional with age and how we can reverse that. Learn more about Alex and his work in this month’s Humans of the Wyss.

What are you working on? 

As a person ages, a lot of aspects of their health go downhill. One reason for this is that certain cell types become more dysfunctional with age. My work centers around figuring out why that happens and how we can reverse it.  

I’m leading the Ichor Project, a Validation Project that uses high-throughput genetic screening to find networks of genes that are most implicated in aging and develop RNA-based therapies to make these old cells act young again.  

The first step is to understand how the cells change. To do this, we take cells from people of varying ages or disease states and measure multiple parameters to determine the differences between them. Instead of focusing on one general disease pathway, we try to integrate all of the measurements and analyze them to see which part of the cell network is changing. Then, we use artificial intelligence (AI) and machine learning (ML) algorithms to determine whether the networks would more closely resemble younger or healthier ones if we tweaked certain nodes in the network, meaning if we modified certain genetic targets. Next, we test these hypotheses in the lab using cell culture in a dish, and then in preclinical disease models.  

What real-world problem does this solve? 

The real-world problem is elderly people suffering from chronic diseases. Though aging itself is not a disease, we’re going after illnesses that are influenced by age. These diseases are often caused by accumulating damage or injury throughout a person’s life, so they do not appear in young people.  

Alex Plesa on Reversing Aging
Alex presented on the Ichor Project at the 2023 Wyss Retreat. Credit: Wyss Institute at Harvard University

The damage might start on a molecular level inside of a cell, like misfolded proteins, but that can lead to cellular damage, like impaired autophagy, which leads to damaged tissues, which leads to organ damage, such as liver dysfunction. 

Right now, our lead program is in fibrotic diseases. Fibrosis, or the conversion of functional tissue to scar tissue, is a hallmark of many diseases whose prevalence increases with aging, like fatty liver disease, chronic kidney disease, and pulmonary fibrosis. Current treatments can slow or stop this process, but cannot revert scar tissue back to functional tissue. We hope to show that our platform can turn back the clock on this process and restore organ function.  

We’re also continuing our discovery work in hematopoietic stem cells, or HSCs, which are the stem cells that make all blood cells. As we age, these cells lose their self-renewal capacity and develop a differentiation imbalance, giving us fewer lymphoid cells and more myeloid cells. Lymphoid cells are responsible for adaptive immunity. Examples include B cells, white blood cells that make antibodies, and T cells, white blood cells that help the immune system by fighting germs to protect our bodies from infections. Myeloid cells are involved in innate immunity, but they can drive inflammation of the whole body.  

What inspired you to get into this field? 

I was always interested in science growing up. Initially, I thought about going to medical school, but then I realized I am more interested in research, discovering new things, and seeing how the body works.  

People normalize aging and believe we cannot do anything to change it, but I came to realize that’s only because we don’t understand it.

Alex Plesa

At some point when I was in college, I saw some TED Talks and did some reading about aging research. I realized it’s an understudied area. People normalize aging and believe we cannot do anything to change it, but I came to realize that’s only because we don’t understand it. Plus, it’s becoming even more of a problem as our population gets older and older. There was this intellectual curiosity aspect that drew me in. 

There’s also the more personal angle, because I’ve seen some members of my family age and pass away. It’s sad to see how people who used to be perfectly fine and functional become a different version of themselves and eventually seem to wither away. When you see that progression, it inspires you to want to change it.  

What continues to motivate you? 

First, the sizable need is still there, and it’s growing. Many demographic projections show that the aging population is soon going to double. This leads to more suffering. Second, we’ve made progress, and there have been some breakthroughs on how we can address aging. More people are getting involved in the field. It gives me hope that this is something we can understand, and then tackle, in the coming decades.  

I like knowing that at some point, this is building towards impacting someone’s life in a beneficial way. That excitement is high enough to make up for any setbacks along the way.

Alex Plesa

What excites you the most about your work? 

Seeing the impact on people. We’re slowly transitioning from more basic biology at the bench to preclinical development, focusing on specific diseases. It’s exciting that at some point, this could one day lead to a therapeutic that makes patients healthier and improves their quality of life.  

What are some of the challenges that you face? 

As we enter this new preclinical phase, transitioning from target identification to therapeutic development, it’s something I’m not accustomed to that requires a different skillset and knowledge base. So, that comes with its own challenges, but it’s also exciting.  

Aging is also a multifactor problem. We’re trying to break it down by looking at specific cells and specific diseases to give us a better understanding, but we still don’t have all the pieces.   

And, because aging is understudied, the path to regulatory approval by the FDA is not clearly laid out. That’s why we’re going after specific chronic diseases, but we hope that eventually we won’t have to wait for people to get sick to be able to use these therapies, but we could use them in a preventative manner.  

Why did you want to work at the Wyss? 

During my initial rotation in George Church’s lab, I was mentored by Noah Davidsohn, and he was working at the Wyss. Once I got here, I realized the Wyss has a lot of resources and is more focused on translating the research into real-world applications, not just publishing papers. Though I had decided not pursue medicine, I was still driven by the idea of helping people and improving their health. When I chose to do research, it was partially because I realized it could be more impactful to work on something that can help an even greater number of people than a single clinician treating individual patients. I want to see my work go into the clinic, so this environment was a great fit.    

What is unique about the Wyss and how has that impacted your work? 

No other place that I know of or worked at has the same opportunities to translate your research into something that will make a real impact. The people and resources at the Wyss are what makes that possible. There’s a lot of knowledge here, not only about how to do basic research, but also how to develop drugs, how to do experiments to bring you closer to the clinic, and what makes most sense from a commercialization standpoint.  

No other place that I know of or worked at has the same opportunities to translate your research into something that will make a real impact.

Alex Plesa

If there isn’t an expert under our roof, the Wyss creates the chance for exposure to more professionals. For example, at a Wyss Diagnostics Grand Rounds event, I met the Director of Hepatology at Brigham and Women’s Hospital, Steven Zucker. I got to chat with him about what their patients need and how we can think more strategically about where to apply our technology next. My colleagues generously connect each other with mentors in their networks with biotech experience. I’ve also met some Lumineers who have shared their journey of spinning out a company from the Wyss, giving me insights on what to do next and how to plan.  

How do you collaborate with and/or receive support from teams across the Wyss Institute? 

Alex Plesa on Reversing Aging
Alex and other members of George Church’s lab at the 2022 Wyss Retreat. He’s enjoyed the opportunities to learn from and collaborate with researchers from across the Institute. Credit: Wyss Institute at Harvard University

The Wyss is a collaborative, interdisciplinary environment. With all of these people under one roof, there are many chances to meet and spark a collaboration. For example, I serendipitously met David Chou at a Wyss social event. We started talking about what we were working on. It was incredibly helpful because once I finished my Ph.D., I switched from working with fibroblasts to working with blood cells, and he was a great resource. The same thing happened with Bogdan Budnik. When I met him, he told me he worked on proteomics, and I explained that I was interested. We did a small pilot and it looked good, so we’re furthering our collaboration.  

The Business Development Team has been great in figuring out what disease to apply the technology to and how to go about eventually spinning this out into a company. Bill Bedell from that team introduced me to Russell Gould, who does computational biology. Now we’re working together, and he’s been instrumental in developing our AI/ML algorithms to advance our discovery platform. The Veterinary Team helped me design and conduct some crucial in vivo experiments. Working with people in other areas of the Wyss has been really enriching and given me a broader, more comprehensive view of what it takes to turn basic research into a life-changing therapy. 

How have your previous work and personal experiences shaped your approach to your work today? 

My Ph.D. experience was interesting because it was pretty hands-off. I went through a few mentors, since Noah left to form Rejuvenate Bio, and did a lot of work independently. I realized there were a lot of gaps in my own experience and knowledge, so I started reaching out to people and setting up collaborations. I think this was important in shaping me as a self-sufficient researcher who is also able to bring different people together from across disciplines to work on the same goal.  

During my Ph.D., a lot of the initial experiments failed. But eventually, things started working. I realized that with enough creativity and determination, even if a problem doesn’t seem solvable, you can figure it out. It gave me the confidence and motivation to persevere. 

When you’re not in the lab, how do you like to spend your time? 

Alex Plesa on Reversing Aging
Alex and other members of the Synthetic Biology Platform had a fun team-building outing at a rock climbing gym back in 2019. Credit: Wyss Institute at Harvard University

My main hobby is rock climbing, primarily bouldering. I also like electronic music, so every now and then I’ll go to electronic music shows. When the weather allows, I enjoy hiking too.  

What’s something unique about you that someone wouldn’t know from your resume? 

I’m an amateur DJ. I’ve been into it since college and play music at different parties, or even my friends’ weddings.  

If you had to choose an entirely different career path, what would it be? 

In college I also considered studying computer science, bridging the gap between AI and consciousness. What does it mean to have intelligence or to be conscious? Or maybe I would study theoretical physics. What are the governing laws of our universe or the fabric of reality?    

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? 

It’s exciting! It’s what drives me every day. A lot of times, progress is slow, but the fact that I can pinpoint that I’m still working towards this goal is what keeps me going. I like knowing that at some point, this is building towards impacting someone’s life in a beneficial way. That excitement is high enough to make up for any setbacks along the way.

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