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Thought Leadership Articles

November 28, 2023

A conversation with Phillip Sharp: Reflections on Dewpoint’s 5th anniversary

For our 5th anniversary, we took the opportunity to interview a few leading voices in the field of science and biotech to hear their reflections on Dewpoint’s journey so far and their aspirations for our next five years. Today, we spoke with Dr. Phillip Sharp, the chair of our Scientific Advisory Board, who was one of Dewpoint’s Therapeutics’ founders in 2018.

Dr. Sharp was awarded the 1993 Nobel Prize in Physiology or Medicine, together with Dr. Richard J. Roberts for “the discovery that genes in eukaryotes are not contiguous strings but contain introns, and that the splicing of messenger RNA to delete those introns can occur in different ways, yielding different proteins from the same DNA sequence”. His current research focuses on small RNAs and other types of non-coding RNAs. Phillip Sharp is currently the MIT Professor of Biology Emeritus and member of the Koch Institute, and was an Institute Professor since 1999. Prof Sharp co-founded Biogen and Alnylam Pharmaceuticals, and has served on the boards of these companies.

What are you most curious about with the science of condensates and how does it relate to your work on micro-RNA?

I have throughout my career in biology and cell biology in particular, tried to pay attention to what I consider breakthrough discontinuities in science. When I see something that rewrites the fundamental mechanisms by which we understand cells, I pay attention and I try to understand how I can use that concept to explain my own unanswered questions. When I saw Tony Hyman’s work in 2009 on liquid-liquid phase transitions, I started to think about the polymer type of physics of those processes. I was convinced that it was something that could explain phenomena related to gene expression and how gene expression became abnormal both in cancer and in genetic diseases.

With my colleagues Arup Chakraborty and Rick Young, we discussed how it could explain the association of a group of enhancers within a given promoter. Rick had already described this phenomenon in his research on transcription at enhancer sites. Those super enhancers are incredibly important as they drive the activity of specific cells.

The idea that a condensate would form and direct or drive the expression of the gene was so appealing and so explicative of many phenomena that we didn’t understand! We had to study that possibility, looking at the physics, the cell biology and the disease relatedness of the process. That became very exciting! Actually, it’s a new paradigm in cell biology.

Originally, we could see this new paradigm through light microscopy and by using historical type resolution in the nucleolus. But now we can see transient processes below the limit of diffraction, which has allowed us to more fully understand very important processes from transcription to RNA splicing to stress granules to synapses. So really, it’s a fundamental new way of looking at cell biology and looking at diseases that are related to these processes.

What is your perspective on the progress that Dewpoint has made so far? How did the work from this biotech contribute to better understanding the role of condensates?

To my knowledge the whole field was really stimulated by Tony Hyman’s work in 2009. It was based on a very abstract observation that these membraneless bodies in the cell have liquid properties and are very sensitive to perturbations as they are formed by phase transitions. We probably started working on this at MIT in mid-2016 and my colleagues and I theorized what we thought were important parameters to understand.

Then, in 2018, Dewpoint was formed by a brilliant group of young scientists who were just as excited as us by this new scientific paradigm. Their goal was really to change the way we understand condensates and understand disease processes specifically related to condensates. They have expertly taken this cell biology concept to a new level of understanding by exploring the diverse processes associated with condensates and relating them to specific genetic diseases. They have begun to develop ways of screening for drugs that could have an impact on those processes.

All of this opens a new window to understand exactly how condensates control the disease process. It’s a new territory. It has its own pharmaceutical challenges, but those are rapidly beginning to be overcome and we are getting closer to moving into patients. It’s only when we move into the clinic that we will really know how impactful this new approach will be, and for that we will need to wait a few more years.

Do you consider we have passed the point where condensates are just an exciting biological curiosity for scientists and are now showing true potential for drug discovery?

People understand that there are condensate subcellular membraneless bodies in cells. The fact that these membrane bodies can have liquid properties and can be dynamic is now commonly accepted.

But the scientific journey does not stop here. Now we need to demonstrate that drugging condensates can be a way of attacking the critical process of a disease or that drugs can have an impact on condensate formation and stability.

That’s why Dewpoint is pursuing a platform breakthrough approach. Dewpoint is driving this field in a unique way in the biotech community as far as I’m aware. It looks very promising. That’s what’s exciting!

Where do you see the opportunities?

There is very promising data that indicates that processes related to condensates can be controlled by small molecule drugs and can have an impact in cardiology for instance. It looks like they could also be impactful in neurological issues where certain cells seem to be, in certain times and conditions, dysregulated relative to condensate formation and biology. So the frontier of the condensate approach is very broad. It can go all the way from leukemia to neuroscience, cardiology and other diseases.

The fact that Dewpoint is opening that door and making tremendous progress -I would say surprising progress- that’s what I find so exciting about the company. In a short period of time, it’s taken a new concept and has shown –although not yet in patients- highly promising approaches to treating critical diseases.

As the co-founder of two successful biotechs – Biogen and Alnylam Pharmaceuticals, what general lessons would you apply to Dewpoint?

I was a co-founder of Biogen. It was a moment in time in which recombinant DNA had just been discovered and practiced in academic labs. The challenge was: how to create private sector activities that would take this technology and create new therapeutics that could be highly impactful for patients? It took us seven years to get to the first stage where a product produced by Biogen was impactful in hairy cell leukemia.

We formed Alnylam in 2002, based on the fundamental discovery made in 1998 that small RNAs are active in cells and they can silence genes. It took us until 2018 to get the first approval for a drug -about 16 years.

Dewpoint is pushing the boundary of a whole new discovery made public in 2009, into biology, into drug development and it’s making enormous progress. I’m very optimistic that it will be highly successful and I anticipate over the next five years we will have demonstrated a beneficial impact on patients. That would be extraordinary!

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Michael Fenn, PH.D.
Head of External Innovation
Dewpoint Therapeutics
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