CONDENSATES: A bold vision for the origin and treatment of undruggable diseases — A conversation with Dewpoint CSO Dr. Isaac Klein
How did the discovery of condensates transform our understanding of the cell?
We thought the cell had just a few important compartments, all of which were membrane-bound organelles, like the nucleus and mitochondria. The rest of the cell was thought of as a “bowl of soup,” where biomolecules float around, randomly interacting with one another without much organization or structure.
But the understanding that biomolecules (RNA, DNA and proteins) can phase-separate and thus form dynamic, liquid-like, compartments called condensates, changed the way we think about cell biology. This new understanding showed us that the cell has an entirely unappreciated level of organization and substructure, in which molecules involved in shared processes concentrate into discrete compartments without the benefit of a membrane.
This has broad implications for how the cell works, how biological processes are regulated, how molecules behave and how cellular function goes awry in disease. Things like environmental changes, mutations, expression levels and posttranslational modifications can alter condensate formation and the function of the pathways constrained in that compartment. It explains an awful lot about cellular physiology and pathophysiology that we never really understood all that well. I think that’s a major contribution to cell biology. To put it another way, we discovered a novel physical property of molecules and a novel principle of cellular organization, with all the resulting implications.
What does this discovery mean for drug discovery and specifically for drugging previously undruggable diseases?
There are vast implications for drug discovery. First, it’s pretty hard to discover and develop a drug for a disease without a solid understanding of the mechanisms that drive the specific pathology. There are many diseases for which we simply had no good mechanistic understanding until condensate biology provided the explanation. Now this allows us, for the first time in many cases, to model a disease correctly and develop drugs for those patients in desperate need of better options. The classic case is ALS (Amyotrophic Lateral Sclerosis). It was entirely unclear what caused ALS until our co-founder, Anthony (Tony) Hyman , discovered that ALS occurs because a condensate is aberrantly formed in neurons.
With this understanding we can model the disease more accurately, look for drugs that target the pathogenic mechanism and develop a drug to reverse that abnormality — it has a much greater chance of working for patients. There are many diseases where this science has explained it for the first time, explained how it really works at its core, and this gives the drug discovery community an opportunity to think about developing drugs for truly grievous diseases through a novel and much more accurate lens.
A second important contribution of condensate biology is it has opened new druggable space. Historically, only a few percent of the proteome were considered druggable by traditional means, but ten-times as many proteins, as well as most RNAs, are predicted to participate in condensate formation. Now that we know condensates can be targeted by therapeutics, and phase separation is a modifiable property of biomolecules, we finally have a lever to pull in “drugging the undruggable.” In fact, the same properties that render a protein prone to condensate formation are exactly those properties that govern condensate formation. We believe one can perturb a biological system and modulate a molecule’s ability to condensate and alter its function. Thinking about modulating target function in a completely new way transforms the undruggable to the druggable.
The third contribution of condensate biology is a deeper understanding of mesoscale biology — let me explain. Essentially, condensates are biomolecular communities or intermediate-sized biological systems. The way I think about it, classic drug discovery approaches are broken into two categories: macro-scale and micro-scale.
The micro-scale is, “Here's a kinase that drives this cancer. I’m going to inhibit that kinase so it doesn’t work anymore.” That's a single target approach – there’s one protein that’s driving a disease so if we stop it from working, we can achieve some derived biological effect. That thinking has been successful to some degree, but biological systems and disease are much more nuanced and tend to have more complex etiology than one dysfunctional protein.
A macro-scale view would be, “Let me find a drug that makes neurons look better in a tissue culture dish or broadly improves their function in way.” That’s a very high-level approach that accounts for the complexity of interactions between a biological system and a potential therapy, but leaves a vast gap in the mechanistic understanding of the disease-therapeutic relationship.
But for the first time, I would argue, we're exploring the meso-scale; pathways and molecules that participate in shared processes are constrained in condensates, they are essentially intermediate biological systems. By treating that system as a therapeutic target, we are not reducing the biology to a single molecular entity and we're not abstracting the biology to this extremely high-scale phenotype — rather we’re right in the middle. We're targeting a specific mesoscale biological system, with the potential to have a much more profound and relevant therapeutic effect.
Taken together, that's a new way of thinking about biology, target identification, drug discovery, patient selection, biomarkers, and so on. Every step of the process needs to be revised and updated through this new lens.
Can you expand on how Dewpoint is adapting this approach to therapeutic areas and applying it to specific diseases?
Let me start with Dewpoint’s approach. Dewpoint treats condensates as a newly identified target, an independent substrate for drug discovery, for all the reasons I previously mentioned. How do we do that? The target we're going after is the condensate.
We start with human genetics. We want to make sure that the target we're going after – the condensate — is supported by solid genetic evidence, one of the highest bars for validation. We do this by scouring the landscape of human genetics associated with specific diseases to look for alterations in biomolecules that are predicted to interfere with their ability to form condensates. We can do this because we have developed a sophisticated understanding of the determinants of phase-separation.
What emerges from this process is an in-silico condensate-disease hypothesis. We then validate this experimentally in normal and disease-relevant models, to pin down the specific condensate of interest and the specific dysfunction in the disease state. Once we’ve built those systems and validated that hypothesis, we are off and running — we can use those systems to screen for condensate modulators (c-mods) with specific phenotypic and functional effects, understand the phenotype-chemistry — functional connection with computational models and develop the best c-mods into drugs. An important piece to this is that the machine we’ve built is entirely disease agnostic, we have yet to find a disease space where we feel we can’t leverage our platform.
How does this approach explain what’s currently being explored in Dewpoint’s pipeline??What’s happening in our labs more broadly?
I'll just start by saying, I know a lot of companies claim there is no limit to the disease space that they can play in, but it’s really true for us. If there are genetics associated with the disease, we can tackle it. But Dewpoint is still a small company, so we've had to choose carefully where to focus internally and what to partner because there are finite resources, and we can’t do everything alone. I wish we could! I would love it if someone gave us 10 billion dollars and we had 10,000 people; we would just tackle everything at the same time, and I'm completely confident that we could.
So, partnering is a key part of our strategy, working with experienced, large pharmaceutical companies helps us build our platform capabilities and work on diseases we could not tackle on our own, like diabetes or heart disease. For those two in particular, we are extremely fortunate to work with Bayer and Novo Nordisk, global leaders who have been exceptional partners.
For Dewpoint’s “owned” pipeline, we’ve selected specific disease areas that are tractable and “bite size” enough for a small biotech to tackle, and where there are patients with high unmet need. For us, that's oncology and rare neurologic disease. Those are areas where the models, the condensate biology, the translational path and the patients’ needs all converge nicely. Importantly, we have really profound, world-leading, internal expertise to tackle them.
The scientific reasons for choosing — I mean we could go anywhere, but you can also ask of the science, “Where are condensates pointing us?” No assumptions, a priori, “Where are condensates playing the most profound role in human disease?” We can answer this question computationally by analyzing human genetics for condensate signatures and asking which diseases are most strongly associated. The answer here also happens to be oncology and rare neurologic disease. It doesn't mean we can't go to other places. But those are the two where we think we have a high chance of success. It comes down to patients, market and science.
Let’s focus on you, Isaac. What brought you to Dewpoint Therapeutics?
I'm a physician scientist and I trained for a long time: medical school, PhD, clinical training, specialty clinical training, subspecialty training, post-doctoral training, on and on… 16 years, I think in all. I did all that because the highest personal achievement I could hope for is to develop new ways to understand and treat disease, to help not just one patient today but all patients for all time. Condensate science, and Dewpoint, have that potential, and that’s why I’m here.?
When I was a physician — I was a breast medical oncologist — it was hugely satisfying to me to help one patient. I loved it and I felt a connection to that person, to help them live a better life, or maybe even save their life. But of profound impact to me is thinking of and advancing an idea that changes the way thousands or tens of thousands, or even millions of people are treated and saving all their lives by virtue of bringing a new science forward. So that's always been my purpose.
In academia, it's hard to do that. Academia is great at empowering scientists to study basic problems in the lab and empowering physicians to treat a patient at the bedside and run clinical trials. But what Dewpoint is doing, that's real bench-to-bedside medicine. It’s taking a scientific idea and bringing it through to patients to improve the way we care for not one patient, but all. And so, Dewpoint was my opportunity to live that dream.?And then, of course, I have been involved with condensate biology in academia for many years, nearly since its inception, in partnership with the thousands of other scientists who fostered and grew the field.
So, I feel a personal and intellectual connection to the science; playing a small part in helping the science reach its full potential and impact is a privilege and service to the field.
You touched upon your training as a physician and practicing oncologist at Dana Farber, how does that guide your work at Dewpoint?
It contributes in a few ways. First, it fuels my sense of urgency. People are literally — this is a little grim, but it's true — people, patients, are dying waiting for us to discover something and get it to them. In the clinic right now, there is someone sitting with their doctor hearing there are no more options. I know because I’ve been that physician with nothing left to offer. We might not know who those patients are individually, but we should know they are there waiting, and think about them every day. What we're doing here is trying to save lives, lives that are being lived and ending while waiting for our discoveries. My goal is to get our company, our science, to those patients as quickly and safely as possible.
The other contribution is, are we asking a question that's relevant for patients? Are we designing our programs, our molecules, our translational strategies in a way that's going to help the greatest number of people, that's safest for patients, that will be the most impactful, that will have the greatest uptake? So, practicing as an oncologist keeps patients in the front of my mind, which I hope gives me a way of looking at our work and our science through a human, patient-centric lens.
What drives you so passionately to make Dewpoint succeed?
It's a responsibility to patients, but also, it's a responsibility to the potential of the science and the thousands of scientists who birthed our field and our company. Look, I believe that condensate science has the potential to transform the way we think about and treat human disease, and Dewpoint is responsible for turning that potential into reality. I know we have the best chance of any company or any group of people in the world to really unpack, realize and maximize what the science can do for medicine and for society.
And so, that's a huge part of what drives me to make Dewpoint succeed. This is the team, this is the company, this is the group of scientists that's best positioned to really show what condensate science can do for humanity.