In the final instalment of our 5th anniversary ‘conversation with’ series, we spoke to leading condensate scientist and Dewpoint co-founder Tony Hyman, to hear more about what inspired him to spend his career working on biomolocular condensates and what are his aspirations for the field over the next five years and beyond.
In addition to being co-founder of Dewpoint therapeutics and serving on the scientific advisory board, Dr. Hyman is director and group leader at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG). His research has played a central role in defining the emergent area of phase separation and biomolecular condensates. In 2002 he was named honorary Professor of Molecular Cell Biology at Dresden University of Technology. He has won numerous prizes, including the EMBO Gold Medal, the Leibnitz Prize, the Schleiden Medal and the 2022 Breakthrough prize for life sciences.
You’ve led the field of condensate research over the past two decades, what is it about condensates that fascinates you?
Imagine the entire population of the earth – 8 billion people, living their lives, interacting. In an instant, conditions change. To respond, a city, the size of Boston, must be created, almost instantly. The city is comprised of several hundred thousand people with specific jobs and all necessary infrastructure for the city to function. And when the job of the city is complete, it must be quickly disassembled, with the parts kept intact, ready to build the next city. Now imagine that this process isn’t taking place in an area the same size as the earth – rather something much smaller, like the great Salt Lake in Utah. Every person trying to do their job is now squeezed in shoulder to shoulder with their neighbor, and more than this, to respond fast enough they are all running at a speed around 3km per second. This analogy is how I think about cells, with these ‘cities’ that pop up and disappear being the condensates. With such complexity, it is still amazing to me that life continues as successfully as it does.
We as scientists know so little about the workings of the cell… even now. Until very recently we knew nothing about condensates. However, those dynamic membraneless compartments that form and dissipate so seamlessly, are responsible for so many things inside the cell! We made the initial discovery of condensates in 2009 when we were working on p granules, an obscure compartment in an obscure nematode. In that model, they were fascinating, but then we started seeing that they were ubiquitous across all walks of biology, that they played a fundamental role in many different diseases, that became extremely surprising.
Today we are seeing how condensates play a key role across multiple diseases. They have given us a completely new way of thinking about treating disease. Whereas traditional drug discovery focuses on individual proteins which have single effects, now we can look at the wider disease modality. By reversing so-called “condensatopathies”, we have the potential to treat diseases for which until now we have not been able to have any significant impact. To me that is incredibly exciting!
What do you think the impact of condensate science could be on the future of medicine?
At Dewpoint, we are conducting experiments which are demonstrating how important condensate modification can be in a wide range of diseases, from cancers to neurodegeneration. We can target diseases which have previously been considered untreatable, but more than that, we are able to have a truly significant impact.
I believe condensate science has the potential to change the way we create medicines in two ways. Firstly, by allowing us to create safer drugs. We know there are a lot of issues in relation to toxic chemicals. Even some of the most effective drugs can have horrible side effects. My great hope is that by modulating the physical chemistry of cells, we can find much less toxic chemicals. If we look at traditional models, where we focus on one protein such as a kinase, we need to remember that there are maybe 500 kinases in a cell, and it’s extremely tricky to distinguish between them even for highly skilled medical chemists, so there is a specificity issue which can lead to side effects. With condensates though, we are looking for c-mods (condensate-modifying drugs) that can dissolve one specific condensate rather than another, and we are already seeing this could well lead to fewer toxic side-effects.
Secondly, and this is a grand aspiration, I hope that through our understanding of condensates we might be able to completely change the process of drug discovery. Today we use a sort of “black magic”, targeting proteins and pathways without really understanding how it will impact the wider system. The result is that many drug-candidates often don’t work or they don’t work as we thought they would. By targeting condensates though, I believe we can develop drugs in a very scientific way that is both robust and reproductible. This will make the process faster and more efficient. Obviously being able to create drugs efficiently will have a huge impact for patients, but I believe it will also have a greater impact on the entire system. Today, this “black magic” approach is the thing that costs us so much time and money and ultimately hinders our innovation.
If we look for example at the world of electronics, companies like IBM, Bell, AT&T have worked out how to deliver reproducibly and reliably, and this has fed back enormously to society in terms of the innovation they are able to bring. Pharma has however never been able to achieve this because they can’t really be certain of their results. But if we can make the drug discovery process reproducible, then we can unleash a huge amount of creativity because these companies will have a more guaranteed income and they will be able to focus more on innovation which will benefit us all.
Due to the ubiquitous nature of condensates, Dewpoint has had a very broad discovery approach. Are there any disease areas you’re particularly excited about?
For me, the most exciting thing about condensates is that we now see the potential to treat diseases which we have not been able to address with traditional drug discovery. Take for example, neurodegeneration, it’s one of the biggest health issue we face in society today – we are all worried that our parents, or us as we grow old, will suffer from dementia, that we will lose ourselves. Other neurodegenerative issues affect young children and sports people. And despite the size of the problem, we have not made any significant progress in any aspect. But today I’m really excited about the work Dewpoint is undertaking in this area. We are seeing that through condensate modification we can have a huge impact, even in the most severe neurodegenerative diseases such as ALS.
You founded Dewpoint five years ago, what achievements are you most proud of?
When Rick Young, Phil Sharp and I started Dewpoint, we set ourselves the challenge of answering three questions- could we use condensates as a model for drug discovery, could we actually modulate the condensate itself in interesting ways, and finally could we develop novel chemistry.
I’m incredibly proud that in just five years we have managed to answer some of these questions. We have demonstrated the potential of condensate modification in multiple disease areas, and we are able to reproduce candidates in a wide range of diseases. We must keep in mind that this is new and pioneering science, it’s not an exact art, you never really know if you’re going to find the answers. But to have gone from an idea to a reproducible pipeline for developing drugs in just five years is a fantastic achievement, and more than we could have hoped for. We now have to look forward to the next phase, to bringing a drug to market and to commercial success. I am confident we have the right team, and we are pursuing the right direction to make that happen.