“A discovery such as condensates, which is so fundamental to cellular biology, will surely have a major impact on how we go about designing and developing drugs”
In the latest installment of our “conversations with” we sat down with Dewpoint co-founder and renowned scientist, Rick Young to ask him for his predictions on how condensate science will influence the field of drug development and his thoughts on the progress that has been made in the five years since he founded Dewpoint.
Dr. Young is a pioneer in systems biology and performed seminal work in understanding gene control and expression and the roles biomolecular condensates play in these processes. He is a member of the Whitehead Institute, Professor of Biology at MIT and an elected member of the National Academy of Sciences and the National Academy of Medicine. Dr. Young has served as an advisor to Science magazine and the World Health Organization and in 2006 was recognized as one of the top 50 leaders in science, technology and business by Scientific American.
What initially led you to explore the world of biomolecular condensates, and when did you realize that they held such potential for changing the way we think about drug development?
For almost half a century I’ve been working on the problem of how to take the information in our genome and create life. However, the conventional models that we’d been working with just didn’t explain many of the fundamental features of this process. The discovery of condensates presented a new model and a new fundamental property of biomolecules in cells. We could now see many compartments beyond the conventional membrane-bound compartments, and this opened up huge opportunities for understanding how cells work and, importantly, what happens when things go awry in disease.
When I first learnt about condensates I was captivated, but the ultimate indicator to me that this was a huge opportunity was that the smartest young scientists I know were also inspired and wanted to join me in this new field. Early on in our study of condensates, two exceptionally talented scientists, Isaac Klein and Anne Boija (now Dewpoint’s Chief Scientific Officer and Head of Cancer Biology, respectively), demonstrated that the protein machines that control genes operate through a condensate mechanism. They went on to ask, how this influenced the way that the most widely used anticancer drugs worked. They found that one of these important drugs – Cisplatin – concentrates in the gene regulatory condensates that drive oncogenes in cancer cells. This work was truly game changing! It made it clear that there was an powerful unrealized opportunity through condensates to not only identify new targets for therapeutics, but also to optimize existing drugs for the treatment of cancers and many other diseases.
How are you and Dewpoint working to challenge conventions in drug development?
Let’s consider how pharma and most biotechs act when looking for new drugs: they first base their hypothesis on the current paradigms about the underlying mechanism of disease, and on the kinds of modalities that might offer a therapeutic opportunity. Then, some of the most talented people in the industry, with substantial financing, spend a decade or more developing a therapeutic. And still, 90% of the time these drugs fail. Our best ideas are advanced by our best people to the point of pivotal clinical trials, only to discover, to our chagrin, that we just aren’t having much impact on the patient. This tells me there must be a limit to our understanding of how human biology works to account for that rate of failure.
So, a discovery such as condensates, which is so fundamental to cellular biology, will surely have a major impact on how we go about designing and developing drugs. It should cause us to rethink everything – how living cells, tissues and organisms work, what disease pathology really is, and how a therapeutic hypothesis might emerge. Otherwise, we will continue to be disappointed with the outcome of the challenging work of developing a successful therapeutic.
But having new knowledge is not going to be enough to really transform drug development. We also need to be brave, to be willing to try outrageously creative things. That’s what we are doing at Dewpoint. We have, for instance, looked at what happens when you physically distract a disease protein, beta-catenin, from what it’s doing in dysregulated tumor cells, by entrapping it into compartments where it can’t do its devious job. This is not a concept that comes from any conventional thinking about how cells work, but it is one way to understand why we need to change how we think about drug development.
With condensates we are opening a universe of opportunities. With so many opportunities though, we as scientists and as a company need to be mindful of how we are applying our efforts. So, the challenge is, how do you take an opportunity of this magnitude and focus the efforts of a lot of really talented people on those diseases where you have the most substantial unmet medical needs, where we can make the most positive impact. And how do we prioritize our efforts to solve those problems?
Do you believe that condensate science may help us to find treatments for conditions we consider untreatable today?
Condensates are a fundamental property of cells, the unit of life, and so I think that by studying condensate science, we will develop the fundamental concepts and approaches to therapy necessary to address unmet medical needs. For example, I believe we’ll come to understand how the molecular assemblies in condensates create very specific localized chemical environments that influence cellular function and drug action. As we gain a better understanding of these condensate environments, we’ll see right away where alterations to cells, caused by genetic or environmental factors, might be reversed to recreate the healthy state of the cell. This will give us new approaches to develop therapeutics for diseases which we just haven’t been able to understand on this level before.
Our study of condensates has done more than give us new insights into how cells work; it has given us a new understanding of how proteins work. Much of our thinking about therapeutic targets has been inspired by the beautiful structures of those portions of proteins that form stable structures in crystals. We often think of proteins functioning like gears in a precise Swiss watch, fitting perfectly together to carry out their job; but we’ve largely ignored the portions of proteins that don’t form those stable structures. Yet we know that these flexible, dynamic parts of proteins have important functions and we realize that they are conserved. They help form condensates that have assembled many proteins with shared functions and they help control condensate behavior. That means they also create the chemical environment that will allow us to drug them when these functional assemblies go awry.
These two things together, our new knowledge of how cells work through compartmentalization of diverse functions, and how proteins collaborate with functional partners in condensate compartments, are forcing us to rethink biological regulation in health and disease. To my mind, now is a wonderful time to rethink therapeutic hypotheses in disease.
You’ve conducted experiments to see how condensate science can help us to improve the safety of drugs. Can you tell us about this and its potential impact for patients?
We very recently published a series of experiments where we asked if FDA-approved drugs go to the compartment in the cell where their target protein lives. And for some of the most effective and least toxic drugs, the answer is they are indeed concentrating in the compartment where their target lives! But for many drugs that are quite toxic and not very effective, they are concentrating in compartments other than where the target they were designed to hit lives. An important concept emerges from these results. You can work very hard to develop a drug that has high affinity and docks nicely with the target in your in vitro systems. But if it goes to the wrong place in cells, it’s not only not going to be less efficacious, but it could create damage to other proteins, other biomolecules in other compartments.
I think this is going to be fundamentally important for new drugs, because in therapeutics development, you’re concerned about therapeutic index. You’re concerned about the concentration at which the drug has some on-target efficacy but also the concentration at which the drug creates some toxicity. Anything at some level creates toxicity – too much water is toxic – so that ratio is really important. Thinking about the patient, if we can extend that ratio by ensuring that a drug is going to the right place once it gets in cells, that’s a huge benefit both to the patient and to the potential success of the drug.
Dewpoint has recently announced collaborations with two AI specialists. How does this new area of science connect with the biology of condensates?
Today at Dewpoint, we are for the first time bringing together biology, chemistry, physics, and artificial intelligence to gain both a fundamental understanding of how life works and an understanding of where it’s going awry. And by combining these disciplines we are conducting experiments in a way that is unique to us. We’re now seeing AI and machine learning coming to play in ways that I had not anticipated, and in ways that are just extraordinarily valuable.
We’ve been looking at where all the proteins in the cell like to collect in order to do their jobs: for any particular function there are many hundreds of proteins that assemble to carry out that function. We think that the special chemistry of each compartment is contributing to selective assembly and function of that compartment. AI is making it possible to learn the chemical features of biomolecules and drugs that are engaged in functional compartments in healthy cells, how this is altered in disease, and how the disease environment might be reversed. We’re just starting to see the preliminary results of what we can do with this new technology and the results are hugely exciting.
But what we have at Dewpoint goes further than just combining biology with AI. We have exceptionally talented biologists, chemists, biophysicists and engineers whose joint contributions are really quite important. Together they’ve created tools like “D.paint” which give them the ability to do high throughput multiplexed cell imaging. It’s a capability that provides the volume and quality of information essential for AI to provide us with valuable new insights. This is already catapulting our understanding of biology and pharmacology and allowing us to take entirely new approaches to design, advance and optimize therapeutics. It’s remarkable to see these exceptionally talented people working across scientific disciplines, to observe people so dedicated to this new approach to develop new medicines, and I’m betting that they will have an outsized impact on our industry in the coming 5 years.