In June 2024, Lis Leiderman, M.D., MBA joined Dewpoint’s Executive Leadership Team as Chief Financial and Corporate Development Officer. With her unique experience as both a medical doctor and an experienced financial leader, she is dedicated to furthering our goal of bringing our groundbreaking therapeutics to the clinic and ultimately to improve the lives of patients. After four months in her new role, she shares her impressions of our science and our culture and her thoughts on the potential for Dewpoint’s future success. 

As a physician, Lis’ true passion is making a difference for patients, and she was looking for a position where she could do just that. She was initially intrigued by the Chief Financial Officer and Corporate Development Officer role at Dewpoint, because she saw the incredible potential that our pioneering and innovative science could have. “We really have the ability to change the treatment paradigm for many patients,” she says, “which is at the heart of why I do this work.”  

From the leadership team to scientists to members of the Finance team during her interview process, Lis saw that same passion and dedication to changing patients’ lives. “Everyone on our team is brilliant and driven,” she says. “We have some of the brightest, most respected scientists in the world, but at the same time they are humble and curious. They are just the kind of individuals that I could see myself working and partnering with. I wanted to join Dewpoint to make a difference and help the company evolve and become more mature to get to that next stage.” 

Revolutionary Science and a Visionary Culture  

Four months after joining the team, Lis sees that her initial impressions of Dewpoint rang true. “I absolutely made the right choice to join the company,” says Lis.  

The more she learns about condensate biology, the more inspired she is about how our science is going to change the world and the way that patients are treated. “What we’re doing is entirely differentiated; we are pushing boundaries and challenging traditional approaches,” she says. “And that just really excites me.” 

Not only is our science a unique differentiator, it’s also the Dewpoint culture, which is driven by the Dewpoint team members who are inspired by the groundbreaking work they do each day.  Lis believes that the culture is equally as important as the science, and she sees the entire team live the Dewpoint values of integrity, inclusion, innovation and impact, from the leadership team throughout the organization. “We are a committed group that is passionate about a like-minded goal and making a positive impact on patients.”  

“The Dewpoint culture is visionary at its core,” says Lis. “We are caring and collaborative in a very open and honest and inclusive fashion, and there’s mutual respect across all levels. People feel valued and know that their work means something.” 

Looking forward to the future  

With our revolutionary science and extraordinary team, Lis sees a bright future for Dewpoint, including in therapeutic areas and opportunities beyond even what we are doing today. She looks forward to working with her team to build additional partnerships and raise capital to continue to show the world what our science is capable of. “I’m inspired for what’s next,” she says. “We’re surrounded by so many people who believe in Dewpoint, including our board and our investors, who are exhilarated to see where our company goes.” 

The post Early Impressions from Dr. Lis Leiderman: “Dewpoint has the Potential to Change the World”  appeared first on Dewpoint Therapeutics.

At Dewpoint, we are working to unlock the full potential of condensate science to discover and develop life-changing treatments for devastating diseases, which until now have been considered untreatable. To achieve our goal, we are navigating the astounding complexity of cellular systems, combining traditional wet-lab experiments with ground-breaking artificial intelligence (AI) and machine learning (ML) models to identify unique drug targets and accelerate our journey towards the clinic. 

To hear more about Dewpoint’s current AI approach and future aspirations, we spoke with Dr. Francis Carpenter, Dewpoint’s Head of Data Science and Engineering, who is leading the development and application of innovative, data-led approaches to enhance and accelerate drug discovery and clinical translation efforts. 

Before joining Dewpoint, Francis was a consultant for both McKinsey & Co and QuantumBlack, where he led cross-functional teams building tools to help biopharma clients leverage state-of-the-art AI approaches to enhance drug discovery and to optimize clinical trials. Prior to this, Francis was a Principal Product Manager at Genomics England and led the team that built the secure cloud-based research environment and bioinformatics workflows used by thousands of researchers to analyze the whole genome sequence data of >150k cancer and rare disease participants. Francis earned his PhD at University College London, in the lab of Professors John O’Keefe, Neil Burgess, and Caswell Barry, where he combined in vivo electrophysiology, chemogenetics and computational modelling to study the mechanisms underlying the brain’s representation of space and how this supports long-term memory. 

Dewpoint is working to develop therapies based on the science of biomolecular condensates – a completely new approach. How does the novelty of the science influence your drug discovery approach? 

Focusing on biomolecular condensates as potential drug targets is indeed a totally new approach and it is opening up many new opportunities for us to discover and develop drugs to treat diseases, which have until now eluded scientists. 

In a traditional drug discovery process, you identify a target protein linked to a disease and then look for or engineer a molecule that can bind to it, to turn it on or off or change its function. While this structure-based process is straight-forward in theory, in practice there are many targets, which, due to their complexity and high levels of disorder, it has not been possible to find drugs for. This approach is also insufficient in cases when the disease is not solely caused by the incorrect functioning of just one protein. 

Condensates are however quite different from traditional protein targets. Condensates are membrane-less organelles, that form and dissolve dynamically within a cell. They concentrate communities of biomolecules, helping either to stimulate, block or otherwise regulate normal cellular functions. However, in many different diseases, from cancers to neurodegenerative and metabolic diseases, we now know that condensates are going awry, driving disease by forming or dissolving inappropriately, disrupting the biochemical processes and signaling integrated within them. We call an aberrant condensate that drives disease a ‘condensatopathy’. To repair condensatopathies, Dewpoint is working to develop condensate modifying drugs (c-mods) that target the elements which influence the formation, dissolution, or physicochemical properties of condensates and consequently modify the disease. However, because condensates are composed of highly dynamic proteins rich in intrinsic disorder, a structure-based approach is often not feasible. Historically, many such proteins, despite their strong, validated ties to the disease, were deemed ‘undruggable’. Modifying the community within the condensate provides a different route to modifying the function of these previously ‘undruggable’ proteins that don’t have a known or potential drug binding site. 

We start by identifying specific target condensates that are causally linked to the disease we’re interested in and use high content imaging and fluorescent markers to characterize the condensate phenotype in both healthy and diseased states. We use the phenotype as a readout to search for c-mods that interact with the target condensate to shift the diseased state back to the healthy state. As the whole experimental process is automated and roboticized we can quickly compare hundreds of thousands of compounds to find the most promising hits. Once we have a potential candidate, we work with our chemistry colleagues to optimize its properties and make it more drug-like, ready for testing in preclinical animal models and eventually patients in the clinic. 

This condensate-focused phenotypic drug discovery approach has really flipped what a lot of people are doing on its head, and what’s exciting is that by using specific disease-causing condensate targets as a readout we are finding novel potential therapies that we couldn’t have found with a structure-based approach. Today at Dewpoint we have several programs that have produced promising preclinical candidates for diseases such as ALS and cancer, which scientists have struggled for decades to find therapies for with traditional approaches. 

You mentioned using the phenotypes of condensate targets to read-out disease states and to find c-mods. How do you go about finding these condensate targets? 

In some of our research programs we’re focused on targets that are well known to have a strong disease link and condensate phenotype, such as TDP-43, MYC or beta catenin. Many of these targets are traditionally considered ‘undruggable’. Our programs differ from other approaches taken in the industry in two fundamental ways. First, we treat the condensate where the ‘undruggable’ protein resides as the target. Second, we use a condensate phenotype-based approach to screen for compounds that modify the function of the ‘undruggable’ target.  

However, many diseases don’t yet have well characterized and validated condensate targets. At Dewpoint, we’ve also developed a scalable computational platform for identifying novel condensate targets. The approach combines human omics evidence of gene-disease associations with knowledge graphs and protein language modelling to identify potential targets that are closely associated with the dysregulated gene network underlying the disease state, and that are likely to phase separate into condensates. From this analysis we generate a shortlist of candidate targets for which we experimentally validate both the disease link and the condensate. We’ve now successfully used this platform in multiple disease areas, and we’re excited by its potential to help us get a foothold in understanding and discovering drugs for diseases that haven’t yet been well studied through a condensate lens.  

AI tools are now routinely used for drug discovery, but with the novelty of your phenotypic approach how are you incorporating AI? 

Many companies are using AI effectively to model the structure of known targets or molecules and to speed up the identification of drugs that can bind to them. But due to the compositional complexity and dynamic properties of condensates, these structure-based AI and ML tools alone aren’t sufficient for us. We’ve therefore had to look at different approaches and technologies and build new tools that appropriately take into account and leverage condensate biology. 

One area of our work in AI, which I think really sets us apart, is computer vision. Condensates are a network-level phenomenon where communities of biomolecules assemble. The condensate phenotypes we image are extremely information rich, encoding the biology and chemistry of their biomolecular networks. To make sense of this wealth of information, we have had to develop AI models to help us decode them. These models are based on approaches built by companies like Meta and Open AI, that are trained on pictures from the internet to differentiate between say images of cats and dogs, but we teach them to identify different types and characteristics of condensates. With the help of these models, we are analyzing the millions of condensate phenotype images we have collected for candidate drugs, to identify what changes in the condensates are linked to the therapeutic profiles we’re looking for. For example, we can identify what change in a specific condensate is typical of drugs that selectively kill cancer cells but not healthy cells. These models have already helped us to find novel compounds that show therapeutic promise but that we would have otherwise missed, because the way they affect the target condensate was unexpected. 

Another example is the models that we have developed to help our chemists ‘expand’ the chemistry around an existing hit compound, to find other compounds with similarly desirable phenotypic effects but more promising chemical properties. In one of our oncology programs, the high-throughput screen and our AI analyses together found a compound with a promising phenotype, but it wasn’t an ideal starting point for a drug because its chemical properties meant that it would be metabolized in the body into a different reactive compound. We developed ML-based methods to identify patterns in the high-throughput screen between the chemical structure of compounds and the phenotypes they induce, and successfully found compounds that retained their biological characteristics, while gaining promising drug-like attributes.  

These are just a couple of examples of the fully integrated, end-to-end data science platform we have built at Dewpoint, which we lovingly named ERSAi – after Ersa, the goddess of dew. ERSAi supports every step of c-mod discovery and development with predictions and analyses, from target discovery to c-mod identification and optimization into clinical translation. ERSAi includes multiple proprietary models, and is trained on the world’s largest condensate database, including >3 petabytes of data and >5 million condensate experiment images. The predictions and analyses from ERSAi are tightly coupled with our wet lab experiments, meaning that its models are continually improving. 

What are you working on next from an AI perspective? 

We’ve already incorporated computational methods and tools into every stage of the drug discovery pipeline, and these tools are helping us to accelerate and optimize the process. But we need to keep innovating, both to refine and improve our existing tools, and to develop or integrate new methods that help address other challenges in the drug discovery process. 

One area we are currently focusing on is a new model to help us better understand the molecular mechanisms of action and interactions of our potential drugs. The way we do phenotypic screening is condensate-target specific but mechanism agnostic. That is, we look for c-mods that have a specific condensate effect, but we don’t specify a single biomolecule target that it has to work through. This means that when we initially have a set of hit compounds, we know their effects converge on the aberrant condensate that drives the disease, but we don’t necessarily know their specific mechanism or how they’re interacting. We can of course find that out experimentally, and there’s lots of assays you can do to try and do that, but they’re usually quite time consuming, and you maybe only do them for a subset. So, we’re now working on using both phenotypic and structure-based methods to infer the type of molecular mechanisms and targets of hit compounds so that we can evaluate at scale each hit compound more efficiently. This will help us to prioritize and progress the hit compounds with the most promising molecular mechanisms and with the highest chance of success in the clinic. 

What are your goals and aspirations for AI and ML at Dewpoint? 

Despite being a biology-first company, I’m proud that we’ve already demonstrated our ability to build and apply cutting-edge computational methods. I believe that our team, under the guidance of experts such as Regina Barzilay (MIT) who sits on our scientific advisory board, can achieve remarkable results in this space.   

In the medium term, I want to expand the number of ways that computational approaches guide and inform our drug discovery process. That means continuing to refine the methods and the approaches that we already have, but also continuing to find and develop new models. I would, for example, like to find a way to better understand the structure and dynamics of the targets and the condensates earlier in the process, so that we can bring methods like structure-based drug design into the equation. We have some ideas about how this might be possible, and I’m excited to work with the team to find a structure-based drug design approach that works despite the challenges and complexities of condensates.  

Long term, I see condensates as having potential in a lot of different disease areas, and I’m really excited about the potential for AI and ML to help scale that up. AI gives us the opportunity to effectively identify and work on many different disease-driving condensates in parallel, allowing us to build a much bigger pipeline of potential treatments for a wider range of diseases. 

What impact do you think that AI will have on the drug discovery industry as a whole?  

I don’t see AI as a stand-alone silver bullet, but I do believe that combining AI with traditional wet-lab approaches will help us identify and design more effective and safer drugs and do so more efficiently. AI is already helping to accelerate the process of drug discovery and development, and I think the potential is there to help us focus on drugs with a higher probability of success, so that we’re not spending so many billions of dollars on trials that have may have been doomed to failure.  

Beyond the discovery of new drugs, I think computational approaches can help us make much more of the opportunities for repurposing drugs. There are a huge number of drugs out there with the potential to be used for other associated indications with common underlying causes, but it hasn’t been economically attractive or feasible to test them. AI gives us a way to open up these opportunities.  

I also hope that AI will allow us to tackle rare diseases more effectively. There is such a huge unmet need, but looking at rare diseases individually, it’s challenging to carry out traditional drug discovery approaches because of the cost involved relative to the economics of a small patient population. There is work being done to overcome this, such as by targeting aberrant condensates which are shared between patients of diverse backgrounds, as is the case for ALS. But to go further, I hope that combining the advantages brought about by leveraging condensate science with computational methods and AI, will really be a game changer here by allowing us to develop drugs in a sufficiently cost-effective way that will, over time, allow us to deliver treatments for these diseases too.  

The post A conversation with Dr. Francis Carpenter: Harnessing Machine learning and Artificial Intelligence to unlock the full potential of condensate science    appeared first on Dewpoint Therapeutics.

At Dewpoint we are embracing all forms of science from biology, chemistry and physics to data science and artificial intelligence (AI) to unleash the potential of condensates and develop treatments for complex diseases such as diabetes, cancers and neurodegeneration. To better understand Dewpoint’s approach and progress we spoke with Dr. Avinash (Avi) Patel, Dewpoint’s Head of Exploratory Sciences and Metabolic Diseases program lead.

Avi is currently spearheading Dewpoint’s work to leverage multi-dimensional big data to gain insights into condensate disease biology. Avi is one of the pioneers in the field of condensate biology. During his postdoctoral training with Dewpoint’s co-founder Tony Hyman, Avi authored several seminal publications that established the connection between biomolecular condensates and human diseases, specifically in neurodegeneration. He discovered that aberrant FUS condensates confer a risk for Amyotrophic Lateral Sclerosis (ALS) disease pathology and made a breakthrough discovery demonstrating the unappreciated role of ATP, as a hydrotrope and its role in regulating protein solubility and condensation in live cells.

You are one of the pioneers of condensate science. Can you tell us what inspires you to work in this field?

I’ve been studying condensates for almost 10 years now. I still remember the first time I heard about them was in 2010, when I was a PhD student at the University of Manchester. Tony Hyman, the scientist who first realized the therapeutic potential of condensates, who later became one of Dewpoint’s co-founders, was giving a talk. When I heard him speak, I was instantly hooked. The thing that really intrigued me was realizing that to understand condensates fully we need to integrate multiple disciplines of science, this really appealed to my own expansive interest in all scientific disciplines.

Tony explained how cellular condensates were first described centuries ago by Physicists Franz Bauer and Santiago Ramon Y Cajal, and again in the early 1900s by Oparin and Haldane who were thinking about the origins of life. But it wasn’t until Hyman and his colleagues took a view that combined physics and biology that we – as a community – fully appreciated the prevalence and fundamental importance of condensates as cellular regulators.

I have been a chemist, a biologist and now maybe you could also call me an emerging data scientist. Condensate science allows me to flex each of these elements, to embrace every discipline of science. This philosophy of bringing ideas and principles together is now at the heart of Dewpoint too, from chemistry, physics and biology to computer science, big data and AI – and that is what is enabling us to uncover novel ways of targeting diseases that the industry has been struggling with for years.

Dewpoint is focused on discovering and developing condensate modifying drugs (c-mods).  How are these different from other therapies and what do you think gives them greater promise?

Traditional drug targets are most often single proteins or single RNAs. Drug developers identify the target and then look for compounds that can switch them on or off, or change their action, and this leads to downstream effects in the cell. But the problem is that this methodology looks at the targets in isolation – not within the complex interrelated system that is the cell.

To think of this in another way – imagine that our target protein is a person. When they are at home, by themselves, they act in a certain way – they can be very free, they can do many different things, they are not influenced by others or external stressors. But as we know, people don’t just stay home alone in isolation, they interact, they move around, they experience stress and outside influences, and all these factors change their behavior. So, if we only study one target in isolation and the effect of drugs on that target in isolation, then we are missing all the complexity of the cell. At Dewpoint, by working on, with and through condensates, we can take a different approach that considers a more holistic view of the cellular functioning and takes into account the complexity.

Condensates are a collection of molecules, such as proteins and nucleic acids. They form and dissolve dynamically within a cell and allow for the partitioning or concentration of key cellular elements required to stimulate or block reactions. If you like, they are confined environments in which the people in our analogy are interacting. In many different diseases, from cancers to neurodegenerative and metabolic diseases, we have found that condensates are going awry, forming and, or dissolving inappropriately – which disrupts the processes that occur within them from happening correctly – we call this a condensatopathy. The drugs that we are working on at Dewpoint, the c-mods, target elements which influence the formation, dissolution or physicochemical properties of condensates and allow us to restore their proper functions. With condensate function restored, all the processes integrated within them can be resumed, to systemically normalize the cellular state.

This approach is already proving to have very broad application. Condensates are fundamental and involved in many, if not all cellular processes, from signaling, transcription, metastasis and the development of resistance mechanisms. This means that our approach will allow us to target a huge breadth of complex diseases from cancers to metabolic and neurodegenerative diseases. Secondly, as we are targeting condensates rather than single proteins, we have been able to go after targets which Pharma has traditionally deemed as ‘un-druggable.’

How do you go about developing drugs that target such complex systems?

Traditional drug discovery relies on a structural approach to biology. Single proteins are isolated, crystallized models are developed and drugs are identified based on a tight fit of the drug within the well-defined three-dimensional structure of the target. At Dewpoint we go beyond this approach. We use new techniques and advanced technology to find novel ways of looking at and impacting cell biology. We incorporate state-of-the understanding of the principles of physics and chemistry which define condensates into a multidisciplinary approach. This allows us to look at cells from a more holistic, whole system perspective, and to develop novel and innovative solutions to challenging health problems.

In our diabetes program, we’re using AI and computer vision to identify new factors that contribute to insulin resistance, a main cause of diabetes. We discover compounds by analyzing changes in cell structures using High Throughput microscopy. AI helps us study these changes across many cells to see how a compound can transform a diseased cell back to a healthy one. Our unique AI technology detects multiple changes that are invisible to the human eye, helping us find patterns. We’re now teaching our AI to understand the physical rules of condensates, guiding us to the right molecules for disease treatment. This approach combines AI with physics and chemistry to explore cell complexity like never before.

You lead the metabolic diseases program at Dewpoint including the diabetes program. Can you give us an overview of this work?

In our diabetes program, we are working in partnership with Novo Nordisk with an aim of identifying drug candidates that will eventually provide life-changing treatments for people with diabetes. Diabetes today affects almost 9% of the world’s population. That’s almost half a billion people, and it is increasing – we’re anticipating it to rise to almost 11% of the world’s population by 2035.  But it’s a very complex and multifactorial disease, which has meant until now we as a scientific community have not been able to do much more than control symptoms via traditional drug discovery.

The approach we are taking today at Dewpoint, is to identify the condensatopathies underling insulin resistance and to find ways to repair them.  A study from Dewpoint’s co-founder Rick Young, showed that the receptors in the liver which transport insulin into the cells actually form condensates. In healthy cells, the condensates are fluid, and behave somewhat like a liquid. In insulin-resistant cells however, the condensates are solid-like; this loss in dynamic properties prevents them from transporting insulin. We are working on repairing this condensatopathy to restore the fluidity; hopefully this will allow us to reverse insulin resistance and diabetes entirely.

Interestingly, Professor Young’s study also found that treatments like Metformin make those solid condensates in insulin-resistant cells a little bit more fluid – not completely reversing the phenotype, but to some degree. Metformin has been used for many years, but its mechanism of action has always been a little mysterious. To see its effect on condensates was a breakthrough and it has given us more information on the systems dynamics at play and hope for our approach.

Dewpoint has always sought partnerships with big pharma companies, including recently with Novo Nordisk in diabetes. Why are these collaborations important and what have you found makes for a successful partnership?

Pharma companies have decades of experience and a proven track record of successfully delivering life-saving drugs to patients. They have expertise in designing and formulating drugs, developing them clinically and helping them reach patients. But they can’t explore every hypothesis and research every angle. So, it makes sense that they work with biotech’s on the cutting edge of innovation.  It’s a very natural collaboration model and many of the products that are launching now actually come from such partnerships.

With Novo Nordisk, we’ve built a strong integrated team, with joint accountability to make the collaboration successful. Personally, I find that the collaboration model has really helped to focus our work.  For example, I might get very excited about certain aspects of condensate science in diabetes biology because it’s such a novel field. However, not all these discoveries will necessarily lead to a product that can be delivered to patients. That’s where our partner, with nearly 100 years of experience in developing diabetes treatments, comes in. They provide valuable insights to ensure we’re focusing on the science that has the most potential to translate into real, impactful products for patients. Their guidance helps me design programs that can truly make a difference.

With AI and computer science, how do you see the industry changing?

Already we are seeing huge changes. As I’ve described, computer science is allowing us to view and understand how to manipulate cells in new ways. This is moving us away from a model of ‘drug hunting’ towards an era where we can engineer new drugs. In the future as we become more adept at utilizing these technologies, I see that the process of creating and getting medicines to the people who need them will become much faster and more reliable. Where we would have spent years analyzing data, computer science allows us to process huge amounts of information in just days. We’re going to be able to use technology to run models that will help us to understand how our drugs will interact in the wider context of the body. This will overcome a lot of the challenges we face when drugs move into the clinic and I believe it will allow us to develop safer and more effective treatments.

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“I believe we are on our way towards a MYC c-mod, says Bede Portz, Dewpoint’s ovarian cancer program lead. Our early prototype MYC c-mods have demonstrated significant tumor growth inhibition in animal models of ovarian cancer.”

Every year over 200,000 women die of ovarian cancer globally, and with current treatment options being limited, this number is predicted to rise. At Dewpoint we believe that condensate science holds the key to developing more effective and better tolerated treatments for ovarian cancer and other solid tumors.

For greater insight on our progress, approach and aspirations we spoke with Dr. Bede Portz, Dewpoint’s ovarian cancer program lead and condensate science expert.

Prior to joining Dewpoint, Bede was a Bright Focus Foundation postdoctoral fellow at the University of Pennsylvania in Dr. James Shorter’s lab, where he worked on developing therapeutic RNAs to combat aberrant phase transitions in neurodegenerative diseases and on non-coding RNA (ncRNA) condensation. Bede did his Ph.D. training in the Center for Eukaryotic Gene Regulation at Penn State.

What is it about condensate science that excites you?

I love biology. If you endeavor to understand how cells work and a new and testable concept emerges that potentially undergirds tons of cell biology, that’s exciting.

Condensates are membrane-less organelles which form and dissipate dynamically inside the cell via a process called phase separation. They are responsible for allowing cells to organize proteins in time and space to regulate chemical reactions and for turning key processes on and off. I’d always wondered how complex processes were regulated within cells, but condensate science has allowed us to understand cellular biology in a whole new way. As an extension of this, we are also able to understand more and more about the pathophysiology of disease through condensates.

There is an increased appreciation in the field that condensate malfunctioning is strongly associated with a variety of diseases. We call this association condensatopathy. These can manifest as condensates containing the wrong components or having the wrong dynamics or material properties. Depending on the context, condensatopathies can result in toxic gain or loss of function, or sometimes both, and it is this misregulation that explains the complex functional outcomes of multiple types of errors that are integrated inside the condensate. At Dewpoint we are currently working to develop small molecules that can modify the aberrant condensates. This has opened countless new potential points of intervention and possible therapeutic avenues and it’s this potential that makes me so excited about condensate science.

Dewpoint is working to develop a treatment for ovarian cancer by targeting the MYC protein. This is a protein that many others have tried and failed to drug. What is it about your approach that you think will make it successful?

Through our ovarian cancer program, we are indeed going after one of the targets that scientists consider to be almost a ‘holy grail’ in oncology. MYC is an oncoprotein responsible for regulating the expression of genes that drive cancer proliferation.  It has been found to be dysregulated in up to 70% of cancers. So obviously other researchers have been trying for years to find ways to target MYC.

We believe that MYC exerts its function in activating genes and amplifying their expression through a condensate. MYC condensates act as an inflection point between stimulus and response – the cell receives signals and it’s deciding via a MYC condensate on the response, for example proliferation. By modulating MYC condensates, we aim to stop cancer cell proliferation.

The high incidence of MYC over proliferation in such a wide range of cancers means that it has huge potential. Right now, we are really focused on proving the approach in ovarian cancer, where upwards of 30% of tumors have MYC amplification, more than the normal number of copies of the MYC gene, pointing to MYC dysregulation being a driver of ovarian cancer. In the future though, I believe that we could apply our approach to many other types of cancer, with equally high unmet need, such as pancreatic and esophageal cancers.

What progress has Dewpoint made towards the development of a MYC c-mod?

I believe we are on our way towards a MYC c-mod. We have developed an assay matrix centered around MYC condensate phenotypes that identifies c-mods that modulate MYC condensates selectively, in cell models of high grade serous ovarian cancer that recapitulate patient-relevant genetics. These compounds in turn selectively modulate MYC-driven gene expression. This assay matrix has been deployed in the improvement of the drug-like properties of our c-mods. The most exciting data have been generated in vivo, with early prototype MYC c-mods demonstrating significant tumor growth inhibition in animal models of ovarian cancer. The degree of tumor growth inhibition elicited by the initial molecules is comparable to the standard of care chemotherapy regimen. Progress like this so early in the medicinal chemistry campaign even defied the expectations of many on the team. There is work to be done, but data so encouraging motivate any amount of effort. 

What are your overarching ambitions for your ovarian cancer program?

The unmet need in ovarian cancer is sky high and the survival rates are not good. This is partly because the cancer is often not detected until the disease is advanced, but also because the existing treatment options are limited. We still rely a lot on chemotherapies. Not only are they really tough on patients from a tolerability point of view, but ovarian cancer regularly develops resistance to them which affects their efficacy.  Other treatment options exist, but they’re not really used with curative intent.

So, our goal is fundamentally to develop a treatment that is more effective and better tolerated than other drugs used to treat ovarian cancer today.

Do you think c-mods can overcome the issue of resistance in oncology?

The resistance problem is one we think about all the time, and it’s critically important. Overcoming resistance has really been built into the program as a key goal since its genesis and at multiple levels. If you think about what condensates do in cells generally – they’re involved in responding to signals and stress, they’re involved in making decisions to grow or to not grow, to execute biochemistry or to not. And these are processes that are hijacked in cancer and that can contribute to resistance. Specifically, MYC itself is implicated in resistance, so it follows that MYC condensates could be mediators of resistance.  It follows that targeting MYC condensates could be effective in ovarian cancers that have become resistant to the standard of care chemotherapies. We are working hard to understand this.

How do c-mods compare to other oncology therapies in terms of specificity?

If we take the example of ovarian cancer, it is genetically a highly unstable and heterogeneous disease. That is a factor that contributes to its poor treatment response and the emergence of resistance. Broadly, cancer therapy falls into two types, targeted therapies that attempt to exploit specific mutations, and broad acting chemotherapies that attack fundamental mechanism of cell growth and division. From a targeted perspective, one looks for specific mutations associated with specific subtypes of ovarian cancer and exploits them with very targeted therapies. These can be effective, but resistance can emerge, and these treatments may be viable options only for very small patient populations harboring specific mutations. Conversely, if we go broad with a chemotherapy, we can treat large sets of patients, but as we are targeting the basic machinery of cell proliferation which is needed not just for tumor cells but also for healthy cells, we end up with drugs with very poor tolerability.

I believe with c-mods may really achieve the best of both worlds, an approach which gives the benefits of a targeted therapy while exploiting a mechanism that’s sufficiently general to be applicable to a very broad number of patients, irrespective of specific mutations.

Take, for example, the mutations associated with ovarian cancer – there is frequent MYC amplification leading to its dysregulation. But there are also mutations in proteins involved in sending signals for cells to grow, signals that are integrated via MYC condensates. You could envision a targeted therapy against one of those signaling proteins that harbors a particular mutation, but where do those signals converge? They all converge in MYC condensates, located on the genome, which act as integrators of stimulus and response. If the functional unit of MYC is a condensate, this might represent an Achilles heel that is specific to a driver of ovarian cancer, but that also exploits upstream drivers, and regulators of MYC. We call compounds that act on the MYC condensate ‘direct c-mods’, and compounds that modulate the upstream drivers and regulators ‘indirect c-mods’.

With condensates being such a new scientific approach, what new technologies and tools have you had to employ to optimize your drug development?

At Dewpoint, we’ve developed an integrated platform that brings together our huge database of condensate knowledge with our experimental science and the latest AI, and imaging. We call it ERSAi.

ERSAi is a c-mod discovery toolbox – the digital twin of our experimental platform – that allows us to optimize the process of drug discovery from target selection to optimization of lead compounds in disease-relevant models. Cell biology is amazingly complex, but this platform of tools allows us to embrace this complexity and create approaches that cast a wide enough net to capture mechanisms that can modulate condensates – either directly or indirectly – but in a specific enough way to allow us to develop targeted therapies.

For our ovarian cancer program, we have used ERSAi to deconvolve the information from our phenotypic screening data and toolbox of secondary assays to accelerate discovery. From the outset of the program, ERSAi provided the opportunity to look at various genetic models of ovarian cancer in our assays to capture the disease relevant composition of condensates and their regulation. We’ve been using AI to build image analysis tools that are fit-for-purpose to decipher the information encoded in the condensate phenotypes of disease-relevant cells and to test and refine hypotheses in a sort of loop.  It’s not a static toolbox, it evolves as we learn more. In service of the program, we’re building new tools to decipher the information encoded in these models and that is a powerful approach.

You’ve been at Dewpoint for more than 3 years, what are the achievements that you are most proud of over this time?

Pride is a dangerous feeling as it can distract you from what really matters. Our goal here is to make a drug that can treat ovarian cancer– today we are still working on that goal.

But, I’m frequently proud of the team. I’m most proud when the team demonstrates a relentless optimism, a willingness to tackle complex problems. To approach a problem in a more unconventional way, to do the harder experiment or build the AI tool that unlocks the next advance for the program. 

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Colorectal cancer is the third most common cancer globally and the second leading cause of cancer-related deaths worldwide. We at Dewpoint are dedicated to translating our revolutionary condensate science into medicines with the potential to overcome this devastating disease.

This colorectal cancer awareness month, we sat down with Dewpoint’s Head of Biology, Ann Boija, to get her take on the huge potential of condensate-modifying drugs (c-mods) to treat colorectal and a range of other cancers by getting to the core of the disease.

Ann is an expert in gene control, cancer biology and condensate biology. Prior to joining Dewpoint almost three years ago, Ann was leading pioneering research focused on the role of condensates in gene control and cancer therapeutic drug activity, in the laboratory of Dewpoint co-founder, Richard A. Young at the Whitehead Institute of the Massachusetts Institute of Technology. Her work has led to several seminal discoveries in the field, including the realization that the transcription factors’ propensity to phase separate, encoded in intrinsically disordered regions, contributes to the regulation of gene transcription, and that partitioning of anti-cancer drugs into condensates influences their activity. Together, these two foundational discoveries have paved the way for how Dewpoint approaches drugging ‘undruggable’ targets and optimizes c-mods for efficiency and safety.

Dewpoint is working to drug biological targets which had been considered undruggable – including beta catenin and MYC. Can you describe how your approach allows you to overcome the hurdles which have made these and other targets so elusive to drug hunters for so long?

Transcription factors are key biological drivers of malignancies but have been difficult to target due to lack of small molecule binding pockets and high degree of protein disorder. Their structure is “spaghetti-like”, taking on many different configurations, which makes it challenging to develop a drug that can effectively bind to them. Disordered regions are known to drive the formation of biomolecular condensates- which are membranelles organelles recently demonstrated to play key roles in regulating most cellular processes. Aberrant condensates associated with pathophysiology – or condensatopathies – drive disease and serve as an integrated node of dysfunction for various disease processes and pathways. By targeting the condensate and taking advantage of its emergent properties, we can expand the target space to include high value disease targets previously deemed undruggable, including beta catenin and MYC.

At Dewpoint we have built an AI-enabled end-to-end platform that nominates condensate disease targets, and using high content, high throughput screening we are able to identify condensate-modifying drugs – or c-mods, in a disease relevant setting. Condensate assays are then used to optimize c-mods to reverse the disease phenotype and corresponding functional consequences. We have further demonstrated that the c-mods identified using our platform translate into in vivo efficacy across diseases. This highlights the promise of leveraging condensate science to target hard to drug oncology targets with the ultimate goal to develop much needed treatments for patients.

How is Dewpoint tackling colorectal cancer by leveraging condensate biology?

Constitutive activation of beta catenin causes transcriptional reprogramming and uncontrolled cell proliferation which drive colorectal cancer. Now, with c-mods, we have a totally new and unique approach to inhibit beta catenin activity by sequestering it in ‘depot’ nuclear condensates. Our data demonstrates that this approach can normalize transcription and reverse uncontrolled proliferation of malignant cells. Importantly, through condensate modification not only are we able to target this previously undruggable protein but we have been able to hone the process so that we can selectively induce depots in malignant cells with high levels of aberrant signaling, while leaving untransformed colon cells largely unaffected. We are particularly excited about this observation given the challenges around gastrointestinal toxicities seen in the clinic using current treatments.

What are the significant differences between c-mods and other colon cancer treatments?

One key difference is that while many other therapies target single biomolecules, condensate modification allows us to target and repair the entire disease-driving processes. This has the potential for a more transformative effect as it can hit all the components involved in driving the disease simultaneously. Focusing on condensates rather than on unique biomolecule targets also greatly reduces the limitations of genetic differences. We know in cancer there is vast genetic diversity between populations, and focusing on a single biomolecule means that a drug may only be relevant to a small subgroup. As the condensate is a central node of dysfunction in the disease, by targeting this node we may have an impact on larger patient populations.

Take the example of beta catenin and Wnt signaling. It’s a complex signaling pathway with many factors involved, but they converge at the condensate. Consistent with this, we see activity of beta catenin c-mods across genetically diverse colorectal cancers as well as a range of additional Wnt-driven cancers, providing opportunities to treat patients broadly.

What benefits do you believe c-mods can bring to patients?

The use of c-mods as potential cancer therapies is a very exciting scientific step forward and it’s opening new possibilities for us to go after a larger portion of the proteome, to include target proteins that we know are key to driving many diseases. I see great potential in c-mods to be transformative as real disease-modifying treatments across genetically diverse subpopulations. Furthermore, we believe they hold the potential to be safer and more tolerable for patients compared to traditional therapies.

At Dewpoint we are seeing the evidence of our approach both through our oncology programs in colorectal and ovarian cancer and in our neurodegenerative disease program in ALS. I am confident that we will be able to apply our learnings from these programs to a wide range of other hard-to-drug oncology targets with compelling biology for diseases with high unmet need.

As 2024 Colorectal Cancer Awareness month is closing, what is your personal hope for this disease?

I truly believe condensate science has the potential to revolutionize the treatment for cancer patients. I am excited and proud to see the progress we have made thus far in translating condensate science into a drug discovery platform that identifies c-mods with anti-tumor activity in diverse translational models. I am optimistic that we will be able to advance our most promising beta catenin c-mod to IND filing during next year. This will open a new, concrete era of hope for colorectal cancer patients.

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Rare diseases are a core pillar of Dewpoint’s development portfolio. With condensates playing fundamental roles in cellular biology and as central nodes of dysfunction in disease, modulating condensates has broad applications which could prove to be game-changing across diseases with unmet medical needs such as ALS and other neurodegenerative and rare diseases.

This rare disease day, we took the opportunity to speak with our Head of Discovery Biology – US, Violeta Yu about the exciting progress we are making in ALS, where Dewpoint has just been awarded a Target ALS Foundation grant, and the potential for condensate science to transform the way we view and treat neurodegenerative diseases in the future.

Violeta is an eminent molecular pharmacologist with 25 years of drug discovery experience. In her career, she used innovative strategies – including condensate–targeted drug discovery, to screen, study, and progress potential therapies towards the clinic in Neuroscience, Oncology, Inflammation, and Metabolic Disorders.  Prior to joining Dewpoint, Violeta led the ALS discovery program at Amgen Inc.

You’re leading Dewpoint’s work in ALS, a notoriously difficult to treat disease area, where many have tried and failed to make progress, how has your approach been different?

It’s true that a treatment for ALS has been elusive, despite this being one of the more well known and studied rare diseases. One factor that has made it so hard to target is the diversity of the disease, only around 10% of patients have a genetically inherited defect while the remaining 90% of cases are sporadic and traced to a combination of genetic or environmental factors. In addition, many of the key proteins that play a role in the disease pathology, such as TDP-43, have been found to be very difficult to drug.

Condensate science has enabled us to take a different view to target the disease. Condensates are membraneless compartments that organize cellular material in time and space and regulate many biological processes. When condensates go awry, they can lead to disease. We call an aberrant condensate associated with a disease ‘condensatopathy’. Despite the genetic diversity between ALS patients, the majority – over 97% – share a common condensatopathy which causes TDP-43, a protein which normally resides in the nucleus to be sequestered and concentrate in cytoplasmic condensates. Research has shown this to be a key driver of disease both through toxic gain of function in the cytoplasm and loss of function in the nucleus.

At Dewpoint we are developing small molecule condensate modifying drugs (c-mods) that will repair the condensatopathy directly, allowing TDP-43 to move back into the nucleus to resume its function. In cellular and animal models of TDP-43 pathology, we have already been able to demonstrate the mitigation of some of the cellular changes induced by the aberrant TDP-43 protein inclusions, including alterations in gene activity and stress-induced damage. Just last month, we were honored to have been awarded a Target ALS Foundation Grant to continue our work in animal models, which will allow us to take great new strides towards bringing our therapy to patients.

 What is your hope for how your ALS treatment could benefit patients?

ALS is a devastating neurodegenerative disease that affects up to 20,000 patients in the US alone each year. Based on our cellular and animal models we have a real hope that our c-mod treatment may be able to reduce progression of ALS, by restoring neuron health through reducing TDP-43 cytoplasmic inclusions and improving TDP-43 function – we think it could be transformative.

But of course, the earlier we can treat people the better the results could be. Once TDP-43 has become aggregated and insoluble, it could be in a state where its function is unsalvageable, so if we can act early, we can stop sequestration in the cytoplasmic condensates and release the TDP-43 while it is still functional, rescuing the impact of TDP-43 loss of function as well as reducing the progress for TDP-43 toxic gain of functions that underlie ALS. In the future I hope we will have the ability to screen for a biomarker that can identify TDP-43 loss of function early. There is a recent discovery that TDP-43 loss of function is seen years before symptoms can be detected¹ so if we could treat ALS that early we might be able to fight the disease before it causes any clinical symptoms at all.

With the c-mod approach having so much potential in ALS, do you think it could be used to treat other neurodegenerative and rare diseases?

Despite diseases having different clinical representations, we are seeing more and more that the same dysfunctional condensate is shared between them. The TDP-43 condensatopathy for example, is seen not only in ALS but also in FTD, Perry Syndrome, CTE, Inclusion Body Myositis and Alzheimer’s – so I think it’s highly possible that we could expect our TDP-43 condensate targeted c-mod therapy to benefit numerous patient populations. I’m excited that we are starting to explore some of these areas.

Now we have this innovative approach, of using condensates (which are composed of a mix of RNA and protein components that act together to modulate biological processes) rather than focusing only on single protein targets, we are finding many other condensatopathies that play key roles in rare and neurodegenerative diseases, so I hope that we will be able to expand our scientific approach and continue our work towards overcoming these devastating diseases which have until now been seen as untreatable.

What can be done to speed up the development of treatments for rare diseases by the industry as a whole?

The major challenge in the rare disease space is, I believe, a general lack of research and dedication in general. We lack animal models, biomarkers, established end-points and defined clinical measures. We also need to work more closely with doctors and patients. Because not much is known, patient diagnosis is delayed, or the early symptoms misdiagnosed. We miss opportunities to learn from patients or for patients to be involved in clinical trials. The small patient population size can make it difficult to get robust data in the clinic. I believe these diseases are not uncurable. More focus, research, education and investment across the board will be vital for overcoming rare diseases.

At Dewpoint we are taking the challenges of rare diseases seriously. We believe that condensate science holds the key to treating many of these diseases and so we are putting the full force of our knowledge, experience and AI-powered discovery platform into finding new treatments. We have been challenging scientific conventions, hypotheses and biases to come up with a novel approach in targeting condensates and I hope that this can lead us to develop compounds with great efficacy not just in translational models but also in the clinic. Today we are progressing the science at a lightening pace – I’m proud of the progress we’ve made, and I can’t wait to see the day when our drugs can make a real difference to patients.

1 • Irwin, K.E., Jasin, P., Braunstein, K.E. et al. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD. Nat Med 30, 382–393 (2024). https://doi.org/10.1038/s41591-023-02788-5

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In the final installment of our 5^th 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 biomolecular 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.

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As we start a new year, we continue our series of conversations with our board members to hear their reflections on Dewpoint’s journey so far and their aspirations for our next five years. Today we spoke with the chair of our Board of Directors, Amir Nashat, who in addition to being the first investor, was Dewpoint’s initial CEO from 2018 until 2020.

Amir has created and invested in a breadth of category-defining biotechnology companies during his 22-year tenure with Polaris Partners. He also serves on the Partners Innovation Fund, the Investment Advisory Committee for The Engine at MIT and helped launch the MIT Sandbox Innovation Fund as its active president. He previously served on the board of the New England Venture Capital Association. He has been named to the Forbes Midas List of “Top 100 Venture Capitalists”.

You were Dewpoint’s initial investor, what was it that made Dewpoint stand out to you as an opportunity?

I’m an engineer by training, I studied chemical engineering at MIT, and so I am used to thinking about systems as a series of chemical reactions happening across space and time. But when I started in biotech, it surprised me that the way people looked at cells was so simplified. Rather than seeing how things constantly moved and changed, the scientific consensus was really to study cells in almost a steady state. Even as a student, I was mystified. We learnt that there were enzymes that could “turn on” a reaction and ones that could “turn off” the same reaction, and I would ask, how does the “on” switch work if the “off” switch is right next to it? If there was one kid that turned the light on sitting next to a kid that turned it off, how would the light ever be on? And I never really got an answer that felt very satisfying.

One evening I found myself In Florida with my friends Rick Young and Phil Sharp, and we started discussing Rick’s new experimental work which modeled how reactions occur outside of an equilibrium. He showed me evidence of how reactions weren’t just governed by the contents of a cell but by the way molecules moved around within them. He introduced me to the idea of condensates, transient, membrane free organelles which form and dissolve dynamically, compartmentalizing and concentrating molecules to enable biochemical processes. This was the piece of the puzzle I’d been missing; the condensates temporarily separated the kid turning the light on from the one who wanted to turn it off, allowing the lights to stay on for just the right amount of time. It was Phil Sharp who said, if you ever want to start a company in this space, the person you need is Tony Hyman, who’s been working on this at the Max Plank institute in Germany for a decade.

About a year later, I got a call from Rick out of the blue, to say he had Tony Hyman sitting in his office and could I come? I was so intrigued that I left the meeting I was in, and drove straight to Cambridge where the three of us spent the afternoon looking at Tony’s latest research on the potential to drug condensates.  Right away I knew we were onto something exciting, so we pulled together investors and started recruiting, mainly chemists directly from the pharma industry. I remember when we interviewed those first 10 or 20 people: each time we described the principles of condensates it was like a eureka moment. For me, condensates really are the most exciting new biology and today, five years in, I’m still so excited by their potential.

What is Dewpoint doing differently from other condensate-focused companies?

In my first conversation with Tony Hyman, he told me that people would see condensates and try to take a typical drug maker approach of trying to quickly find molecules to target specific regions or proteins, looking for a single pathway to act on. But Tony believed there was a bigger opportunity, that through condensate modification we had the potential to change the entire course of many different diseases. So I think this is really Dewpoint’s biggest difference. We have taken the time to fully understand the biology, why proteins move the way they do and how they collaborate to cause diseases. As well as going deep into the science, we’ve also gone broad, today we are researching diseases from cancer to neurology which is only possible because of these strong foundations, and the support of our investors who believed in us enough to commit to this 10-year runway.

How important have partnerships been to Dewpoint’s progress so far?

We knew from the start that to fully understand condensates we needed to go deep in our research, and to do this we needed investors who had the vision to support us through the first 10 years. Getting investment for something so different can be a challenge, but the science combined with our founders Tony, Rick and Phil is just such a strong combination! Investment does remain a challenge though, for us as with most biotechs. The market has shifted, interest rates are high, and we need to work to keep bringing in capital to maintain innovation in parallel with now running clinical trials.

We’ve also been lucky to have built really strong partnerships with the pharma industry, which have allowed us to extend the breadth of the pipeline and move much faster than we could have done alone. Our earliest, with Bayer was a very natural fit. They are experts in small molecules, and they saw the potential of our work to bring a new way of using small molecules for new applications. They brought tangible experience in cardiology, nephrology and pulmonology which has allowed us to really push forward, and will help us to get drugs to patients suffering from these diseases much faster.

What challenges did you face early on?

At the very beginning, the team did something which our competitors didn’t, they compared what you got when you drugged a condensate in a test tube vs. a condensate in a cell. In the test tube, we got many false positive and negative results — the translation to cells just wasn’t good enough. The condensate is so complex, with up to 50 different proteins at play, and things shifting all the time, that so you can’t recreate reactions by pulling out 1 or 2 things, you have to study them in their native habitat. On top of that, we found we needed to look at the entirety of reactions, so we collected data in video, tracking how 50 or 60 things moved simultaneously. This meant that our first challenge was not one of biology, but one of data, and how to process such a staggering amount.

To solve this, we had to really invest in tech, in data processing and in machine learning. We had to invent a lot of technology and go outside of our normal sphere, even buying an advanced graphics company. Technology is still a major theme for Dewpoint and just recently we announced a new partnership with Chemify, a chemistry AI and automation technology platform that will support us in extending and speeding up our development process.

What is the next hurdle that Dewpoint will need to overcome?

Our early data in animal models has shown that we can create drugs that solve challenges no one has been able to overcome before.  We’re looking at drugs for diseases like cancers and ALS, which could transform diseases outcomes. But it’s still early, and our challenge now is to prove that the drugs work in humans. Moving into human trials comes with lots of challenges, some of these will be unique to condensates, but some are just part of the process. People forget that half of all drugs that go into phase 3 fail because of the process and manufacturing part of their submission. So, we can have the best science and the best drugs, but we need to make sure we also have the specialists to deal with all the technical aspects that are required to get our drugs to market.

But these are problems for every platform biotech – typical growing pains – and something which I believe our CEO, Ameet Nathwani, has the vision and experience to overcome.

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“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. 

The post A conversation with Rick Young: Condensates, unlocking the next generation of therapeutics appeared first on Dewpoint Therapeutics.

“I think Dewpoint’s team is on a very promising pathway” says Dr. Eckhardt, EVP at Bayer.

As we celebrate our 5th anniversary, we are taking the opportunity to reflect on the achievements of the Dewpoint team to date and looking forward to the work still required to bring the science of condensates into the clinic and to patients. To put this in context, we interviewed a leading voice in the field of science and biotechs, Jürgen Eckhardt – a former Dewpoint board member and Head of Pharmaceutical Business Development, Licensing & Open Innovation and Member of the Executive Committee for Bayer, as well as Head of Leaps by Bayer, the impact investment arm of Bayer.

One of the first investors in Dewpoint, Juergen is a medical doctor and venture investor in healthcare, biotech, and agriculture with more than 20 years of experience. He is a strong believer that scientific breakthroughs can help us overcome some of humanity’s biggest challenges, including to cure and prevent chronic disease and to feed an ever-growing world population in a sustainable way – in short: science for a better life. He holds an MD from the University of Basel, Switzerland, and an MBA from INSEAD in Fontainebleau, France.

You first started your engagement with Dewpoint 5 years ago when you led the partnership deal with Bayer, what was it about the science of condensates that caught your interest?

Even though I studied medicine and cellular biology for many years, I only relatively recently had a view of the working of cells that was based on a very simplistic model. This meant that many key questions around why certain drugs did or didn’t work, or why they only worked in some people remained unanswered. However, learning that condensates existed was sort of an aha moment that opened up a whole new area of understanding and insight for me.

Historically, the model for finding new drugs was based on a sort of ‘lock and key’ model. We identified target proteins that were malfunctioning and searched for drugs that could influence them and change reactions. This linear model has been the standard in the industry for 100 years. But I think condensate science will be able to change this and open a whole new set of possibilities. Through the work of Dewpoint and pioneers like Tony Hyman (Dewpoint’s co-founder), we already have a totally new understanding of holistic disease mechanisms, and we can contemplate impacting entire disease systems rather than single reactions. The possibilities here could be huge and may allow us to treat diseases that we haven’t been able to before and completely change the experience for patients.

How do Bayer and Dewpoint complement each other through their partnership?

Bayer is and always has been very strong in the field of medicinal chemistry. We developed aspirin in the 19th century using this approach and we have maintained our skills in this field as our core strength. Now, we are looking at how we can complement this with new expertise and ideas.

So, when we heard about Dewpoint, we got excited, not just because of the potential of condensates themselves, but also thinking about how we could combine our expertise in medicinal chemistry with this new area of biophysics that Dewpoint is an expert in. We believe that these two areas of expertise combined can generate more interesting drug candidates that are truly transformational for patients.

Additionally, Bayer has significant experience in bringing drugs to market, which we know is not a straightforward process, and it can be an area where many drugs fail. So, we are in a strong position to support Dewpoint and help them make sure that our collaboration leads to drugs that can reach patients who need them, faster – and ultimately that’s what we are here for – to treat disease and positively impact patients’ lives.

How do you see the progress that Dewpoint has made over the last 5 years, and what do you think are the opportunities and challenges for the next 5 years?

Dewpoint has made tremendous progress. You know, when they all started, Dewpoint’s team was working with a very raw idea. There was a danger that the idea might become too broad and get lost in the science, but I’m proud to see that the team has really translated all of their knowledge into something very tangible. They have taken all their insights and learnings and built a very strong pipeline and an efficient discovery platform. It has been a real joy to observe that move from the broad view towards the labs and real drug targets that are showing promise in early-stage experiments. I believe we are now less than 24 months away from being in the clinic, with drugs that have a potential to significantly impact patients’ lives.

As for the challenges, well, there is just so much potential with this technology, and there is so much that we could learn and do… but for a small company, there are also limitations. I think Dewpoint will need to retain a clear focus in order to be very output driven. When it comes to drug development, we know challenges are endless and many, many fail on the way. So, you have to be flexible, you have to iterate and learn as you go. But I think Dewpoint’s team is on a promising pathway and I feel very, very confident in the future of this biotech company.

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