Thought Leadership Articles

June 3, 2024

Embracing the full spectrum of scientific disciplines to overcome diabetes and other complex diseases

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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Michael Fenn, PH.D.
Head of External Innovation
Dewpoint Therapeutics
Dewpoint Therapeutics
451 D Street, Suite 104
Boston, MA 02210
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