Clifford P. Brangwynne, PhD, professor of Chemical and Biological Engineering at Princeton University and a Howard Hughes Medical Institute (HHMI) investigator.

More than a century after the fluid nature of protoplasm was established, a Cambridge, MA, startup emerged from stealth mode today with $50 million in Series A financing toward applying more recent pioneering research in biomolecular condensates—transient droplets of protein and RNA formed through liquid-liquid phase separation—to discover drugs for a variety of diseases.

Nereid Therapeutics says its drug discovery platform is based on proprietary technologies aimed at precisely measuring, interrogating, and controlling phase separation in mammalian cells. Those technologies have been developed by the lab of Clifford P. Brangwynne, PhD, professor of Chemical and Biological Engineering at Princeton University and a Howard Hughes Medical Institute (HHMI) investigator.

While it is known that phase separation and biomolecular condensate formation in mammalian cells play roles in disease processes, it has been difficult to measure the impact of therapeutics on those processes until now. Nereid says it will be able to do so in living cells, and generate predictive, quantitative metrics on therapeutic impact, by applying soft matter physics and new technologies such as machine learning-enabled mapping and measurement to understand these cellular processes, compared with other efforts using qualitative measurements based on traditional cell biology approaches.

Five years ago, Brangwynne and colleagues realized a need for new technologies to probe, control, and understand liquid-liquid phase separation in cells. Nereid says its technologies allow the company to screen molecules from its 10-million molecule library to learn which interventions may affect cellular processes involved in diseases.

“We can use these approaches as fingerprints of the underlying biomolecular driving forces at play in cells, and then ask how those driving forces are modulated when subjected to therapeutics,” Brangwynne told GEN. “We think that it’s a really completely new way of understanding how to modulate the phase behavior within a living cell.”

“We can apply this system to dozens and dozens of different diseases, and that’s why people are so excited about it,” added Brangwynne, who chairs Nereid’s Scientific Advisory Board.

Cancer and Neurodegenerative Diseases

Nereid says its drug discovery efforts will focus initially on forms of cancer and neurodegenerative diseases where pathological protein behaviors appear to be governed or influenced by phase transitions.

The company isn’t specifying which cancers or neurodegenerative disorders it is targeting, though Brangwynne said the company’s drug discovery approaches “are readily applicable to dozens and dozens of different structures in the cell, and diseases associated with them.”

Nereid’s $50 million should help it rapidly scale up operations and advance its science from discovery to IND-enabling studies. The financing comes entirely from Apple Tree Partners (ATP), a life sciences venture capital firm with $1.5 billion in capital commitments.

In addition to the capital, ATP—which has one of its major offices in Cambridge—provides strategic and operational support. Spiros Liras, PhD, a venture partner at ATP, joined with Brangwynne to form Nereid earlier this year, with Liras additionally serving as the company’s interim CEO.

Brangwynne, a biophysicist specializing in soft matter physics, is a founder of the field of biomolecular condensates, having discovered and elucidated the biophysical principles underlying how liquid-liquid phase separation drives the organization, material properties, function, and dysfunction of the membraneless organelles. Among his awards are a 2018 “Genius” grant from the MacArthur Foundation, the 2020 Wiley Prize in Biomedical Sciences, and a 2020 Blavatnik National Awards Laureate in Life Sciences.

Brangwynne’s desk includes books stretching back to the 19th century that detail research into cellular structure—including “Investigation on Microscopic Foams and on Protoplasm,” written in 1894 by Otto Bütschli. A professor of zoology at the University of Heidelberg, Bütschli was heralded as the “Architect of Protozoology,” first theorized in 1878 that the structure of protoplasm was alveolar or foam-like. Another cell biology pioneer focusing on part of the protoplasm, Edmund Beecher Wilson, PhD, detailed the widespread existence of liquid-like organelles within the cytoplasm in a lecture published in 1899 in Science.

However, until recently, researchers lacked an understanding of the molecular driving forces, including the physics, needed to fully explain the structure and function of membrane-less organelles.

Gaining Understanding

That began to change in 2009, when Brangwynne, then a postdoc at the Max Planck Institute of Molecular Cell Biology and Genetics, joined his supervisor, Director and Research Group Leader Anthony A. Hyman, PhD, and co-authors in publishing a paper in Science. Their paper applied the concept of phase separation to P granules, clusters of RNA and RNA-binding proteins found in the worm Caenorhabditis elegans, concluding: “Such phase transitions may represent a fundamental physicochemical mechanism for structuring the cytoplasm.”

In 2012, Brangwynne, Hyman, and Timothy J. Mitchison, PhD, of Harvard Medical School reported in Proceedings of the National Academy of Sciences that nucleoli had similar liquid-like properties and relied similarly on phase separation. The following year, UT Southwestern Medical Center biophysicist Michael Rosen, PhD, and colleagues published in Nature how sharp liquid–liquid phase separations and rapid condensation of micrometer-sized liquid-like droplets were enabled by multivalent macromolecules such as RNA molecules and proteins with intrinsically disordered regions (IDRs).

By 2015, no fewer than five papers independently demonstrated that IDRs were crucial to the phase transitions of biomolecular condensates. “2015 was a transition point,” Brangwynne observed. “That was when suddenly everybody started to take notice. The citations started to skyrocket, and it has just built and built and built since then.”

Especially gratifying, he said, was seeing biologists detail cell organization and function using terms straight from soft matter physics—ideas of material properties, viscosity, viscoelasticity, surface tension: “That’s exciting to see that whole conceptual framework from non-living soft matter has been brought into biology, and I’m very proud of that.”

Fresh Thinking

Liras was drawn to Brangwynne’s work because of his fresh approach to studying the cell using optogenetics, without perturbing cellular function. In 2018, Brangwynne and colleagues published a pair of papers describing the development of two novel tools in the journal Cell: Corelet, a rapid, light-activated tool for mapping local and global phase separation; and CasDrop, a CRISPR-Cas9-based optogenetic technology designed to enable controlled liquid condensation at specific genomic loci.

“I’m a chemist by background, and the idea that these biomolecular condensates become essentially reaction vessels was so intuitive to me, but it’s something that we never actually considered in anything that I had done in drug discovery before. It’s a really fresh way of thinking about cellular biology,” said Liras, who joined ATP from Biogen, where he established and led the company’s External Portfolio Innovation unit.

“Each one of these technologies in their own right are pretty important and really innovative. But what makes them very special is the connectivities, the whole continuum of induction of a phase separation, of the ability to visualize a perturbed function in a quantitative way, in a non-intrusive way, to cellular function,” Liras said. “It’s contemporary, it has the potential to produce novel therapeutics across a number of disease areas. The science has broad applicability because what essentially triggers physiologically the formation of these liquid droplets, and the function they perform is not a rare event.”

In a preprint posted October 21 on bioRxiv, Michele Vendruscolo, PhD, of University of Cambridge, and colleagues estimated that about 40% of the human proteome consisted of ‘droplet-driving’ proteins capable of undergoing spontaneous liquid-liquid phase separation under physiological conditions.

Drug Discovery’s “Holy Grail”

“What this technology allows us to do is visualize, induce the formation of these liquid droplets, visualize them clearly, study the phase diagrams in a quantitative way, and understand concentrated effect. When you’re actually modulator functioning anyway with small molecules or therapeutics, how much do you need to do what?” Liras said. “That’s the Holy Grail of drug discovery, to be rational and informed about the function and concentration of a therapeutic. That’s why we’re very excited about this technology.”

Liras has a seat on Nereid’s board, as do two other ATP partners: Seth Harrison, MD, the venture firm’s founder and managing partner, who serves as Nereid’s Chair; and ATP venture partner and Chief Scientific Officer Michael Ehlers, MD, PhD.

Nereid is not alone in trying to translate the promise of biomolecular condensates into new drugs.

In September, Boston-based Dewpoint Therapeutics raised $77 million in a series B financing toward developing its own drug discovery platform based on biomolecular condensates. Dewpoint—which raised $60 million in its Series A fundraising in January 2019—has also identified cancer and neurodegeneration as therapeutic areas of interest, but also includes cardiovascular disease, and metabolic disease.

ARCH Venture Partners led Dewpoint’s financing, with participation from new investors Maverick Ventures and Bellco Capital, and existing investors EcoR1 Capital, Polaris Partners, Samsara BioCapital, Innovation Endeavors—and Leaps by Bayer, created by Bayer to establish new companies and invest in early-stage technologies with breakthrough potential to “fundamentally change the world for the better.”

In November 2019, Dewpoint launched an up to $100 million option, research and license collaboration agreement with Bayer designed to apply Dewpoint’s condensate platform with Bayer’s small-molecule library to develop new treatments for cardiovascular and gynecological diseases. Last July, Dewpoint announced an exclusive up to $305-million collaboration, plus potential royalties, with Merck to leverage Dewpoint’s platform to develop a novel mechanism for treating HIV.

In the Works

Neireid says it has its own collaborations with biopharma giants in the works: “We can deploy our approaches for just about any disease therapeutic, and that’s why people are coming out of the woodwork as potential partners, looking to partner with us from existing large biotech companies,” Brangwynne said, declining to disclose names.

Besides big-name partners, Nereid is focused on building upon strengths that include the technologies developed by Brangwynne, and what Liras said was the company’s ability to scale up operations as it translates its technologies to drug R&D.

“When applied to a drug discovery campaign, you need to be able to actually study large signals from machine learning obviously. You also need to be able to study a large number of compounds. It’s just the ease of connectivity that is very important, because it allows for a very, very aggressive and contemporary drug discovery screening campaign,” Liras said. “That will be a pretty strong distinction of Nereid early on as we implement this technology.”

Liras added he had engaged with “some very well-endowed scientists in the field of cell biology that confirmed my enthusiasm about this. My viewpoint was from the whole thing of drug discovery, and I was really excited about it, and I still am very excited about it. We are very excited by the disruptive potential of this new science of liquid-liquid phase separation. We think that it provokes a different way to think about drug discovery.”

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