According to most biology textbooks, the main organizing principle of the cell is the membrane. Lipid bilayers envelop organelles, including the nucleus, mitochondria, and endoplasmic reticulum, to keep some proteins inside and others outside.
The rest of a cell's internal machinery is described as floating in the cytoplasm, with proteins sometimes clashing with binding partners, substrates, and small molecule drugs.
Many scientists suddenly realized that their favorite proteins were undergoing biologically relevant phase transitions and they hadn't even realized it.
Biomolecular condensates are aggregates of membraneless molecules, such as proteins and nucleic acids, that organize themselves dynamically to perform a wide range of cellular functions.
There is a growing appreciation for the importance of biomolecular condensates and this is forcing cell biologists to rethink the classical model of the cell.
There are many examples of molecular aggregates. For example glycogen granules in liver and muscle cells, lipid droplets in fat cells, pigment granules in some skin and hair cells and crystals of various types. These structures were first observed by O. F. Müller in 1786.
Research over the past decade has shown that disturbances in condensate behavior play a causal role in a myriad of human diseases.
In amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1, a strong body of literature indicates a causal role in the deregulation of biomolecular condensates.
From the start, it seemed possible that these transient droplets could serve as cellular reaction vessels: speeding up reactions by concentrating the reactants or slowing them down by separating the reactants. More recently, researchers have unraveled their biological role in both health and disease.
In 2012, Michael Rosen, explored the biophysical properties of biomolecular condensates.
The association with the disease began to crystallize shortly thereafter. Paul Taylor, a neurologist at St. Jude Children's Research Hospital, was working to understand the genetics of neurodegenerative diseases and reported in 2013 in Nature that conserved mutations in HNRNPA2B1 and HNRNPA1 were associated with amyotrophic lateral sclerosis (ALS).
In 2015, a complete renaissance was underway. In that year, five papers independently demonstrated that biomolecular condensates were crucial for the phase transitions of biomolecular condensates.
Because biomolecular condensates are prevalent throughout the proteome, these findings have captured the imaginations of cell biologists around the world.
Research on the importance of phase transitions in ALS, in particular, has taken off. Hyman, co-founder of Dewpoint, reported with colleagues that FUS forms membrane-less organelles at sites of DNA damage and in the cytoplasm during stress, and that mutations in FUS that are linked to ALS lead to to aberrant phase transitions.
It appears that ALS-related mutations that affect the dynamics of membrane-less organelle formation make some of these structures more persistent than they would naturally be. Taylor estimates that disturbances in phase transitions account for over 90% of ALS cases.
Other neurodegenerative diseases could also be linked to liquid-liquid phase separation. In 2017, Ankur Jain and Ron Vale proposed that a large set of repeated expansion disorders - including Huntington's disease and muscular dystrophy as well as ALS - could involve the formation of aberrant RNA droplets.
In 2018, Taylor and his colleagues reported that soluble tau species, one of the main culprits of Alzheimer's disease, can form condensate.
Cancer also appears to involve the biology of organelles without a membrane.
“Condensate biology is the kind of science that will rewrite textbooks - and, we believe, rewrite medicine,” said Cary Pfeffer, M.D., acting CEO of Faze and partner at Third Rock Ventures.
Faze Medicines is founded by renowned scientific leaders in the field of biomolecular condensates:
Roy Parker, Ph.D., is a pioneer in the study of the class of condensates known as RNP granules with a focus on RNA components and their role in neurodegenerative diseases as well as other diseases.
Mike Rosen, Ph.D., is a leading expert in the formation, regulation and functions of biomolecular condensates with an emphasis on the multivalent interactions that are essential to their formation.
J. Paul Taylor, M.D., Ph.D., is a pioneer in the field of liquid-liquid phase transitions who made fundamental discoveries defining how mutations that modify these phase transitions impact neurodegenerative diseases.
Ron Vale, Ph.D., is a leading expert in molecular motor proteins who recently demonstrated how repeated expansion RNAs can lead to the formation of pathogenic condensates.
Other companies are carefully studying biomolecular condensates.
Not long ago, Nereid Therapeutics was launched with funding of $ 50 million, and Transition Bio debuted with undisclosed seed funding. Dewpoint Therapeutics, a precursor to condensates, has signed agreements with two major pharmaceutical partners since its launch in 2019. Dewpoint and Nereid also work on neurodegenerative conditions, as well as cancer applications.
Faze Medicines focuses on applications in neurodegenerative diseases, but has yet to disclose specific drug targets.
In the short term, all of these companies hope to reverse the harmful biology of condensate. As they learn to control the composition and behavior of condensate, these companies could also tackle new targets.
For example, rather than directly inhibiting a certain harmful molecule, a drug could lock it in a condensate.
Condensates allow us to think about drug discovery in a different way.
The biggest pharmaceutical companies are keeping an eye on this development. Dewpoint has already partnered with Bayer on cardiovascular and gynecological diseases and Merck & Co. on HIV.
Faze Medicines also plans to partner with large companies, says Cary Pfeffer, the company's interim CEO and partner at Third Rock Ventures.
Novartis Venture Fund, Eli Lilly and Company and AbbVie Ventures have all joined the fundraising syndicate, he says, highlighting the interest of large pharmaceutical companies in condensate.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.