The DeForest Research Group is a buzzing hivemind of engineers, chemists, and biologists based on the south end of the University of Washington campus.
Led by Cole DeForest, a professor of chemical engineering and bioengineering and a faculty member in the Institute for Stem Cell and Regenerative Medicine, the lab has spent more than a decade developing newer and better classes of programable hydrogels – gelatin-like, water-based capsules that are good for mimicking the natural habitats of human cells, making them useful for tissue engineering, drug delivery, wound healing, and other applications in the lab and, increasingly, the clinic.
Over the last several months alone, DeForest and his team have either led or supported multiple research efforts that have showed how hydrogel technology could be used as the basis for innovations in cell transplantation, for injecting cells as medicine, and, most recently, for controlling biochemical processes inside living cells.
The tools of protein engineering are rapidly improving, enabling faster design-build-test-learn cycles compared to traditional synthetic polymers.
Looking closely at this string of studies, it’s apparent that the biomaterials business is changing rapidly across the field and in the lab. DeForest speaks to this evolution. “When we started twelve years ago, we really made our name by using synthetic chemistry to create tunable biomaterials. We still have that expertise. But one theme in our more recent efforts is the incorporation of the modern-day tools of protein engineering and chemical biology, which allows us to design, build, test, and learn much faster than we ever could before.”
“Classically, tissue engineers alter cell fate from the outside-in by controlling the properties of the materials cells grow on. Using designed proteins that undergo triggered assembly inside cells, we can now affect fate from the inside-out with programmable materials.” – Dr. Cole DeForest
The use of computational protein engineering technology to engineer transient, membrane-less organelles inside living cells is the subject of a new study led by the DeForest Research Group in collaboration with the Baker Lab in the Institute for Protein Design (IPD). The results of the investigation appear in the journal Cell Biomaterials. DeForest is the senior author of the paper. The first author is Nicole Gregorio, PhD, a former graduate student mentored by DeForest. ISCRM faculty member David Baker, who is the Director of the UW Institute for Protein Design and 2024 Nobel Prize winner in Chemistry for “computational protein design”, is also an author.
Recalling high school biology may bring back memories of structures within our cells, like the nucleus, mitochondria, lysosomes, and Golgi Apparatus, each with its own shape and purpose. Less well-known, perhaps, but of particular significance to the new study, are temporary structures, dubbed biomolecular condensates. In nature, these condensates provide more transient order within cells, appearing on demand to carry out various life-sustaining functions.
The use of computer-designed proteins to engineer temporary workstations inside cells could yield new insights about life-sustaining cellular processes.
In the investigation, the team used de novo computer-designed proteins to control when the condensates form and to tune the stiffness of the condensates, giving the field a new way to generate insights about the ways in which these liquid compartments organize cellular activity, and to understand how changes in different properties contribute to disease progression and provide greater spatial and temporal control over cellular processes.
According to DeForest, there are pros and cons to working with synthetic materials and designed proteins. Traditionally, the former offers more versatility and can be easier to encode with desired functionalities. However, says DeForest, “there’s a lot of flexibility that comes with having a micro-organism generate a hydrogel that more closely matches the make-up of living tissues.”
Groundbreaking partnership creates new tool to probe and modulate cellular biology and organization.
While scientists have constructed hydrogels from protein-based materials before, the collaboration between the DeForest and Baker teams breaks new ground by using computer-designed proteins that do not exist in nature, vastly expanding the number of potential building blocks available to researchers. In a key feature, the investigators wired the de-novo proteins with molecular switches that allow for unprecedented control over the location and composition (e.g. stiffness and texture) of the formed hydrogel.
In a 2024 study, published in PNAS, the DeForest and Baker labs unveiled a new class of hydrogels built from computer-design proteins, that were capable of spontaneously forming inside of cells. Now, Dr. Gregorio has taken the breakthrough a step further by using a small molecule trigger to dictate when such condensates form, and with what stiffness.
“We know that the stiffness of these organelles can change with aging and disease,” says DeForest. “When the condensates stiffen, it’s kind of the equivalent of shrinking the door, which disrupts the flow of nutrients, waste, or other particles. Now we have a tool to change the size of that door on demand; it’s another engineering knob to probe and modulate basic biology.”
Looking ahead, the researchers aim to develop the capacity to not only put up condensates when they want to, but to take them down in hopes of peering into cellular memory of the chain of events that may have led to unwanted stiffening. “The cell is a complicated structure,” says DeForest. “I think it’s exciting that we’re gaining new tools to unpack another level of organization through this powerful pairing of biomaterials and protein-based technologies.”
In a related article in Nature Reviews Materials, the DeForest Research Group explores how the field has evolved from natural proteins to rationally engineered systems, and now to de novo designs powered by AI. These advances unlock unprecedented control over material properties, enabling responsive hydrogels, programmable nanoparticles, and so much more. This manuscript was co-led by Dr. Gregorio and Cyrus Haas (co-advised PhD student with the King lab), with invaluable input from protein-designer Neil King.