David Baker’s lab at the University of Washington is announcing two major leaps in the field of AI-powered protein design. The first is a souped-up version of its existing RFdiffusion2 tool that can now design enzymes with performance nearly on par with those found in nature. The second is the release of a new, general-purpose version of its model, named RFdiffusion3, which the researchers are calling their most powerful and versatile protein engineering technology to date.

Last year, Baker received the Nobel Prize in Chemistry for his pioneering work in protein science, which includes a deep-learning model called RFdiffusion. The tool allows scientists to design novel proteins that have never existed. These machine-made proteins hold immense promise, from developing medicines for previously untreatable diseases to solving knotty environmental challenges.

Baker leads the UW’s Institute for Protein Design, which released the first version of the core technology in 2023, followed by RFdiffusion2 earlier this year. The second model was fine-tuned for creating enzymes — proteins that orchestrate the transformation of molecules and dramatically speed up chemical reactions.

The latest accomplishments are being shared today in publications in the leading scientific journals Nature and Nature Methods, as well as a preprint last month on bioRxiv.

A better model for enzyme construction

In the improved version of RFdiffusion2, the researchers took a more hands-off approach to guiding the technology, giving it a specific enzymatic task to perform but not specifying other features. Or as the team described it in a press release, the tool produces “blueprints for physical nanomachines that must obey the laws of chemistry and physics to function.”

“You basically let the model have all this space to explore and … you really allow it to search a really wide space and come up with great, great solutions,” said Seth Woodbury, a graduate student in Baker’s lab and author on both papers publishing today.

In addition to UW scientists, researchers from MIT and Switzerland’s ETH Zurich contributed to the work.

The new approach is remarkable for quickly generating higher-performing enzymes. In a test of the tool, it was able to solve 41 out of 41 difficult enzyme design challenges, compared to only 16 for the previous version.

“When we designed enzymes, they’re always an order of magnitude worse than native enzymes that evolution has taken billions of years to find,” said Rohith Krishna, a postdoctoral fellow and lead developer of RFdiffusion2. “This is one of the first times that we’re not one of the best enzymes ever, but we’re in the ballpark of native enzymes.”

The researchers successfully used the model to create proteins calls metallohydrolases, which accelerate difficult reactions using a precisely positioned metal ion and an activated water molecule. The engineered enzymes could have important applications, including the destruction of pollutants.

The promise of rapidly designed catalytic enzymes could unleash wide-ranging applications, Baker said.

“The first problem we really tackled with AI, it was largely therapeutics, making binders to drug targets,” he said. “But now with catalysis, it really opens up sustainability.”

The researchers are also working with the Gates Foundation to figure out lower-cost ways to build what are known as small molecule drugs, which interact with proteins and enzymes inside cells, often by blocking or enhancing their function to effect biological processes.

The most powerful model to date

While RFdiffusion2 is fine-tuned to make enzymes, the Institute for Protein Design researchers were also eager to build a tool with wide-ranging functionality. RFdiffusion3 is that new AI model. It can create proteins that interact with virtually every type of molecule found in cells, including the ability to bind DNA, other proteins and small molecules, in addition to enzyme-related functions.

“We really are excited about building more and more complex systems, so we didn’t want to have bespoke models for each application. We wanted to be able to combine everything into one foundational model,” said Krishna, a lead developer of RFdiffusion3.

Today the team is publicly releasing the code for the new machine learning tool.

“We’re really excited to see what everyone else builds on it,” Krishna said.

And while the steady stream of model upgrades, breakthroughs and publications in top-notch journals seems to continue unabated from the Institute for Protein Design, there are plenty of behind-the-scenes stumbles, Baker said.

“It all sounds beautiful and simple at the end when it’s done,” he said. “But along the way, there’s always the moments when it seems like it won’t work.”

But the researchers keep at it, and so far at least, they keep finding a path forward. And the institute continues minting new graduates and further training postdocs who go on to launch companies or establish their own academic labs.

“I don’t surf, but I sort of feel like we’re riding a wave and it’s just fun,” Baker said. “I mean, it’s so many, so many problems are getting solved. And yeah, it’s really exhilarating, honestly.”

The Nature paper, titled “Computational design of metallohydrolases,” was authored by Donghyo Kim, Seth Woodbury, Woody Ahern, Doug Tischer, Alex Kang, Emily Joyce, Asim Bera, Nikita Hanikel, Saman Salike, Rohith Krishna, Jason Yim, Samuel Pellock, Anna Lauko, Indrek Kalvet, Donald Hilvert and David Baker.

The Nature Methods paper, titled “Atom-level enzyme active site scaffolding using RFdiffusion2,” was authored by Woody Ahern, Jason Yim, Doug Tischer, Saman Salike, Seth Woodbury, Donghyo Kim, Indrek Kalvet, Yakov Kipnis, Brian Coventry, Han Raut Altae-Tran, Magnus Bauer, Regina Barzilay, Tommi Jaakkola, Rohith Krishna and David Baker.

— Andrea Chartock is now the head of Washington’s Office of Economic Development and Competitiveness, a division of the state Department of Commerce.

Chartock spent more than 21 years with international development company DAI, working on United States Agency for International Development (USAID) initiatives in countries including Liberia and Moldova. Her most recent efforts focused on economic growth in Ukraine before USAID was defunded this year.

Commerce Director Joe Nguyễn said that Chartock “has the experience and dedication needed to elevate our existing business community and foster growth in innovative ways.”

The department earlier this year scaled back a key economic development program amid the state budget crunch. The department currently manages more than $8 billion across 485 programs, Nguyễn said in April.

— Julie Brill, Microsoft’s former chief privacy officer, has joined the board of directors of the enterprise software company Ethyca.

“Ethyca’s approach puts privacy, security, and policy at the heart of enterprise data infrastructure. I’m excited to help guide the company as it works with global organizations to scale AI responsibly,” Brill said in a statement.

Brill left Microsoft in July after more than eight years. Her title included corporate vice president for Global Privacy, Safety, and Regulatory Affairs. Brill is also serving as an expert in residence at Harvard University. She previously shared plans to open a consultancy this fall.

— Microsoft CEO Satya Nadella named Rolf Harms, a corporate vice president at the tech giant, as an advisor on AI economics to work with the company’s top leaders. Business Insider obtained a November memo from Nadella to Microsoft executives announcing Harms’ expanded role.

Harms has been with Microsoft for nearly two decades and penned a foundational whitepaper in 2010 addressing the economics of cloud computing.

“We need to rapidly rethink the new economics of AI across the company — just as we once did with the cloud,” Nadella wrote, according to BI. “This platform shift is all about building a new AI factory and family of Copilots and agents that drive diffusion and usage across the full stack.”

— Seattle Reign FC and Seattle Sounders FC announced Sean Coury as chief financial officer. Coury joins the soccer clubs from Bezos Academy, where he served as CFO of the educational nonprofit launched by Amazon founder Jeff Bezos. He previously worked in financial roles at the Bill & Melinda Gates Foundation and Apptio, where he helped the Bellevue, Wash., company go public.

The Reign and the Sounders last month hired Ro Vega as chief marketing officer.

— Francois Ajenstat is leaving his position as chief product officer at the software company Amplitude. Ajenstat was previously CPO at Seattle’s Tableau Software, where he spent 13 years, followed by a brief run at Salesforce that ended in 2023. Earlier in his career, Ajenstat was with Microsoft for a decade, holding titles including technical evangelist, product manager and senor director of environmental sustainability.

— The University of Washington’s Institute for Protein Design (IPD) has multiple leadership changes.

UW biochemistry professor Neil King is now IPD’s deputy director as Lance Stewart, former interim executive director, retires from the organization. King was previously an associate professor at IPD, and Nobel Laureate David Baker will stay in his role as director.

“When I joined the IPD in 2013, it was clear that helping to build the IPD would be a once-in-a-lifetime opportunity to contribute and observe firsthand the development of a whole new industry based on computationally designed proteins,” Stewart said on LinkedIn.

The IPD made three additional hires:

• Jenny Cronin is now director of translational research, joining IPD from AI2 Incubator, a Seattle-based startup organization. Cronin is also a venture partner with Pack Ventures, a fund that backs startups with UW connections.
• Roseanne Hampton Reich is assistant director of administration. Her past roles include positions at lululemon, UW’s Division of Nephrology, Seattle Children’s and others.
• Justin English is director of strategic development, previously working as an assistant professor at the University of Utah. English holds a PhD in pharmacology. 

— Alex Pettit is returning to Oregon to serve as the state’s digital transformation projects director. Pettit has previously held top technology roles for Oregon, Texas and Oklahoma, and was most recently Colorado’s chief technology officer for nearly six years.

“This next chapter allows me to bring hard-won experience from the field and apply it to familiar soil. I’m honored to once again contribute to Oregon’s technology future — helping modernize legacy platforms, evolve our enterprise architecture, and prepare for the demands ahead,” he wrote on LinkedIn.

— Brian Bishop is CEO of Portland, Ore.-based Skip Technology, a startup building long-duration, grid-scale batteries. Bishop takes over for Brennan Gantner, who co-founded the hydrogen bromine battery company seven years ago.

Bishop has more than 30 years of engineering, manufacturing and management experience in a variety of electronics-focused businesses. He was previously with Salt Creek Capital, which acquires and recapitalizes small companies.

— Kelly Goetsch has taken a new title at e-commerce logistics startup Pipe17, moving from chief operating officer to president. The Seattle startup announced a $17.5 million Series A round earlier this year.

Goetsch has also helped lead the creation of the first open standard to unify how commerce systems communicate, including AI-powered selling channels and payments, logistics and fulfillment. The effort was overseen by the nonprofit Commerce Operations Foundation, which released the initial standard this week.

— Tom Mara, executive director of SIFF, has left the nonprofit following the decision not to renew his contract, the Seattle Times reported. Mara previously ran the popular Seattle radio station KEXP, then joined SIFF in 2022.

The following year Mara announced the organization’s purchase of the historic Cinerama, a movie theater previously owned by Microsoft co-founder Paul Allen that ceased operations during the pandemic. The acquisition was celebrated by many, but the venue has struggled financially.

Editor’s note: This series profiles six of the Seattle region’s “Uncommon Thinkers”: inventors, scientists, technologists and entrepreneurs transforming industries and driving positive change in the world. They will be recognized Dec. 11 at the GeekWire Gala. Uncommon Thinkers is presented in partnership with Greater Seattle Partners.

Before he launched a venture-backed biotech startup, prior even to landing a research role in one of the world’s premier academic labs, Anindya Roy arrived in the U.S. with two suitcases and $2,000 in the bank.

Roy grew up in rural India in a home that lacked electricity and running water during his childhood. A passion for science fueled his ambitions, leading him to earn degrees at the University of Calcutta and the Indian Institute of Technology in Kharagpur.

Then he made the bold leap in 2008 to pursue his PhD at Arizona State University, which led to a postdoctoral fellowship with David Baker, a University of Washington professor who last year won a Nobel Prize in Chemistry.

In 2023, Roy co-founded Seattle-based Lila Biologics, which uses the AI-powered protein design technology developed in the Baker lab to pursue cutting-edge medical therapies.

“Anindya is a brilliant and determined scientist and innovator who has made key contributions across diverse areas of science,” Baker said, “and is charting a most exciting path forward with Lila.”

Dr. Sheila Gujrathi, a biotech executive and chair of Lila’s board of directors, described Roy as “a thoughtful and creative problem-solver who approaches each challenge with genuine humility. He stands out not just for his innovative thinking, but also for his sincere kindness and integrity.”

Unlocking potential

In the lab at ASU, Roy focused on protein engineering for sustainable energy resources, but he was eager to apply those skills to medicine. He sent an email to Baker who invited him for an interview and tour of his protein creation lab, which delivered a kid-in-a-candy-shop kind of experience.

“That was the most exciting thing because it was such an amazingly diverse set of computational protein design problems, aiming to solve so many different kinds of things,” Roy recalled.

He jumped at the postdoc opportunity, joining the lab that is part of the UW’s Institute for Protein Design (IPD). There he began exploring the groundbreaking tools for creating proteins from scratch, ultimately pursuing a molecule that showed promise in cancer care and the treatment of fibrotic diseases that form scar tissue in various organs.

Roy eventually entered the IPD’s Translational Investigator Research Program, which gives entrepreneurial scientists the support and training to begin commercializing their discoveries. Two years ago, he and Jake Kraft, a fellow IPD postdoc, licensed the molecule they worked on at the UW and launched Lila.

While Roy has found success in his research, scientific inquiry can be slow-going and frustrating. To unwind he turns to intense weight training and goes to live shows — he caught Lady Gaga this summer and loves house music. Roy also whips up French pastries and tortes worthy of “The Great British Bake Off.”

And sometimes he reflects on the unlikely journey that led him to launching his own company.

“Whenever I get kind of discouraged or depressed about things, I look back at my career trajectory and how far I’ve come,” Roy said. “That does give me a lot of strength.”

The power of science

His startup is also making confidence-boosting progress. Lila has raised $10 million from investors and released two AI-powered platforms for creating therapeutic proteins. One is focused on targeted radiotherapy, generating proteins that precisely bind to tumors and carry radioactive isotopes that zap cancerous cells. The other platform is used to build long-acting injectable drugs that slowly release medicine over weeks or months.

In September, the seven-person startup announced a collaboration with pharmaceutical giant Eli Lilly to develop therapies for treating solid tumors.

Roy is grateful for U.S. support of the basic research that underpins the work being done at universities, institutions and companies nationwide. He’s also worried about federal funding cuts being pursued by the current administration that threaten America’s leadership in scientific innovation.

Because while he has been doing de novo protein design for more than a decade, Roy is still amazed by what the technology can do and how fast it’s evolving.

“This is almost like science fiction,” Roy said. “Years ago, you never imagined what we are doing right now. You are designing molecules in the computer, and you are putting them in actual living systems, and it’s doing what it’s supposed to do. It is pure science fiction.”

A Seattle biotech startup born from a Nobel laureate’s lab has landed $12.7 million and partnerships with pharmaceutical giants Pfizer and Kite Pharma by using AI to design proteins that mount a multi-pronged attack on diseases.

Accipiter Biosciences emerged from stealth today with a leadership team that includes researchers who worked at the University of Washington’s Institute for Protein Design under David Baker, a 2024 Nobel Prize in Chemistry winner for his breakthroughs in building proteins from scratch.

The company is using artificial intelligence tools developed at the institute to engineer de novo proteins that have the unusual ability to bind multiple cellular targets at once, potentially amplifying their illness-fighting impact.

“We want to establish this new modality,” said Matthew Bick, Accipiter Bio’s co-founder and CEO. The strategy, he added, could unlock new ways to more effectively treat complicated diseases.

There’s evidence that combinations of drugs sometimes perform better than single therapies, but the challenge has been coordinating their actions so they work together at the same location.

In some forms of cancer, for example, multiple cell functions need to be turned on simultaneously to produce helpful molecules that work synergistically to create an effect “that is not just additive, it’s multiplicative,” Bick said.

The approach could also speed U.S. Food and Drug Administration approval and cut costs. Typically, when two drugs are combined to treat a condition, each must undergo its own expensive Phase 1 safety trial, followed by an additional trial testing them together. A single multi-functional drug would need just one Phase 1 trial.

Multiple avenues to drug therapies

Accipiter Bio has entered into a collaboration and license agreement with Pfizer to research and engineer new molecules. The deal provides an upfront payment for the startup and the potential to earn more than $330 million if Accipiter Bio hits certain milestones and through royalties.

“With Accipiter’s platform technology and collaboration, Pfizer aims to solve complex therapeutic problems with biologics that may have previously been unattainable,” said Jeffrey Settleman, Pfizer Oncology R&D’s chief scientific officer.

Accipiter Bio also has an agreement with the oncology drug company Kite, which is owned by Gilead Sciences, to design proteins for use in cell therapies. The arrangement similarly includes initial funding with the possibility of milestone payments and royalties. Kite has the option of acquiring molecules created through the arrangement and develop them into therapeutics for global sales.

On top of those efforts, Accipiter Bio has four of its own drug-development programs. Two programs are preparing for formal FDA discussions about human testing — a stage called pre-IND .

Bick would not provide details on the efforts, but said the company is researching agents for treating cancers and irritable bowel syndrome, among other ailments.

Funding and leadership

Flying Fish Partners and Takeda co-led the seed round. Additional investors are Columbus Venture Partners, Cercano Capital, Washington Research Foundation, Alexandria Investments, Pack Ventures and Argonautic Ventures.

“We’ve reached the point where computation isn’t just speeding up biology,” said Heather Gorham, principal at Flying Fish Partners and Accipiter board member. “It’s expanding what’s biologically possible.”

The startup launched in March 2023 and previously raised about $800,000 to get off the ground. Bick was a senior fellow in Baker’s lab for more than seven years and later a senior director for Seattle’s Neoleukin Therapeutics.

Accipiter Bio has 17 employees. The leadership team has three members in addition to Bick.

• Javier Castellanos, co-founder and chief technologist, was a graduate student with Baker; co-founder and CTO of Cyrus Biotechnology, another protein design startup; and a past director at Neoleukin.
• Hector Rincon-Arano, co-founder and chief scientist, was with Seagen (now a division of Pfizer) for more than seven years where he helped take a therapeutic from proof-of-concept to the first step of getting a new drug approved. He was also briefly at Neoleukin.
• William Canestaro, chief operating officer and chief strategy officer, has worked on the business and investing side of biotech with roles at the UW’s Michael G. Foster School of Business, Washington Research Foundation, Pack Ventures, Pioneer Square Labs, Cyclera Therapeutics and others. He has served on the board of directors for multiple startups.

Building on experience

While the strategy of using AI to build a new class of proteins could open the door to groundbreaking therapies, drug development is a risky business.

Neoleukin was a biotech company co-founded by Baker that spun out of the UW in 2019. The startup’s lead drug candidate, an engineered protein used in cancer treatment, under-performed in a Phase 1 trial. Neoleukin laid off many of its employees before merging with another company.

The three co-founders met at the startup and gained valuable technical and strategic lessons from the experience, Bick said. That included the need to have multiple drug programs running at once and insights into preventing immunogencity, which is an unwanted immune response to foreign bodies.

“We were part of the team,” he said, “that took the first fully de novo protein into patients.”

Researchers from Nobel Laureate David Baker’s lab and the University of Washington’s Institute for Protein Design (IPD) have used artificial intelligence to design antibodies from scratch — notching another game-changing breakthrough for the scientists and their field of research.

“It was really a grand challenge — a pipe dream,” said Andrew Borst, head of electron microscopy R&D at IPD. Now that they’ve hit the milestone of engineering antibodies that successfully bind to their targets, the research “can go on and it can grow to heights that you can’t imagine right now.”

Borst and his colleagues are publishing their work in the peer-reviewed journal Nature. The development could supercharge the $200 billion antibody drug industry.

Before the advent of AI-based tools, scientists made antibodies by immunizing animals and hoping they would produce useful molecules. The process was laborious and expensive, but tremendously important. Many powerful new drugs for treating cancer and autoimmune diseases are antibody-based, using the proteins to hit specific targets.

Baker, who won the Nobel Prize in Chemistry last year, was recognized for his work unraveling the molecular design of proteins and developing AI-powered tools to rapidly build and test new ones. The technology learns from existing proteins and how they function, then creates designs to solve specific challenges.

In the new research, the team focused on the six loops of protein on the antibody’s arms that serves as fingers that grab its target. Earlier efforts would tweak maybe one of the loops, but the latest technology allows for a much bigger play.

“We are starting totally from scratch — from the loop perspective — so we’re designing all six,” said Robert Ragotte, a postdoctoral researcher at IPD. “But the rest of the antibody, what’s called the framework, that is actually staying the same.”

The hope is that by retaining the familiar humanness of most of the antibody, a patient’s immune system would ignore the drug rather than mount an offense against an otherwise foreign molecule.

The researchers tested their computer creations against multiple real-world targets including hemagglutinin, a protein on flu viruses that allow them to infect host cells; a potent toxin produced by the C. difficile bacteria; and others.

The lab tests showed that in most cases, the new antibodies bound to their targets as the online simulations predicted they would.

“They were binding in the right way with the right shape against the right target at the spot of interest that would potentially be useful for some sort of therapeutic effect,” Borst said. “This was a really incredible result to see.”

Borst added that the computational and wet lab biologists worked closely together, allowing the scientists to refine their digital designs based on what the real-life experiments revealed.

The software used to create the antibodies is freely available on GitHub for anyone to use. Xaira Therapeutics, a well-funded biotech startup led by IPD alumni, has licensed some of the technology for its commercial operations and multiple authors on the Nature paper are currently employed by the company.

While the antibodies created as part of the research demonstrated the software’s potential, there are many more steps to engineering a potential therapy. Candidate drugs need to be optimized for additional features such as high solubility, a strong affinity for a target and minimizing immunogenicity — which is an unwanted immune response.

Before joining IPD four years ago, Ragotte was a graduate student doing conventional antibody discovery and characterization using animals.

The idea that one day you could get on a computer, choose a target, and create a DNA blueprint for building a protein was almost unimaginable, he said. “We would talk about it, but it didn’t even seem like a tractable problem at that point.”

The Nature study is titled “Atomically accurate de novo design of antibodies with RFdiffusion.” The lead authors include Nathaniel Bennett, Joseph Watson, Robert Ragotte, Andrew Borst, DéJenaé See,
Connor Weidle and Riti Biswas, all of whom were affiliated with the UW at the time the research was conducted, and Yutong Yu of the University of California, Irvine. David Baker is the senior author.

Additional authors are: Ellen Shrock, Russell Ault, Philip Leung, Buwei Huang, Inna Goreshnik, John Tam, Kenneth Carr, Benedikt Singer, Cameron Criswell, Basile Wicky, Dionne Vafeados, Mariana Sanchez, Ho Kim, Susana Torres, Sidney Chan, Shirley Sun, Timothy Spear, Yi Sun, Keelan O’Reilly, John Maris, Nikolaos Sgourakis, Roman Melnyk and Chang Liu.