GCE4ALL leads global advancements in genetic code expansion for advanced therapies

For billions of years, all life on Earth, from tadpoles to humans, have relied on the same 20 amino acids to build proteins — the fundamental building blocks of life.

But what if that list of fundamental amino acids was expanded to include any chemical ability of our choosing? What new potential could be unlocked? Imagine a future where researchers can design proteins with unprecedented precision, creating targeted therapies for diseases like cancer or developing advanced diagnostic tools that can detect conditions at their earliest stages. This exciting potential is at the heart of pioneering research at Oregon State University, where scientists are working to introduce new amino acids into proteins, fundamentally transforming their functions.

The Oregon State University National Center, Genetic Code Expansion For All (GCE4All) — the world’s first of its kind — specializes in optimizing, developing and broadly disseminating groundbreaking genetic code expansion technologies.

Genetic code expansion is a cutting-edge tool that enables researchers to add new building blocks to proteins, endowing them with special features that have endless applications in science and technology.

Bolstered by prestigious grants from the National Science Foundation (NSF) and the National Institute of Health (NIH), the center is positioned to have a strong global impact, driving innovation across various fields of science and medicine.

GCE4All was selected as one of 11 national pilot projects to receive $234K from the NobleReach Foundation. In partnership with NSF, the goal of this funding is to accelerate the translation of NSF-funded research into biotechnologies and bio-inspired designs with significant commercial and societal impacts.

Led by director Ryan Mehl, the center is developing an ultrafast protein labeling system with the NSF, that targets a specific protein in live cells without compromising their function. The ultimate goal is to enhance our ability to study life at the molecular level, leading to advancements in research, medicine and biotechnology.

The center also received funding from the National Institutes of Health and Agilent Scientific Instruments to purchase a first-of-its-kind mass spectrometer. Agilent recently acquired e-MSion, an Oregon State startup that developed electron capture dissociation technology.

“Agilent technology is a sister technology that allows for the acceleration of genetic code expansion because it proves to academic and industrial partners that GCE4All is making the noble, engineered proteins we intend,” Mehl said.

A scientist in the GCE4All lab holds a test tube up to the light.

GCE4All center director Ryan Mehl works with graduate students in the laboratory.

Revolutionizing protein research and therapeutics with GCE

GCE4All, launched in 2022, is funded by the NIH as a Biomedical Technology Optimization and Dissemination Center for $5.6M over five years. Mehl and the NIH anticipate that effective GCE tools’ reliability and usability would drive significant research breakthroughs.

“All life on the planet uses the same amino acids. Now instead of limiting ourselves, we can introduce fundamentally new amino acids and chemistry into proteins,” Mehl said. “It’s a toolkit that allows you to both study proteins in a very precise way and manipulate proteins if you need to do engineering from a therapeutic or diagnostic standpoint.”

The tools created by GCE4All are not exclusive; instead, they are intended to be shared with the broader research community to foster collaboration and drive more breakthroughs. GCE technologies will promote discoveries in determining how health-related physiological processes go wrong to cause pain, cancer, heart disease, diabetes, Parkinson’s and many other diseases. The improved technologies promise to enable the development of more sensitive and specific diagnostic tests and more effective therapeutics.

“Genetic code expansion is a gateway to better science and medicine."

For instance, in cancer diagnosis and imaging, GCE enables the development of proteins engineered to bind specifically to cancer cells. These proteins can be linked to radioactive chemicals, which serve as imaging agents, allowing precise visualization of cancer cells within the body. A critical aspect of this process is the need for quick attachment of the radioactive chemicals to the engineered proteins, opening access to people with diverse cancers. GCE provides clean and fast attachment chemistry, ensuring the imaging agent can be attached to the protein quickly before being injected into the patient.

Similarly, GCE could revolutionize diabetes treatment. Currently, diabetes management involves monitoring glucose levels and administering insulin. GCE could allow for the direct monitoring of insulin levels, which are typically at low levels and short-lived in the body. By attaching monitoring agents to insulin using GCE, treatment can become more accurate and safer.

“Genetic code expansion is a gateway to better science and medicine. There is no way I couldn’t access all the GCE potential alone, but I can train as many people as possible,” Mehl said.

Mehl started exploring GCE technology during his postdoc at the Scripps Research Institute. His fascination with studying protein function was limited by the use of the natural 20 amino acids, so adding new amino acids was obvious. He joined Franklin & Marshall College, establishing a research lab with undergraduates to study and develop genetic code expansion. Despite initial excitement for GCE, many researchers struggled with the technology, prompting his desire to provide training and educational tools.

By 2009, hundreds of new amino acids were encoded into life, but these tools lacked robustness. In 2011, Mehl moved to Oregon State University to start a facility assisting researchers. “The Department of Biochemistry and Biophysics had a lot of researchers who wanted to find out how these tools worked, and the College was very supportive of me starting a facility to help people,” Mehl said. In 2021, he sought NIH funding to expand and improve the tools, ensuring genetic code expansion could empower broader scientific research.

To achieve this, GCE4All offers online training materials, hands-on workshops and conferences that bring together the growing GCE community, including developers, users and prospective users. There is also a bulletin board on their website to facilitate discussions.

Partnering with Addgene, a nonprofit plasmid repository, GCE4All offers a PermaPhos Kit for academics and nonprofit organizations, make phosphorylated proteins of their choosing. Nearly every protein in humans is phosphorylated during its cellular lifetime to regulate cellular processes but these modifications are hard to make and study. The kit contains various substances needed to produce genetically engineered recombinant proteins with directly encoded phosphorylated serine.

The method allows scientists to make proteins with phosphoserine without needing special enzymes called kinases. These proteins can then be used to study the phosphoserine modification effects on cell signaling, protein function and protein interactions.

Since 2022, GCE4All has received 420 requests for their resources on Addgene from researchers around the world. Plans are currently underway to have another kit deposited on Addgene related to the center’s selections technology.

A researcher wearing a lab coat performs cell culture work.

Postdoctoral researcher Anamika Singh performing cell culture work in the GCE4All laboratory.

Education and industry collaboration at GCE4All

Education is another cornerstone of the GCE4All mission because greater access will transform future science. Since Mehl arrived in Corvallis in 2011, he has overseen a lab course where undergraduate students learn GCE technology for protein synthesis.

Last year, Mehl and Kari Van Zee, associate head of the Department of Biochemistry and Biophysics, revamped the molecular techniques lab course. Instead of making modified proteins, students became builders of new genetic code expansion tools.

“Our seniors love the ability to let loose and tackle their own ideas. It’s empowering, making new proteins the world has never seen and studying them to see what new properties they might possess. The course is designed to give students a taste of real cutting-edge science,” Mehl said.

Oregon State’s new strategic plan, “Prosperity Widely Shared,” prioritizes creating a university that fuels a thriving world. This includes integrating research and teaching with strong partnerships with public and private stakeholders — a realm in which GCE4All excels.

“Oregon State wants to advance our student training to make the leaders in the next generation of industry. Having a foundation in fundamentally new technology provides students a huge leg up in the future,” Mehl said. “We are developing new GCE technology needed by the industry and also training students in GCE — then we match them up in research projects so they can explore this space together.”

Mehl and the Office of the Provost established GCE4All Fellows to help graduate students build relationships with industry partners. Second and third-year students are paired with industry companies who approach GCE4All with challenges needing solutions. The commercial collaborators fund the student for 10 weeks to work on solving a key industry problem. Two students recently finished their projects and were extremely successful, Mehl said.

GCE4All has partnered with several startup biotechnology and pharmaceutical companies, and Mehl expects the number of partnerships to continue to grow.

In August, GCE4All will host its third international GCE conference and sixth training workshop at OSU. This year is special, Mehl says, because for the first time, industry leaders will present their use of GCE in advancing therapies for human health. Academic developers, academic users and industry members will brainstorm ways to advance the GCE field at the conference and leave the workshop with new tools to bring back to their respective fields.

The Oregon State University Genetic Code Expansion Center stands at the forefront of pioneering genetic technologies, driving innovation across scientific disciplines. With robust funding and a commitment to collaboration, the center continues to expand the boundaries of protein research and therapeutic development. By prioritizing universal access to advanced tools and partnering with industry leaders, GCE4All not only accelerates scientific discovery but also cultivates a new generation of leaders ready to shape the future of biotechnology and medicine worldwide.