What if we could combine technology and medicine to boost the body’s natural ability to fight off life-threatening diseases like cancer — without patients having to undergo harsh treatments like chemotherapy and radiation?

Ambitious questions like this are at the forefront of an innovative research collaboration at UW Medicine, created by Hannele Ruohola-Baker, PhD, the associate director of the Institute for Stem Cell and Regenerative Medicine (ISCRM). She sees artificial intelligence as the future of regenerative medicine and has teamed up with researchers from the Institute for Protein Design (IPD) on a collaboration informally known as DREAM, short for Designed Regeneration for Medicine.

In their shared lab space, located in Seattle’s high-tech South Lake Union neighborhood, ISCRM and IPD researchers are using stem cell biology, protein design and artificial intelligence to develop new treatments for cancer, COVID-19 and other urgent health challenges.

“Artificial intelligence is really entering the space of protein design and biology,” says Ruohola-Baker. “In the next five years, these fields are going to change the future of medicine.”

Collaborating to design better cures

Head shot of Dr. Hannele Ruohola-Baker, PhD
Hannele Ruohola-Baker, PhD

The DREAM collaboration began with an intriguing observation. The Ruohola-Baker lab, which studies stem cell regeneration, noticed something unusual: When they gave fruit flies chemotherapy or radiation, the flies’ cancer cells would die, but the cancer stem cells survived.

They learned that the dying cancer cells send out a distress signal to cancer stem cells, which triggers a cell-to-cell signaling pathway called Tie2. This tells the cancer stem cells to go into a sleep mode that shields them from damage during chemotherapy or radiation. Then, when treatment ends, the cancer stem cells “wake up” and can begin growing and dividing again, leading to a cancer relapse.

Because the Tie2 pathway is also found in human stem cells — both healthy and cancerous — the Ruohola-Baker team wanted to know if they could use protein design to regulate pathways like Tie2, preventing cancer stem cells from entering this protective sleep mode.

They brought their discovery to IPD’s researchers, who suggested using tiny, computer-designed structures called nanocages. These microscopic protein scaffolds are created with powerful computational-design software, which uses artificial intelligence to design synthetic proteins that will snap together into nanocages. The nanocages would bind to Tie2 receptors on a cell’s surface, giving the researchers control over the cell’s activity and the Tie2 pathway.

Working together, IPD designed and ISCRM tested several nanocages that successfully inhibited the Tie2 pathway. By keeping only the cancer stem cells “awake” during treatment, while allowing healthy, noncancerous stem cells to enter protective sleep, scientists can target cancer more effectively and reduce damage to healthy tissues.

Being able to control pathways like Tie2 could also help calm inflammation caused by infection, promote healing by encouraging cell regeneration and even block viral infection before it happens.

“Now, we can take what nature already does and do it better. We’re not just waiting and seeing what happens; we’re really designing this regeneration by designing the proteins,” says Ruohola-Baker.

The DREAM team proved that nanocages can be used to influence cellular pathways in the body, lowering cancer stem cells’ defenses. But just keeping the cancer cells “awake” wasn’t enough — they also needed a more targeted and effective way to kill them. So they decided to take on one of the most aggressive, treatment-resistant cancers around.

WATCH this video to learn how the Institute for Protein Design uses artificial intelligence and computational design to create synthetic proteins that can lead to new medicines.

Headshot of Julie Mathieu, PhD
Julie Mathieu, PhD

Using proteins to kill cancer
Imagine replacing multiple rounds of chemotherapy or radiation with a simple dose of cancer-killing nanocages. That’s one possibility that Julie Mathieu, PhD, an ISCRM researcher, is investigating through the partnership with IPD.

Mathieu’s research focuses on a different cell pathway, called TRAIL. This pathway is a network of protein molecules that triggers cell death in tumor cells. Mathieu, an assistant professor of comparative medicine, seeks to use IPD’s nanocages to unlock TRAIL’s cancer-killing potential. By designing a nanocage that can regulate the TRAIL pathway, Mathieu and her colleagues hope to precisely target cancer cells to induce cell death.

Mathieu is testing this approach on renal cell carcinoma, the most common form of kidney cancer. Renal cell carcinoma kills nearly 15,000 people in the U.S. each year and is especially resistant to drugs, so there is an urgent need for more effective treatments.

With colleagues in the Ruohola-Baker lab, Mathieu experimented on a renal carcinoma cell line to test whether the nanocages could boost TRAIL activity and trigger cell death. They found that IPD’s nanocages helped TRAIL kill the cancer cells — without harming healthy cells.

For patients with aggressive cancer, these discoveries could be a powerful combination. First, inhibiting the Tie2 pathway would stop the cancer stem cells from entering their protective sleep, while allowing healthy, noncancerous stem cells to go into sleep mode. Second, using nanocages to boost TRAIL receptors would help to kill both cancer cells and cancer stem cells. After treatment, the noncancerous stem cells can wake up again and begin regrowing tissue.

“It’s very important to specifically target cancer stem cells, because if you leave even a few of them, it can lead to a relapse,” says Mathieu. “We can do that by using Tie2, so they don’t go to sleep and lie in wait, and then by using TRAIL, to make sure we really kill them without killing healthy cells. And we can do that using de novo designed proteins.”

Donor support moves research forward
Ruohola-Baker sees many areas of potential in the innovative research her team is undertaking. There’s the promise of developing lifesaving treatments and cures for some of the most difficult diseases. And there’s the opportunity to enhance Seattle’s reputation as a technology leader by spinning off biotech companies that can turn DREAM discoveries into marketable technologies.

“Seattle is a mecca for protein design,” says Ruohola-Baker. “The time is now, and this is the place to do it. With this wonderful collaboration, we have an opportunity to really change the way human health is going to be treated in the future.”

Donor support is key in maintaining their momentum. Having support throughout the research and development process, says Ruohola-Baker, is essential to protecting their intellectual property and hard work. That includes patenting the novel technologies and techniques developed through their collaboration.

Donor support can also fast-track research. For example, additional funding would enable Mathieu’s team to do more testing, using preclinical models, of the designed proteins that target cancer stem cells. These tests make sure the proteins are safe and effective and help identify the best way to deliver them to patients — an important step that would bring them closer to clinical trials.

Support from generous donors has already been invaluable in research that combines stem cell biology and designed protein technology, and Ruohola-Baker and her colleagues are appreciative of how philanthropy can advance their work.

“It is the vision of our donors that gives us the opportunity to push the field forward to a level where it hasn’t been before,” says Ruohola-Baker.

Written by Stephanie Perry

Learn how scientists at IPD are using protein design to help us reach a pandemic-free future.

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