From Patients to Proteins

A pediatric oncologist makes her life even more hectic by going back to school to get a Caltech PhD

By Michael Rogers

Kathy Sakamoto (left) in her lab at UCLA's Mattel Children's Hospital, where she conducts research on leukemia. At right, she receives her PhD and congratulations from Caltech president David Baltimore at commencement in June.

As she entered her early 40s, Kathy Sakamoto, PhD ’04, was in the prime of her career. A pediatric oncologist at UCLA, Sakamoto was a tenured associate professor with her own lab, dedicated to research into leukemia. Between treating her young patients, pursuing her research, teaching, and handling administrative duties, she spent what little free time she had with her husband, a busy cardiologist. That’s when she decided to get a PhD at Caltech.

It was 2000, and Caltech had recently joined UCLA’s STAR (Specialty Training and Advanced Research) program, which gives MDs who want to focus on research the opportunity to return to school to develop their scientific skills and get their PhDs. Most doctors who sign up have just completed a medical residency program. It is rare for a seasoned physician like Sakamoto to go back to school.

“My peers here thought I was crazy,” says Sakamoto during a recent interview in her office at the UCLA Mattel Children’s Hospital. “A lot of them thought I couldn’t do it. They’d say, ‘Why do you have to do it? You already have so much on your plate.’ Now that I have my doctorate and I’m writing PhD after my name, they’re shocked. I’ll show a title slide at a talk and they’ll say, ‘You actually got your degree?’”

Sakamoto’s interest in science developed early, while she was growing up in El Sereno, a working-class suburb of Los Angeles less than 10 miles from Caltech. “I had an interest in science and medicine from watching medical shows on TV,” she says. “But I didn’t know what those professions were really about until I volunteered in a hospital in high school.” Sakamoto excelled in science classes in school and received encouragement from her parents, who only had high-school educations.

Sakamoto went to Williams College in Massachusetts, graduating in 1979, and then spent a year as a technician in a genetics lab at the City of Hope in Duarte, east of Los Angeles. She attended the University of Cincinnati Medical School, where she met her future husband, and then went to Children’s Hospital in Los Angeles in 1985 for a one-year internship, followed by a two-year residency in pediatrics, treating kids with a wide variety of illnesses. A rotation in pediatric oncology, in which she treated children with leukemia, sparked her interest in the field. She followed her residency with a three-year fellowship at Children’s Hospital, specializing in hematology and oncology.

“When I saw kids with leukemia, I thought, ‘That’s why I decided to go into medicine,’” she says. “I love the intense relationship with the families—following the children over a long time and seeing how they do. Children have completely different kinds of tumors from adults. There are more molecular and genetic problems underlying the tumors in children. We’re dealing with more interesting questions from a scientific point of view. The potential for research was phenomenal, so I thought it would be a good area to study.”

In 1990, she became a postdoctoral research fellow in hematology and oncology at UCLA, working with the current director of the UCLA Jonsson Comprehensive Cancer Center, Judy Gasson. She focused on children with acute myeloid leukemia (AML), a frequently lethal form of the disease, with only a 50–60 percent survival rate. She began a project that she’s still working on today, analyzing a protein that controls genes that are critical for cell growth and survival. Sakamoto found that the protein is overproduced in the bone-marrow cells of patients with acute leukemia but not in normal individuals. She also found that overproduction of the protein in AML patients is associated with an increased risk of relapse and poor survival.

Sakamoto became an assistant professor in pediatrics at UCLA in 1994, and four years later was named an associate professor. In 1999, she became eligible for a sabbatical and says that she wanted to learn something new. Since she didn’t want to be away from her husband, Kenneth Sakamoto, a cardiologist in Torrance, she searched for a project within the Los Angeles area. She had attended a couple of talks by Caltech associate professor of biology Ray Deshaies—who uses biochemical techniques to investigate cell growth and function—and found his work interesting, so she called him up, and asked if she could work in his lab.

“Ray was interested in translating his research into a clinical area, and I’m interested in clinical work,” Sakamoto says. “Some of his collaborators were developing a cancer therapy, and he wanted to transfer that to patients. I’d gain expertise, use my own knowledge, and translate that to patient care. To take what we learn in the lab and help patients—that’s a dream.”

Deshaies’s idea was to use an enzyme called ubiquitin ligase (the first member of this large family of enzymes was cloned and characterized by Caltech colleague Alexander Varshavsky) and get it to attack a protein implicated in cancer. “It works like cutting timber,” he says. “When you want to clear-cut the old growth in a forest, you mark the trees that you can cut with a ribbon. Ubiquitin is like the ribbon and the cancer-causing protein is like the old-growth trees in the forest. It would be a completely new way of making drugs.” Deshaies had one major problem: despite the potential for a discovery with commercial applications, he couldn’t find anyone in his lab interested in pursuing the project.

“Most of the people who come to my lab have a basic-research mindset, and this project was too applied for them,” Deshaies says. “This would link basic research with the possibility of developing new drugs. I figured that Kathy, being a medical doctor, would be the ideal person to do it, and I knew if I didn’t take her, it probably wouldn’t get done.”

The project also was a good fit because it was fairly narrowly focused. Deshaies knew that with Sakamoto’s obligations at UCLA, she wouldn’t have much time to do open-ended research. “Typically, when someone comes to my lab, the idea is less well-formed,” he says. “So you do exploratory experiments. In her case, from day one, we had a good idea of the sequence of experiments. So the project did not stray from the original trajectory. Given the limits of her time, it had to be a project like this.”

But six months would never be enough to complete the work, and as her sabbatical was ending in 2000, Sakamoto decided to stay on to get her PhD through the STAR program. She had wanted to get a doctorate earlier in her career at UCLA, but was advised at the time not to bother. “The logic back then was that I already had grants and was writing papers.” But this time, “I thought that as long as I was going to be at Caltech, it was an opportunity that I couldn’t pass up.” It was an opportunity that would mean doing two jobs at once, since she’d have to continue her clinical work and research activities at UCLA, and then find time for her graduate studies at Caltech.

“I already had 10 years of lab experience, so I was able to pick things up,” Sakamoto says. Although she stopped taking on new graduate students at UCLA, she admits that juggling the life of a student and a physician/professor was a challenge. After her sabbatical ended, she had to resume most of her UCLA obligations, including eight weeks of clinical duties each year. “I’d be at UCLA on Monday and Tuesday, and at Caltech the rest of the week and weekends. Sometimes I’d start an experiment at Caltech in the morning and come back to UCLA that afternoon to finish a different experiment. It took a toll on me physically.”

Working in the Deshaies lab as a researcher, Sakamoto also had to learn new investigative techniques, which she mostly picked up from other graduate students, some of whom were roughly half her age. “That was humbling,” admits Sakamoto. “I had to go to a lab where I knew nothing. I knew I’d have to start all over again and make mistakes. My peers were great.”

Her fellow graduate students quickly discovered that Sakamoto was a fast learner. “I taught her a little yeast genetics, biochemistry, and cell biology,” says Wenying Shou, PhD ’01, a former Deshaies graduate student. “When she came she wanted to do mammalian biology. I told her that yeast is an excellent model system because it allows one to draw rigorous conclusions. So she decided to learn yeast biology in addition to carrying out her mammalian project. That was impressive. Here was a doctor and she was willing to make an investment to learn basic biology. She was a very good student and picked things up fast. Now, as I get older and mastering a new field becomes more taxing, Kathy has remained an inspiration for me.”

For the first year, Sakamoto’s research went well. Collaborating with colleagues at Yale, she was able to develop a molecule that would link a ubiquitin ligase to a cancer-causing protein, and thereby bring about the elimination of the cancer-causing protein. But when she attempted to make it work inside cancer cells, there were setbacks. “I spent a lot of time over the next two years troubleshooting,” she says. “In science, many experiments fail. I started questioning whether I had made the right decision.”

She started to talk about quitting, but her husband urged her to keep going. “She had invested quite a bit of time,” says Kenneth Sakamoto. “It had been a little stressful, not seeing as much of each other. But to give up didn’t make sense.”

“If I commit to something, I like to see it through to the end,” says Kathy Sakamoto. By the fall of 2002, she started getting promising results. “That’s when I could see the light at the end of the tunnel.”

Says Deshaies, “We showed it was feasible that you could effect specific elimination of a disease-causing protein by mobilizing the ubiquitin ligase to attack the protein. Now we have to come up with a drug like that which can penetrate into cells. We tested the idea and it seems like it has legitimacy. It would be a completely new way of making drugs. It would be huge.”

Deshaies admits that while he initially had some reservations about having Sakamoto in his lab, since he knew she wouldn’t be around as much as the typical graduate student, the arrangement ultimately worked very well. “The fact is, this woman is motivated, she’s very organized, and she has good management skills that a 20-year-old doesn’t have. She was quite productive for the amount of time she was in the lab. She came up with plenty of technical solutions to problems.”

Deshaies says that her medical background was helpful to different degrees. “If you asked me if her medical knowledge assisted in the projects of other students, my answer would be that the impact was probably minimal, since my lab does not do clinical or translational research. On the other hand, if the question is whether people in my lab benefited from having an MD around who was likely to have a different viewpoint, then my answer is, of course, it is always beneficial to have different points of view in a creative environment.” Deshaies says that Sakamoto’s clinical contacts were also an asset. While she was earning her PhD, Sakamoto found the time to organize a seminar series at Caltech, bringing in some of the top medical researchers from UCLA to give talks.

As for Sakamoto, she says that the Caltech experience opened up a new research direction, taught her new skills, and has enhanced her credibility as a scientific investigator. “It has really opened doors and given me opportunities that I didn’t think would come up. For example, since I got the PhD, I received two NIH grants. Before it was more of a struggle.”

Although Sakamoto still has lab space at Caltech and plans to continue her Institute project with a new NIH grant, most of her time is now spent back at UCLA, taking on new graduate students, trying to transfer what she learned at Caltech to her leukemia research, and seeing patients. “I want to do both clinical work and research. Obviously, what we’re doing in cancer therapy is not always working. We need to generate better treatments. But if we didn’t intervene, our patients would all die. At the least, we give them hope.”

And for all the anguish she faces from seeing many of her young patients die, Sakamoto says that what she gets in return keeps her going. “It gives me motivation to see the kids. The kids whom I treat and see are extremely courageous. It’s inspiring for me.”

Sakamoto admits that treating children with cancer would burn her out if she were doing it all the time, and says that her research provides her with more than a buffer. “Research gives me an opportunity to think more broadly—in terms of helping a lot of people with cancer instead of just the one person I could help as a clinician. At the same time, keeping up the clinical work helps me ask the important questions that I can apply to research. In science, you never leave your work. You’re always thinking of experiments or questions. Things come to you while driving to work or when you’re in the shower. You’re living and breathing your research. It’s 24 hours a day.

“My goal is to do the best science possible and to continue seeing patients,” she says. “The ultimate goal is to find a cure for cancer, but realistically, it’s not that simple. There’s no magic pill for cancer. Tumor cells can develop resistance to drugs. Every type of cancer is potentially different. It’s very complicated. There’s a lot to learn and a lot of questions that need to be answered.

“I think of all the sacrifice I’ve made,” she says. “Since I started at UCLA, it took 15 years to get here, but this is what I want to do. I couldn’t think of doing anything else.”