One Small Protein, One Giant Step for Science

Terumi Kohwi-Shigematsu ’71 has made groundbreaking discoveries that changed scientific orthodoxy and may one day lead to treatments for common cancers.

By Todd Farley
Photos Submitted by Terumi Kohwi-Shigematsu

Terumi Kohwi-Shigematsu’s journey from a Washington College chemistry graduate in 1971 to a 2017 Fellow at the American Academy for the Advancement of Science (AAAS) is far from a straight line. Rather, it’s a tale of twists and turns, crossing continents, defying strict gender roles, and weaving through multiple universities and academic majors.

Kohwi-Shigematsu first came to the U.S. as a 9-year-old in the late 1950s, when her father’s banking job saw him assigned to New York City for a three-year stretch. Kohwi-Shigematsu didn’t speak a word of English but quickly settled into her new American life. The real “culture shock” came when she returned to Japan, where her elementary school peers bullied her for her strange American ways. It took her a year to regain her Japanese language skills.

When Kohwi-Shigematsu was a junior in high school, her father was again posted to the U.S., this time to Washington, D.C. The family settled in Bethesda, Maryland, and because universities in Japan had no programs to accept transfer students from abroad, Kohwi-Shigematsu set her sights on attending an American college. To persuade her parents to allow her to stay after their return to Japan, she needed a college that offered a safe environment and was financially feasible.

One visit to Washington College was all it took.

“It was there I was most comfortable and felt at home,” Kohwi-Shigematsu explained. She is extremely grateful that the College awarded her a full scholarship to cover her tuition, room, and board for her junior and senior years after her family returned to Japan.

At Washington, Kohwi-Shigematsu thrived. She appreciated the close connections between students and professors and how smart and conscientious her fellow chemistry students were, how thorough and thoughtful her professors were, and how difficult the work could be. She and the other chemistry majors often worked late into the evening, attempting to identify the “unknown chemicals” assigned to each student. Many nights, it was close to midnight when they walked back to the dorms together.

“At Washington College, every exam I took felt like an entrance exam for my graduate program,” she said.

Kohwi-Shigematsu had always wanted to be a doctor, like her great-grandfather, who was a doctor for the last Tokugawa Shōgun in Japan. After medical training in France, he returned to Japan in 1869 to assist the Shogun during the brief Boshin War. He treated wounded soldiers regardless of whether they were allies or enemies and established the foundation for the Red Cross in Japan. Unfortunately, Kohwi-Shigematsu, as a foreign student, could not get a student loan to attend medical school in the U.S., so she opted for a career in scientific research.

After Washington, Kohwi-Shigematsu went to Johns Hopkins University to study chemistry, thanks in part to the advice from and influence of Washington College professors Joseph McLain, Frank Creegan, and John Conkling.

“These professors convinced me that knowledge of chemistry is foundational to understanding all biological processes, so I wanted to study more about chemistry and quantum mechanics to understand how our bodies function,” Kohwi-Shigematsu said.

However, her lack of physics knowledge hampered Kohwi-Shigematsu’s studies, and she did not pass the first oral exam (the first of the two doctorate-qualifying exams).

Terumi Kohwi-Shigematsu at her graduation in 1971

A banner on a Lawrence Berkeley Laboratory shuttle bus

A close-up of the banner featuring Kohwi-Shigematsu ’27

A close-up of the banner featuring Kohwi-Shigematsu ’27

“The Johns Hopkins department chair told me in his office that I might as well become a secondary school teacher!” she said. She was dismayed that he would end her research career so flippantly before it had even begun. She looked out the window and saw that it was starting to snow, with the fresh flakes quickly absorbed into the ground.

She turned back to the chair and said, “My physics may be analogous to how snow falls and settles on the ground. Once the ground is thinly covered by snow, it begins to accumulate rapidly.”

“That sounds like a Japanese poem,” the chair replied. “OK, you can take the second main oral exam in six months.”

Catching up on physics in six months was not easy. Kohwi-Shigematsu is forever grateful to James C. Walker, a physics professor at Hopkins, who kindly guided and monitored her progress. She passed the oral exam with honors. Many years later, after she became an independent principal investigator, she was invited to give a talk at the Johns Hopkins Medical School and met up with Walker. He said that he always remembered her as an intelligent student. Kohwi-Shigematsu thought he had misremembered her, as she had sought his help after failing the oral exam. But Walker said, “Solving equations in physics is easy. But facing and solving life’s problems is difficult. It requires both intelligence and self-confidence.” Kohwi-Shigematsu still finds his words a source of encouragement.

When she was near completing her doctorate in chemistry at Johns Hopkins, Kohwi-Shigematsu realized that this had never been her goal. She had always wanted to do basic medical science, searching for the root cause of diseases and how to cure them, and this degree would take her on a different path. She decided to pivot and follow her dream. Instead of transferring to biology at Hopkins, which would have taken seven more years to earn a doctorate, she took the entrance exam and was accepted into the graduate program in pharmaceutical sciences at the University of Tokyo. There, she earned a doctorate in biochemistry in three years.

“That was the end of my educational career as a student,” she said.

At the University of Tokyo, she met her lifelong collaborator and husband, Yoshinori Kohwi, who earned his doctorate the same year. Kohwi-Shigematsu, with a newborn daughter named Minoree, followed her husband to northern Japan when he was offered a university job. As a woman, Kohwi-Shigematsu could not get hired as faculty.

“They had what I would call a very strict culture against females pursuing professional careers,” Kohwi-Shigematsu said.

Kohwi-Shigematsu was not deterred. In the early 1980s, she was awarded a National Institutes of Health (NIH) Fogarty International Fellowship. Her husband quit his job, and the couple moved to Seattle, where both did post-graduate work at The Fred Hutchinson Cancer Center. After the completion of her fellowship, the La Jolla Cancer Research Center (now the Sanford Burnham Prebys) recruited Kohwi-Shigematsu, and she was given the freedom to do her own research.

“At La Jolla, I got my NIH research project grant (RO1) very quickly and made myself independent,” she said. Scientific collaboration with her husband started at La Jolla, where he also received an NIH grant to set up his lab. Their collaboration has continued for 40 years.

From 1984 to 1996, Kohwi-Shigematsu remained at La Jolla before spending nearly two decades as a senior scientist at the Lawrence Berkeley National Laboratory. Since 2015, she has been a professor at the University of California at San Francisco. Overlapping with this, she was a visiting professor at the Karolinska Institute, Stockholm, Sweden, for three years.

Solving equations in physics is easy. But facing and solving life’s problems is difficult. It requires both intelligence and self-confidence.

For the last four decades, Kohwi-Shigematsu has been researching SATB1 (“SAT-BEE-ONE”), a nuclear protein she and her husband discovered. Together they have been trying to figure out how this protein, located in the nuclei of cells, functions, and it has brought them many surprises.

“SATB1 is our baby,” Kohwi-Shigematsu laughed, “but it’s now spreading quite a bit in the scientific world.”

Their study of DNA and how it can adopt an unusual single-strand structure (non-B-DNA) that is different from the normal double-helix (B-DNA) form led to the discovery of SATB1.

“When I was at the University of Tokyo, I thought maybe DNA doesn’t have to be in a double-stranded configuration at all times,” she said. “Maybe other configurations are important as well.” The scientific community did not readily accept this idea.

In the early 1990s, the Kohwi team (Kohwi-Shigematsu and her husband) devised a unique chemical method to detect various non-B-DNA structures formed by unique DNA sequences inside cells. Among these, they found DNA sequences that had the strong ability to be continually unzipped or unwound under specific conditions. She realized that if such DNA features are biologically important, a protein must recognize and bind such unique DNA sequences. This led the team to isolate and identify SATB1. Apparently, SATB1 recognizes a unique DNA backbone structure before adopting a fully unwound, single-stranded DNA configuration.

Importantly, Kohwi-Shigematsu’s study of SATB1 showed that proteins could act more globally than originally thought.

“In the early 1980s, people started identifying proteins that control gene expression called transcription factors. It was generally understood that a transcription factor binds to a specific DNA sequence to primarily regulate a single target gene,” she said. In other words, the common scientific understanding was that a specific protein controlled a specific gene’s function. However, SATB1 controlled the expression of multiple genes simultaneously. “SATB1 was found to be a genome organizer that forms three-dimensional (3D) conformation of DNA complexed with many transcription factors and other nuclear proteins. The large DNA-protein complex mediated by SATB1 orchestrates the transcriptional activities of hundreds of genes all at once, not one-to-one.”

The most intriguing property of SATB1 and why it was a breakthrough discovery at the time is its ability to turn on and off hundreds of genes, enabling cells to acquire new functions. “After birth, when certain cells are still growing and differentiating, SATB1 directs them to develop into specific cell lineages, such as immune cells with specific activities,” Kohwi-Shigematsu said.

How SATB1 selects specific genes for regulation based on cell type remains largely unknown. To date, most studies examining the significance of SATB1 function have been conducted by deleting SATB1.

The first deleterious health effects caused by deleting SATB1 were discovered in the immune system, where a lack of SATB1 leads to impaired T cell development and, therefore, an ineffective immune system with an increased risk of autoimmune diseases. These studies proved that SATB1 is essential for proper immune function.

Kohwi-Shigematsu subsequently learned that SATB1 has key roles in many other types of cells. For example, SATB1 in neurons regulates neuronal function. A mutation of SATB1 leading to neurodevelopmental disorders was reported by another group (Hoed et al, American Society of Human Genetics, 2021). Kohwi-Shigematsu’s team also found major behavioral issues in mice when SATB1 was deleted from specific regions of their brain.

When SATB1 is deleted, various cell types in the salivary glands do not properly develop, resulting in insufficient saliva that lacks the correct components, which leads to a poor quality of life. SATB1 is also essential for the proper growth of teeth and skin, as a lack of SATB1 results in deformed teeth and skin that does not thicken as it should.

While SATB1 plays an essential role in establishing and maintaining good health, it can also cause health problems if over- or under-expressed.

“It’s all about having the right level at the right place and time,” Kohwi-Shigematsu said.

Also, SATB1 protein expression at high levels in cancer cells can be a worst-case scenario, as it helps the cancer spread to other cells and correlates to lower survival rates.

“SATB1 is necessary for metastasis in many cancer types,” she said. “When its expression is increased, it promotes metastasis. When it is deleted, metastasis does not occur.”

Kohwi-Shigematsu’s team was the first to demonstrate SATB1’s significant role in promoting breast cancer metastasis (published in Nature, 2008).

Since then, SATB1 has been shown to increase metastasis in as many as 19 epithelial cancers, including pancreatic, head and neck, and skin cancers. Based on this, SATB1 is potentially a good cancer therapeutic target. However, while eliminating SATB1 could kill cancer cells, it might also kill normal cells that express SATB1. So, this strategy would have significant side effects that must be balanced with any therapeutic benefits.

While her most recent work is not yet at a stage where clinical therapies can be fully realized, Kohwi-Shigematsu’s team has identified a new form of SATB1 protein in cancer cells that is biochemically distinct from its counterpart in normal healthy cells. The team has devised a method to specifically eliminate this SATB1 protein. By doing so, they found that cancer cells prone to metastasis were killed while sparing normal cells. Once these findings are completed and published, Kohwi-Shigematsu hopes that their results will stimulate the cancer research community, and SATB1 research might one day lead to the prevention or cure of metastatic cancers.

“It is my sincere wish that the scientific community understands SATB1, especially the mechanistic aspects of SATB1 function, which is more advanced than what they mostly know about how nuclear proteins regulate 3D DNA,” she said. She hopes that someday, SATB1 research will help those suffering from difficult-to-cure diseases.

But if Kohwi-Shigematsu and her team have become a leading light in the world of science, she’s never forgotten her start at Washington College. For nearly a decade, she has been welcoming interns (generously funded by The Hodson Trust) from the College to spend the summer working in her California lab, giving those students an opportunity to expand their scientific experience and knowledge.

For Olivia Oakley ’21, a Bachelor of Science graduate who majored in biology, her 2019 internship with Kohwi-Shigematsu’s team in San Francisco put her on a career path from which she would never waver. Oakley says she learned a “slew of lab skills” under Professor Kohwi-Shigematsu, including cell culturing and PCR techniques, prepping slides, and imaging them under a microscope before processing, interpreting, and analyzing them. While most of that work was new to her at the time, it has become the bulk of her new job in a Georgetown University lab.

“I do a lot of microscopy work, studying protein interactions, which is very similar to what Kohwi-Shigematsu’s lab does,” Oakley said. “I would say that internship kick-started my career, that the expertise I garnered under her mentorship helped me get where I am today.”

Neuroscience major Amy MacNair ’25 said she found her 2023 San Francisco internship with Kohwi-Shigematsu equally influential, although in a slightly different way.

“I did significantly more advanced science than ever before,” MacNair says. “I learned many lab techniques and used much more high-level equipment than ever before, so when I took a genetics class back at school, it felt extremely straightforward compared to what I did in Kohwi-Shigematsu’s lab.”

But as educational as MacNair found the work, it also helped her realize that lab work might be more “solitary” than she really wanted.

“I had never had any exposure to long-term research or the beauty of research, but I also realized I missed the liveliness of group work,” she said. “So now I will be attending Ohio State for a physical therapy degree in conjunction with a doctorate in rehabilitation sciences, meaning I’ll be able to both complete research and work with patients.”

It should be no surprise that Kohwi-Shigematsu continues to affect the lives of Washington College students many decades after she matriculated there, as the College never left her heart. She was one of only four chemistry majors in the class of 1971 (along with Del Boardman, George Williams, and Edward Schulman), and all have remained close, regularly meeting for dinners and reunions over the years. Kohwi-Shigematsu emphasizes how “bonded” the four are.

“And all three of our professors,” she said. “Those people are the people who produced us.

“We were exceptionally fortunate at Washington College, and Chestertown is still my home,” Kohwi-Shigematsu smiled, “my second home.”

Olivia Oakley ’21 interns at Kohwi-Shigematsu’s lab in 2019.

Amy MacNair ’25 prepares materials at Washington.