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Yoshito Kishi, Organic Chemist Who Climbed ‘Mount Everest’ of Synthesis, Dies at 85

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{shortcode-be29865d8a9c7908fa05930b7f2d42574eaa573c}t took Harvard chemistry professor Yoshito Kishi more than 100 steps to synthesize halichondrin B, a potent anticancer agent found naturally in sea sponges in amounts too low to even study. Despite completing his initial synthesis, Kishi continued to study the molecule and improve his methods for two decades, a decision Harvard chemistry professor Eric N. Jacobsen called “unusual in the field.”

Eventually, Kishi and pharmaceutical company Eisai developed the agent into an effective cancer drug called eribulin that currently treats liposarcoma and metastatic breast cancer. Compared to the commonly-used drug dacarbazine, a 2016 FDA clinical trial of 143 patients found eribulin improved the median survival rate from 8.4 months to 15.6 months.

Kishi, well-known for synthesizing complex toxins, also developed a reputation for his diligence.

Kishi came to the lab at 9 a.m. and left at midnight from Monday to Saturday, also stopping by on Sunday to conduct research, according to Tohru Fukuyama, who worked in Kishi’s lab for almost eight years.

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“Everybody in this field works hard, but his work ethic was legendary,” Jacobsen said.

A chemistry professor at Harvard for 28 years, Kishi died on Jan. 9 at the age of 85.

Kishi was born in Nagoya, Japan, where he spent his childhood. After receiving his undergraduate and Ph.D. degrees from Nagoya University, he came to Harvard as a postdoctoral fellow and worked with chemistry professor and Nobel laureate Robert B. Woodward, who established the field of complex natural product synthesis.

Kishi returned to Japan as an associate professor at Nagoya University before becoming a chemistry professor at Harvard in 1974, joining a group of organic chemists that helped establish Harvard’s reputation for organic synthesis.

“The luminaries in the field like Woodward, Corey, Kishi, Evans — these are people that really ushered in the way that the entire generation of organic chemists think about how to construct molecules,” said Theodore A. Betley, the current chair of Chemistry and Chemical Biology.

From 1989 to 1992, Kishi was chair of Harvard’s Chemistry and Chemical Biology Department. He became an emeritus professor in 2002 but continued his research and published papers until his death.

Conquering Molecular Mountains

Kishi is celebrated in the field of organic synthesis for his total syntheses of complicated natural products, such as halichondrin B, the anticancer molecule that became eribulin, and palytoxin, an extremely poisonous agent produced by some marine corals and algae.

Alexander Wei, a former Harvard chemistry graduate student and currently a professor at Purdue University, said palytoxin was one of the most toxic non-protein compounds known at the time of its isolation in the 1960s and “one of the largest molecules that anybody had ever tried to isolate.” In 1994, Kishi became the first to create the molecule in the lab.

“With his synthesis of palytoxin, he essentially showed that molecules of any complexity, no matter how complex they are, in principle and in practice can be synthesized in the laboratory,” Jacobsen said. “So a lot of people refer to that synthesis as the ‘Mount Everest’ of the field.”

In addition, Jacobsen said, Kishi’s work on halichondrin B gave new meaning to the work of organic synthesis.

“How do you benefit humanity from the ability to make complex molecules? I really think Kishi really opened the world's eyes to that,” he said.

René Peters, who was Kishi’s postdoctoral fellow in 2000, wrote in an email to The Crimson, “I think that this courage to break new ground and face the greatest challenges was typical of Yoshito Kishi.”

Kishi is also known for his contributions to theory about acyclic stereocontrol, which Jacobsen said allowed scientists to control “the shapes of molecules as you build them based on the shapes of the building blocks.” Kishi also helped improve the Nozaki–Hiyama–Kishi reaction, which bears his name, by noticing that a small amount of nickel was critical for catalyzing this reaction, according to Betley.

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‘Master of Understatement’

Kishi’s humility often stood out. Wei said one thing “unique to Kishi Sensei is that he was a master of understatement.”

Jacobsen said Kishi would say “very self-effacing things, a little bit joking, but in a very genuine way.”

“Unlike many academics, he didn’t say very much in meetings because he was actually usually very quiet. But when he did say something, it was incredibly thoughtful, and everybody was listening because they knew that he would only speak if he had something very important to say,” Jacobsen said. “His colleagues really valued his insight and his perspective and that made him a very, very special colleague.”

Betley said he appreciated the time Kishi, already an emeritus professor when Betley joined, took to talk to him as a junior colleague.

“Oftentimes when I would ask him for 10 minutes to talk about science, the direction of the department, whatever the case may be, the conversations easily stretched into an hour,” he said.

Peters, now a chemistry professor at the University of Stuttgart, wrote that one evening in the lab, Kishi “said that he had just rediscovered in his desk his asymmetric total synthesis of tetrodotoxin (the poison of puffer fish), which he had completed 28 years earlier, but had not published.”

Kishi told Peters that he had not published around 30 completed total syntheses.

“He was mainly concerned with satisfying his scientific curiosity. He didn’t really care about the public image and reputation,” Peters wrote.

‘Warmth That Was Really Well Hidden’

The Kishi lab was a balance of intensity and humor. Fukuyama, a former professor at the University of Tokyo and Rice University, said members of the lab had to “work very hard for him because he himself worked so hard.” To avoid a 70-minute commute, Fukuyama even brought a sleeping bag to spend some nights in the lab.

Wei said the Kishi lab was the only lab in the department to have a lounge space with a TV. Although Kishi sometimes watched sports on it, Wei said he believes the “true reason” was to help his students relax during long nights in the lab.

Nonetheless, Kishi also had a “warmth that was really well hidden,” according to his former graduate student and Columbia University professor Milan N. Stojanovic. Wei said that Kishi had a “wicked sense of humor” and “a very surprisingly playful side to him.”

Laura Blumberg, who joined Kishi’s lab in 1994 as a graduate student, said Kishi’s work ethic might make his lab sound “almost like torture, but somehow it wasn’t because he had a softer side.”

University of Tennessee professor and former Harvard postdoc Michio Kurosu said some of his favorite memories were picnics in May or June, when Kishi would take his group to places around Massachusetts and Maine.

Kishi cherished his family very much, Fukuyama said, noting that the chemist would often bring his two daughters to visit his office on Sundays.

Additionally, Kishi liked to covertly check on his team as they worked, according to former lab members. Tan Choon Hong, a former Harvard postdoc and now a professor at Nanyang Technical University wrote in an email that Kishi “occasionally will sneak up behind me.” After observing him for some time, Kishi would ask him “to perform a thin-layer chromatography on the spot.” Former Harvard chemistry graduate student Margaret C. Hsu said she left cookies she baked on the filing cabinet, and Kishi “would just come by and check on the lab and sneak a cookie.”

Science, Sports, and Sushi

In the small amounts of spare time he had, Kishi enjoyed baseball and golf. Blumberg said Kishi would often take postdocs golfing, even bringing graduate students at times.

A baseball player in high school, Kishi was a fan of the Boston Red Sox, especially Japanese pitcher Daisuke Matsuzaka; however, he was less impressed with Boston cuisine.

“He was always complaining about not being able to have a good sushi, for example. Like this was the biggest thing that he had trouble with,” Stojanovic said.

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Kishi remained a passionate scientist for his entire life, according to his former colleagues. Jacobsen said that “he was a very vigorous and energetic person to the very end, but he was passionately excited about the work that he was doing.”

According to Peters, Kishi dedication to chemistry shone through even in his last years.

“Last July he wrote me ‘I am now bed-resting at home to deal with a medical problem, I do feel I am getting better, but the pace of recovery is frustratingly slow. My goal is to get back to chemistry by the end of summer,’” Peters wrote. “I think that this demonstrates his enormous passion for science.”

Correction: March 23, 2023

A previous version of this article misspelled the name of former Boston Red Sox pitcher Daisuke Matsuzaka.

—Staff writer Austin H. Wang can be reached at austin.wang@thecrimson.com.

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