Sam Karlin, mathematician who improved DNA analysis, dead at 83

By Dan Stober

Sam Karlin, 83, an influential Stanford math professor whose wide-ranging pursuits included a significant contribution to DNA analysis, died Dec. 18 at Stanford Hospital after a massive heart attack.

Known for his mathematical brilliance, his love of argument, his widespread interests, a competitive spirit and—perhaps surprisingly—an innate skill in the care and nurturing of graduate students, Karlin worked with his characteristic intensity and enthusiasm until the very end of his life. "He was an energetic character," said Mathematics Department Chair Rafe Mazzeo. "I think he even tired out his postdocs."

Karlin intentionally changed his major line of research every seven years to stay fresh and learn new topics, said his friend and former grad student Burt Singer, professor of demography and public affairs at Princeton University. This approach was effective: Over the course of his career, Karlin made fundamental contributions to game theory, analysis, mathematical statistics, a subfield of mathematics known as total positivity, probability and random processes, mathematical economics, inventory theory, population genetics, bioinformatics and bimolecular sequence analysis.

He was a pioneer in the application of mathematics and statistical models to problems in biological sequence analysis. He worked in this field for the last 20 years or so. He wrote many important papers in bioinformatics, but probably the most influential was a series of papers with Stephen Altschul in the early 1990s laying out the statistical foundation for BLAST, the most frequently used piece of software in computational biology.

Researchers use the software to attempt to learn the function of a new DNA sequence from an organism of interest. "BLAST is the first thing applied to figure out what we have found," said Russ Altman, a Stanford professor of bioengineering, genetics and medicine.

"Because of the common descent of all living things, it is often possible to learn a lot about a new DNA sequence by finding out what is known about other sequences that are similar," Altman said. BLAST compares the new sequence to an enormous database of sequences. "It estimates the significance of the match between the input sequence and the 'hits' that are pulled out. This is where Sam's contribution was—he worked out the statistical theory for how to judge which matches really meant something.

"So BLAST is basically the Google of biological research."

Karlin's work in bioinformatics was so important to him in recent years that when asked what his field was, he would say he was a molecular biologist.

Karlin was known for his strong opinions and his energy in expressing them. "He was a complicated person. A real workaholic, a dominating personality," Mazzeo said. Singer described Karlin's personality as outgoing, "to put it mildly."

Singer has a clear memory of what it was like to be outside Karlin's office at Stanford. "The door was closed, but it might just as well have been open. You could hear the shouting," he said. A visitor might leave the office "white as a sheet," Singer said, but would nonetheless realize the value of Karlin's ideas and, usually, the fact that Karlin was well intentioned.

With his numerous graduate students, Karlin showed a different side. He was generous, with an unerring knack for "understanding where you were at, what you were capable of," and knowing when to push students and when to leave them alone, Singer said. "I thought he was just a wizard at dealing with PhD students." Karlin kept up with his students—there were more than 70—after they left Stanford, helping them gain promotions and awards.

After his death, a group of his colleagues wrote that "to describe the collection of his students as astonishing in excellence and breadth is to understate the truth of the matter. It is easy to argue—and Sam Karlin participated in many a good argument—that he was the foremost teacher of advanced students in his fields of study in the 20th century."

Karlin was born in Yonova, Poland, in 1924. His family immigrated to Chicago when he was a small child and struggled financially through the Great Depression. He was raised in a strict Orthodox Jewish household but broke with religion in his early teens and remained an atheist for the rest of his life. Much later, he would tell his children that walking down the street without a yarmulke on his head for the first time was a milestone in his life.

Karlin took his undergraduate degree from the Illinois Institute of Technology before earning his doctorate in mathematics from Princeton University in 1947 under the direction of the celebrated Salomon Bochner. After a stint at the California Institute of Technology, he arrived at Stanford as a professor of mathematics and statistics in 1956.

He was the author or coauthor of 10 books and more than 450 published papers, and the recipient of many awards and honors, including membership in the American Academy of Arts and Sciences and the National Academy of Sciences. He was awarded the National Medal of Science in 1989.

His early work in game theory opened the way for analysis of games of pursuit and evasion, as in airplane duels between fighters and bombers. In the 1950s he became fascinated by the development of dynamic inventory theory, bringing his game-theory perspective to the problem of helping factory owners or retailers optimize their ordering.

Karlin and his first wife, Elsie, had three children, sons Kenneth and Manuel, and daughter Anna. The marriage ended in divorce; Karlin was eventually remarried to Dorit Carmelli, who was a graduate student when they first met at the Weizmann Institute of Science in Rehovot, Israel. For six years, starting in 1970, Karlin divided his time between Stanford and the Weizmann Institute, where he became head of the Department of Applied Mathematics.

Carmelli said from the couple's Palo Alto home that her husband was not a man swayed by formalities. They lived together for years before marrying 10 years ago—because an official marriage license held little value for him. He won numerous professional awards but kept them in a drawer. Honesty was the virtue most important to him, she said.

Karlin was a tennis player, an avid football fan and reader of the New York Times. And, yes, Carmelli said, her husband had strong opinions at home as well as in the office: "He was a great debater. You always had to prove it clearly that you were right, if you were on the other side."

Like her husband, Carmelli is a research scientist, a veteran of SRI in Menlo Park, known for her long-running studies of twins. Together they would fly to Philadelphia to enjoy the wide-ranging discussions of the American Philosophical Society, founded in 1743 by Benjamin Franklin.

At his urging, all three of Karlin's children followed his path into science. Kenneth is a professor of chemistry at Johns Hopkins University in Baltimore, Manuel is a physician in Portland, Ore., and Anna is a professor of computer science at the University of Washington in Seattle.

"He was the happiest person I have ever known, because he loved what he did so much. He was also a loving, supportive and generous parent, but he pushed us (his kids) very hard and held us to standards that were hard to achieve. It was difficult in some ways," remembered Anna Karlin. But the math courses he pushed her to take aided her career, and the music lessons he enforced came in handy when she began playing guitar in Severe Tire Damage, the first band to play live on the Internet. (She didn't tell him much about the band, certain he would have told her to stop wasting time and get back to her research.)

"He was the kind of person who left his mark on everyone who knew him. If you were involved with him in any way, he had an impact. You wouldn't forget him," she said.

Karlin is survived by his wife, Dorit Carmelli of Palo Alto; children Kenneth of Baltimore, Manuel of Portland, Ore., and Anna of Seattle; stepson Zvi Carmelli of Germany and Israel; and nine grandchildren.

A memorial service has been held.

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