Michael Levitt wins Nobel Prize in chemistry

Michael Levitt, PhD, professor of structural biology at the Stanford University School of Medicine and professor of computer science by courtesy at the School of Engineering, has won the 2013 Nobel Prize in Chemistry.

Levitt, 66, is the second faculty member of Stanford's medical school to win a Nobel Prize this week. On Oct. 7, Thomas Südhof, MD, professor of molecular and cellular physiology, won the 2013 Nobel Prize in Physiology or Medicine.

Levitt, who holds U.S., British and Israeli citizenship, shares the $1.2 million prize with Martin Karplus, PhD, of the University of Strasbourg in France and Harvard University, and Arieh Warshel, PhD, of the University of Southern California "for the development of multiscale models for complex chemical systems."

Levitt's work focuses on theoretical, computer-aided analysis of protein, DNA and RNA molecules responsible for life at its most fundamental level. Delineating the precise molecular structures of biological molecules is a necessary first step in understanding how they work and in designing drugs to alter their function.

"This is a recognition of the importance of computing in biology," said Levitt at a press conference after the announcement from the Nobel committee. He described the call from Sweden as "like having five double espressos."

Sharing with friends

Levitt and Warshel worked together in the 1970s in the laboratory of Shneior Lifson, PhD, at the Weizmann Institute of Science in Israel. "We had the idea about doing computer calculations on the large molecules that make life possible," said Levitt, who said he was relieved to hear he's sharing the prize with Warshel.

"One would hate to win the prize if people who also deserved it didn't get it," said Levitt, who holds the Robert W. and Vivian K. Cahill Professorship in Cancer Research at Stanford's School of Medicine. "So I was very pleased to hear their names."

Levitt is a member of Bio-X, a Stanford initiative that unites experts in biology, medicine, chemistry, physics and engineering.

"We are really excited on the computer side of things to see the world's biggest science prize go to someone who uses computers to make discoveries," said Jennifer Widom, chair of the Comptuter Science Department. Levitt is one of the first of this type of scientist to win a Nobel Prize.

"Michael is a real pioneer in science," said Joseph Puglisi, PhD, professor and chair of structural biology. "He was one of the first people to apply computers to biology, which is a huge field right now. This is such a deserved Nobel Prize."

Stanford President John Hennessy, PhD, agreed. "This is the strength of the research being done at Stanford, where today we mark the 10th anniversary of the Clark Center and Bio-X, the interdisciplinary initiative of which Mike is a member," Hennessy said. "The Nobel Prize is not only fitting recognition of the significance of Mike's work to medicine and another extraordinary honor for Stanford, it is further proof of the success and impact of interdisciplinary collaboration."

Levitt's award marks Stanford's thirtieth Nobel Prize.

Blazing a trail

Levitt's early work pioneered computational structural biology, which helped to predict molecular structures, compute structural changes, refine experimental structure, model enzyme catalysis and classify protein structures. His basic research set the stage of most subsequent work in the rapidly growing field. It also led to practical methods for antibody humanization that are key for modern anticancer therapy, such as the drug Avastin.

"Molecules work because of their structure," Levitt said. "And cells worked because of where things are placed inside. The only way to interfere is to first learn their three-dimensional structure. If you wanted to change a city but had no idea of where the buildings are, you would have no idea where to start."

Levitt credits his family, particularly his wife, Rina, an artist, for supporting him. "I am a very passionate scientist, but passionate scientists often make very bad husbands," he said. He and his wife have three sons and three grandchildren.

Levitt was born in 1947 in Pretoria, South Africa, and was raised there until he went to London to attend King's College to obtain a degree in physics. But then there was a hitch in his plans.

He received his PhD from Cambridge University in 1972 and was a postdoctoral scholar at the Weizmann Institute of Science in Israel from 1972 to 1974. 

"Enthralled by John Kendrew's BBC 1964 television series "The Thread of Life," I wanted desperately to do my PhD at the Medical Research Council in Cambridge," Levitt wrote in 2001 in an article in Nature Structural Biology. "Alas, there was no room for any new postgraduate students in 1967!"

Kendrew had received the Nobel Prize in Chemistry in 1962 for determining the structure of myoglobin using X-ray crystallography; "The Thread of Life" was an introduction to the concepts of molecular biology.

The program at Cambridge was full, however, but Levitt was accepted to attend the following year. In the interim, he went to study in the laboratory of Lifson at the Weizmann Institute, where his fellow Nobel laureate Warshel was then a doctoral student. At the institute, he was immediately plunged into the relatively new fields of structural biology and computers.

Building Golem

"I was in my 20s. Someone handed me a programming manual and asked me to write a program," said Levitt. He, Warshel and Lifson were working on a way to predict the energy of molecular structures and the forces that act upon them as they assume three-dimensional states. The computer at the institute, a machine custom built in 1963, was called Golem, after an inanimate creature in Jewish folklore. It cost $10 million to build.

"Whereas computers now have memory capacities measured in gigabytes, the memory of my first machine was less than one megabyte," Levitt said. "Nothing is that slow. It was thousands of times less than the cheapest machines today."

Levitt believes the computer industry deserves a large part of the credit for the work he's been able to accomplish throughout his career.

"Computers and biology go together. Biology is very complicated, and computers are such wonderful, powerful tools. And they just keep getting more and more powerful."

Uniting computational chemistry and biology

Working together, Levitt and Warshel designed a computer program they called CFF that was capable of performing the first energy-minimization calculations for entire protein structures. The first two proteins they analyzed were myoglobin and lysozyme. In 1969, Warshel took the computer program with him to the laboratory of Martin Karplus, PhD, at Harvard University. Karplus and others then refined the program to simulate protein dynamics, an advance that Levitt credited in the Nature Structural Biology article with moving the field of computational chemistry into the field of biology.

Proteins consist of strings of molecules called amino acids, like beads on a necklace. Unlike a necklace, however, proteins don't coil upon themselves passively but instead assume specific three-dimensional shapes governed by the interactions among the atoms of their amino acids – some of which attract each other and some of which push one another away. Laws of chemistry and physics dictate that the protein molecule will assume a conformation that balances these push-pull forces in a way that minimizes its energy state. These laws also affect how two or more molecules interact to carry out enzymatic interactions or other biological interactions.

"Proteins are not just good to eat, but they have specific shapes," Levitt said. "Although they consist of many thousands of atoms, they are governed by the same laws that govern the structure of bridges and houses. Everything is highly organized."

After Levitt earned his PhD from Cambridge University in 1972, he returned to the Weizmann Institute as a postdoctoral scholar from 1972 to 1974. He studied with Francis Crick at the Salk Institute from 1977 to 1979, then returned to the Weizmann Institute as a faculty member until coming to Stanford in 1987.

"This is wonderful news," said Axel Brunger, PhD, professor and chair of molecular and cellular physiology as well as professor of neurology and neurological sciences at Stanford. "He's made so many important contributions to computational biology, including the first computer simulations of proteins. His work has helped many scientists, including myself in my work."

"I went to sleep last night very excited about the work that's been done in my lab this week," said Levitt. "Yesterday someone in my lab devised a new way to do a calculation thousands of times faster than before. When something becomes so fast, it opens up whole new possibilities. So, of course I'm excited about the Nobel. But I am passionate about my research. Passion is really important for anything you do; it's a general requirement."

One of the first things Levitt did after learning of the award was to update the status on his Facebook page. "That was the most important thing," he said, joking. He also called his mother, Gertrude, 98, who lives in London. "She was very happy," said Levitt. "I am hoping she can come to Stockholm with me."

Levitt eschews titles, including doctor or professor. "Call me Michael, or Mike," he insists. He and his wife together designed a two-dimensional wire sculpture for the 2013 Burning Man festival in Nevada. Rina, the artist, designed the piece, called "Unity." Levitt, of course, used a computer to calculate the exact shape and dimensions the single long wire outline should assume.