Albert Lasker
Basic Medical Research Award

Award Presentation by Michael Brown

Michael Brown

Biblical scholars tell us that the Book of Ecclesiastes was written by King Solomon of Jerusalem. The book deals with the fleeting nature of life and includes the famous passage, "For everything there is a season, and a time for every purpose under the heavens: A time to be born and a time to die; A time to plant, and an time to pluck up that which is planted; A time to break down and a time to build up." Solomon was describing things he could see, but his wisdom applies to things we cannot see, including the proteins that make up living cells. Proteins, too, have a time to be born and a time to die. This year's Lasker Basic Science Award is given to three scientists who taught us how proteins die. In so doing, they taught us how cells live.

Let me remind you that proteins are the workers in the beehive of the cell. They catalyze the set of reactions that we call life, and they are traffic cops that regulate the timing of every event. Proteins tell our cells when to be born and when to die.

A turning point in biology was the discovery that proteins are nothing more than strings of chemicals called amino acids. A typical protein has 500 amino acids lined up in a strict order dictated by the genetic code. Indeed, a major purpose of the Human Genome Project is to tell us the order of amino acids in all of our proteins.

The importance of proteins was first appreciated in the 1930s, and biologists soon turned to figuring out how proteins were made. If we can understand how proteins are made and how this information passes from one generation to the next, we will understand life itself. This worldview led to the rise of molecular biology and its three great discoveries: first, recognition of DNA as the hereditary material; second, elucidation of the structure of DNA which told us how it replicates; and third, unraveling of the machinery that turns the DNA code into a protein string.

The molecular biologists gave little thought to the mechanism by which protein strings are disassembled. Indeed, they couldn't believe that their beautiful proteins were ever broken down at all.

And yet, annoying bits of evidence suggested that proteins had a time to die. The most important insight came from Rudolph Schoenheimer right here in New York City. Schoenheimer is not a household word like Watson-Crick, and yet he exposed the other side of the Watson-Crick coin. Schoenheimer fled from Nazi Germany in 1934, and he was given a job by Hans Clarke at Columbia's College of Physicians and Surgeons, one of the few places in the world where isotopes were being made. Schoenheimer fed isotopically labeled amino acids to animals and observed their incorporation into proteins. But the labeled proteins did not live forever. Indeed, the body destroyed its proteins precisely as fast as they were made. In the steady state, if the body made 1,000 molecules of a protein every hour, it also degraded 1,000 molecules every hour. Schoenheimer called this "the dynamic steady state."

Schoenheimer's work did not revolutionize biology—at least not right away. As late as 1955, Jacque Monod, an intellectual icon of molecular biology, proclaimed that "there [is] no conclusive evidence that the protein molecules within the cells of mammalian tissues are in a dynamic steady state." Although Schoenheimer's work was disputed, it laid the foundation for the discovery that we honor today.

That discovery begins with another victim of the Nazis, Avram Hershko. Avram was born in 1937, in a small Hungarian village where his father was a schoolteacher. The Nazis sent Avram's mother and father to different concentration camps—one East and one West. For years each of them thought the other was dead. Avram remained with his mother and miraculously they all survived—although most of their relatives did not. In 1950, when Avram was 13, the family emigrated to Israel.

Israel's remarkable attribute is its maintenance of a scholarly tradition even during the most perilous times. Avram attended the Hadassah Medical School of the Hebrew University of Jerusalem, where he earned both an M.D. and a Ph.D. degree. After serving as a physician in the Israeli army, Avram followed the well-traveled Israeli path of postdoctoral study in the United States. In 1969, he moved to San Francisco, where he worked with the late Gordon Tomkins, a hypnotic figure who mesmerized a cadre of young scientists. Tomkins introduced Avram to the dark side of molecular biology—protein degradation. They studied the regulation of an enzyme in animal cells. They found that the enzyme was degraded much more rapidly than other proteins, and this rapid degradation allowed the enzyme concentration to change rapidly in response to regulatory signals.

In 1972, Avram returned to Israel where he joined the Technion, Israel's MIT. He decided to study protein degradation at the biochemical level. He was fortunate to have a bright graduate student, Aaron Ciechanover. Aaron was a Sabra. Born in Haifa in October 1947, he is one month older than his country. Aaron earned his M.D. at the Hebrew University, and like Avram he served as an Army physician. In 1976, Aaron entered Avram's laboratory to earn his Ph.D., and that's when the fireworks began.

Avram and Aaron set up a cell-free system to measure the degradation of proteins in test tubes. They soon learned that multiple enzymes were required. Following the biochemist's classic paradigm, they separated the enzymes, and here they made their revolutionary discovery. When the enzymes selected a protein for destruction, they identified it by attaching a lethal tag. For the unfortunate protein, that tag was a Texas death sentence—there was no appeal. The protein was immediately disassembled into amino acids. The surprising aspect was the nature of the death tag. The tag was a protein—a very small protein called ubiquitin. But how is one protein, ubiquitin, attached to another protein, its target? The ubiquitin-tagging reaction had no precedents in biology so Avram and Aaron were on their own. They no longer had a paradigm to follow.

Over the five years from 1976 to 1981, Avram and Aaron dissected the ubiquitin-tagging reactions methodically, thoroughly, and elegantly. They found that three enzymes were required, acting one after the other. Each enzyme picked up ubiquitin and passed it to the next enzyme in the chain, like relay runners passing a baton. At the end of the line, the protein left holding the ubiquitin was doomed.

Hershko and Ciechanover published their findings in 10 remarkable papers, culminating in a masterful review that put the whole ubiquitin pathway together. Along the way they had help from several colleagues. The most important was Irwin Rose at the Fox Chase Cancer Center in Philadelphia. When the breakthrough work was finished, it was Ciechanover's turn for a postdoctoral fellowship in the U.S. He traveled to MIT where he met our third honoree, Alex Varshavsky.

Varshavsky had come to MIT by the most improbable path of all. He was born in 1946 in Moscow and he earned a Ph.D. in biochemistry at Moscow's Institute of Molecular Biology. The story behind Varshavsky's escape from Russia is more riveting than a novel by John Le Carré. Suffice it to say, he used a clever ploy to fool the KGB into allowing him to attend a scientific meeting in Finland. From there he escaped to Sweden and eventually he ended up at the U.S. consulate in Frankfurt. His visa application was about to be rejected when he had the inspiration to telephone David Baltimore, a Nobel laureate at MIT. He had met Baltimore briefly during David's visit to Moscow and he hoped David would remember him. Whether he remembered him or not, Baltimore responded, and he influenced the State Department to allow Varshavsky to enter the U.S. Penniless and without prospects, Varshavsky turned up at MIT. A faculty member, Alex Rich, invited Varshavsky to give an impromptu seminar. His lecture so impressed the faculty that Varshavsky was offered an assistant professorship on the spot.

Varshavsky studied histones, which are proteins that bind to DNA and establish the architecture of chromosomes. Histones are the only proteins that carry a ubiquitin tag and live to tell the tale. In the early 1980s, Varshavsky obtained from Japan a mutant clone of hamster cells that had a problem. When grown at elevated temperatures, these cells developed a deficiency of ubiquitinated histones. The cells also had another problem. They could not divide properly. Somehow ubiquitin deficiency stopped the cell cycle. Varshavsky asked a simple question: Was the deficiency of ubiquitinated histones caused by a failure of the enzymes that transfer ubiquitin to proteins? In the most improbable event of this whole story, who should turn up at MIT but Ciechanover, one of only two people in the world who knew how to study the ubiquitin transfer reaction. Ciechanover had not come to MIT to work with Varshavsky—he was working with another professor. Yet, fate brought Varshavsky and Ciechanover together. Even in retrospect, it is nearly impossible to calculate the probability that this meeting would even occur. It was largely the result of the Nazis who got Schoenheimer to New York and Hershko to Haifa and whose destruction of Moscow led eventually to Varshavsky's arrival at MIT. Maybe there is a God who has chosen these people. At MIT Varshavsky, Ciechanover, and graduate student Dan Finley set out to determine whether the mutant hamster cells had a defect in the Hershko/Ciechanover ubiquitin relay. And this is precisely what they found. When grown at elevated temperatures, the hamster cells had a block in the first enzyme of the ubiquitin transfer reaction. This block explained their deficiency of ubiquitinated histones and their failure to divide.

But the ubiquitination defect raised another question: What about protein degradation? Up to this point Hershko and Ciechanover had worked with isolated enzymes. The mutant hamster cells provided an opportunity to learn whether ubiquitination is required for protein degradation in living cells. And indeed that is just what they found. The mutant cells could not degrade their proteins.

The findings in the mutant hamster cells immediately moved ubiquitination to center stage in biology. No longer was this an elegant set of reactions that occurred in test tubes. Ubiquitination was crucial to cellular protein degradation, and it had something to do with cell division.

After making these discoveries in animal cells, Varshavsky switched to yeast, where the ubiquitination pathway could be studied with the full power of genetics. He added important chapters to the ubiquitin story, including the first insights into a mechanism by which cells choose the proteins that are to be degraded. Time prevents me from describing these accomplishments or the later contributions of Hershko and Ciechanover. Suffice it to say, these three scientists established the fundamentals of the ubiquitination system and its role in biology.

Before closing, let me tell you how important ubiquitination has turned out to be. Ubiquitination-triggered protein degradation is at the very core of biology. It influences not only normal cell division, but also the disordered cell division and differentiation that lead to cancer. Ubiquitination is responsible for the inflammatory process that leads acutely to fever, shock and death—and chronically to arthritis and other degenerative diseases. Several human genetic diseases result from defects in ubiquitination. I estimate that 1 out of 10 papers in current biology journals deals with ubiquitination in one system or another. Let me give you just one example.

You all know that cells in the body follow a precise series of reactions in order to divide. Proteins called cyclins control these events. When cyclins drop, it is a signal for the cells to enter the next phase of the cycle. The sudden fall in cyclins is caused by sudden ubiquitination, which leads to their degradation. The degradation allows the cell to enter the next phase of the cycle. We owe our active bodies to the ubiquitin relay that was discovered by Hershko and Ciechanover at the Technion and put into full biological context with Varshavsky.

I hope that this brief introduction gives you a feel for the elegance of the work of our three honorees and its fundamental importance to life. It is with great honor that I present them to you as recipients of the first Albert Lasker Basic Science Award of the new millennium.