Albert Lasker Award
for Special Achievement in Medical Science

Award Presentation by Joseph Goldstein

Joseph Goldstein Woody Allen once described his movies as slices of real life with all the boring parts cut out. Daniel Koshland, Jr., the recipient of this year's Lasker Special Achievement Award in Medical Science, would not qualify as an actor in a Woody Allen film because, as far as I can tell, there's never been a dull moment in his 78 years. Dan was born into one of San Francisco's most distinguished families. In 1853 his great great granduncle founded Levi Strauss & Co., the world's largest brand-name garment manufacturing company. His father, Daniel Koshland, Jr., Sr., was vice-president, president, and chairman of the board of Levi Strauss for 57 years, from 1922 to 1979. At Levi Strauss, the elder Koshland pioneered the hiring and training of minority employees many years before the term "affirmative action" was invented.

By the eighth grade, Dan Jr. realized that he was a born puzzle solver, and his fascination for math, physics, and chemistry exceeded his interest in jeans—spelled with a "j." In 1933, the other kind of genes—spelled with a "g"—somehow did not capture the attention of this 13-year-old wunderkind. After all, 1933 was 10 years before Avery, McCarty, and MacLeod, and 20 years before Watson and Crick.

Even though Dan decided not to go into the family clothing business, he followed in the footsteps of his father and grandfather and became the third-generation Koshland to enter college at the University of California at Berkeley, where he majored in chemistry. The next five years, 1941–46, were spent working with Glenn Seaborg at the University of Chicago on the top-secret Manhattan project, where his team purified the plutonium that was used to make the atomic bomb at Los Alamos. At the end of the war, Dan remained at the University of Chicago to obtain a Ph.D. in organic chemistry.

Atomic energy was a perfect outlet for Dan. From early childhood to this very day, he has been notorious for his combination of high energy output, low energy of activation, and catalytic personality. So it's not surprising that in the early 1950s he became intrigued with the energetics of enzymes. He focused on the crucial event in the action of an enzyme: the momentary union that occurs when an enzyme meets its substrate. The fleeting nature of this enzyme-substrate complex held the key to understanding how enzymes speed up the rate of chemical reactions by as much as 100,000-fold. Dan developed new methods to monitor the active site of an enzyme, and in 1957 he discovered that enzymes are flexible molecules that conform to the shape of the specific substrates on which they work. True to his sartorial roots, he likened this interaction between substrate and enzyme to a "hand in the glove," and called it the induced-fit theory of enzyme dynamics. Once the enzyme (the glove) wraps around its substrate (the hand), the substrate induces a rearrangement in the atoms of the active site that enables the enzyme to cleave a chemical bond in the substrate. This new theory flew in the face of the standard dogma of the day—the "lock and key theory" of Emil Fischer, which viewed the enzyme as a rigid molecule that allows only special substrates to fit into its surface in a fixed way, just as a key fits a lock.

Emil Fischer, the recipient of the Nobel Prize in Chemistry in 1902, was a formidable figure for the 36-year-old Koshland to challenge. So its not surprising that most biochemists initially greeted the induced-fit theory with great skepticism. One referee wrote that the "Fischer lock and key theory has lasted over 50 years and will not be overturned by an embryonic scientist." Stirred, but not deterred by the criticism, Koshland devised ingenious techniques over the next 10 years to validate his model. One of his methods, called the reporter group technique, allowed him to monitor the active site of an enzyme by covalently attaching an environmentally sensitive probe such as a flourescent molecule or a radioactive tracer to a region near the enzyme's active site. By the 1970s his theory was confirmed by the X-ray crystallographers, who visualized directly the induced fit of enzymes as they wrapped around their substrates. Today, the "hand in the glove" theory has replaced the "lock and key" theory in all the standard textbooks. Koshland's concept of flexible enzymes whose shape and catalytic activity could be changed by small molecules stimulated Jacques Monod to formulate his famous model for the allosteric binding of oxygen to hemoglobin.

In 1966, Koshland performed the first chemical mutagenesis of an enzyme by converting the serine residue in the active site of a protease to a cysteine using a selective chemical reagent. This single amino acid change rendered the enzyme catalytically inactive. This now-classic experiment was the first example of enzyme engineering, which has now become standard as a result of Michael Smith's invention of DNA-mediated site-directed mutagenesis in 1978.

In the mid-1970s Koshland turned to more complex biological systems and began to study how bacteria respond to chemicals in their environment—a system called bacterial chemotaxis. He chose this system because it exhibited a simple behavior that could be analyzed genetically as well as biochemically. This was a bold and visionary move for a pure enzymologist who was trained as an organic chemist. To make a long story short, Koshland discovered that bacteria swim toward attractants and away from repellents through the actions of two types of proteins: receptors and signal transducers. Receptors on the cell surface detect the external chemicals and transmit their signals to signal transducers, which are regulatory proteins inside the cell. The activity of the regulatory proteins is switched on or off by a novel form of covalent modification called methylation. Methylation was a new paradigm in signal transduction—another example of Koshland's ingenuity and creativity. With the availability of recombinant DNA, the receptors and modifying enzymes that regulate bacterial chemotaxis have now been cloned, and the X-ray crystal structures of several of these proteins have recently been solved by Koshland and his colleagues. At a molecular level, bacterial chemotaxis is the best understood simple adaptive system in all of biology, and it now serves as a model for the more complex sensory systems of higher organisms, such as vision, hearing, and smell.

The American author F. Scott Fitzgerald once wrote that "there are no second acts in American lives." At the risk of being audacious, I will modify Fitzgerald's quote to say that there are three acts in the life of Dan Koshland. I've just told you about Act 1—the visionary biochemist. Now for Act 2—the tireless institution-builder. Historically, the biological sciences at Berkeley had developed around 12 small departments that were scattered all over the campus and involved 3000 graduate and undergraduate students and 300 faculty members (out of Berkeley's total faculty of 1000). This loosely organized structure did not encourage the type of interdisciplinary collaborative research that opens new fields and makes for an exciting ambiance.

In the early l970s the first rumblings of an earthquake in molecular genetics were beginning to be felt in the Bay Area, and by 1973 the Big Revolution in recombinant DNA and gene cloning had exploded at Stanford and UCSF, bypassing Berkeley. Dan Koshland quickly perceived that a New Biology was on the horizon, and if modern biological research were to flourish at Berkeley, a bold and dramatic action was needed: the walls separating the 12 isolated departmental fiefdoms must come tumbling down. This would make it easier for Berkeley biologists to enter into creative collaborations with each other as well as with colleagues in chemistry and physics. Almost single-handedly, Dan became the tutelary spirit to explain the New Biology to the Deans and Powers-That-Be at Berkeley, and with their blessings he spearheaded a massive intellectual and physical reorganization that combined the 12 small biology departments into three large departments. He also led the effort to persuade the California state legislature to provide funds to completely renovate one existing building and to build from scratch two new life sciences buildings, one of which is named Koshland Hall in recognition of Dan's leadership role.

The reorganization took 10 years and hundreds of committee meetings. The end result is a coherent, effective, reinvigorated, and peppy life sciences faculty that now ranks among the leading 3 or 4 institutions in attracting the very top graduate students and postdoctoral fellows. Like UCSF and Stanford, Berkeley is now on the front (fault) line for the next Big One.

Several of the then-young faculty members whom Koshland personally recruited to Berkeley in the late 1970s/early 1980s to assist him in the reorganization include the now-prominent leaders on campus such as the molecular biologist, Bob Tjian; the cell biologist, Randy Scheckman; the developmental biologist, Gerry Rubin; and the neurobiologist, Corey Goodman. All of you in academia who have ever been involved in committee work can certainly appreciate the difficulties and frustrations that Dan faced in his quest to save Berkeley from mediocrity by reconfiguring the lives of 300 faculty members. Thank goodness for biomedical science that Dan ignored Milton Berle's one-liner on committee chairmen—"they're a special breed of people who love to save minutes and waste hours."

Now for Act 3 in the life of Dan Koshland—the eloquent public communicator of science. Dan is widely recognized as one of the grand statesman of science as a result of his 10-year editorship of Science magazine. As editor from 1985 to 1994, he became the voice of science in America and the world. He oversaw the transformation of Science from a good but stodgy journal into the classy publication that we all take for granted today. He expanded the coverage of public affairs to make the magazine our most influential scientific publication in public policy. He also enlivened its pages with more than 200 editorials that he personally wrote during his decade of editorship. Most of his editorials dealt with timely, serious, and controversial topics, such as sequencing the human genome, civil rights and the AIDS epidemic, drunk driving, and spousal abuse. But some had a lighter and more humorous tone. One of my favorites was published in the December 2, 1988 issue entitled "The Golden Median," in which Dan celebrates "tongue in cheek" the glorification of mediocrity that began a decade ago with the abolition of the grade F in high schools and colleges and has now taken over all society, including the Olympic Games in which gold medals are awarded to those who are in the middle of the pack and silver medals to those on either side of the middle person. Fidelity has become more popular because everyone tends to look and think alike, and so there is no temptation to stray. A major medical benefit of the Era of the Golden Median, according to Koshland, is the decline of heart attacks since mediocrity has selected for types who never do today what you can put off until tomorrow. Cancer has also declined since the general lack of exertion has led to less inhaling of ozone. But, surprisingly, despite these medical advances, people are dying at a younger age because all of their neurons have atrophied, a result of the most prevalent disease of the Era of the Golden Median—boredom. A typical example of Koshland wit.

Dan has recently made an extraordinary gift to the U.S. National Academy of Sciences to build a public science museum on the Academy's grounds in Washington, D.C. near the statue of Albert Einstein. This "hands on" museum will be devoted to teaching children how science works and will be named in honor of Dan's late wife, Marian Koshland, an eminent immunologist who shared Dan's deep love of science and passionate concern that it be understood by the public. Like his father, Dan is perpetuating the Levi Strauss tradition of philanthropy and public service—a tradition that is obviously in the genes (no pun intended).

Dan Koshland is a rare bird. His career in science is exemplified by a distinction that is achieved by only a handful of scientists who are held in universally high esteem by their colleagues because of their human qualities of honesty, kindness, unselfishness, originality, and wisdom, and in Dan's case there's also wit. By the F. Scott Fitzgerald standard, Dan has accomplished the impossible in his quest for elevating science to its highest level. He has performed Three Acts in one life—and all have been class acts—the visionary biochemist, the tireless institution-builder, and the eloquent public communicator. And there's no sign yet that the curtain has fallen on any one of Koshland's Three Acts.