The Nobel Prize in Chemistry 1997
Paul D. Boyer, John E. Walker, Jens C. Skou
The first 21 years of my life were spent
in Provo, Utah, then a city of about 15,000 people, beautifully
situated at the foot of the Wasatch Mountains. Hardy Mormon
pioneers had settled the area only 70 years before my birth in
1918. Provo was a well-designed city with stable neighbourhoods,
a pride in its past and a spirit of unbounded opportunity. The
geographical isolation and lack of television made world
happenings and problems seem remote.
My father, Dell Delos Boyer, born in 1879 in Springville, Utah, came from the Pennsylvania Boyers, who in turn came from an earlier Bayer ancestry in what is now Holland and Germany. A small portion of my Boyer DNA has been traced to John Alden, famous as a Mayflower pilgrim who wooed for another and won for himself. Dad's education, at what was then the Brigham Young Academy, was delayed by the ill health he had endured in much of his youth. Through his ambition, and the sacrifices of his family, he acquired training in Los Angeles to become an osteopathic physician. He served humanity well. More by example than by word, my father taught me logical reasoning, compassion, love of others, honesty, and discipline applied with understanding. He also taught me such skills such as pitching horseshoes and growing vegetables. Dad loved to travel. Family trips to Yellowstone and to what are now national parks in Southern Utah, driving the primitive roads and cars of that day, were real adventures. Father became a widower when the youngest of my five siblings was only eight. Fifteen years later he married another fine woman. They shared many happy times, and she cared for him during a long illness as he died from prostate cancer at the age of 82. Prostate cancer also took the life of my only brother when he was 76. If our society continues to support basic research on how living organisms function, it is likely that my great grandchildren will be spared the agony of losing family members to most types of cancer.
Recently I scanned notes on a diary that my mother, Grace Guymon, wrote in her late teens, when living near Mancos, Colorado. The Guymons were among the Huguenots who fled religious persecution in France. My French heritage has been mixed with English and other nationalities as the Guymons descended. Mother's diary revealed to me more about her vitality and charm than I remembered from her later years, which were clouded by Addison's disease. She died in 1933, at the age of 45, just weeks after my fifteenth birthday. Discoveries about the adrenal hormones, that could have saved her life, came too late. Her death contributed to my later interest in studying biochemistry, an interest that has not been fulfilled in the sense that my accomplishments remain more at the basic than the applied level. Mother made a glorious home environment for my early years. During her long illness and after her death, all of the children helped with family chores. One of my less pleasant memories is of getting up in the middle of the night to use our allotted irrigation time to water the garden.
The large, gracious home provided by Mother and Dad at 346 North University Avenue has been replaced by a pizza parlor, although an inspection a few months ago revealed that the irrigation ditch for our garden area (now a parking lot) can still be found. Mother had a talent for home decorating. I often read from a set of the Book of Knowledge or Harvard Classics while lying in front of the fireplace, with a mantel designed and decorated by her. Staring into the glowing coals as a fire dims provided a wonderful milieu for a youthful imagination. I also remember such things as picnics in Provo Canyon, and the anticipation that I might get to lick the dasher after cranking the ice-cream freezer. My older brother, Roy, and I had a play-fight relationship. I still carry a scar on my nose from when I plunged (he pushed me!) through the mirror of the dining room closet. I am told that I had a bad temper, and remember being banished to the back hall until civility returned. Perhaps this temper was later sublimated into drive and tenacity, traits that may have come in part from my mother.
The great depression of the 1930s left lasting impressions on all our family. Father's patients became non-paying or often exchanged farm produce or some labor for medical care. Mother saved pennies to pay the taxes. The burden of paper routes and odd jobs to provide my spending money made it painful when my new Iver Johnson bicycle was stolen. We were encouraged to be creative. I recall mother's tolerance when she allowed me, at an early age, to take off the hinges and doors of cupboards if I would put them back on. My first exposure to chemistry came when I was given a chemistry set for Christmas. It competed for space in our basement with a model electric trains and an "Erector" set. After school the neighborhood yards were filled with shouts of play; games of "kick-the-can," "run-sheepy-run," "steal-the-sticks," as well as marbles, baseball and other activities. In our back yard we built tree houses, dug underground tunnels and secret passages, and made a small club house. The mountains above our house offered other outlets for adventuresome teenage boys. Days were spent in an abandoned cabin or sleeping under the sky in the shadow of Provo peak. We even took cultures of sour dough bread to the mountains and baked delicious biscuits in an a rusty stove. Mountain hikes instilled in me a life-long urge to get to the top of any inviting summit or peak.
Provo public schools were excellent. At Parker Elementary School, a few blocks from my home, I fell in love with my 3rd grade teacher, Miss McKay. Students who learned more easily were allowed to skip a grade, and I entered the new Farrer Junior High school at a younger age than my classmates. This handicapped me in two types of sporting events, athletics and courting girls. Girls did not want to dance with little Paul Boyer; boys were quite unimpressed with my physique. As I grew my status among fellows improved. Once I got into a scuffle in gym class, the instructor had the "combatants" put on boxing gloves, and I gave more than I received. It wasn't until late high school and early college that I gained enough size and skill to make me welcome on intramural basketball teams.
I was one of about 500 students of Provo High School, where the atmosphere was friendly, and scholarship and activities were encouraged by both students and faculty. I participated on debating teams and in student government, and served as senior class president. I still have a particularly high regard for my chemistry teacher, Rees Bench. I was pleased when he wrote in my Yearbook for graduation, "You have proven yourself as a most outstanding student." I graduated while still 16, and thought myself quite mature. I wish I had saved a copy of my valedictorian address. I suspect it may have sparkled with naivete.
It was always assumed that I would go to college. The Brigham Young University (BYU) campus was just a few blocks from my home and tuition was minimal. It was a small college of about 3,500 students, less than a tenth of its present size. As in high school, I enjoyed social and student government activities. Friendships abounded. New vistas were opened in a variety of fields of learning. Chemistry and mathematics seemed logical studies to emphasize, although I had little concept as to where they might lead. A painstaking course in qualitative and quantitative analysis by John Wing gave me an appreciation of the need for, and beauty of, accurate measurement. However, the lingering odor of hydrogen sulfide, used for metal identification and separation, called unwanted attention to me in later classes. "Prof" Joe Nichol's enthusiasm for general chemistry was superbly conveyed to his students. Professor Charles Maw excelled in transferring a knowledge of organic chemistry to his students. Biochemistry was not included in the curriculum.
Summers I worked as a waiter and managerial assistant at Pinecrest Inn, in a canyon near Salt Lake City. One summer a college friend and I lived there in a sheep camp trailer while managing a string of saddle horses for the guests to use. A different type of education came when as a member of a medical corps in the National Guard I spent several weeks in a military camp in California.
As my senior year progressed several career paths were considered; employment as a chemist in the mining industry, a training program in hotel management, the study of osteopathic or conventional medicine, or some type of graduate training. Little information was available about the latter possibility; but a few chemistry majors from BYU had gone on to graduate school. I have a tendency to be lucky and make the right choices based on limited information. A notice was posted of a Wisconsin Alumni Research Foundation (WARF) Scholarship for graduate studies. My application was approved, and the stage was set for a later phase of my career.
Before leaving Provo, a most important and fortunate event occurred. A beautiful and talented brunette coed, with one year of college to finish, indicated a willingness to marry me. She came from a large and loving family, impoverished financially by her father's death when she was 2 years old. She had worked and charmed her way nearly through college. My savings were limited and hers were negative. But it was clear that my choice was to have her join with me in the Wisconsin adventure or take my chances when I returned a year later. It was an easy decision. Paul, who had just turned 21, and Lyda Whicker, 20, were married in my father's home on August 31, 1939. Five days later we left by train to Wisconsin for my graduate study.
A few months after our arrival our new marriage almost ended. I was admitted to the student infirmary with diagnosed appendicitis. Through medical mismanagement my appendix ruptured and I became deathly ill. Sulfanilamides, discovered a few years earlier by Domagk, saved my life. Last summer I read an outstanding book, The Forgotten Plague: How the Battle Against Tuberculosis Was Won and Lost, by Frank Ryan. The book gives a stirring account, the first I have read, of Domagk's research and how he was not allowed to leave Hitler's Germany to receive the 1939 Nobel Prize.
Fortunately, the Biochemistry Department at the University of Wisconsin in Madison was outstanding and far ahead of most others in the country. A new wing on the biochemistry building had recently been opened. The excitement of vitamins, nutrition and metabolism permeated the environment. Steenbock had recently patented the irradiation of milk for enrichment with vitamin D. Elvehjem's group had discovered that nicotinic acid would cure pellagra. Petersen's group was identifying and separating bacterial growth factors. Link's group was isolating and identifying a vitamin K antagonist from sweet clover. Patents for the use of dicoumarol as a rat poison and as an anticoagulant sweetened the coffers of the WARF, the Foundation that supported my scholarship. Among younger faculty an interest in enzymology and metabolism was blossoming.
Married graduate students were rare, and the continuing economic depression made jobs hard to find. But my remarkable wife soon found a good job, and I settled into graduate studies. During our Wisconsin years she gained a perspective of art while employed in Madison's leading art retail outlet. It was years later before Lyda finished a college degree, became a professional editor at UCLA, and worked with me on the eighteen-volume series of The Enzymes. Our contacts in graduate school and through Lyda's employment gave us life-long friends; one was Henry Lardy, from South Dakota farm country. He and I were assigned to work under Professor Paul Phillips. Henry was highly talented, and it was my good fortune to work along side him. Phillips' main interests were in reproductive and nutritional problems of farm animals. Henry developed an egg yolk medium for sperm storage that revolutionized animal breeding.
We were encouraged by Phillips to explore metabolic and enzyme interests. I did not realize that it was unusual to be able step across the hall and attend a symposium on respiratory enzymes in which such biochemical giants as Otto Meyerhof, Fritz Lipmann, and Carl Cori spoke. Evening research discussion groups with keen young faculty such as Marvin Johnson and Van Potter, centered on enzymes and metabolism, broadened and sharpened our perspectives. One evening I presented my and Henry's evidence for the first known K+ activation of an enzyme, pyruvate kinase. Henry kept score on the interruptions for questions or discussions-some 35 as I recall. This superb training environment set the base for my career.
My Ph.D. degree was granted in the spring of 1943, the nation was at war, and I headed for a war project at Stanford University. A few weeks after my arrival in California, on my birthday, July 31, our daughter Gail was born. I became somewhat more involved in home duties and more deeply in love with Lyda.
The wartime Committee on Medical Research sponsored a project at Stanford University on blood plasma proteins, under the direction of J. Murray Luck, founder of the nonprofit Annual Review of Biochemistry and other Reviews. Concentrated serum albumin fractionated from blood plasma was effective in battlefield treatment of shock. When heated to kill microorganisms and viruses, the solutions of albumin developed cloudiness from protein denaturation. The principal goal of our research project was to find some way to stabilize the solutions so that they would not show this behavior. Our small group found that acetate gave some stabilization and butyrate was better. This led to the discovery that long chain fatty acids would remarkably stabilize serum albumin to heat denaturation, and would even reverse the denaturation by heat or concentrated urea solutions. Other compounds with hydrophobic portions and a negative charge, such as acetyl tryptophan, were also effective. Our stabilization method was quickly adopted and is still in use. From the Stanford studies I gained experience with proteins and a growing respect for the beauty of their structures.
In marked contrast to the University of Wisconsin, Biochemistry was hardly visible at Stanford in 1945, consisting of only two professors in the chemistry department. The war project at Stanford was essentially completed, and I accepted an offer of an Assistant Professorship at the University of Minnesota, which had a good biochemistry department. But my local War Draft Board in Provo, Utah, had other plans and I became a member of the U.S. Navy. The Navy did not know what to do with me, the war with Japan was nearly over, and I became what is likely the only seaman second-class that has had a nearly private laboratory at the Navy Medical Research Institute in Bethesda, Maryland. In less than a year I returned to civilian life. In the spring of 1946 I, my wife, and now two daughters, Gail and Hali, became Minnesotans. But I had unknowingly acquired a latent California virus to be expressed years later.
Minnesota has generally competent and honest public officials, good support of the schools and cultural amenities, and an excellent state university. It was a fine place to rear a family, and soon our third child, Douglas, was born. A golden era for biochemistry was just starting. The NIH and NSF research grants were expanding at a rate equal to, or even ahead, of the growing number of meritorious applications. The G.I. bill provided financial support that brought excellent and mature graduate students to campus. New insights into metabolism, enzyme action, and protein structure and function were being rapidly acquired.
Housing was almost unavailable in the post war years. Initially we coped with an isolated, rat-infested farm house. In 1950, after my academic competence seemed satisfactorily established, we built a home not far from the St. Paul campus where the Department of Biochemistry was located. I served as contractor, plumber, electrician, finish carpenter etc. My warm memories of this home include looking at a sparkling, snow-covered landscape, while seated at the desk in the bedroom corner that served as my study, and struggling with the interpretation of some puzzling isotope exchanges accompanying an enzyme catalysis. The understanding that developed was rewarding and perhaps one of my best intellectual efforts. However, it did not seem that the approach would give answers to major problems.
During my early years at Minnesota I conducted an evening enzyme seminar. One participant in our lively discussions was a promising graduate student from another department, Bo Malmstrom, who became a renowned scientist in his field, and is now a retired professor from the University of Göteborg. In 1952 my family spent a memorable summer at the Woods Hole Marine Biological Laboratories on Cape Cod. A sabbatical period on a Guggenheim Fellowship in Sweden in 1955 was especially rewarding. There I did research at both the Wenner-Gren Institute of the University of Stockholm with Olov Lindberg and Lars Ernster, and at the Nobel Medical Institute, working with Hugo Theorell's group. Professor Theorell received a Nobel Prize that year, exposing us to the splendor and formality of the Nobel festivities.
Along the way, I was gratified to receive the Award in Enzyme Chemistry of the American Chemical Society in 1955. In 1959-60 I served as Chairman of the Biochemistry Section of the American Chemical Society. In 1956 I accepted a Hill Foundation Professorship and moved to the medical school campus of the University of Minnesota in Minneapolis. Much of my group's research was on enzymes other than the ATP synthase. But solving how oxidative phosphorylation occurred remained one the most challenging problems of biochemistry, and I could not resist its siren call. Mildred Cohn reported that mitochondria doing oxidative phosphorylation catalyzed an exchange of the phosphate and water oxygens, an intriguing capacity. An able physicist and a pioneer in mass spectrometry, Alfred Nier, made gaseous 18O and facilities available to me, and some experiments were run using this heavy isotope of oxygen. However, much of our effort over several years was directed toward attempting to detect a possible phosphorylated intermediate in ATP (adenosine triphosphate) synthesis using 32P as a probe. The combined efforts of some excellent graduate students and postdocs, most of whom went on to rewarding academic careers, culminated in the discovery of a new type of phosphorylated protein, a catalytic intermediate in ATP formation with a phosphoryl group attached to a histidine residue.
By then, time and queries had stimulated the latent California virus. Change was underway. In the summer of 1963, I and a group of graduate students and postdocs who came with me, activated laboratories in the new wing of the chemistry building at the University of California in Los Angeles (UCLA), located on a beautiful campus at the foot of the Santa Monica mountains. We soon found that the enzyme-bound phosphohistidine we had discovered was an intermediate in the substrate level phosphorylation of the citric acid cycle. It was not a key to oxidative phosphorylation. The experience reminds me of a favorite saying: Most of the yield from research efforts comes from the coal that is mined while looking for diamonds.
In 1965 I accepted the Directorship of a newly created Molecular Biology Institute (MBI) at UCLA, in part because of my disappointment that oxidative phosphorylation had resisted our efforts. A building that was promised failed to materialize, but through luck and persistence adequate funds were obtained, partly from private resources, and promising faculty were recruited. The objective was to promote basic research on how living cells function at the molecular level. I believe the best research is accomplished by a faculty member with a small group of graduate students and postdocs, who freely design, competently conduct and intensely evaluate experiments. To spend time with such a group I soon found ways to reduce my administrative chores. Probes of oxidative phosphorylation continued, and, as 1971 approached, we hit pay dirt. We recognized the first main postulate of what was to become the binding change mechanism for ATP synthesis, namely that energy input was not used primarily to form the ATP molecule, but to promote the release of an already formed and tightly bound ATP.
In the following decade, the other two main concepts of the mechanism were revealed, namely that the three catalytic sites participate sequentially and cooperatively, and that our, and other, data could be best explained by what was termed a rotational catalysis. These previously unrecognized concepts in enzymology provided motivation and excitement within my research group. Richard Cross, a postdoctoral fellow trained with Jui Wang at Yale, capably probed tightly bound ATP. Jan Rosing, a gifted experimentalist from Bill Slater's group in Amsterdam, and Celik Kayalar, an intelligent, innovative graduate student from Turkey, formed a productive pair that unveiled essential facets of cooperative catalysis. David Hackney, a postdoc from Dan Koshland's stable of budding scientists at Berkeley, was an intellectual leader in our 18O experimentation that led to rotational catalysis. Dan Smith, Michael Gresser, Linda Smith, and Chana Vinkler (from Israel) as postdocs, and Lee Hutton, Gary Rosen and Glenda Choate as graduate students, established the participation of bound intermediates in rapid mixing and quenching experiments, and conducted 18O exchange experiments that clarified and supported our mechanistic postulates.
In ensuing years, other aspects of the complex ATP synthase were explored that solidified our feeling that the binding change mechanism was likely valid and general, and promoted its acceptance in the field. I will resist telling you here about the number, properties, and function of the six nucleotide binding sites, of the probes that agreed with rotational catalysis, of the unraveling of the complex Mg2+ and ADP inhibition, of the generality of the mechanism and other synthase properties revealed by studies with chloroplasts, E. coli, and Kagawa's thermophilic bacterium. It was a pleasure to work on such problems with Teri Melese, a postdoc who excelled in enthusiasm as well as capability, and Zhixiong Xue, an exceptional graduate student that I first met while leading a biochemical delegation to China, with Raj Kandpal a scholarly postdoc from India, with the productive postdocs John Wise (from Alan Senior's lab) and Rick Feldman (from David Sigman's lab), with Janet Wood during her sabbatical, and with June-Mei Zhou and Ziyun Du (on leave from Academia Sinica laboratories in China) as well as Dan Wu, Steven Stroop, and Karen Guerrero as graduate students. Special mention should be made of three excellent Russian researchers, Vladimir Kasho, Yakov Milgrom and Marat Murataliev, from the laboratory of Vladimir Skulachev, a respected leader in bioenergetics. With the latter two I am now writing what will likely be my last paper reporting research results. Other welcome postdocs, visitors, and graduate students at UCLA worked with other problems, including the Na+,K+ -ATPase that Skou first isolated, and the related Ca++ transporting ATPase of the sarcoplasmic reticulum. During these active years it was a pleasure to receive peer recognition in the form of the Rose Award of the American Society for Biochemistry and Molecular Biology, the preeminent society in my field (I served as its President many years earlier).
An unexpected benefit of my career in biochemistry has been travel. The information exchanged and gained at scientific conferences and visits has been tremendously important for progress in my laboratory. My travelophilic wife and I thoroughly enjoyed being guests of the Australian and South African biochemical societies while visiting their countries. Meetings or laboratory visits in Japan, Sweden, France, Germany, Russia, Italy, Wales, Argentina, Iran, and elsewhere gave us a world perspective. Manuscripts that have to be produced, sometimes a bit unwillingly, offer the challenge to present speculation and perspective often not welcome by editors of prestigious journals. It was in a volume from a conference dedicated to one of the giants of the bioenergetics field, Efraim Racker, that the designation "the binding change mechanism" was introduced. Conferences at the University of Wisconsin provided opportunity to publish thoughts about rotational catalysis that had not been enthusiastically endorsed at Gordon Conferences, where information is exchanged without publication. These travels have strong scientific justification. They provided the opportunity for exchange of information, to test new ideas, to gain new perspective, and to avoid unnecessary experiments. The milieu encourages innovation and planning, as well as providing a stimulus and vitality that fosters research progress.
Other events that make up a lifetime continued. Through fortunate circumstances, Lyda and I obtained a building lot at a price that a professor could afford, in the hills north of UCLA, overlooking the city and ocean. The home we built (I was again contractor and miscellaneous laborer) has served as a focal point for family activities, and a temporary residence for grandchildren attending UCLA. The home meant much for my research, as I could readily move between home and lab, and the ambiance created was supportive for study and writing.
The study of life processes has given me a deep appreciation for the marvel of the living cell. The beauty, the design, and the controls honed by years of evolution, and the ability humans have to gain more and more understanding of life, the earth and the universe, are wonderful to contemplate. I firmly believe that our present and future knowledge of all that we are and what surrounds us depends on the tools and approaches of science. I was struck by how well Harold Kroto, one of last year's Nobelists, presented what are some of my views in his biographical sketch. As he stated, "I am a devout atheist--nothing else makes sense to me and I must admit to being bewildered by those, who in the face of what appears to be so obvious, still believe in a mystical creator." I wonder if in the United States we will ever reach the day when the man-made concept of a God will not appear on our money, and for political survival must be invoked by those who seek to represent us in our democracy.
It is disappointing how little the understanding that science provides seems to have permeated into society as a whole. All too common attitudes and approaches seem to have progressed little since the days of Galileo. Religious fundamentalists successfully oppose the teaching of evolution, and by this decry the teaching of critical thinking. We humans have a remarkable ability to blind ourselves to unpleasant facts. This applies not only to mystical and religious beliefs, but also to long-term environmental consequences of our actions. If we fail to teach our children the skills they need to think clearly, they will march behind whatever guru wears the shiniest cloak. Our political processes and a host of human interactions are undermined because many have not learned how to gain a sound understanding of what they encounter.
The major problem facing humanity is that of the survival of our selves and our progeny. In my less optimistic moments, I feel that we will continue to decimate the environment that surrounds us, even though we know of our folly and of what has happened to others. Humans could become quite transient occupants of planet earth. The most important cause of our problem is over population, which nature, as with other species, will deal with severely. I hear the cry from capable environmental leaders and organizations for movement toward sustainable societies. They are calling for sensible approaches to steer us away from impending disaster. But their voices remain largely unheard as those with power, and those misled by religious or nationality concerns, become immersed in unimportant, self-centered and short range pursuits.
From Les Prix Nobel. The Nobel Prizes 1997, Editor Tore Frängsmyr, [Nobel Foundation], Stockholm, 1998
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.
Copyright © The Nobel Foundation 1997