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dolittle

Russell Doolittle, considered an illustrious colleague and treasured faculty member, who made extraordinary contributions to the field of molecular evolution and the study of the clotting of blood, died Friday, Oct. 11, 2019, from complications of metastatic melanoma. He was 88 years old.

 

Doolittle was born Jan. 10, 1931, in New Haven, Connecticut. He attended Wesleyan University from 1948 to 1952. He served in the United States Army, arriving in Korea a few days before the armistice in July of 1953. After his discharge from the Army in 1954, he married Frances Tynan in 1955, who was his beloved wife for 64 years. He received a master’s degree in education from Trinity College in Hartford in 1957 while teaching science at New Milford High School. At the end of 1957 he entered the doctorate program of the Department of Biological Chemistry in the Harvard Medical School, where he performed his doctoral research in the laboratory of J. Lawrence Oncley. Following his graduation in 1961, he spent a year teaching at Amherst College. Then, in 1962, the siren song of scientific research drew him to the laboratory of Birger Blombäck at the Karolinska Institutet in Sweden, where he spent two years on a postdoctoral fellowship from the National Institutes of Health. In 1964, he joined the laboratory of S. Jonathan Singer as an assistant research biologist in the Department of Biology at UC San Diego. In 1965, he accepted the position of assistant professor in what’s now the Department of Chemistry and Biochemistry and in 1987, he was also appointed in what is now the Division of Biological Sciences, ultimately becoming a member of the Section of Molecular Biology.

 

At UC San Diego, Doolittle initiated his independent career by resuming his study of the amino acid sequences of fibrinopeptides, which are short fragments of protein released during the clotting process from the soluble blood protein, fibrinogen. He began this work during his time in the Blombäck laboratory. He and Professor Blombäck had shown that the differences between mammal species in the amino acid sequences of these short peptides provided evidence of evolutionary relationships. When he took up these studies at UC San Diego, he set up a collaboration with the San Diego Zoo to obtain blood drawn from animals. (This led to an article in a local periodical about “Dr. Doolittle” at the zoo.)

 

During his time in Sweden, Doolittle realized that the rate at which the sequence of amino acids in fibrinopeptides changed with time provided information about the history of speciation over tens of millions of years before the present—the period of time over which the separation of species within the different orders of animals occurred. Choosing the cetartiodactyla order of pigs, camels, llamas, mule deer, reindeer, red deer, cape buffalo, bison, goats, and sheep and comparing the sequences of the fibrinopeptides from them, Doolittle created a family tree for these species. He then used sequences of fibrinopeptides to establish a phylogeny of the primate order of macaque, green monkey, baboon, drill, gibbon, chimpanzee, and man. Both of these efforts were seminal studies in the nascent field of molecular evolution, which has exploded over the last 50 years.

 

Doolittle continued his study of molecular evolution even after he turned his attention to fibrinogen itself, rather than its fibrinopeptides. He was among the first to create an online compendium of all the amino acid sequences available at the time so that he could update the data routinely rather than rely on the publication of printed versions. This personal project was the forerunner of the massive data banks available online that now employ large staffs and are generously supported by the governments of the United States and the European Union. He also began studies of the amino acid sequence of the complete molecule of fibrinogen from the lamprey, the member of the phylum of chordates most distant from mammals. Results from these studies allowed him to extend his quest for the ancestors of fibrinogen into invertebrates. Eventually, using techniques in the emerging field of molecular genetics, Doolittle was able to find a protein in sea cucumbers that shares a common ancestor with chordate fibrinogen, thus extending its evolutionary history.

               

With his interest in the evolution of proteins, Doolittle continued aligning sequences of amino acids and building family trees. In 1996, he published a phylogeny that included the divergence between plants, fungi, and animals dating from a billion years ago. He also advised others who were doing similar work around the world. This lifelong interest in evolution prompted him to engage in public debate with advocates of “creation science.” He retained his files holding his arguments throughout his lifetime.

           

In the 1970s, Doolittle continued his study of fibrinogen, the molecule in the blood that produces the clots that staunch bleeding but also can accumulate in the wrong places, causing strokes and heart attacks. He set out to determine the sequences of the amino acids in the three polypeptides that comprise human fibrinogen, 1,810 amino acids in all. At the time this was a monumental undertaking that tested the limits of the existing techniques, but Doolittle accomplished it.

             

Eager to do more, Doolittle set out to discover clues to the three-dimensional structure of fibrinogen, which at the time was considered a waste of time. Still, with careful examination, he deduced that a molecule of fibrinogen consisted of three balls of protein connected by two long cables of protein, and that a large portion of one of the polypeptides was a structureless coil extending out into the solution. On the basis of this proposed structure, he proposed a detailed molecular mechanism as to how the fibrinogen, once the fibrinopeptides were removed, could polymerize into the long fibers that cause the blood to clot. His proposal for the structure of fibrinogen and the way in which it polymerized were soon validated by the electron micrographs of Robley Williams. These micrographs, however, did not validate all of his predictions of the molecular details of the process, so Doolittle designed a series of elegant experiments. The results of these experiments were consistent with his proposal. The ultimate validation of his mechanism would require an atomic structure of fibrinogen, which up to that time had defied the techniques of X-ray crystallography.  This requires crystallizing the molecule, exposing that crystal to a beam of X-rays, and performing an intricate analysis of the extremely complex diffraction pattern. These are complex procedures that he had never performed before. Undaunted, Doolittle learned the methods, and persevered until he obtained several atomic structures, including that of the entire molecule of fibrinogen, again validating his proposals. In this way, he provided a final proof of his molecular explanation for the clotting of blood.

 

One of Doolittle’s most important and broadly relevant contributions was his work on comparative protein sequence and structure. In the days before DNA sequencing and gene cloning became universal tools of biology, Doolittle established the first searchable computer database of protein sequences by using snippets of data that he received from around the world. With the introduction of cloning and DNA sequencing, molecular biologists were also getting snippets of gene sequences. Doolittle understood that he could link the two. In doing so, he allowed molecular biologists to understand the genes they were cloning as well as their functions. Doolittle also provided key new insights into the evolutionary conservation of genes and the nature of gene families. He established the first building blocks of the human genome project that put our understanding of biology at a gene level into hyperdrive in the 1970s and 1980s, setting the stage for future discoveries. Doolittle was a true pioneer in early gene science. He led the way to how it is used and understood today.

           

For the elegance and importance of his work, Doolittle was elected a member of the National Academy of Science in 1984. He received a Guggenheim Fellowship in 1984, the Paul Ehrlich Prize in 1989, and the John J. Carty Award for the Advancement of Science in 2006. Over the years, he was chosen to present 18 named lectures to various university faculties and scientific societies.

           

One of the amazing aspects of Doolittle’s scientific career was his insistence on being at the bench performing or directing the experiments himself. He sat with his staff for hours at a time double-checking the transcription between the original publication and his growing atlas of amino acid sequences. He performed, or directly supervised his assistants, in the thousands of digestions, chromatographic separations, chemical reactions, and analyses required to determine the amino acid sequences of the polypeptides of fibrinogen. He went with his students to New England to gather samples from the lampreys to obtain the fibrinogen for his studies. He mastered the novel, complicated procedures of molecular genetics necessary to discover the ancestor of fibrinogen. He, as well as his students, performed the synthesis of the peptides to provide evidence for his proposals that explained the polymerization of fibrinogen. When Doolittle realized that crystallography and obtaining the patterns from the diffraction of X-rays and their analysis were needed to validate his proposals, techniques to which entire laboratories are exclusively devoted, he mastered them with the help of scientists in the laboratories of Joe Kraut and Xuong Nguyen-Huu at UC San Diego. Alongside his graduate student and his postdoctoral fellow, he made crystals, collected diffractions at the synchrotron at Berkeley, applied the Fourier transforms, and, on the computer screen, inserted the molecular models into the electron densities that resulted.

           

In addition to the time spent in the laboratory and lecturing, Doolittle served UC San Diego at large. Soon after becoming a member of the Department of Chemistry and Biochemistry, he played a major role in establishing the basic science programs for the undergraduate curriculum, as well as the basic science curriculum in the School of Medicine, which was in the process of being created. He was chairman of the Department of Chemistry from 1981 to 1984. During his tenure, Bill Trogler, Don Tilley, Joe O'Connor, and Dan Donoghue accepted offers and joined the faculty. In addition to serving on 25 committees of the Academic Senate over the last 51 years, he was also chairman of the Academic Senate, chair of the Executive and Policy Committee, and member of the university-wide Academic Council in the academic year of 1977 and 1978. During his tenure, a move among the members of the Academic Senate to censure Chancellor William McElroy was rapidly gaining adherents. Doolittle approached his role as chairman of the Academic Senate with even-handedness and refrained from voicing his own opinion on the subject. He allowed the various committees to investigate the complaints and accusations and, following the distribution of their reports, oversaw the vote on the censure, which was in favor and which eventually led to the Chancellor's resignation. At the end of Doolittle’s term as chairman, and all of the exhausting and time-consuming soul searching, one of his colleagues pinned a sign on his door that read: “Remember Cincinnatus,” which Doolittle left in place for several months as a reminder that he wanted to return to his research.

               

Among one of the many unusual aspects of his life was running for the House of Representatives in the election of 1968. When the Democratic Party of his district failed to find a candidate in what was then a deeply Republican area, Doolittle volunteered. He received 47 percent of the vote in the Democratic primary, losing to a much more conservative Democrat in a district that extended into Orange County at the time. A radical plank in his platform related to firearms: while Doolittle conceded that the Constitution seemed to guarantee a right to bear arms, it said nothing about ammunition. Consequently, he proposed that there should be a number of strict regulations on its sale. The voters failed to send him to Washington.

               

Doolittle was devoted to his wife Fran and their sons Larry and Will. He often engaged his sons in mutual endeavors—recruiting them as assistants in his many do-it-yourself projects around the house or involving them in special collaborations. Consequently, Larry Doolittle became interested in computing and wrote programs in his father’s laboratory, aligning sequences and computing evolutionary distances. He also helped his father construct an automated amino acid sequencer. Will Doolittle helped maintain and distribute the ever-expanding sequence database, and once rebuilt the engine of the family Volkswagen Beetle with his dad.

               

Russell Doolittle also enjoyed running during his younger years. After enrolling in a health study at the university, he began participating in marathons. He made California’s top 100 marathon runners list in his age group, and his fastest Boston Marathon time, at age 48, was 3 hours and 20 minutes.

               

Doolittle was known to have high standards for scientific research, a willingness to do the work to meet those standards, and expectations of the same from his peers. When relaxing, he was an entertaining raconteur with many amusing stories, which he presented in a way guaranteed to elicit happy laughter from his audience. He was also a mentor to younger scientists who were drawn to him and found him willing to listen and give advice freely. He always had a good word to say about his younger colleagues, and he was an enduring friend.

               

Doolittle is survived by his wife Fran and sons Larry and Will Doolittle; his four grandchildren, who range in age from 16 to 30, and his siblings Donald Doolittle and Kathy Gunther, who both reside in Connecticut.

 

Donations can be made in Russell Doolittle’s memory, by making checks payable to UC San Diego Foundation for the Russell Doolittle Scholarship Endowment, Fund #F-6651-6651. Please mail checks to UC San Diego Gift Processing, 9500 Gilman Drive, #0940, La Jolla, CA 92093-0940. Donations can also be made online at https://espi.ucsd.edu/make-a-gift; type 6651 in the Search for More Giving Options field. Arrangements for a celebration of life ceremony are pending.