William F. Dove
Overview of my professional trajectory
My professional trajectory has followed a path that has emerged from exchanges between Questions and Answers. Over time, the world of colleagues supporting these exchanges has grown to include members of my laboratory, department, university, and field of science at large. In effect, each step along this path into the unknown has involved a Community – actual or virtual. I aim to give a sense of each of these in essays I have written describing my experience in that Community.
My early education was broad from public schools in Maine, Montclair New Jersey, and Oak Park Illinois to Phillips Academy Andover “Youth From Every Quarter” coupled with an Exchange year at The Oundle School in England. This broad education culminated in the liberal arts curriculum of Amherst College [see Coming Late to the Core Curriculum]. This breadth was then focused at Caltech whose small, nimble size allowed me to join rigorous experimental chemistry to issues in biology [see Running the Rapids with Norman Davidson]. The worldwide Community interested in the intersection between chemistry and biology using the discipline of genetics then gained a cohesive name “molecular genetics” in the newly established Laboratory of Molecular Biology in Cambridge England. Luckily, my time at the MRC Cambridge also led to finding my personal “soul mate” in Alexandra, also a postdoctoral fellow, sharing a lab module with me [see From MRC-Cambridge to Madison]. The family that Alexandra and I have raised and continue to support has created a different path of Questions and Answers running in parallel to the one I describe on this site.
The subsequent development of my professional career in science from chemistry to biology can be summarized retrospectively as “A Genetically Assisted Ascent from Replication in Microbes to Cancer in Humans”.
The tabs on this website provide links to selected Research Publications, Reviews, Commentaries, and Archival Collections. The Photo tab identifies many of the lab colleagues who have shared in the hard work and camaraderie along this path from lambda to Physarum to the self-renewing intestinal epithelium in humans. Alexandra and I look back from time to time and recognize how fortunate we are to have worked in research in molecular genetics during an era so explosive in emerging new knowledge. Our lives have been enriched both by the remarkable pioneers who have cleared a path for us to follow, and by each of the talented lab associates who have accompanied us, enjoying for themselves the pleasure of learning a truth never known before.
Trained in chemistry, my limited skills in biology mandated my studying the biology of a “simple virus”, the bacteriophage lambda. I learned to use genetic analysis to analyze lambda’s replication system. This way to understand a complex (not “simple”) biological process stayed with me. Equally important, the dynamic exchange of Questions and Answers within the phage community formed my view of how science best proceeds. The senior phage researcher Al Hershey and the junior scholar Ira Herskowitz illustrate the character of the Phage School that has played a formative role in my professional development.
Lambda’s life strategies taught me many lessons in biology. The level of understanding of its complexity deduced by genetic analysis gave courage to my research group to attempt to understand growth and differentiation in Physarum polycephalum. This protist presents several biological features that enticed us to establish a genetic analysis of eukaryotic replication: the natural synchrony of its well-known syncytial growth phase provides sufficient material for a biochemical analysis of each stage in the nuclear replication cycle; and the haploidy of the meiotic product, the myxamoeba, encourages mutant isolation. Over a span of almost three decades, a series of advances in the biology and molecular genetics of Physarum created a platform that remains to be built upon to address Questions that are best Answered within the biology of this protist (see Tim Burland’s review).
Research with microrganisms – lambda and Physarum – proceeds at a pace set by their cell division time. Mammalian cells in culture have similarly rapid division, but fail to display the phenotypes of the intact mammalian organism. For genetic analysis, the haplophase created by meiosis provides a major entrée into the mutational analysis of issues in mammalian biology. However, the nine-week interval required for gestation and sexual maturation of mice and rats requires patience and parallel planning.
Our laboratory has been one of those developing efficient germline mutagenesis in the mouse and mapping of its genome [Francois Jacob essay and Vern Chapman Washington DC 2011 Lecture]. These two essays present comments on some of the early stages in the development of the molecular genetics of the mouse. These early stages have been amplified since by a series of able, committed scientists from our lab and around the world. The mouse biologists joining the laboratory developed the patience and appreciation of the mouse necessary to address an issue in human biology using mouse genetics [Moser et al.]
The developments in germline mouse mutagenesis by Alexandra, Dave McDonald, and Derek Symula were initiated in a collaboration to study the inborn error in phenylalanine metabolism, phenylketonuria (PKU) with Vernon Bode at Kansas State University, also a veteran of the phage lambda campaign. Several mouse strains mutated in phenylalanine metabolism have been developed [McDonald et al. and Shedlovsky et al.] The model C57BL/6J-Pahenu2/+ has been made available by The Jackson Laboratory to investigators at large, and has been used in more than 100 investigations ranging from pathophysiology to targeted gene editing.
Recently, the extension of efficient germline mutagenesis to the laboratory rat has brought forward rat biologists to address issues most clearly presented by that genus [Amos-Landgraf et al.] In contrast to the known molecular target of PKU, the discoveries emerging from the evolutionary conservation studies have identified molecular players in the early detection and progression of colon cancer. Finding molecular signals conserved from the mouse and rat to the human has become a useful strategy in the de novo discovery of previously unknown signals [see Ivancic et al. re serum proteins enhanced in level in patients with growing pre-malignant colonic adenomas and Pleiman et al. re a regulator of colon cancer progression].
These reports consummate the goal imagined when I joined the faculty of the McArdle Laboratory for Cancer Research in 1965. Can we connect through chemistry and genetics advances with model organisms to issues in human biology?
I shall not be adding new students or fellows, so 2019 marks the final experimental investigations from the laboratory. However, the ideas generated remain alive with me, and feed discussions with interested members of my communities, and sometimes to written commentaries. For example. I have recently summarized my connection with the community of geneticists in the series of Perspectives essays edited with my senior faculty colleague, Jim Crow [Tapestry essay]. My connection to the McArdle community started with Harold Rusch, the director who hired me and supported my independence longterm [Rusch tribute]. It expanded with my faculty colleague, Howard Temin, who also trained at Caltech [Temin publication]. Beyond the focal efforts of our laboratory in the biology of phage lambda and the genetics of Physarum and the mouse, the McArdle Laboratory has provided a rich scientific context in two areas crucial to the advances we have enjoyed. One is the use of the laboratory rat in cancer research. The rat has a long history in McArdle, from Van Potter to Henry Pitot to the current practitioners – Jim Shull, Jill Haag, and Michael Gould. The other is a deep understanding of the physical organic chemistry of carcinogens and mutagens by James and Betty Miller and Peter Brookes (a sabbatical visitor of Charles Heidelberger) synergizing with my doctoral studies in chemistry at Caltech. The nirosamides were shown to be directly acting (SN1) alkylating agents, in contrast to mutagens used in Drosophila and microbes such as EMS and NMG. These required metabolic activation (SN2). In mammals metabolic activation occurs in the liver, at a distance preventing efficient diffusion of the active product to the germline. On the basis of this chemical argument, McArdle was able to fund an expansion of its animal space (James Miller, PI), enabling our laboratory to develop ENU-mutagenesis of the mouse germline in the absence of prior funding! The successes in the ENU mutagenesis of the mouse germline, in McArdle and elsewhere, led to the finding by our Physarum alumna Lilianna Solnica-Krezel as a post-doctoral researcher at Harvard. Lila demonstrated the power of ENU mutagenesis, in contrast to EMS, for germline mutagenesis in the zebrafish [Solnica-Krezel et al.]
A major share of the research in the DoveLab, and in McArdle at large, has been supported by the National Cancer Institute. The McArdle community – faculty, staff, and students – will continue to occupy the center of my professional efforts, continuing to try to connect the advances in basic science with the realities of cancer in humans.
My CV lists Positions, Key Findings and a complete list of research publications.
This site has been constructed with the help of my family and Linda Clipson, Alexandra’s and my longterm colleague in McArdle.
Last updated on July 3, 2019.