This issue of Systems Biology in Reproductive Medicine (SBiRM) is dedicated in honor of Dr. Gordon H. Dixon’s (25 March 1930 – 24 July 2016) many contributions to our understanding of how nuclear chromatin structure guides development and his mentorship to the generation of scientists who continue to contribute to the Genomics Revolution. Researchers who published with or were influenced by Dr. Dixon were contacted and invited to contribute to this Special Issue, and we apologize to those whom we were not able to contact. Many responded with comments indicating that although unable to directly contribute, how well-respected Gordon was as a mentor and collaborator and noted his pioneering work on protamines, sperm chromatin structure, evolution, and male reproductive developmental biology. The eight papers included in this Special Issue cover a range of topics and the network of authors influenced by Dr. Dixon and his scientific contributions, with a focus on members of his program at the University of Calgary. Dr. Dixon’s work spans multiple institutions that included University of Toronto, University of Washington, University of British Columbia, as well as University of Calgary. The reach of his program is presented by the personal statements of each of the authors that follows in this Preface and reflects how the training, research, and/or field of study of the contributors was influenced by Dr. Dixon. The personal statements of the contributing authors are listed below in the order that their respective papers appear in this issue, beginning with Dr. Peter Davies, the most senior contributor, and concluding with Dr. Helen Tempest who while at the University of Calgary, after Gordon retired, felt the presence and impact of his work.
Peter L. Davies: Gordon H. Dixon (GHD) wrote an inspiring review on ‘Mechanisms of Protein Evolution’ in the 1966 2nd edition of ‘Essays in Biochemistry’. It was written only 13 years after the discovery of double helix DNA structure, at a time when the genetic code had just been deciphered, nucleic acid sequencing was tortuous, and protein sequencing was THE way to study gene variation and mutation. GHD was able to capture the emerging field of molecular biology in this article and illustrate how protein evolutionary mechanisms were being deduced from tiny amounts of data. I read ‘Mechanisms of Protein Evolution’ as an undergraduate student at University of Wales, UK and was fascinated by the emerging links between protein divergence and the evolution of species. GHD’s review encouraged me to continue the study of biochemistry at the graduate level, which led in turn to a career in research. In 1968, I was accepted into the graduate program in the Department of Biochemistry at the University of British Columbia, not realizing that GHD had moved there from Toronto. When I found out he was in the department I was told Gordon’s lab was full. But I made many friends in his lab and followed their work on rainbow trout spermatogenesis, histone modification, and protamine expression with great interest.
My opportunity to work with Gordon came in 1974 as a post-doctoral fellow when GHD returned to Canada from Sussex, UK to set up a new lab at the University of Calgary’s Medical School next to the Foothills Hospital. By this time, it was realized that eukaryotic messenger RNAs had poly (A) tails and the isolation of protamine mRNA had been achieved and perfected in the GHD lab by Lashitew Gedamu. One of the collaborative projects that I worked on with Lashitew in Calgary was a study of the proteins bound to protamine mRNA that formed messenger ribonucleoprotein (mRNP) particles. My planned project as a new independent investigator and Assistant Professor at Queen’s University (Kingston, ON) in 1977 was an examination of mRNP particles in developing muscle. But a friendship formed at UBC with one of GHD’s graduate students, Choy-Leung Hew, changed all that. Choy had worked with Gordon on haptoglobins and was an expert in protein chemistry. He joined the faculty at Memorial University of Newfoundland in 1974, and soon after developed an interest in the recently discovered antifreeze proteins (AFPs) of marine fishes. Choy recruited me to the study of AFPs to assist with the molecular biology aspects because I had gained experience in mRNA isolation, cDNA synthesis, and nucleic acid sequencing from my research with GHD in Calgary. It was a fortuitous transition as AFPs have been an extremely productive field for investigating protein structure-function relationships. However, some of the most fascinating insights about AFPs are those that relate to protein evolution – the theme of the review article GHD wrote over 50 years ago that is echoed here. Our review on protein evolution features examples from the field of AFPs, but with some parallels to protamines. ‘Protein evolution revisited’ by Peter L. Davies and Laurie A. Graham.
Ken Kleene: I was introduced to spermatogenesis in the lab of Norman Hecht at a time when the only molecular studies originated from the lab of Gordon Dixon. Research in my lab at the University of Massachusetts Boston emphasized two aspects of spermatogenesis. With a background in Developmental Biology, I was intrigued that spermatogenesis and early animal development both involve translational regulation whose mechanisms were totally unknown in any system. I was also intrigued by evidence from many labs that the patterns of gene expression in spermatogenic cells differ radically from those in other cell types in the mammalian body. My research alternated between the nature and functions of atypical patterns of gene expression in spermatogenic cells, and the mechanisms of translational regulation. My approach combined comparative genomics to identify conserved regulatory elements and transgenic mice to study mutations in those elements. My publications include critical reviews to define scientific issues clearly, comparative genomics to identify conserved regulatory elements, and transgenic mice to study mutations in those elements.
The pioneering studies of Gordon Dixon were instrumental in defining the directions and strategies of my research, and I referred to them often during the 35 plus years that I studied spermatogenesis. ‘Gordon Dixon, protamines, and the atypical patterns of gene expression in spermatogenic cells’ by Kenneth Cole Kleene.
Rodney Balhorn: While I only had the pleasure of meeting Gordon once, that meeting and many years of his research before and after that meeting contributed a great deal to the evolution of my science and the passion I developed for studying the structure and function of protamines. I first became aware of his work when I entered graduate school. My thesis research, which focused on characterizing the post-translational modification of the lysine-rich histone H1 by phosphorylation, and how it related to histone synthesis and cell division, followed in the footsteps of the studies he conducted years earlier on fish protamine phosphorylation and paralleled the work he had begun at the same time on histone phosphorylation. As I look back upon and compare the progression of our research efforts over the years, I am amazed by how much of an influence his work had on my own. The more his research taught us about these highly charged little proteins called protamines, the more intrigued I became with the effect they had when they bound to DNA. Although Miescher and Kossel were the first to isolate and begin characterizing the protamines in 1874, I always considered Gordon the father of modern protamine research….and myself a student (of his published work) that he only met once but influenced so profoundly. ‘New monoclonal antibodies specific for mammalian protamines P1 and P2’ by Rod Balhorn, Klaus Steger, Martin Bergmann, Hans-Christian Schuppe, Stefanie Neuhauser, and Monique C. Balhorn.
Jovita Mezquita-Pla: I contacted Dr. Gordon H. Dixon and his laboratory, recommended by my mentor at that time, Dr. Cristóbal Mezquita (Physiology, Faculty of Medicine, UB, Barcelona, Cat), based on the scientific trajectory of Dr. Dixon in the field of Metabolism, and then of Molecular Genetics and Nuclear Proteins. I worked in his laboratory from 1981 till the end of 1985, and there I discovered that Molecular Genetics was the clue for understanding how the genes are registered and the messages, that make life possible and in progress, could be made and sent away.
Dr. Dixon’s laboratory environment offered me this opportunity, and also it was then and there the decisive moment (as stated by Henry Cartier-Bresson). Yes, it was then the best moment to progress in the field of genetic engineering and recombinant DNA technologies, after the very near preceding fears and phantoms on methodologies had vanished. These methodologies represented indeed a great jump for the acquisition of relevant scientific knowledge, and they have been a continuous peaking since then.
I cannot say why, but Canada had always been in my childhood imagination, and then, all of a sudden, we were there, working. I want to express my huge gratitude to Dr. Gordon H. Dixon for accepting me in his laboratory, for providing me with an unprecedented environment, for everything I learned during those years, and for his great humanity. ‘Gordon H. Dixon’s trace in my personal career and the quantic jump experienced in regulatory information’ by Jovita Mezquita-Pla.
J. Christopher States: I joined Gordon’s laboratory as a post-doctoral fellow in summer 1980. That time was during the early days of recombinant DNA technology development and was very exciting. The experience led to my gaining expertise in this new technology and a deeper understanding of molecular biology that formed the foundation for my research career. My independent research started with molecular genetics and molecular biology of human DNA repair, and has since moved into arsenic toxicology. My laboratory broke ground on reproductive toxicology of arsenic exposure in relation to cardiovascular disease and now focuses on dysregulation of miRNA expression and mRNA splicing in arsenic-induced carcinogenesis. ‘Impact of prenatal arsenic exposure on chronic adult diseases’ by Jamie L. Young, Lu Cai, and J. Christopher States.
Stephen A. Krawetz: When I joined Gordon’s group in 1983 it was just as PC computers and genome databases were being introduced into the laboratory. Dr. Dixon was known for always being on the cutting edge of new technologies and approaches and offered me to take up the challenge of applying this technology just as the new field of Bioinformatics was born to illuminate rapid evolution. This along with other opportunities led to a series of publications from sequencing technologies to one of the first automated image analysis systems for nucleic acids and sequence interpretation to various analysis paradigms, and the development of nucleic acid based biomarkers for CMV. This typified Dr. Dixon’s prolific laboratory with an engaging blend of cultures where I had the good fortune to gain enriching experiences both in the laboratory and beyond the bench from three of the contributors to this issue, States, Mezquita, and Oliva, among others. Gordon was an extremely generous mentor, always allowing us to explore new directions, and collaborations across multiple Departments and Institutions to advance the core laboratory projects, as our careers unfolded. This was demonstrated by the search for a mammalian protamine gene. Being in Calgary, Alberta, our selection of a bovine model was a natural choice with Dr. Robert Church, a geneticist rancher on faculty. This led to the description of various assorted alleles for protamines and other genes with their application to livestock. The attributes I gained as a mentee under Gordon Dixon are reflected in the paper included in this issue. This paper summarizes the work from Dr. Sellappan Selvaraju’s group who as a visiting scientist spent a wonderful productive year in my laboratory and has continued to develop the bovine project. My work is now primarily focused on the human fathers’ contribution to the birth of a healthy child. ‘Current status of sperm functional genomics and its diagnostic potential of fertility in bovine (Bos taurus)’ by Sellappan Selvaraju, Sivashanmugam Parthipan, Lakshminarayana Somashekar, B. Krishnan Binsila, Atul P. Kolte, Arunachalam Arangasamy, Janivara Parameswaraiah Ravindra, and Stephen A. Krawetz.
Rafael Oliva: I consider that Dr. Gordon H. Dixon has been one of the most influential researchers in the characterization of protamine and chromatin in spermatogenesis and I had the privilege to perform a postdoctoral training in his laboratory between 1986 and 1989, at the Faculty of Medicine, University of Calgary (Alberta, Canada). The research developed included the study of the chromatin structure transitions in spermatogenesis and the evolution and function of protamine genes. The knowledge that I gained during this period and his human and scientific qualities had a very substantial influence in my research career, as it is exemplified in the current manuscript. ‘Identification of a complex population of chromatin-associated proteins in the European sea bass (Dicentrarchus labrax) sperm’ by Ferran Barrachina, Dafni Anastasiadi, Meritxell Jodar, Judit Castillo, Josep Maria Estanyol, Francesc Piferrer, and Rafael Oliva.
Helen G. Tempest: Whilst I unfortunately never had the pleasure of meeting Dr. Gordon H. Dixon, I first became exposed to his body of work as a young postdoctoral fellow at the University of Calgary (2006–2008) where for several decades he had spent a significant part his career. His pioneering scientific contributions have significantly furthered our understanding of the nuclear packaging of DNA in sperm cells. Prior to joining the University of Calgary my research had concentrated on the chromosomal basis of male infertility and evolutionary comparative genomics. Given my research focus, I was particularly interested in Dr. Dixon’s exploration of the evolution of protamine genes and how protamines were critical for chromatin structure in sperm. His scientific advancements undoubtedly contributed to the evolution of my infertility research to incorporate nuclear organization of the genome in sperm cells. We and others hypothesize that this chromatin organization may be an essential prerequisite for fertilization, and early embryogenesis as reflected in the review and hypothesis paper in this issue. I am extremely grateful for the inspiration that Dr. Dixon’s work provided me with to pursue research in sperm chromatin organization and I look forward to continuing to advance this field of research. As such, I am deeply honored to participate in this Systems Biology in Reproductive Medicine Special Issue dedicated to Dr Dixon’s scientific achievements in the field of reproductive medicine. ‘Does genome organization matter in spermatozoa? A refined hypothesis to awaken the silent vessel’ by Dimitrios Ioannou and Helen G. Tempest.
These papers cover clinical application, human and animal studies, and developments in protein, protamine, spermatogenesis, and other areas of research that arose from being part of the Dixon connection. This breadth shows the reach of Dr. Dixon’s work, and its lasting and continued scientific impact. It is with profound respect and appreciation that we present this Special Issue of Systems Biology in Reproductive Medicine dedicated to Dr. Gordon H. Dixon.
Respectfully,
Stephen A. Krawetz, Ph.D.,
SBiRM Editor-in-Chief
Special Issue Co-Editor
Wayne State University
Detroit, MI, USA
Raphael Oliva, M.D., Ph.D.,
Editorial Board Member
Special Issue Co-Editor
University of Barcelona
Barcelona, Spain