Professor Nigel Emptage pays tribute to Lincoln Fellow, Professor David Vaux, who retires today after nearly 50 years of scientific exploration and academic life. David is Professor of Cell Biology, Tutor in Medicine and Nuffield Research Fellow in Pathology.
I guess all good things come to an end. The retirement of David marks 25 hugely enjoyable years of our working together as Lincoln’s Medical and Biomedical Tutors and his departure is going to leave quite a void. By the time I arrived in Lincoln, David had already crafted teaching methods that have served generations of Lincoln students well. It all began at their interview, questions so fiendish that were a candidate able to arrive at an answer then we knew they would be more than a match for anything Oxford could throw at them. Finals results across the years have ratified his approach in spades, exceptional students, realising potential that sometimes they didn’t see for themselves. And let’s not forget the farewell, a celebratory picnic in the grounds of Blenheim Palace so lavish that I’m sure the Duke of Marlborough looked jealously on. The joy at these picnics was indicative of David’s interaction with the students, each taken on a personal academic journey with enthusiasm, kindness and care. His teaching never failed to reveal his love of the subject and yet despite encyclopaedic knowledge he always asked a question or two for which he did not yet have the answer.
It is David’s ability to identify the next question that has made him not only an inspiring teacher but an outstanding scientist. His scientific career began while he was himself an Oxford medical student, a fascination for mononuclear phagocytes led him to undertake a DPhil during which he was one of first to attempt to make monoclonal antibody reagents recognising intracellular antigens. For those in the know these had been expected to be completely non-immunogenic. His first paper in 1982 was a two-author letter to Nature in describing this work. Still, that wasn’t keeping him busy enough, so while completing the experiments for this paper and his DPhil he was also a clinical student and a new father. David has always liked to keep busy!
After clinical training, house jobs and a senior house officer post, all in Oxford, David moved to full-time research once more. Having spent a summer in New York at the Rockefeller University during his graduate work, he was keen to return to the USA and soon found himself in the cell biology department at Yale University. Here he refined the approach to monoclonal antibody production and developed a fascination for alphavirus assembly. He introduced a method of paired in vitro immunisation to generate and select internal image anti-idiotype antibodies to recapitulate intracellular protein-protein interactions, the subject of his first patent. Using this approach, he established the direct interaction between the cytoplasmic domain of the E2 spike glycoprotein of the virus coat and the surface of the genome-laden capsid assembling in the cytoplasm. Further confirmation of this interaction came from his new thawed frozen section immunocytochemistry EM technique.
These successes secured David an offer to establish his own group in the cell biology programme at the European Molecular Biology lab in Heidelberg where he turned his attention to the problem of selective trafficking in the multiple steps of the mammalian secretory pathway. Following work on the post-translational maturation of viral proteins that enter this pathway in infected cells, he developed an interest in selective retention of resident proteins in early compartments of this pathway, a mechanism that had then just been shown to depend on their display of a C-terminal tetrapeptide flag, KDEL. Although he was scooped in the identification of the receptor for this sequence, his work did provide insights into the complexity of the composition and morphology of the endoplasmic reticulum, the first station in a secretory or plasma membrane protein's journey from the cytoplasm. One of the new morphological features that he described in detail in the living cell for the first time was a network of nuclear envelope tubules invaginating into the nucleus of many cell types. The structure bears some resemblance to the tubular parts of the well-described endoplasmic reticulum stretching through the cytoplasm, so it became known as the nucleoplasmic reticulum (NR).
After several years in Germany, the sirens' call to return to Oxford became too loud and David returned to join Lincoln College as the Nuffield Research Fellow in Pathology and become a group leader in the Dunn School. The timely emergence of laser scanning microscopy allowed him to advance his studies of the NR by optically cutting sections through living cells and constructing 3-D views of the entire nucleus with all its NR channels on display for the first time. Subsequently, he showed that the NR is dynamic, regulated, heritable in progeny cells and able to form de novo in interphase nuclei. Using a novel stable isotope pulse label method that he devised to exploit the development of a unique NanoSIMS microscope, he demonstrated that new NR selectively incorporates the most recently synthesised lipids and proteins, suggesting that it is not a simple mechanical convolution of an existing structure. This insight drove ongoing studies that have uncovered links to normal cellular aging and rare premature aging syndromes, as well as hormonal regulation of NR abundance in endometrial cells during the menstrual cycle, failure of which may be associated with infertility in humans. Most recently, he used an old in vitro evolution approach to show that subclones of immortal tumour cells repeatedly selected for high or low NR abundance develop distinct patterns of gene expression. All the high NR subclones show a very similar shift in gene expression, and these changes include some of those already known to be associated with cellular aging.
Publication of his work on NR morphology led to many discussions with colleagues on possible protein substrates that might either cause these structures or use them functionally. A comment from Professor Christian de Potter suggested that the gene product of Breast Cancer Gene 1 (BRCA1) might have NR associations and David spent much effort looking at the intranuclear distribution of inactive and active pools of this protein in the nucleus and elsewhere. This led to work that included the confirmation that this DNA damage responding protein could be found in mitochondria as well as the nucleus, and that it also has an association with the leading edge of migrating cancer cells. Immunoprecipitation and pulldown experiments implicated BRCA1 interactions with cytoskeletal anchor proteins of the ezrin, radixin and moesin family, and subsequent mutation experiments showed that the ubiquitin ligase activity of BRCA1 is essential in limiting cancer cell migration. This is consistent with observations that hormone-sensitive tumours that lose BRCA1 function tend to show earlier metastasis and drives continuing efforts to identify the key ubiquitination targets of BRCA1, which may reveal new therapeutic avenues to limit or prevent metastasis.
A chance conversation during a college lunch sparked a new research direction for David that evolved over two decades. He had discovered a region of CNS acetylcholinesterase (AChE) resembling the amyloid-beta peptide, the main component of amyloid plaques in Alzheimer’s disease. This AChE segment formed toxic amyloid, seeded amyloid-beta aggregation, and could initiate plaque formation in a mouse model. Intent on developing this idea fully David co-founded a biotech startup focused on inhibiting early amyloid formation. Although early results in C. elegans (a nematode worm) were promising, translation to mammalian systems proved difficult, and the company eventually moved away from amyloid inhibition.
Of course, David always had another question and the biophysical studies of AChE peptide involved experiments using plate readers that occasionally gave anomalous results. This led him to discover that amphiphilic peptides distorted surface curvature, inspiring a patented instrument for non-contact surface tension measurement. This led neatly to a collaboration with physicist Dr. Chiu Fan Lee, resulting in papers on hydrophobic-hydrophilic interfaces in amyloid formation. The work has now expanded to other systems, especially islet amyloid precursor peptide (IAPP), co-secreted with insulin. In vitro studies show insulin and IAPP interactions, along with membrane surfaces, play critical roles in granule formation and amyloidogenesis. Disruptions in these interactions may impair insulin secretion long before visible amyloid deposits appear—potentially contributing to the early stages of type II diabetes.
Last week, a chance encounter with David in Chapel Quad revealed that he is planning to do yet more experiments and so his scientific story continues. I, on the other hand, was asked to write just a couple of paragraphs and have already got rather carried away. I do hope you forgive me, it would have seemed remiss to not adequately capture the considerable accomplishments of my long-standing colleague and friend.
Professor Nigel Emptage
Tutor in Physiology and Pharmacology, Professor of Neuropharmacology and Head of the Department of Pharmacology, University of Oxford