G0S8: regulator of G-protein signaling 2

Our most cited paper (as of 2019) was an analysis of the G0S8 gene, later named RGS2 (Siderovski, Heximer & Forsdyke, 1994). At that time we were unable to show increased expression of the mRNA in response to lectin alone. Later we reported that, like RGS1, there was indeed a response to lectin in the absence of cycloheximide (Heximer, Cristillo & Forsdyke, 1997). Siderovski and Heximer later devoted much of their professional lives to the study of the RGS family of genes.

In 2019 I was invited to write for the historical record a scientific retrospective by an editor of the Scandinavian Journal of Immunology (Forsdyke, 2019 "On certain two-signal perspectives on lymphocyte activation and inactivation, thymic G-quadruplexes, and the role of aggregation in self/not-self discrimination"). When preparing this, I reviewed a letter of recommendation I had written for Siderovski in 2012, parts of which were copied directly to the paper. Since the letter fleshes out the scientific and political background of the discovery of RGS2 more fully, it is included below, without further commentary.

 

To: Headship Selection Committee Dept. Biomedical & Molecular Sciences
From: Donald R. Forsdyke
Date: 12th March 2012
Topic: Candidacy of David P. Siderovski

I am delighted to see David’s name on the shortlist (5th March). I have read his CV and think I can provide a wider perspective that may be of help. I have not read the other CVs, so this should not be taken as opposing other candidacies. David’s publications record that he has worked both in my laboratory at Queen’s and in that of Tak Mak in Toronto.

At the end of his second undergraduate year in 1987, and armed with NSERC funding, David applied for summer work in my laboratory. His academic record was superlative and this was to be maintained in the years ahead. In fact, during my two decades at Queen’s, I had never before seen so impressive an academic record. He was in a class apart from the rest. This record was matched by his contribution to the laboratory, and he returned the following summer at the end of his third year at Queen’s.

Nearing the end of his 3-4 months in the laboratory, he came to me one day in 1988 with the Queen’s Calendar. There was a clause stating that, if a student could make a sufficient case, he could be excused a prescribed course, and take a course that would be mutually agreed between student and professor. He proposed that he not take the 4th year practical biochemistry labs, but instead spend the entire year in my laboratory. His unusual plan was accepted by the powers that be, and it was agreed that he would write a thesis, along the lines of a MSc. Thesis, which would be duly examined.

David graduated in 1989 with the Prince of Wales Prize. Given his momentum, had I had better funding I could probably have persuaded him to stay on for graduate work. Too late, MRC funds came in October 1989. In 1990 I was able to recruit Scott Heximer (Ph.D 1996). You will note from the CV that David went to work with Tak Mak and did not get his Ph.D. until 1997. Herein lies an interesting tale.

I will begin with some personal background. In 1966 I was interviewed by Sir Peter Medawar and Avrion Mitchison at the NIMR at Mill Hill. They saw a freshly-minted Cambridge biochemist who might be persuaded to track down the surface receptor by which antigens stimulate lymphocytes. I argued that, although very interesting, even more interesting were the intracellular pathways activated when the receptor was occupied. By differential RNA labeling, I had already obtained “blips” showing that a host of new mRNAs were being made. These could correspond to proteins concerned with immunological signaling, and switching from quiescent to proliferative states. To cut a long story short, they said no, and I came to Queen’s in 1968.

The 1970s were marked by (i) my failure to persuade the immunological establishment that positive selection by “self” was instrumental in the generation of lymphocyte repertoires, (ii) the sudden emergence of recombinant DNA technology, and (iii) the identification of an antibody-like receptor on B-lymphocytes. Then, in the late 70’s there emerged a technology – “subtractive cDNA hybridization” – which promised to help me identify my mRNA “blips.” In Toronto, Tak Mak saw similar promise for identifying the T-lymphocyte receptor. We both needed an urgent technology upgrade. In 1980 Mak took a sabbatical with Howard Temin at Wisconsin, and Roger Deeley – newly arrived with tablets of recombinant wisdom from the NIH – kindly took me into his laboratory for a 6 month mini-sabbatical.

In 1984 Tak Mak reported the successful cDNA cloning of the T-lymphocyte receptor by a post-doc, and in 1985 I reported the successful cDNA cloning of a group of lymphocyte activation genes. Mak’s Nature paper was accompanied by much fanfare and a commentary proclaiming “The T-lymphocyte Antigen Receptor – Elusive No More.” My paper, presenting three cDNA clones as examples of the group, was published in a low profile journal. Nevertheless, I immediately began to receive requests from leading US laboratories for recombinant samples. With money from the newly established American Foundation for AIDS Research, I was able to keep on my technician and fund a graduate student. But with many cDNA clones to characterize, we needed more hands. David’s arrival in the lab in 1987 was timely.

Genes we identified have become “household words.” The first reported (1985) were chemokine ligand 3 (CCL3; binds HIV coreceptor), Early Growth Response 1 (EGR1 transcription factor), and the Fos oncogene (previously identified by others). Genes reported later were no less spectacular. At some point, David, realizing that his studies with Mak in Toronto were going nowhere, asked me to send him one of the cDNA clones that, unlike our other clones, had given a smeared blot indicating possible membership of a gene family. In Kingston, our work on the gene led to a long paper (1994) with, as is my practice, the junior contributor’s name (David’s) as first author. David was then able to bring the full resources of the Mak and Amgen empires to further study the gene and its product – Regulator of G Protein Signaling 2. As you can see (publication list) – the RGS proteins have occupied much of David’s professional life.

Over the years I have had only occasional email communications with David, but have watched with great admiration his rise, with Scott Heximer (with whom he sometimes co-publishes), to become a world authority on G-protein signaling, an area of great general importance to many tissues as well as lymphoid. Prior to going to the USA, he came at my invitation to give a seminar. He was then deeply interested in an Assistant Professorship at Queen’s. Despite my appeals to the Head of Department that, with David, we were in a different ballpark (i.e. a special opening should be negotiated for him), nothing materialized. This was very disappointing.

I hope this has effectively relayed my high estimation of David’s academic and organizational skills. To round off the tale we can note that, when reviewing the cDNA cloning of the T lymphocyte receptor in 2007, Tak Mak posited that delays were due to “numerous technical hurdles and inaccurate concepts” that “conspired to stymie” researchers. It can now be seen that in the 1970s I had an accurate concept, namely positive selection of lymphocyte repertoires, but was stymied by technical hurdles and lack of funds. David’s free contribution in the 1980s partly compensated for the latter. Also in the 1980s the accuracy of my concept became apparent when Jonathan Sprent in the USA rediscovered positive selection (not knowing of my work). All this led to a Nobel Prize in 1996 to Zinkernagel and Doherty for key evidence (1974) supporting positive selection (although it was not so interpreted by them at the time).

I wish the Committee well in its deliberations.

  


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Page established 2019 and last edited on 15 Sep 2019 by Donald Forsdyke