EJ Steele: Biography of Scientific Achievements : - Somatic Selection Theory & Reverse Transcriptase Model Somatic Hypermutation (prepared for Australian Senate Inquiry 6.3.01)

I am an immunologist and research scientist with an international reputation in the field of immunoglobulin gene diversity (genetic/evolutionary aspects) , the specific subject area of the two Honours theses in question, Student A 1997 and Student B, 2000 . Here I outline my main scientific achievements. However the respected Sydney Morning Herald columnist and Quadrant editor P. P. McGuinness has succinctly and accurately (in my opinion) summarised this record in the context of my formal submission to this Senate Inquiry, and can be read as a precis of the novelty and significance of my research without necessarily reading my own text below ( see his article in The Sydney Morning Herald 1.3.01 p.12, copy enclosed) .

The mechanism of somatic hypermutation is one of the last remaining enigmas of modern immunology. Elucidation of the mechanism has implications not only for understanding the diversification of rearranged immunoglobulin variable genes (V[D]Js) during immune responses but also for our understanding of evolutionary genetic mechanisms in general.

I am the originator of the "Reverse Transcriptase Model" of somatic hypermutation (Steele & Pollard 1987). This hypothesis grew out of my earlier development of the "Somatic Selection Theory" (1979) which invoked a reverse transcriptase-coupled soma-to-germline feedback loop to explain the molecular evolution and diversification of immunoglobulin variable (IgV) genes (See Books 1 & 3). Since 1987 I have, with various colleagues, published molecular data on key features of the RT-model as well as publishing analytical reviews of the field - including publication of two books (Books 2 & 3). These publications, many by invitation, have summarised and analysed the extant data in the field as they relate to the confirmation or refutation of key predictions of the RT-model (and additionally, how the data relate to the DNA sequence structure of germline V genes, ie. the "evolutionary" implications of the model, see Blanden et al 1998b).

At the time of writing, the RT-model is consistent with all extant data in the field (see Steele & Blanden 2001). In the past 14 years I have been invited to present my group's data and analyses to 13 international meetings in Australia and overseas. The year 2000 was an important milestone indicating broader international acceptance of the work as evidenced by the invitation to present a paper at the meeting on "Hypermutation of Antibody Genes" (July 5-6, Royal Society, London) and its subsequent publication (after refereeing) in the "Philosophical Transactions of The Royal Society" (EJ Steele, RV Blanden Phil. Trans. Roy. Soc: Series B vol 356, 61 - 66, 2001). Moreover, the year 2000 witnessed the acceptance and publication (after refereeing) of a key overview letter in Science (EJ Steele,RV Blanden, vol 288, June 30 2000, pp. 2318-2319). All of the developments since 1987 have been carried out with minimal research funding; they have been achieved by careful deployment of available resources and collaboration with colleagues, such as RV Blanden and GW Weiller/AJ Gibbs of ANU; GW Both of CSIRO; ALM Bothwell of Yale Medical School, USA; JW Pollard of Albert Einstein College of Medicine, NY, USA and earlier on (in 1987) the provision of somatically mutated VDJ clones by K Rajewsky, Institute of Genetics, University Cologne, Germany.

All of my refereed publications in the past five years (* = relevant to this biographical sketch.; ¶= invited) :

1.* Steele, E.J., Rothenfluh, H.S. and Blanden, R.V. (1997) Mechanism of antigen-driven somatic hypermutation of rearranged immunoglobulin V(D)J genes in the mouse. Immunology & Cell Biology 75: 82-95

2.*¶ Blanden, R.V., Rothenfluh, H.S. and Steele, E.J. (1998a) On the possible role of natural reverse genetics in the V gene loci. In : Kelsoe, G. and Flajnik, M. (Eds) Current Topics in Microbiology & Immunology 229: 21-32. (refereed equivalent)

3.* Weiller, G.F., Rothenfluh, H.S., Zylstra, P., Gay, L., Averdunk, H., Steele, E.J. and Blanden, R.V. (1998) Recombination signature of germline immunoglobulin variable genes. Immunology & Cell Biology. 76: 179-185.

4.* Blanden, R.V. and Steele, E.J. (1998) A unifying hypothesis for the molecular mechanism of somatic mutation and gene conversion in rearranged immunoglobulin variable genes. Immunology & Cell Biology. 76:288-293.

5.*¶ Blanden, R.V., Rothenfluh, H.S., Zylstra, P., Weiller, G.F., and Steele, E.J. (1998b) The signature of somatic hypermutation appears to be written into the germline IgV segment repertoire. Immunological Reviews 162: 117-132. (Premier review journal of discipline; by invitation only; refereed equivalent)

6.* Zylstra, P., Rothenfluh, H.S, Weiller, G.F., Blanden, R.V. and Steele, E.J. (1998) PCR amplification of murine immunoglobulin germline V genes : strategies for minimisation of recombinant artefacts. Immunology & Cell Biology. 76: 395-405.

7.* Steele, E.J. and Blanden, R.V. (2000) Lamarck and antibody genes Science 288: 2318-2319.

8.* Blanden,R.V. and Steele, E.J. (2000) Misinterpretation of DNA sequence data generated by polymerase chain reactions Molec. Immunol. 37: 329.

9.*¶ Steele, E.J. and Blanden, R.V. (2001) The reverse transcriptase model of somatic hypermutation Phil. Trans. Roy. Soc: Series B 356: 61-66.

My dozen career-best publications (* = relevant to this biographical sketch; ¶= invited; R= refereed; R'= refereed equivalent):

1.* Steele, E.J. Somatic Selection and Adaptive Evolution: On the Inheritance of Acquired Characters. Williams-Wallace, Toronto, 1979; 2nd Edition. University of Chicago Press, Chicago, 1981. Italian translation 1982.

2. * Steele, E. J.,A.J.D. Bellett, P.J. McCullagh and B, Selinger. (Editors )Evatt Revisited : Interpretation of Scientific Evidence . Centre for Human Aspects of Science and Technology, University of Sydney, NSW, Australia. 1989.

3.* Steele, E. J. (Editor) Somatic Hypermutation in V-Regions CRC Press, Boca Raton, Florida , USA. 1991.

4.*¶ Steele, E.J., Lindley, R.A. & Blanden, R.V. Lamarck's Signature: How retrogenes are changing Darwin's natural selection paradigm Frontiers of Science. Series editor Paul Davies. Allen & Unwin , Sydney, 1998; Addison-Wesley-Longman (Perseus Books) Reading MT, 1998. Russian & Chinese translations pending 2001.

5.*R Gorczynski, R.M. and E.J. Steele (1980) Inheritance of acquired immunologic tolerance to foreign histocompatibility antigens in mice. Proc. Natl. Acad. Sci. (USA) 77: 2871-2875. (Communicated by Howard M. Temin ).

6.*R Steele, E.J. and J.W. Pollard (1987) Hypothesis : Somatic Hypermutation by gene conversion via the error prone DNA -to- RNA -to- DNA information loop. Molec. Immunol. 24: 667-673.

7.*R¶ Rothenfluh, H.S.Blanden, R.V. and Steele, E.J. (1995) Evolution of V Genes : DNA sequence structure of functional germ-line genes and pseudogenes. Immunogenetics 42: 159-171.(Invited 20th Anniverary Review)

8.*R Steele, E.J., Rothenfluh, H.S. and Blanden, R.V. (1997) Mechanism of antigen-driven somatic hypermutation of rearranged immunoglobulin V(D)J genes in the mouse. Immunology & Cell Biology 75: 82-95.

9.*R Blanden, R.V. and Steele, E.J. (1998) A unifying hypothesis for the molecular mechanism of somatic mutation and gene conversion in rearranged immunoglobulin variable genes. Immunology & Cell Biology.76: 288-293.

10.*R'¶ Blanden, R.V., Rothenfluh, H.S., Zylstra, P., Weiller, G.F., and Steele, E.J. (1998b) The signature of somatic hypermutation appears to be written into the germline IgV segment repertoire. Immunological Reviews 162: 117-132.

11.*R¶ Steele, E.J. and Blanden, R.V. (2001) The reverse transcriptase model of somatic hypermutation Phil. Trans. Roy. Soc: Series B 356: 61-66.

12.* Steele, E.J. and Blanden, R.V. (2000) Lamarck and antibody genes Science 288: 2318-2319.

Evidence of impact of my contributions to the immunoglobulin gene diversity field :

Some of the main evidence for impact and contribution to the field is already listed above. However I can make the following additional points. The first concerns the proportion of papers or books published by invitation. Since 1987 when the RT-model first appeared, I have published 2 books and 21 papers relevant to the field; 1 book and 11 papers were written by invitation. The critical year, as an indicator of acceptance or high impact of contributions was 2000 (see above). The second concerns the quality of the publication outlets - of 21 papers/letters published in refereed journals since 1987 ten have appeared in high impact/quality journals: 1 has appeared in Proc. Natl Acad Sci , 2 in Immunol Rev , 1 (a letter) in Molec Immunol. 1 (an anniversary review) in Immunogenetics, I in Phil. Trans. Roy. Soc, , 1 in Eur J Immunol, 1 in Mol Cell Biol, and 1 (a letter) in Science and 1 (a letter) in Nature. The third concerns invitations to conferences - of the 21 scientific conferences attended since 1987, 13 were by invitation to present a paper.

There are also indications that my research is having an impact well beyond the immunoglobulin gene discipline. Thus the my recent book with coauthors RV Blanden and RA Lindley Lamarck's Signature was listed on four occasions in 1999 in the New Scientist best selling top 10 science books (once in Oxford and San Francisco, and twice on the Melbourne lists). This book is now being translated into Russian and Chinese.

Other indications are the invitation to write articles for high impact general publications both within and outside science viz. an article for an internet general biology journal Steele, E.J. and Blanden, R.V. (1999) "What is Lamarck's Signature."in HMS Beagle, an internet science magazine issue 56, June 11.

Full text at: www.biomednet.com/hmsbeagle/56/viewpts/op_ed; an article in the quality UK newspaper The Independent viz. Steele, E.J., Lindley, R.A. and Blanden, R.V.(1999) "Genetic Notes - Embarrassment of the Neo-Darwinists" in the Comment section of the issue of May 8 1999; and an article in Australia's intellectual affairs magazine Quadrant viz. Steele, E.J. (2000) The evidence for Lamarck Quadrant No. 364 Vol XLIV Number 3 (March), 47 – 56.

Lastly there is another indicator of impact way beyond the discipline. I have been invited to attend and present a paper to an elite international conference organised by Veridian Systems Division/ERIM International of Veridian Corp in the USA entitled "Quantum