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Letter from Ted Steele (author of "Lamarck's Signature")

email Date:     Thu, 11 Mar 1999 14:55:55 +1100 (EST)
To:        Gert Korthof
From:    Ted Steele Ted_Steele@uow.edu.au
Subject: Your review of "Lamarck's Signature"

Dear Gert :

Many thanks for contacting me. You have done a very good objective job in
reviewing our book. The best and most comprehensive we have seen thus far
from a "general reader" (although it is clear from your deep grasp of the
subject matter you are more than just a general reader). For your
information we have yet to see anything like this from a professional
within the somatic hypermutation or experimental molecular evolution fields.

Every so often we say to ourselves " wouldn't it be nice to have all our
published work evaluated on the basis of the evidence". You have really
attempted to do this, and largely succeeded - on behalf of the authors of
"Lamarck's Signature" please accept our sincere thanks.

Given that there is so much molecular data to integrate to truly appreciate
why the title of our book appropriately represents our position ("the
somatic pattern is written into the germline DNA ", even for non-antibody
genes, below) it is gratifying that you made such a detailed effort to come
to grips with the problem.

We do have a few things to comment on and these are listed below.

  1. In the second paragraph of your review you highlight the real enigmas
    presented by the apparent pristine "open reading frame" structure of the
    chicken V-pseudogenes as well as the recombination process and the
    "integration footprint" (ie.the Weiller signature predicted by cDNA
    retrotranscipts of pieces of rearranged pre-mRNA of V genes acting as gene
    conversion donors (is there another simple rational explanation?). Further
    on you highlight the difference between the "germline configuration" and
    the "somatic configuration" - and our comment would be, that without this
    stark molecular difference the soma-to-germline analysis would be wellnigh
    impossible. But in paragraph 2 you also state:
    " Some of the steps of this mechanism (from somatic RNA to germline DNA)
    do occur in organisms and are mentioned in the textbooks. For example some
    pseudogenes are thought to have arisen by reverse transcription from mRNA,
    followed by insertion into the chromosome."
    It should be pointed out that the words "some pseudogenes" grossly
    understates the situation for non-immunoglobulin "housekeeping" genes.
    Thus for example in W-H Li and D Graur's "Fundamentals of Molecular
    Evolution"
    (1991 Sinaure & Associates) you will note in Table 2 entitled
    "The number of retropseudogenes and the number of parental functional genes"
    that pretty well most single-copy/limited-copy "house keeping genes"
    examined (as to 1991!) have as their counterparts multiple copies of
    retropseudogenes (discussed and cited on pages 200-202 of "Lamarck's
    Signature"
    ). Further, in any extended chromosomal locus (eg. humans) you
    might randomly select, and which has been completely sequenced, you will
    find that retroelements of all types dominate the DNA sequence landscape
    (eg. Rowen et al The Complete 685-Kilobase DNA Sequence of the Human
    ß T Cell Receptor Locus
    in Science vol 272 , June 21 1996).
  2. In paragraph 2 you then go on to state :
    "What is not 'proven' is that these individual steps occur together"
    Our comments are two fold. All the DNA sequence structural evidence
    directly implies that the steps must have occurred together. This deduction
    is identical to all conclusions on retrogenes, pseudo or otherwise viz.
    evidence for RNA intermediate structures such as a lack of introns and
    polyA tails written into DNA. The additional "retro" feature we add is the
    documentation of the evidence for 'somatic selection' (at the intact
    antibody protein level!) of germline V sequences.*
  3. The section entitled : "Revolutionary genetics: genes that don't behave"
    You ask via way of a question mark whether our detailed analysis of "the
    genetics and evolutionary uniqueness of the immune system" may have been
    "unintentional?". Not at all, this was quite intentional - because if these
    facts are fully grasped old fashioned and rigid views of genetics
    (neo-Darwinian or otherwise) have to be abandoned. This then allows the
    emergence of a new set of operational genetic rules which might be dubbed
    the "New (Retro-) Genetics".
  4. The section entitled : "Should 'Darwin's Natural Selection Paradigm' be changed?"
    At the end of the first paragraph you cite an anonymous reviewer (ref 13)
    and say " The indirect evidence is interesting, but open to other interpretations".
    Our response is blunt : If there are other interpretations we would like to
    hear them - to this point plausible alternative genetic explanations have
    not been advanced (And it is for this reason that we rhetorically contrast
    our explanations with the non-scientific 'divine intervener').
    We have read the review at this Website and in particular the use of the
    "anonymous" comments (which we should point out have been added recently to
    this Website review - they were not in the original review of Dec 1998-Jan
    1999). This is a shallow attempt to explain some of the data. Large
    tracts of data are ignored or not understood at all (see footnote *).
    We have found this to be a common mistake of neophyte critics - they focus on
    one aspect of the data, without realizing that "Lamarck's Signature"
    constitues a multifaceted set of genetic features all of which require a
    rational explanation. In short, if the anonymous reviewer had understood
    the data he/she would not have drawn the conclusions published on that
    Website.
    In the second paragraph you make the point "So the subtitle of his book is
    a little bit misleading. Even if the soma-to-germline route would be
    proven,it would not follow that other organs/tissues apart from the
    immunological system could behave in the same way. It would not be a
    general mechanism."
    At the moment I suppose this is the legitimate and conservative position to
    take - but it should be tempered and balanced by the realisation that
    "retrogenes" (DNA sequences in the genome that have been processed by
    reverse transcription via an RNA intermediate template sequence) are
    general (not restricted to antibody genes) and widespread in the genome
    (eg. see point 1 above: Table 2 in W-H Li and D Graur's "Fundamentals of
    Molecular Evolution"
    [1991 Sinaure & Associates] and Table 2 in Rowen et al
    in Science vol 272, June 21 1996).
  5. The point in the last paragraph of your review is well taken. We did
    omitted defining (paradoxically!) "retrogenes". So an appropriate
    definition is :
    retrogenes : DNA sequences in the genome that have been processed by
    reverse transcription via an RNA intermediate template sequence.

    We will endeavour to clean up these blemishes if the book goes to a new edition reprint.
Before closing I would like to state that our data and analyses have been
peer reviewed and published in quite a few professional journals these past
few years ie. we have passed through many critical 'negative selection
gates' in science and as yet we have not been refuted by the professionals
in the field. Our most recent definitive paper which closely approximates
and underpins the book is:

Blanden RV, Rothenfluh HS, Zylstra P, Weiller GF
& Steele EJ 1998 The signature of somatic hypermutation appears to be
written into the germline IgV segment repertoire.
Immunological Reviews 162 : 117 - 132.

Publication here is by invitation only and is thus an
indicator of how the professional circle in this area of molecular
immunology (somatic hypermutation) view the plausibility of our work thus far.
I will sign off by bringing your attention to a a very important recent
development. Some direct independent proof of the reverse trancriptase
process in somatic hypermutation of antibody-related genes ( the genes that
encode the T cell receptor) has just been published in the Journal of
Immunology
(Jan 15 1999) by A. Mellor's group at the Medical College of
Georgia, in Augusta, Georgia. An Abtstract of the paper is pasted below.

It seems (as we have always suspected) that evidence like this would emerge
in the most unlikely of situations - and that is what appears to have
happened; in T cells, in vitro not in vivo ( note that for a couple of
years there has been evidence that T cell receptor V genes can hypermutate
in certain situations; and we predicted in 1993 that T cell receptor genes
should in fact hypermutate).
Their key concluding statement is : " Evidence is presented for the
presence of cDNA reverse transcripts of the TCR alpha-chain within the
hybridoma, suggesting a role for reverse transcriptase in the generation of
mutations."

We have read the paper carefully and cannot fault it. This represents
independent confirmation by a group of molecular immunologists new to the
somatic hypermutation field. They stumbled across the phenomemon by
accident, then described it meticulously.

So I hope I have commented on most of the relevant points in your book
review. Feel free to use any of this response in future e-mail
communications with other correspondents or on your Website.

Thanks again for contacting us and reviewing "Lamarck's Signature".


Ted Steele
Dr. Edward J Steele
Associate Professor
Department of Biological Sciences
University of Wollongong
Northfields Avenue
Wollongong NSW 2522
AUSTRALIA

Phone No. 61 (0)2 42 213434
Fax No. 61 (0)2 42 214 135
E-mail Address Ted_Steele@uow.edu.au

Copy :
Robert V Blanden ( Robert.Blanden@anu.edu.au )
Robyn A. Lindley ( Robyn_Lindley@uow.edu.au )


footnotes
The full Abstract of that paper is : Journal of Immunology 1999 Jan 15;162(2):871-7

Alternative splicing and hypermutation of a nonproductively rearranged TCR alpha-chain in a T cell hybridoma.
Marshall B, Schulz R, Zhou M, Mellor A
Institute of Molecular Medicine and Genetics, Program in Molecular Immunology, Medical College of Georgia, Augusta 30912-3175, USA. marshall@immag.mcg.edu

[Medline record in process]

Like Ig genes, TCR genes are formed by somatic rearrangements of noncontiguous genomic V, J, and C regions. Unlike Ig genes, somatic hypermutation of TCR V regions is an infrequent event. We describe the occurrence of spontaneous hypermutation in a nonproductively rearranged TCR alpha-chain gene in a clonal T cell hybridoma that had lost its productively rearranged alpha-chain. The mutating hybridoma was eventually supplanted in culture by a nonmutating variant that had restored an open reading frame in the nonproductively rearranged TCR alpha-chain through the use of cryptic splice sites in the V alpha region. Evidence is presented for the presence of cDNA reverse transcripts of the TCR alpha-chain within the hybridoma, suggesting a role for reverse transcriptase in the generation of mutations.
PMID: 9916710, UI: 99113748


Other footnotes are

*In general :
  • a] they display a significant deficit of stop codons and point mutation-generated pseudogenes below numbers expected from random point mutation;
  • b] codon-by-codon analysis of the V coding segments shows an excess of amino acid replacement changes in the "antigen contact" CDR regions yet amino acid silent changes in framework (FW) regions;
  • c] the highly non-random distribution and type of insertion deletion events - within coding regions there are insertions or deletions of triplet codons or multiples therepf ( which preserve the translational reading frame, even in chicken pseudogenes) and in the flanking non-coding regions there are variable length insertions and deletions clustered around the transcription start site, within the leader (L-V) intron and immediately downstream of the 3' (righthand) edge of the V coding segment;
  • d] heavy chain V chicken pseudogenes contain 3' (righthand end) terminii with pieces of D sequence, all in the preferred reading frame and the 3' ends of both the H and L chain V pseudogenes show evidence of nucleotide additions and trimmings diagnostic of somatic V(D)J rearrangement ( thus implying the reverse transcription-coupled soma-to-germline flow of genetic information, a conclusion reached independently of us by the molecular evolutionist M. Nei and his group (Ota T & Nei M 1995 Evolution of immunoglobulin VH pseudogenes in chickens, Mol. Biol Evol 12 : 94-1002; this is cross referenced in: Rothenfluh HS, Blanden RV & Steele EJ 1995 Evolution of V genes : DNA sequence structure of functional germline genes and pseudogenes Immunogenetics 42 : 159-171);
  • e] dendrogram analysis of 5' flanking sequences compared with the transcription unit or V coding region segments indicates that the flanking and coding regions are evolving indepently ( implying hyper recombination events targetted to transcription/V coding units);
  • f] recombination analysis using the Phylogenetic Profiles algorithm ( also called the Weiller Algorithm after Georg Weiller who developed it) within familes of mouse (VH186.2-related) and human (Vk) germline V segments shows that major sites of recombination coincide with the borders of the L-V intron, the transcription start site and the 3' end of the V segment ( logically deduced and interpreted as the predicted homologous recombination events of soma-to-germline integration predicted by the particular species of V(D)J retrotranscripts generated (say) by the hypothesised reverse transcriptase-coupled somatic hypermutation process)**

** See recent J. Immunol paper by Marshall et al, above¶

Return-Path: Ted_Steele@uow.edu.au
Date: Fri, 12 Mar 1999 11:40:16 +1100 (EST)
X-Sender: ejsteele@sci-pop.uow.edu.au
To: Gert Korthof
From: Ted Steele Ted_Steele@uow.edu.au
Subject: Addendum

Dear Gert :

Can I make an Addendum to what I sent you yesterday. I overlooked your reference 5*) - a good point because you only ask this question(s) if you have really understood the modus operandi of the immune system.

We think the evolutionary value is in "genetic housekeeping" as we outline on page 185 of "Lamarck's Signature" ie. maintenance of a functional V repertoire (irrespective of specific V sequences) over evolutionary time.

Best regards

Ted

These email comments reference my review version 2.2. In version 3.0 corrections are added.
*) Reference 5 is now included in the text: 'the philosophy of the immune system is "to prepare for the unknown".' [gk]




"The Independent" newspaper (London, UK) Saturday May 8 1999 "Comment" page

Genetic Notes - Embarrassment of the neo-Darwinists

by Edward J. Steele, Robyn A. Lindley and Robert V. Blanden



    Fifty years before Charles Darwin's seminal Origin of Species the French biologist Jean Baptiste de Lamarck published his view on how animals evolved. A core idea , uniformly accepted by his peers, was that organisms adapting to a changing environment altered their bodily and behavioural characteristics and passed these acquired characteristics to their progeny. This is Lamarckian inheritance and is probably one of the most emotive issues in contemporary science (apart from the metaphysical issue of whether an all-powerful "God" exists).

Historical ironies abound. Both Charles Darwin and his grandfather Erasmus accepted Lamarckian modes of inheritance. The notion is overt in all of Charles Darwin's evolutionary analyses. Thus in 1868 he published his theory "Pangenesis" to explain the origin of genetic variations in nature because his evolution theory assumed the pre-existence of such genetic variation in populations of plants and animals, which are then subjected to natural selection to sort out the parents for the next generation - a process which the philosopher Herbert Spencer coined the term "survival of the fittest". Therefore Darwin considered that, during a somatic, or bodily, change necessary for a particular adaptation, the body cells of the excited target organ would emit genetic material or "gemmules" (also termed "pangenes") which were considered to be minute representations of each normal or altered bodily component. These were discharged from the active organ into the bloodstream , thus allowing them to enter the germ cells (eggs and sperm) and be genetically transmitted to the next generation.

Darwin's late-19th-century and 20th-century followers, the neo-Darwinists, have been particularly embarrassed by his genetic speculations and have, where possible, expunged them from the scientific record. Lamarck's contribution to modern genetics has been demonised; many interesting acquired inheritance phenomena have been suppressed.

It began in earnest in 1885 when August Weismann erected his now famous conceptual barrier protecting germ cells from any genetic changes within the soma or body of the organism and thus forbidding any form of acquired inheritance. Despite the intellectual efforts of heavy weight critics such as Arthur Koestler and Sir Fred Hoyle, neo-Darwinism sustained by Weismann's genetic chastity belt has reigned supreme throughout the 20th Century, a development which would have mystified if not horrified Darwin.

We have all been witnesses therefore to the triumph of the "Darwinian dogma", that evolution proceeds only by the natural selection of chance events. In this century we have the tragic story of the Austrian biologist Paul Kammerer wonderfully told by Arthur Koestler in his 1971 book The Case of the Mid-Wife Toad and then the bizarre aberration of the so-called Lamarckian theory promulgated by Joseph Stalin's head of Soviet agriculture T.D. Lysenko (who, in the course of a ruinous 30 year career destroyed Soviet agriculture, biology and genetics).

So at the end of a turbulent and violent century neo-Darwinism apparently remains impregnable - much like Communism just prior to its dramatic implosion. Are neo-Darwinism and Weismannism, which reached their zenith during the Cold War, on the verge of a similar collapse?

We have marshalled and analysed the available molecular evidence on the functioning and evolution of the antibody genes of the immune system in a new book. Without a Lamarckian soma-to-germline gene feedback process it is difficult , if not impossible, to explain a large number of striking features of the DNA sequence structure of these genes. The challenge is for those other scientists, who really understand these data , viz. molecular immunologists, to come up with a better scientific explanation .We don't think there is one - outside of course those non-scientific propositions evoking an "intelligent gene manipulator" or, if you will a " divine intervener" as playing a role in evolution.

Edward J Steele, Robyn A Lindley and Robert V Blanden are the authors of 'Lamarck's Signature : How retrogenes are changing Darwin's natural selection paradigm ' ( Allen & Unwin).





From: John.Hoyland@rbi.co.uk
Mime-Version: 1.0
Date: Wed, 19 May 1999 11:46:21 +0100
Subject: Re: Letter Steele,Lindley & Blanden?
To: Ted Steele <Ted_Steele@uow.edu.au>
Cc: Maggie.McDonald@rbi.co.uk
Status:
Thanks for your message. I'm afraid my advice was not to run your letter.

Yours sincerely, John Hoyland (Letters)

______________________________ Reply Separator
Subject: Letter Steele,Lindley & Blanden?
Author: Ted Steele <Ted_Steele@uow.edu.au> at INTERNET
Date: 19/05/99 09:49

Dear Sir/Madam::

On or about April 22 we submitted the letter below via your Sydney (Australia) office (via e-mail). We have noted that as the May 15 issue of New Scientist the letter has not been published and we were wondering if a decision "yes" or "no" has been made by your office to publish our letter.
We would greatly appreciate a response as soon as you are able.
Thanking you

Dr. EJ Steele



LETTER TO EDITOR, NEW SCIENTIST - submitted 22.4.99

Dear Sir,

   The review of our book "Lamarck's Signature" by Laurence D. Hurst, New Scientist, April 17, 1999, PP 60-61, entitled "Cut off their tails" is a mixture of ignorance and misrepresentation. As far as we are aware, no-one in our discipline area (Molecular Immunology) has commented like Hurst, possibly because they don't have a viable alternative explanation for the mass of data published in the scientific literature that we have used to underpin the discussions in our book. Furthermore, since publication of the book, cDNA intermediates predicted by our reverse transcriptase model of somatic hypermutation of immunoglobulin and T cell receptor genes have been found by Marshall et al (Journal of Immunology, 1999, 162:871-877), adding further weight to our analysis. If Hurst had read and understood the references cited in the book he may not have written such an ignorant review. Finally we must confess our astonishment at Hurst's obsession with the amputation of rat's tails. His notion that we should have seriously considered the possibility that rats might deliberately bite their tails off is truly astounding. We are not aware of any record of spontaneous self-mutilation by animals. It seems that only humans indulge in such things, both physically and mentally.

Yours sincerely

E. J. Steele, R. A. Lindley (Wollongong University)
and R. V. Blanden (Australian National University)

Communicating author:
Dr. EJ Steele

Associate Professor
Department of Biological Sciences
University of Wollongong
Northfields Avenue
Wollongong NSW 2522
AUSTRALIA
Phone No. 61 (0)2 42 213434
Fax No. 61 (0)2 42 214 135
e-mails : Ted_Steele@uow.edu.au
& coauthors : Robert.Blanden@anu.edu.au,
Robyn_Lindley@uow.edu.au


email
Date: Mon, 26 Feb 2001 09:33:58 +1100
To: Gert Korthof
From: Ted Steele ejsteele@uow.edu.au
Subject: Re:Changed URL

Dear Gert :

My first book should have been cited and/or either one of two experimental papers I published with Gorczynski.(see below)

  • Steele, E.J. Somatic Selection and Adaptive Evolution : On the Inheritance of Acquired Characters. First Edition. Williams-Wallace, Toronto, 1979: Croom-Helm, London, 1980.2nd Edition. Revised with an author's Postscript , University of Chicago Press, Chicago, 1981.
  • 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).
  • Gorczynski, R.M. and E.J. Steele (1981). Simultaneous yet independent inheritance of somatically acquired tolerance to two distinct H-2 antigenic haplotype determinants in mice. Nature 289: 678-681.

However these events occurred a long time ago. Those who know the field are aware of the priority - it is cited in many of my publications, and in letters published by me and colleagues during and after a plagiarism/priority dispute with Prof John Cairns in the late 1980s (references to these letters are also pasted below) which was followed by a News & Views in Nature by Howard Temin(1989) (see ref on pages 193-196 and page 270 of "Lamarck's Signature" ).

  • Steele, E. J. (1989) Immunol. Cell Biol. 67 : 151-152 and the letter by Blanden RV, Fenner, F, Both GW, Reed K and Rolfe BJ published along side it in the same issue.
  • Steele , E.J. (1989) Mechanism of directional mutations ? Molec. Reprod. Develop. 1 : 231-232.
  • Howard Temin(1989) "Retrons in Bacteria", Nature 339: 254-255.
  • Steele, E. J. and J. Cairns.(1989) Dispute resolved. Nature 340 : 336.
I will try to get to that issue of Nature - but it seems to me it does not add anything new to what we have known for over 20 years now on generalised reverse transcription - there is a lot of unbelievable American hype and rubbish being published right now on the human genome. To get an accurate picture of the important microvariability you would need to sequence thousands of human genomes (clearly impossible). The important job is to interpret what we have against a back drop of biological principles that have been, and are, being discovered on a smaller scale.

Thanks again.

Ted

Dr. EJ Steele
Associate Professor
Molecular Immunology & Evolution Laboratory
Department of Biological Sciences
University of Wollongong
Northfields Avenue
Wollongong NSW 2522
AUSTRALIA


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Copyright © 1999 G.Korthof/EJ Steele First published: 12 Mar 1999 update: 8 Aug 2001