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The role of the majorhistocompatibility (MHC) genes in the devil cancer

Chapter 4 – The science selected for study

4.5 Is the lack of genetic diversity in devils a reason for cancer transmission? transmission?

4.5.2 The role of the majorhistocompatibility (MHC) genes in the devil cancer

belong) at the end of their natural existence? To which O’Brien replied – ‘rubbish’.

The second question was, if vaccines were created against the devil cell-lines isn’t there the danger of the devils developing an autoimmune disease? O’Brien replied – ‘sure’.

Regardless of the lack of studies the devil researchers remain committed to the allograft hypothesis and to the conviction that a lack of genetic diversity in the devils’ MHC genes was why the cancer could establish in a new host.

was also to undertake the first study of the Tasmanian devil MHC genes with her PhD student Hannah Siddle and research assistant Claire Sanderson; it was published in Immunogenetics in August 2007. 66 In this latter paper they stated ‘[w]e have made the first genetic library for the Tasmanian devil, a spleen cDNA library, and have isolated and characterized full-length MHC Class I and Class II genes’.67 It explains the methodology; ‘RNA and DNA was extracted from spleen, blood, kidney and liver from a single male Tasmanian devil’ and ‘DNA was extracted from the blood of five additional devils’.68 It concludes

[t]his study has provided the fundamental information required to study the MHC biology of Tasmanian devils in relation to DFTD. We have isolated Class I and Class II DAB sequences, which are likely to be involved in immune response and antigen presentation, and have developed markers to study MHC diversity in wild populations. Extensive polymorphism studies of the classical Class I and Class II MHC loci are now in progress in our lab.69

At the same time, August 2007, Woods et al published in EcoHealth a paper stating ‘[a]

lack of MHC expression is unlikely to account for the failure of the devil’s immune system to reject the DFTD allografts because the tumor cells, which were analyzed by constructing a cDNA library, all expressed MHC class Ia and Class II genes. 70 They proposed an alternative explanation ‘that there is a lack of genetic diversity within the devil population and the “cancer graft” MHC types are identical to those of the host’

concluding that a ‘lack of diversity at MHC genes’ results in a ‘failure of the DFTD tissue to be recognized as “non-self” by the host’s immune system.’71 They cite as

TP, Graves JAM & Miller RD, 2006, Reconstructing an Ancestral Mammalian Immune Supercomplex from a Marsupial Major Histocompatibility Complex, PLoS Biology, Vol. 4(3), pp 0317-0328

66 Siddle HV, Sanderson C & Belov K, 2007, Characterization of major histocompatibility complex class I and class II genes from the Tasmanian devil, Immunogenetics, Vol. 59, pp 753-760

67 ibid, p 753

68 ibid, p 754

69 ibid, p 759

70 Woods GM, Kreiss A, Belov K, Siddle HV, Obendorf DL & Muller KH, 2007, The Immune Response of the Tasmanian Devil (Sarcophilus harrisii) and Devil Facial Tumour Disease, EcoHealth, Vol 4(3), pp 338-345, p 343

71 ibid.

evidence the August 2007 paper by Siddle et al, which claims samples were taken from a single, male Tasmanian devil (Individual I) and DNA was extracted from the blood of five additional devils.72 There is no mention of taking samples from devil tumor cells for analysis. The Siddle et al paper also does not confirm that the lack of MHC is the reason why the tumours proliferate.

However, in October 2007, Siddle, her supervisor Kathy Belov and DPIPWE devil researchers published a further paper in PNAS (referred to in the previous chapter in section 3.3).73 In this article they claimed ʻ[t]his novel disease arose as a direct result of loss of genetic diversity...ʼ. 74 In 2008 Wood confirmed that the DFTD cells had not been examined for MHC markers.75 There are still no studies published indicating an investigation of MHC markers on the devil DFTD cells.

On the Save the Tasmanian Devil website in 2007 Belov is quoted as saying “[i]n the case of devils from eastern Tasmania, genetic diversity at the MHC is so low, and the MHC type of tumour and host are so alike, that the host does not see the tumour as

‘non-self’”.76 Woods is also quoted as saying ‘we now have a tool to measure immune response genes and we are now in search of devils whose MHC might be different from the MHC of the tumour’.77

72 Siddle HV, Sanderson C & Belov K, 2007, Characterization of major histocompatibility complex class I and class II genes from the Tasmanian devil, Immunogenetics, Vol. 59, pp 753-760, p 754

73 Siddle HV, Kreiss A, Eldridge MDB, Noonan E, Clarke CJ, Pyecroft S, Woods GM & Belov, K, 2007, Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial, PNAS, Vol 104, No. 41, pp 16221-16226

74 ibid, p 16221

75 Personnal interview with Greg Woods in Hobart, 14 November 2008

76 Anon, 2007, A lack of genetic diversity, Save the Tasmanian Devil. Available at:

http://www.tassiedevil.com.au/tasdevil.nsf/TheProgram/BFD7236BFF934B62CA2576D200174180 last accessed 17 August 2010

77 ibid.

In 2010 Siddle, Belov, Jones and colleagues from the University of Sydney’s Faculty of Veterinary Science published a paper in the Proceedings of the Royal Society B journal.

In this study they undertook a comprehensive screen of MHC diversity in devils and concluded overall levels were low. In an apparent about turn they conclude

‘[c]ounterintuitively, we postulate that the immune system of devils with a restricted MHC repertoire may recognize foreign MHC antigens on the surface of the DFTD cell.’78 A subsequent media report in May 2011 in The Australian newspaper stated

‘[w]ith almost identical DNA across the whole population, Tasmanian devils are like

‘walking zombies” spreading cancer by biting each other, University of Adelaide researchers say’.79

However, the hypothesis that a lack of genetic diversity in the devil MHC genes is the reason why the cancer could establish in a new devil host was eventually abandoned. In a 2012 interview Kathy Belov told Rachel Carbonell on the ABC program The World Today ‘that in trying to prove the theory her team instead debunked it’. 80 It had been made public by Assistant Professor York that the devils’ MHC was not involved as discussed below.

Assistant Professor Ian York of Microbiology and Molecular Genetics at Michigan State University had provided a credible challenge to the hypothesis. Posted on his website he relates an encounter with Elizabeth Murchison (the young Tasmanian scientist who struggled to get access to the devils cell lines for experiments at Cold

78 Siddle HV, Marzec J, Cheng Y, Jones M & Belov K, 2010, MHC gene copy number variation in Tasmanian devils: implications for the spread of a contagious cancer, Proceedings of the Royal Society B, published online. Available at: www.rspb.royalsocietypublishing.org last accessed 12 March 2010

79 Peddie C, 2011, Lack of genetic diversity contributes to Tasmanian devil cancer deaths, The Australian.

Available at: www.theaustralian.com.au/news/breaking-news/devils-in-the-lack-of-diversity/story-fn3dxity-1226054415704 last accessed 13 May 2011

80 Carbonell R, 2012, Tasmanian devil facial tumour theory debunked, ABC The World Today. Available at: http://www.abc.net.au/worldtoday/content/2012/s3523185.htm last accessed 31 December 2012

Springs in the US).81 She had informed him that tissue transfers undertaken between devils were unsuccessful. On reflection Professor York posted the following on his website:

Murchison told me that Tasmanian Devils — even those in the same sub-population — vigorously reject each others’ skin grafts. This is what’s supposed to happen with skin grafts, of course. It implies that the Devils do not, in fact, have the same MHC; and in my opinion it’s a much stronger experiment than those in the original homogenous-MHC paper. If Devils reject skin grafts from each other, then they ought to reject tumors from each other — in other words, even if the tumor can take in one individual, then it should be rejected in another, so the tumor should not spread throughout the population. The skin graft finding hasn’t, as far as I know, been published, but if it holds up, it’s a strong argument against homogenous MHC.82

York concludes that the devils’ MHC is not involved in the transmission of the cancer.

DPIPWE research notes (Attachment C) confirm Murchison’s claim stating ‘[a]ll eastern devils tested ‘in vivo’ allograft experiments - total of 8 animals - all showed host-graft or graft-host rejection’. It further states:

[t]here is diversity present in the MHC class II but only one family of genes has been examined; and then, there’s class III. This class II diversity gives validation for Kreiss’s uniform host-graft rejections in the skin graft experiments. MHC class II are found on the immunologically competent stem cells and their progenitors - they help to recognise exogenous antigens (microbiological/parasitological/viral).

At the time of writing, April 2013, the MHC research appears to have been abandoned but the search for a vaccine or a resistant population, possibly on the west coast, continues.