Anthony Clifford Allison

Anthony Clifford Allison (21 August 1925 – 20 February 2014) was a South African geneticist and medical scientist who made pioneering studies on the genetic resistance to malaria.[2] Clark completed his primary schooling in Kenya, completed his higher education in South Africa, and obtained a BSc in Medical Science from the University of the Witwatersrand in 1947. He earned his PhD from the University of Oxford in 1950.[1] After working at the Radcliffe Infirmary for two years, he worked as post-doctoral student to Linus Pauling in 1954. After teaching medicine for three years at Oxford, he worked at the Medical Research Council in London. In 1978 he simultaneously worked at the International Laboratory for Research on Animal Diseases (ILRAD) as its Director, and at the World Health Organization's (WHO) Immunology Laboratory, both in Nairobi. He later became the Vice President for Research at Syntex Corporation (1981-1994).

Anthony Clifford Allison
Born(1925-08-21)21 August 1925[1]
East London, South Africa
Died20 February 2014(2014-02-20) (aged 88)
Belmont, California, United States
NationalitySouth Africa
Other namesTony Allison
Alma materUniversity of the Witwatersrand
Known forGenetic resistance to malaria
CellCept
Spouse(s)Helen Green (divorced)
Elsie M. Eugui
ChildrenMiles and Joseph Mark
Scientific career
FieldsMedicine
Human genetics
InstitutionsRadcliffe Infirmary
University of Oxford
International Laboratory for Research on Animal Diseases
Syntex

While a graduate student at Oxford, Allison joined a vocational Oxford University Expedition to Mount Kenya in 1949. He first noticed from blood samples he collected that there was an unusually high occurrence of sickle-cell trait in its less harmful (heterozygous) condition. He conceived the idea that it could be an advantageous adaptation to people constantly exposed to malaria. After he completed his doctoral research at Oxford in 1953, he investigated further. In 1954 he discovered, confirming his preconception, that people with sickle-cell trait are resistant to the deadly falciparum malaria.

In the 1970s, Allison had worked out the enzyme, inosine monophosphate dehydrogenase, as a key molecule of the immune response in autoimmune diseases and in organ transplantation. Based on this, he tested the otherwise abandoned antibiotic, mycophenolate mofetil, as an inhibitor of the enzyme. After experimental success, with his wife, Elsie M. Eugui, he developed a safer derivative which was eventually approved as an immunosuppressive drug called CellCept.[3] He contributed more that 400 technical papers and edited 12 books.

Biography

Allison was born in East London, Eastern Cape, South Africa. His father was a World War I British veteran and keen polo player, who left Britain in 1919 for better farming life in East Africa.[4] His father had a chrysanthemum farm at Mawingo in upper Gilgil, Kenya, overlooking the Great Rift Valley, where he spent most of his childhood. He entered boarding school for his primary education. He returned to South Africa for higher education and obtained his BSc in Medical Science at the University of the Witwatersrand in Johannesburg. In 1947 he entered Merton College, Oxford, from where he earned his DPhil with medical degree in 1952.[1] He then found employment at the Radcliffe Infirmary, Oxford, where he worked for two years till 1954. However, most of his 1953 work was in Kenya. Receiving the George Herbert Hunt Travelling Scholarship for 1953,[5] he joined the Nobel laureate Linus Pauling at the California Institute of Technology for post-doctoral research in 1954. He returned to England to take up teaching in medicine at University of Oxford. After three years in Oxford he was employed in the Medical Research Council in London, where he worked for twenty years. He first joined the MRC National Institute for Medical Research, and then the Clinical Research Centre. In 1978 he was appointed as Director of the International Laboratory for Research on Animal Diseases (ILRAD) in Nairobi, Kenya. He simultaneously worked at the World Health Organization's (WHO) Immunology Laboratory in Nairobi. In 1981, he became the Vice President for Research at Syntex Corporation at Palo Alto, California. As Syntex was acquired by Hoffman LaRoche in 1994, he was given retirement. He continued to teach human genetics at Stanford University and participated in many therapeutic programmes at Alavita Pharmaceuticals.[6]

He spent his last 30 years at his home in Belmont, California. He died on 20 February 2014 as a result of complications of the end stage of pulmonary fibrosis, which he had been suffering from.[3][7] He was survived by his second wife, and two sons.[2]

Personal life

Allison developed an early interest in human evolution. Growing up in Kenya, he made close contact with paleoanthropologists such as Louis Leakey, who made important fossil discoveries at Olduvai Gorge in Tanzania. One of his teachers at University of the Witwatersrand was Raymond Dart, the discoverer of an extinct hominid Australopithecus africanus.[3] He was strongly influenced by Charles Darwin's books, On the Origin of Species and The Descent of Man, while still a teenager. As he put it, he "became a convinced Darwinian."[8]

Allison married Helen Green (7 February 1923 – 26 December 2011) while teaching at Oxford. After they had two sons, Miles and Joseph Mark, they soon divorced.[9] By then Allison met an Argentinian biochemist, Elsie Eugui, a visiting scientist in his laboratory at the Clinical Research Centre.[6] Allison found true partnership in profession as well as interest in Eugui, and married her. They were together for the rest of his life. They shared their passion in music, art, deep-sea fishing, hiking, bird-watching, and wine tasting.[2]

Achievements

Sickle-cell disease and resistance to malaria

In 1949 Allison participated in a vocational Oxford University Expedition to Mount Kenya. He took up the task of collecting blood samples from Kenyans for analyses of blood groups and genetic markers such as for sickle-cell disease. At the time it was a scientific puzzle that the disease was prevalent even though it killed people before they reached puberty, before they can have children to pass on the lethal gene.[4] He found that the prevalence of sickle-cell trait (heterozygous condition) among people inhabiting coastal areas was higher than 20%.[8] (At the time the highest record was 8% among African-Americans.)[10] He was posed with the question as to why such a deadly disease (in homozygous condition) would be more prevalent in a localised area in the form of a less lethal heterozygous form. He formulated a hypothesis that it was because it had selective advantage towards malaria. Because the region was malaria endemic, acquiring a genetic mutation, but not the lethal form, could confer resistance to Plasmodium falciparum. To test his hypothesis he had to wait four years until he completed his medical course. He returned to Nairobi in 1953 to start his experiments. He selected volunteers of the Luo people, who came from malaria hyperendemic area around Lake Victoria. Under experimental infection, volunteers indicated partial resistance to malaria. Then he found children naturally infected with malaria in Buganda. He discovered that children with heterozygous trait had significantly low number of parasites in their blood. This implies further that heterozygosity in children acquired better survival rate against malaria. His final results reported in 1954 from nearly 5,000 East Africans indicated the overall picture: sickle-cell trait confers resistance to malaria.[11][12][13][14]

When Allison introduced the genetic theory of malaria resistance, it was largely received with scepticism.[4][15] The reason was there were observations that malaria was equally found among homozygote and heterozygote patients in some East Africans.[16] Further it was experimentally demonstrated that malaria could be induced in African-Americans having heterozygous alleles.[17] But Allison argued that if selective pressure would operate children between six months and four years of age are most important for population study because survival is most critical to reach reproductive stage among these children. His arguments were proved right by subsequent studies among children of East, Central, and West Africa, showing 90% protection from malaria among children with heterozygous allele.[18][19][20][21]

CellCept

In the 1970s while working at the Medical Research Council, Allison had investigated the biochemical cause of immune deficiency in children. He discovered the metabolic pathway involving an enzyme, inosine monophosphate dehydrogenase,[3] which is responsible for undesirable immune response in autoimmune diseases, as well as for immune rejection in organ transplantation. He developed an idea that if a molecule that could block the enzyme is discovered, then, it would become an immunosuppressive drug for autoimmune diseases and organ transplantation. In 1981 he decided to go for drug discovery and approached several pharmaceutical companies, which turned him down one by one as he had no primary knowledge on drug research. However, Syntex liked his plans and asked him to join the company with his wife.[6] He became Vice President for Research. In one of their experiments the Allisons used an antibacterial compound, mycophenolate mofetil, which was abandoned in clinical use due to its adverse effects. They discovered that the compound had immunosuppressive activity.[22][23] They synthesised a chemical variant for increased activity and reduced adverse effects.[24][25][26][27][28] They subsequently demonstrated that it was useful in organ transplantation in experimental rats.[29][30] After successful clinical trials,[31] the compound was approved for use in kidney transplant by the US Food and Drug Administration on 3 May 1995,[32] and was commercialised under the brand name CellCept.[33][34]

Controversy

In 1982 Allison and Eugui reported in the Christmas issue of The Lancet the discovery of immunity to malarial parasite (Plasmodium falciparum) by production of free oxygen radicals in the immune system.[35] A quick response came from Ian Clark, former PhD student of Allison, and W.B. Cowden and G.A. Butcher, both of the University of Newcastle Medical School in New South Wales, who claimed that the scientific ideas were originally theirs, and accused Allison of stealing the idea.[36] Clark further stated that he had developed the concept back in the spring of 1982, and submitted his report to Nature, which rejected it because it was considered "out-of-purview" of the journal. Clark eventually published his work in the January issue of Infection and Immunity.[37] In August 1982, Clark had given Allison a draft copy of his manuscript; Allison's own experimental result was published in December. Reacting to the accusation, Allison explained that his experiment was independent of Clark's, and returned the accusation that while Clark was his student, he had claimed two works as his own, which were not. It was generally agreed that the original idea was that of Clark's.[38] A reconciliation paper was published in February 1983, jointly written by all the scientists involved.[39]

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References
  1. Levens, R.G.C., ed. (1964). Merton College Register 1900-1964. Oxford: Basil Blackwell. p. 373.
  2. "Anthony Allison". Legacy.com. Retrieved 15 July 2014.
  3. Spinney, Laura (2014). "Anthony Allison". BMJ. 348 (mar24 20): g2243–g2243. doi:10.1136/bmj.g2243.
  4. Spinney, Laura. "REDISCOVERING TONY ALLISON". Intelligent Life. The Economist Newspaper Limited. Archived from the original on 18 July 2014. Retrieved 15 July 2014.
  5. Anonymous (1953). "Universities and Colleges: University of Oxford". British Medical Journal. 1 (4821): 1227–1228. doi:10.1136/bmj.1.4821.1227-a. PMC 2016292. PMID 13042200.
  6. Watts, Geoff (2014). "Anthony Clifford Allison". The Lancet. 383 (9925): 1290. doi:10.1016/S0140-6736(14)60635-8.
  7. Sollinger, Hans W. "Obituary Anthony (Tony) Allison" (PDF). crippenandflynnchapels.com. Archived from the original (PDF) on 29 July 2014. Retrieved 22 July 2014.
  8. Allison, Anthony C (2002). "The discovery of resistance to malaria of sickle-cell heterozygotes". Biochemistry and Molecular Biology Education. 30 (5): 279–287. doi:10.1002/bmb.2002.494030050108.
  9. Emma (4 January 2012). "Helen Green Allison, MA Oxon, MA John Hopkins, MBE: A founding mother or father of The National Autistic Culture". Autism Society of Kent County. Archived from the original on 9 August 2014. Retrieved 20 July 2014.
  10. Diggs, LW; Ahman, CF; Bibb, J (1933). "THE INCIDENCE AND SIGNIFICANCE OF THE SICKLE CELL TRAIT". Annals of Internal Medicine. 7 (6): 769–778. doi:10.7326/0003-4819-7-6-769.
  11. ALLISON, AC (1954). "The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria". Transactions of the Royal Society of Tropical Medicine and Hygiene. 48 (4): 312–8. doi:10.1016/0035-9203(54)90101-7. PMID 13187561.
  12. ALLISON, AC (1954). "Protection afforded by sickle-cell trait against subtertian malareal infection". British Medical Journal. 1 (4857): 290–294. doi:10.1136/bmj.1.4857.290. PMC 2093356. PMID 13115700.
  13. ALLISON, AC (1954). "Notes on sickle-cell polymorphism". Annals of Human Genetics. 19 (1): 39–51. doi:10.1111/j.1469-1809.1954.tb01261.x. PMID 13208024.
  14. Allison, AC; Ikin, EW; Mourants, AE (1954). "Further observations on blood groups of East African tribes". The Journal of the Royal Anthropological Institute. 84: 158–168. doi:10.2307/2844008. JSTOR 2844008.
  15. Edington, GM; Lehmann, H (1956). "Sickle-cell trait and malaria in Africa". Bulletin of the World Health Organization. 15 (3–5): 837–42. PMC 2538267. PMID 13404460.
  16. Foy, H; Brass, W; Moore, RA; imms, GL; Kondi, A; Olouch, T (1955). "Two surveys to investigate the relation of sickle-cell trait and malaria". British Medical Journal. 2 (4948): 1116–9. doi:10.1136/bmj.2.4948.1116. PMC 1981318. PMID 13260675.
  17. Buetler, E; Dern, RJ; Flanagan, CL (1955). "Effect of sickle-cell trait on resistance to malaria". British Medical Journal. 1 (4923): 1189–91. PMC 2062141. PMID 14363831.
  18. Raper, AB (1956). "Sickling in relation to morbidity from malaria and other diseases". British Medical Journal. 1 (4973): 965–6. doi:10.1136/bmj.1.4973.965. PMC 1979846. PMID 13304395.
  19. Allison, AC (1954). "The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria". Transactions of the Royal Society of Tropical Medicine and Hygiene. 48 (4): 312–8. doi:10.1016/0035-9203(54)90101-7. PMID 13187561.
  20. Bezon, A (1955). "[Possible resistance of subjects with sickle cell trait to endemic falciparum malaria]". Medecine Tropicale : Revue du Corps de Sante Colonial. 15 (4): 423–427. PMID 13279283.
  21. Power, Harry W. (1975). "A model of how the sickle-cell gene produces malaria resistance" (PDF). Journal of Theoretical Biology. 50 (1): 121–127. doi:10.1016/0022-5193(75)90027-2. PMID 1092922.
  22. Allison, Anthony C (2000). "Immunosuppressive drugs: the first 50 years and a glance forward". Immunopharmacology. 47 (2–3): 63–83. doi:10.1016/S0162-3109(00)00186-7. PMID 10878284.
  23. Allison, AC; Kowalski, WJ; Muller, CD; Eugui, EM (1993). "Mechanisms of action of mycophenolic acid". Annals of the New York Academy of Sciences. 696 (1): 63–87. doi:10.1111/j.1749-6632.1993.tb17143.x. PMID 7906496.
  24. Nelson, PH; Eugui, E; Wang, CC; Allison, AC (1990). "Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid". Journal of Medicinal Chemistry. 33 (2): 833–838. doi:10.1021/jm00164a057. PMID 1967654.
  25. Eugui, Elsie M.; Allison, Anthony C. (1993). "Immunosuppressive Activity of Mycophenolate Mofetil". Annals of the New York Academy of Sciences. 685 (1): 309–329. doi:10.1111/j.1749-6632.1993.tb35881.x. PMID 8363235.
  26. Allison, AC; Eugui, EM (1996). "Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF)". Clinical Transplantation. 10 (1 Pt 2): 77–84. PMID 8680053.
  27. Allison, AC; Eugui, EM (1993). "The design and development of an immunosuppressive drug, mycophenolate mofetil". Springer Seminars in Immunopathology. 14 (4): 353–80. doi:10.1007/bf00192309. PMID 8322167.
  28. Allison, AC; Eugui, EM (1993). "Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil". Immunological Reviews. 136 (1): 5–28. doi:10.1111/j.1600-065x.1993.tb00652.x. PMID 7907572.
  29. Bechstein, WO; Suzuki, Y; Kawamura, T; Jaffee, B; Allison, A; Hullett, DA; Sollinger, HW (1992). "Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats". Transplant International. 5 (Suppl 1): S482–3. doi:10.1111/tri.1992.5.s1.482. PMID 14621853.
  30. Kawamura, T; Hullett, DA; Suzuki, Y; Bechstein, WO; Allison, AM; Sollinger, HW (1993). "Enhancement of allograft survival by combination RS-61443 and DUP-785 therapy". Transplantation. 55 (4): 691–4, discussion 694–5. doi:10.1097/00007890-199304000-00001. PMID 8475537.
  31. Taylor, DO; Ensley, RD; Olsen, SL; Dunn, D; Renlund, DG (1994). "Mycophenolate mofetil (RS-61443): preclinical, clinical, and three-year experience in heart transplantation". The Journal of Heart and Lung Transplantation. 13 (4): 571–82. PMID 7947873.
  32. "Risk Evaluation and Mitigation Strategy (REMS) Under Review for CellCept and Myfortic". U.S. Food and Drug Administration. Retrieved 23 July 2014.
  33. Donlon, Diane M (15 June 1995). "New Agent to Prevent Kidney Transplant Rejection Now Available". Stanford University. Retrieved 23 July 2014.
  34. "CellCept registry data demonstrated superior long-term organ transplant outcomes". Roche.com. F. Hoffmann-La Roche Ltd. Archived from the original on 26 July 2014. Retrieved 23 July 2014.
  35. Allison, Anthony C; Eugui, Elsie M (1982). "A RADICAL INTERPRETATION OF IMMUNITY TO MALARIA PARASITES". The Lancet. 320 (8313): 1431–1433. doi:10.1016/S0140-6736(82)91330-7. PMID 6129509.
  36. Clark, I.A.; Cowden, W.B.; Butcher, G.A. (1983). "FREE OXYGEN RADICAL GENERATORS AS ANTIMALARIAL DRUGS". The Lancet. 321 (8318): 234. doi:10.1016/S0140-6736(83)92603-X. PMID 6130259.
  37. Clark, IA; Hunt, NH (1983). "Evidence for reactive oxygen intermediates causing hemolysis and parasite death in malaria". Infection and Immunity. 39 (1): 1–6. PMC 347899. PMID 6822409.
  38. Sattaur, Omar (1983). "Cheating charge rocks malaria research". New Scientist. 97 (1345): 423.
  39. Clark, I.A.; Cowden, W.B.; Butcher, G.A.; Hunt, N.H.; Allison, A.C. (1983). "FREE OXYGEN RADICALS IN MALARIA". The Lancet. 321 (8320): 359–360. doi:10.1016/S0140-6736(83)91664-1.
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