Section 3 -

Australian Nobel Laureates in Medicine Robin A. Cooke Mayne Medical School and Queensland Health Pathology Services Brisbane, Australia

Introduction: Alfred Nobel 1833-1896 was born in Stockholm, Sweden. He made a fortune from making explosives, in particular dynamite. He never married and in his will he established a trust, the interest on which would be distributed annually in the form of prizes to those who, during the preceding year shall have conferred the greatest benefit on mankind. The first Australian Nobel Laureate was Howard Florey 1898-1968. He studied medicine in Adelaide, obtained a Rhodes scholarship to Oxford in 1921 before completing his course, and spent virtually the rest of his professional life working in Oxford. He was an experimental pathologist and won his Nobel prize in 1945 for his part in purifying penicillin and making it useable as a chemotherapeutic agent. Alexander Fleming working in St Mary's Hospital in London first recognised the fungus Penicillium notatum which had biological properties that caused the death of staphylococcal organisms. He demonstrated some of the properties of this substance which diffused into the medium on which the fungus was growing. Ernst Chain was a chemist who emigrated from Berlin and joined Florey's research unit in Oxford. In 1939 they decided that they would attempt to isolate the antibacterial substance that Fleming had identified. Before they could do this they needed large quantities of the medium in which the P. notatum was growing. The laboratory scientist Norman Heatley designed a large amount of ingenious implements to help them grow enough fungus to produce material from which Chain could extract the active principle. Much of this development was done during the air attacks on Britain during the Second World War. It was Florey's wife Ethel who conducted the clinical trials of this material and demonstrated its 'magical' properties in treating infections which would otherwise be fatal. Florey and Heatley made a hazardous journey by aeroplane from London via Lisbon, Portugal, to the United States in late June 1941 taking with them samples of the culture of P. notatum and their notes on how to extract the active principle they called penicillin. With the help of John Fulton, a fellow Rhodes Scholar from Oxford days and now a prominent American scientist and physiologist working at Yale University, he was able to enlist support from a government research laboratory in Peoria, Illinois, to help him produce penicillin in large quantities. This research laboratory worked at improving the yield of penicillin, and a number of commercial companies began to help as well. Merck was the most helpful of these and managed to produce penicillin in commercial quantities. US Government backing for the project was engineered by another of Florey's associates from an earlier period in which they worked together when they were young post graduate students. The company engineers designed vast tanks in which they finally grew a mould that produced large amounts of penicillin. The culture medium they used was corn-steep liquor which in the corn growing areas of the mid west of the United States was readily available. It remained a sad part of Florey's life that he gave the Americans the culture and all of the methodology his team had developed, freely and without charge. All he asked in return was for a small quantity of the purified penicillin to assist with his further experiments in England. None of this ever happened and the company took out patents on the production of penicillin and the royalties were paid in the US and not in the UK. The production of penicillin made it possible to treat wounded soldiers in Normandy when the allied troops invaded France on June 6 th 1944. As a result of the availability of penicillin the deaths and morbidity from infections following battle wounds were considerably less in this campaign than in any previous battles in history. When it came time to consider the awarding of Nobel prizes for the discovery and application of penicillin there was a considerable amount of animosity between all three of the final recipients, Florey, Fleming and Chain. Florey received many honours for his discovery including being given the title of Lord Florey. A Howard Florey Institute of Medical Research was established in the Melbourne University in 1963 and it continues to be an important research centre in Australia. Fleming gave many lectures on his discovery of penicillin and in this later period of his life he used to make small culture plates of the P.notatum which he sealed and gave as presents to his friends and colleagues. One of these colleagues was James McCartney who was head of the public health laboratory services in London during World War 2 and subsequently became professor of microbiology in the University of Adelaide. His widow, Peggy, kindly loaned me one of these culture plates that had been given to James by Alexander Fleming. In the 1950's one of my colleagues was awarded a Rockefeller Foundation Fellowship to work in one of the laboratories in the US where penicillin and other antibiotics were being investigated. He remembers with great fondness the state of excitement in this laboratory in those days when new antibiotics were being isolated from samples of fungus and moulds collected from all parts of the world. The second Nobel laureate was Frank Macfarlane Burnet 1899-1985. He was a virologist and immunologist and a contemporary of Howard Florey. He graduated in medicine from Melbourne University in 1922 and spent the years 1925-27 working in the Lister Institute in London. He returned to Australia in 1928 and took up his first position in the Walter and Eliza Hall Institute which was built in the grounds of the Royal Melbourne Hospital in 1915. Unlike Florey he decided to remain in Australia, and as a result of his researches he was able to establish the Hall Institute as a world renowned centre of research particularly in the newly developing field of immunology. Burnet's laboratory notes have been bound and catalogued. They are kept in the historical section in the Library of the University of Melbourne. They are a record of the wide variety of subjects that he investigated. One topic that was of particular interest to me was Q fever. This was identified by a Brisbane pathologist, Edward (Ted) Derrick in 1936. He referred material to Burnet for confirmation and assistance with the identification of the infectious agent. Burnet's comment on the first sample of tissue from guinea pigs was that he thought it was not a Rickettsia, but on January 1st 1938 he saw organisms in his experimental mice that convinced him it was indeed a Rickettsia which was ultimately named after him - Rickettsia (later) Coxiella burnetii. He was awarded the Nobel Prize in 1960 for his discovery of acquired immunological tolerance. The title of his Nobel lecture was 'Immunological Recognition of Self'. He also identified the role of the thymus in the immune system. In 1976 the Queensland Institute of Medical Research established an annual lecture to commemorate the work of the first two directors of the institute. On this occasion they invited a number of the most distinguished Australian medical scientists to attend this lecture and to receive the award of fellowship of the QIMR. 'Mac' Burnet was one of these Fellows. I met Burnet in New Guinea in the 1960's when he was visiting as an adviser to the fledgling University of Papua Guinea and the Institute of Medical Research. At that time the particular interest in New Guinea was the investigation of the disease kuru. Carlton Gadjusek led a big team of researchers in the National Institutes of Health in Washington. This led to the hypothesis of a slow virus and prion disease. Gadjusek received his Nobel Prize for this in 1976. (He shared the prize with Baruch Blumberg who found the hepatitis B virus [called at first Australia antigen]). I visited Gadjusek at the NIH a few weeks after the announcement of the prize and while I was there I was taken to see the chimpanzee colony where he and his associates carried out the inoculations of brain from human sufferers into Chimpanzees. The chimps developed exactly the same symptoms that the human patients had. When he was working in Papua New Guinea he used to send his 'gear' ahead of him care of the Pathologist, Port Moresby, (me), so when the boxes started to arrive I would know that I could expect to hear his booming voice coming along the road in the next week or two. The Walter and Eliza Hall Institute that 'Mac' Burnet put on the international stage was established with a grant of 1 million pounds from the Walter and Eliza Hall trust which was founded by Eliza after Walter's death. Their money came mainly from a gold mine in Mount Morgan outside Rockhampton where I have been working in the last six months. The Halls were among the foundation shareholders of the Mount Morgan Gold Mining Company Ltd. This company was established in 1886 and was one of the richest gold mines in the world. The gold was so fine that when the rock was crushed, a great deal of the gold was washed away with the sluicing. As a result, the tailings still contain a large amount of gold. At that time the Central Queensland town of Rockhampton was a busier port than the port of Brisbane and it was thought that it should be the capital of Queensland. Some of the money from the gold mine was put into building a number of stately buildings along the riverfront. The Customs House was an important building because in those days all transport was by sea. The headquarters of the Mount Morgan Mining Company like many of the other heritage buildings has been renovated and it is now the headquarters of the Australian Broadcasting radio station for Central Queensland. The gold from Mount Morgan was brought into this building and stored in two vaults on the ground floor. These vaults had brick walls two feet thick and very strong doors. When the ABC took over the building these rooms were used as soundproof rooms for editing interviews. They are now more used as storage areas. It is of interest to the IAP that one of the other foundation shareholders of the Mt Morgan Mining Company, William D'Arcy left the Rockhampton area while the mine was operational and settled in England. He then obtained a contract from the Shah of Iran to search for oil. He was successful in finding oil and this was the beginning of the British Petroleum Company. While he made a large amount of money from the gold mine in Mount Morgan he made very much more from the oil fields in Iran. When he established the forerunner of the British Petroleum Company in 1906 he appointed Lord Strathcona the first benefactor of the IAP who was at that time chairman of Burmah oil, to become chairman of his company. John Eccles 1903-1997 graduated in medicine from the University of Melbourne in 1925, was Rhodes Scholar in the same year and went to Oxford where he worked in the laboratories of Charles Sherrington. There he began his studies of synaptic transmission in nerves and became a neurophysiologist. He returned to Sydney in 1937 and spent the rest of his professional life in appointments in Australia and New Zealand. He used cats and frogs to study the electrophysiological activity at the neuromuscular junctions. While working in New Zealand in 1951 he succeeded in inserting microelectrodes into nerve cells of the central nervous system and recorded the electrical responses produced by excitatory and inhibitory synapses. From 1952-1966 he was professor of physiology at the Australian National University in Canberra where he studied the biophysical properties of synaptic transmission, concentrating particularly on the ionic mechanisms of sodium and potassium exchange at the membranes of the cells at the neuromuscular synapses. For this work he received the Nobel Prize in 1963. The professor of physiology in the University of Queensland when I was a student had worked with Eccles in New Zealand and he spent a great deal of time talking to us about inserting microelectrodes and micropipettes into nerve cells. He never showed us what these were or demonstrated them to us. I am afraid he was a deadly dull lecturer and he failed to stimulate in me an interest in physiology. I met this professor in New Guinea about 10 years later when he was advising the Institute of Medical Research and conducting some physiological investigations in Papua New Guinea. He was an extremely entertaining dinner guest. Perhaps I had just grown older and was able to appreciate him much better than when I had been a student. Peter Doherty 1940- is an immunologist who obtained his Nobel Prize in 1996 for finding the specificity of the cell mediated immune defence. The title of his Nobel lecture was 'Cell mediated immunity in virus infections.' Peter grew up in Brisbane at the same time as I did. Even though we did not meet, some of our experiences of growing up were similar. After graduation from the Veterinary faculty of the University of Queensland he went to Edinburgh where he did a PHD. He returned to Australia to work at the Australian National University in Canberra. It was there in association with a young PHD student from Switzerland, Ralph Zinkernagel, that he made the observations that ultimately led to his Nobel Prize. Like so many of his predecessors and contemporaries he went overseas, in this case to St Jude's Children's Hospital in Memphis Tennessee where there was infinitely more money available for research than there was in Australia. Since getting his Nobel Prize he now spends most of his time in Australia where he is Laureate Professor at the University of Melbourne, and a Burnet Fellow at the National Health and Medical Research Council of Australia. He maintains his appointment at St. Jude's Hospital and is leading Australian Science in international collaborative research projects. Soon after getting his Nobel Prize he was made the Australian of the year and in this capacity he was able to help to raise the profile of medical research in Australia, to solicit funding from government and private organizations, and to stimulate young researchers. Robin Warren, an anatomical pathologist, and Barry Marshall, a gastroenterologist, were awarded the Nobel Prize in 2005 for showing that peptic ulcers and gastric cancer are caused by the organism Helicobacter pylori. Robin Warren was born in Adelaide in 1937 and graduated in medicine from Adelaide University in 1961. The title of his Nobel lecture was 'Helicobacter - the ease and difficulty of a new discovery'. Barry Marshall was born in 1951 in the gold mining town of Kalgoorlie in Western Australia. He graduated in medicine from the University of Western Australia in 1974. The title of his Nobel lecture was 'Helicobacter connections'. It is comforting to know that research of the caliber for which Nobel prizes are awarded can be done by people working without the benefit of multimillion dollar laboratories equipped with the most modern equipment. Robin Warren was honoured at the annual meeting of the Royal Collage of Pathologists of Australasia early in 2006. When I met him there he told me that he had applied for the job I left in Papua New Guinea. It was fortunate that he did not get the job due to administrative delays in Papua New Guinea at the time, or he might not have gone on to get a Nobel Pize. Fortunately for him he went to work instead with Rolf ten Seldam, the professor of pathology in Perth. At that time Rolf was a keen protagonist for the use of the Warthin-Starry stain for identifying organisms in tissues. When Robin observed what came to be the Helicobacter organisms in gastric biopsies of patients with acute gastritis and peptic ulcer he used this stain to identify the organisms. At that time I am fairly sure that ten Seldam's laboratory was the only one in Australia where the stain was used. He was able to interest a young gastroenterology registrar, Barry Marshall, in investigating the presence of these organisms more thoroughly. In the 1980's their first papers were received with a great deal of scepticism. Warren already had Helicobacter in his stomach so it was Barry Marshall who volunteered to swallow a culture of the organism, demonstrate its presence in his gastric fluid and demonstrate the symptoms of acute gastritis which it caused. He then reversed these changes with triple antibiotic therapy. The Nobel Prize is awarded to no more than three investigators for any individual significant finding. Throughout the world there are many scientists whose work is probably worthy of a Nobel prize but for many reasons Nobel Prizes are often awarded for work that was done many years before the awarding of the prize. There is a considerable element of luck in who gets such prizes. As examples there are two of my contemporaries in Brisbane who have done work which may be worthy of a prize and it will be interesting to see whether either of them is successful. John Kerr introduced the concept of apoptosis which has generated such a vast amount of research and research papers in the past 20 years. A few years ago he was awarded the Paul Ehrlich prize. A very high percentage of people who have won this award have gone on to win a Noble as well. Ian Fraser more recently has developed a vaccine to human papilloma virus and the early trials indicate that it is extremely effective in preventing carcinoma of the cervix. Ian gave the first vaccinations in Brisbane to some young women on August 29. References Lax E. The mold in Florey's Coat – The story of the Penicillin Miracle. New York: Henry Holt: 2005. Burnet Sir M. Changing Patterns – an atypical autobiography. Melbourne: Heinemann: 1968. Doherty P. The Beginner's Guide to Winning the Nobel Prize. Melbourne: Miegunyah Press:2005. Prepared for the International Congress of the IAP Montreal, Canada, Sept, 2006. Australian Pathologists and the Nobel Prize History of Medicine Session. Australian Nobel Laureates in Medicine. Howard Florey 1898 - 1968. Experimental Pathologist Nobel prize 1945 for his part in purifying penicillin and making it useable as a chemotherapeutic agent. Frank Macfarlane Burnet 1899-1985. Virologist and Immunologist. Nobel Prize 1960 for his theory of Clonal Selection. John Eccles 1903-1997 Neurophysiologist. Nobel Prize 1963 for showing how nerve cells transmit messages by the ionic exchange of Na and K at synapses. Peter Doherty 1941 - Immunologist. Nobel prize 1996 for finding the function of the body's transplantation antigens which attach to "non self" tissue and cause graft rejection. The complex is destroyed by the body's normal immune mechanism that removes viral infections. The immune mechanism attacks fragments of virus that adhere to the surface of the transplantation antigens. Robin Warren and Barry Marshall. Anatomical pathologist and Gastroenterologist. Nobel prize 2005 for showing that peptic ulcers and gastric cancer are caused by the organism Helicobacter pylori. In every country in the world there are scientists who have made discoveries that might lead to a Nobel prize. May I mention 2 of my own contemporaries who fall into this category - John Kerr who introduced the concept of Apoptosis as a type of cell death, and Ian Frazer who has produced a vaccine to HPV that may lead to the eradication of cervical cancer.