Medicine

Vishva M. Dixit, vice president of Early Discovery Research at Genentech, will be awarded the Dr A.H. Heineken Prize for Medicine 2022. The award honours his pioneering biomedical research on apoptosis, the process of programmed cell death, and necrosis, where cell death is caused by factors outside the cell such as infection or trauma. His discoveries have provided mechanistic insight for new clinical treatments, including immunotherapy in cancer patients.

The Heineken Prizes are the Netherlands’ most prestigious international science prizes. Every two years they are awarded to five distinguished researchers. The Royal Netherlands Academy of Arts and Sciences is responsible for the nomination and selection process. During the first week of June, a 2022 laureate will be announced every weekday. Previous laureates of the Dr A.H. Heineken Prize for Medicine include Karl Deisseroth (2020) and Peter Carmeliet (2018). The award was established in 1989 by Alfred H. Heineken.

About the study
Dixit studies how the cells of the body die, and how our bodies regulate the process of apoptosis. Every second, your body replaces about a million cells because they are old, damaged or mutated. As the biomedical researcher himself explains: ‘We live because we are continuously dying.’ Dixit discovered which enzymes are involved in apoptosis, and how they activate each other in a chain reaction. This knowledge could be used, among other things, for enhancing immunotherapy in cancer patients, with immune cells initiating this chain reaction, killing cancer cells.

In addition to this ‘silent’ form of cell death, there is also ‘loud’ cell death: necrosis. This occurs, for example, in the case of a cut, burn or infection. Dying cells alert immune cells to come and clear away the danger: they trigger an inflammatory response (inflammatory signalling). Dixit discovered that cells have different sensors for specific forms of danger, but that they trigger the inflammatory process in the same way. The discovery of one of these so-called receptors, NLRP3, is of importance for treating inflammation that is not caused by pathogens (bacteria, viruses or fungi) and that can contribute to degenerative conditions such as arthritis, atherosclerosis and Alzheimer’s disease. Dixit’s research group discovered drugs that specifically inhibit NLRP3. This will make it possible to treat sterile infections in the future, without reducing resistance to pathogens.

Jury praises significant contribution of clinical treatments
Dixit’s early findings revealing the fundamental mechanism of apoptosis form the basis of advanced therapies now used in clinics. The jury, with chair René Medema, director of Science Policy at the Netherlands Cancer Institute, said it was confident that Dixit’s future research would have a similar impact on the treatment of numerous diseases, including cancer, autoimmune diseases, and infections. In addition to these important scientific discoveries as a ‘leader in apoptosis research’, the jury says Dixit is a highly dedicated mentor for postdocs and his students. The jury is awarding the prize to Dixit because of his drive to disseminate knowledge about the immune system to a wide audience. The fact that he actively promotes science education in low- and middle-income countries also factored into the jury’s decision.

About Vishva Dixit
Vishva Dixit (Kisii, Kenya, 1956) studied medicine at the University of Nairobi in Kenya. In 1981, he moved to the United States for a medical residency training programme at Washington University in St. Louis. In 1986, he joined as an Assistant Professor the Pathology Department at the University of Michigan, where he was appointed full Professor in 1995. Beginning in 1997, he held various positions at the biotech company Genentech, and he has been vice president of Early Discovery Research since 2005. Between 1999 and 2008, he was also a professor of Pharmaceutical Chemistry at the University of California. Dixit has more than fifty patents to his name. In addition to the Dr A.H. Heineken Prize for Medicine, awards he has received include the Vilcek Prize, the Gutenberg Research Award, and the Dawson Prize in Genetics.

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The Royal Netherlands Academy of Arts and Sciences has awarded the Dr A.H. Heineken Prize for Medicine 2020 to Karl Deisseroth, Professor of Bioengineering and of Psychiatry and Behavioural Sciences at Stanford University in California, and Investigator of the Howard Hughes Medical Institute in Maryland, USA. Deisseroth is receiving the prize for developing optogenetics — a method to influence the activity of nerve cells with light — as well as for developing hydrogel-tissue chemistry, which enables researchers to make biological tissue accessible to light and molecular probes. Both discoveries play an important role in current brain research.

Deisseroth took brain research a decisive step further
Deisseroth discovered that it is possible to use light of a certain wavelength to switch on a certain group of nerve cells, and if desired at the same time switch off another group with light of a different wavelength. This capability enables spectacular effects, such as influencing an individual subject’s perceptions and movements, and even higher brain functions. One can, for example, alter learning and memory, or change the motivation of an individual for specific actions. Already used around the world for scientific discoveries, optogenetics marks the onset of a true revolution in both basic science and neuropsychiatry, leading to mechanistic research and understanding of crippling conditions such as blindness, Parkinson’s disease, epilepsy, addiction, and depression.

The light-sensitive and transparent brain
Deisseroth first published on his optogenetics discovery in 2005. It had been known for many decades that some microorganisms have light-sensitive ion conduction (through pumps and channels). For example, certain algae are dependent on light to guide movement; when light shines on them, ion channels open and positively-charged ions flow into the cell, causing the single-celled alga to swim towards the light. In July 2004, Deisseroth succeeded in implanting the DNA that encodes these channels into rodent nerve cells and causing light-sensitivity, and over the next decade he developed ways to target specific nerve cell types — and even single cells — in living mice. As a result the targeted cells in the brains of mice could be stimulated with light to control behavior, far more precisely than with medication or electrical stimulation which affect multiple groups of brain cells.
In 2013, Deisseroth and his colleagues introduced another important technology, hydrogel-tissue chemistry. The initial form, called CLARITY, is a way of making brain tissue transparent and accessible to molecular labels, thus allowing researchers to see more clearly how the brain is constructed. Conventional microscopy techniques show nerve cells in detail, but these are two-dimensional images of wafer-thin slices. Some scanning technology, such as MRI and CT, displays three-dimensional images, but shows no details of cells. Achieving transparency through creation of a hydrogel-tissue hybrid, researchers can search through intact brain tissue and investigate which cells are connected and what kind of information they transmit; hydrogel-tissue chemistry variants have also allowed visualizing proteins anchored deep within tissue, reversibly changing tissue dimensions, and labeling and sequencing of RNA molecules in cells within native environments. Widely used for scientific discovery, these methods have also been applied by Deisseroth and colleagues to human tissue, including in patients with autism, epilepsy, and Alzheimer’s disease.

About the laureate
Karl Alexander Deisseroth was born in Boston (Massachusetts) in 1971 and studied biochemistry at Harvard University. He works one day a week in the clinic as a psychiatrist, spending the rest of his time on fundamental neuroscience research. Deisseroth has a tremendous record of achievements, as appears from his many discoveries and publications. In 2010 the journal Nature Methods proclaimed optogenetics to be its “Method of the Year”. Over the past ten years, Deisseroth has received more than 80 patents for his development of optogenetics and related technologies.
Deisseroth has won dozens of fundamental science prizes, including the McKnight Foundation Scholar Award, the National Academy of Sciences Lounsbery Award, the Breakthrough Prize, the Else Kröner Fresenius Prize for Medical Research, and the Kyoto Prize. Last year the journal Nature Biotechnology declared him the Number 1 “translational researcher across all fields”. He is an elected member of all three US National Academies (Sciences, Medicine, and Engineering).

The Royal Netherlands Academy of Arts and Sciences has awarded the Dr A.H. Heineken Prize for Medicine 2018 to Peter Carmeliet, Professor of Medicine at the University of Leuven (Belgium).

The effects of growth factors on blood vessels and nerve cells
Peter Carmeliet received the Dr A.H. Heineken Prize for Medicine for his research into the effects of growth factors on endothelial and nerve cells and for his efforts to develop treatments for vascular and neurological disorders based on his research findings.
Peter Carmeliet is world-renowned for his studies on growth factors and their effects, both in health and disease. For several decades now, he has been at the forefront of research investigating how growth factors control vascular endothelial cells at the molecular level.
Carmeliet studied vascular endothelial growth factor (VEGF) in particular and discovered that it also affects the growth of nerve fibres (axons). He discovered that placental growth factor (PIGF) affects the development of blood vessels and nerve bundles in embryos but also plays an important role in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
More recently, Carmeliet showed how vascular endothelial cells regulate the transport of fatty acids and sugars to underlying tissues, thereby playing a critical role in cardiovascular diseases and cancer.
Basic research of this kind may eventually lead to new therapeutic interventions, for example in the treatment of paediatric brain tumours, metastasis and neurodegeneration. Carmeliet is also attempting to develop new therapies based on his research into PIGF. The antibodies that he has developed are currently being tested clinically in patients with medulloblastoma and diabetic retinopathy.

Researcher
Peter Carmeliet was born in Leuven, Belgium, in 1959. While studying medicine at Leuven, he also trained at the University of Maryland in Baltimore (USA) and the University of California in San Francisco (USA). He received his PhD from the University of Leuven in 1989.
Carmeliet’s post-doctoral appointments include positions at Harvard Medical School (Boston, USA), the Whitehead Institute at MIT (Cambridge, USA), the University of Leuven, and the University of Brussels.
He founded his own research group in Leuven in 1996 and was appointed a full professor there in 1998. The following year, he was appointed professor at Maastricht University. From 2008 to 2015, he was Director of the Centre for Cancer Biology (CCB) at the Flanders Interuniversity Institute for Biotechnology (VIB). There are now more than sixty researchers in his group.
Carmeliet is a member of the German National Academy of Sciences Leopoldina and the Royal Netherlands Academy of Arts and Sciences. His many awards and honours include the Ernst Jung Medical Award (2010), the Joseph Maisin Prize for Excellence (2010) and the European Academy of Sciences’ Blaise Pascal Medal in Medicine and Life Sciences (2011). He has an honorary doctorate from Johann Wolfgang Goethe University in Frankfurt (Germany).

Article
— Interview with Peter Carmeliet in De Groene Amsterdammer (Dutch)

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The Royal Netherlands Academy of Arts and Sciences has awarded the Dr A.H. Heineken Prize for Medicine 2016 to Steve Jackson, Professor of Biology at the University of Cambridge (United Kingdom).

DNA repair: the Achilles’ heel of cancer cells
Steve Jackson received the Dr A.H. Heineken Prize for Medicine for his fundamental research into DNA repair in human cells and for the successful application of knowledge of that process in the development of new cancer drugs.
DNA molecules in our cells are continuously being damaged. Healthy cells can signal such damage and trigger various repair mechanisms, such as a mechanism that reconnects broken DNA strands.
Jackson investigated how cells know what type of repair is needed and what signal is given to start the correct repair process. Moreover, he successfully applied that knowledge in medical research.
In cancer cells, one or more DNA repair methods are often defective. Consequently, they cannot be properly controlled. Jackson explores mechanisms of DNA repair and looks for new drugs that kill cancer cells by breaking down their recovery capacity even further. He exploits a concept called ‘synthetic lethality’. It is now clear that this concept has potential. In 2014, a new drug became available to treat a certain type of ovarian cancer. Clinical application trials for other cancer types are in progress.

Researcher
Steve Jackson was born in 1962 in Nottingham (United Kingdom). In 1983, he gained a bachelor degree in biochemistry at the University of Leeds. In 1987, he was awarded a PhD for molecular biology research at the University of Edinburgh, after which he moved to Berkeley, California (United States).
Jackson returned to the United Kingdom after four years. In Cambridge, he took up a position at the Wellcome Trust and Cancer Research UK Institute, which is part of the University of Cambridge. In 2004, the institute was renamed ‘The Gurdon Institute’. He has also been an Associate Faculty with the Sanger Institute in Hinxton near Cambridge since 2012.
Jackson’s two hundred research articles have been referred to on more than thirty thousand occasions.
In addition to being a researcher, Jackson is also an entrepreneur. In 1997, he set up KuDOS Pharmaceuticals to apply his DNA repair knowledge to new cancer drugs. In 2011, together with private investors, Jackson set up a second company, MISSION Therapeutics, to apply his knowledge to more cancer drugs.

More information
— Website The Gurdon Institute and Department of Biochemistry, University of Cambridge

Article
— Interview with Stephen Jackson in De Groene Amsterdammer (Dutch)

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Professor Alitalo received the Dr A.H. Heineken Prize for Medicine 2014 for his pioneering research on how and when lymph and blood vessels grow, and how that knowledge could help us find interventions to treat cancer and other diseases.

Researcher
Prof. Kari Alitalo was born in Kuopio (Finland) in 1952. As a young man, his ambition to advance medical practice made him decide against studying maths. He ended up studying medicine at the University of Helsinki, the same institution in which he obtained his Ph.D. in 1980.
After spending about five years in the west coast of the U.S., where he worked with famous scientists like Michael Bishop and Harold Varmus, he returned to Helsinki in 1986.
In 1993, Alitalo was named Academy Professor of Molecular Biology of Cancer by the University of Helsinki.
Since 2013, Alitalo has been Director of the Wihuri Research Institute, a private institute founded in 1944 to study vascular biology and diseases of vascular systems. He also leads a Centre of Excellence in translational cancer research at the University of Helsinki.
Alitalo ranks among the most-cited cancer and cell biology researchers in Europe. With more than 550 published papers to his name, he has been cited more than 55,000 times.
He is member of the Academy of Europe and the Swedish Royal Academy of Sciences, and foreign member of the U.S. National Academy of Sciences. He has been awarded many prestigious prizes, including the Prix Leopold Griffuel (France), the Louis-Jeantet Prize for medicine (Switzerland) and the InBev-Baillet Latour Health Prize (Belgium).
The blood and lymphatic vascular systems are essential for circulating fluid, sources of energy, oxygen, antibodies and immune cells around the human body.
For 18 years, Professor Kari Alitalo has been at the forefront of research on how this crucial transport system is constructed and maintained in the healthy body and how it is affected by disease. He has also been among the leaders in using this new knowledge to find better treatments for cancer and vascular disease.
Alitalo is best known for his discovery of biomolecular mechanisms that promote and regulate the growth of lymphatic and blood vessels.
The importance of lymphatic vessels for fluid regulation and the immune system has been known for more than a century. Most of that time however, it was completely unclear how vessels knew where to grow, when or how medicines could be used to influence their behaviour. Such knowledge is vital for developing treatments for diseases of the vascular system itself, such as lymphoedema that results in abnormal accumulations of fluid in the body. It could also help greatly in tackling cancer, since tumour cells often use lymphatic vessels to travel to other organs.
Alitalo and his co-workers were the first to discover a molecular ‘switch’ that, if appropriately stimulated, induced epithelial tissue in skin to transform into lymphatic vessels. He subsequently discovered the growth factor that is key to this trigger. Since then four more switches and four more growth factors have been identified, and Alitalo was involved in three of those discoveries.
Thanks to Alitalo, this basic knowledge is currently being used very actively in the search for new medicines. Three molecular compounds are now in the early stages of implementation as drugs: one is to treat lymphoedema, another targets blood vessels in tumours that might inhibit their growth, and yet another could slow down cancer metastasis by blocking new growth of lymphatic vessels.
Taken together, Alitalo’s pioneering work has contributed impressively to what we now know about how our body builds and controls its vascular systems, and how one day we may be able to use that knowledge in treating many devastating diseases.

More information
— Personal page on website University of Helsinki

Article
— Interview with Kari Alitalo in De Groene Amsterdammer (Dutch)

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Hans Clevers has been awarded the Dr A.H. Heineken Prize for Medicine 2012 for his unique understanding of how tissue growth is regulated, both in normal development and in cancer.
Hans Clevers commenced his career in science by studying cells in the human immune system and signalling proteins that influence the development of immune cells. His findings quickly turned out to have much wider implications, however.
It became clear that the cellular chain reactions he had unravelled together constitute a crucial mechanism determining the direction of cell division and growth, not only in human beings, but also in other mammals, amphibians, worms and even insects.
Will the cells that make up a tiny embryo gradually grow into an entire stomach or intestine? Or will they furnish a daily supply of fresh intestinal epithelium cells in the adult? Or will the same regulatory mechanism be disrupted, causing the stem cell to suddenly change into one that develops into intestinal cancer?
Clevers’ findings and his visionary in-depth investment in new research methods and animal models helped found a new and flourishing field of medical research. Its quest is to identify stem cells, which have the ability to grow into new tissues and organs, and work to harness that ability to replace damaged tissue or even organs. Clevers’ laboratory has already succeeded in isolating stem cells and causing them to grow into miniscule stomachs.
Equally important is how his work is helping us discover why healthy stem cells sometimes turn into intestinal cancer cells, which genetic factors increase the chance of that happening, and what we may be able to accomplish with medication in future.
At present, Clevers’ discoveries are most tangible in the world of science. He has published hundreds of articles in leading journals such as Science, Natureand Cell, sources of tens of thousands of citations by other researchers around the world. Each one of his discoveries, however, also has the potential to bring about monumental changes in the medical world.

Further reading
Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Science. 1997 Mar 21;275(5307):1784-7.
The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H. Cell. 2002 Oct 18;111(2):241-50.
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Nature. 2009 May 14;459(7244):262-5.
Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H. Cell. 2010 Oct 1;143(1):134-44
Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es J, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. Nature. 2011 Jul 4. doi: 10.1038/nature10337.

Biography
Hans Clevers was born in 1957. He studied medicine and biology at Utrecht University and obtained his PhD there in 1985, studying under clinical immunologist Professor R.E. Ballieux. He then spent four years at the Dana Farber Cancer Institute at Harvard Medical School in Boston, USA.
Clevers returned to Utrecht in 1991 and was appointed Chairman of the Department of Immunology. When the focus of his worked shifted, he was appointed Professor of Molecular Genetics and Director of the Hubrecht Institute, both in 2002. In these positions, he has become one of the leading figures in Dutch science.
Clevers’ international reputation has brought him numerous grants and awards, for example the Dutch Spinoza Award, the Swiss Louis Jeantet Prize, the American Katharine Berkan Judd Award, the Israeli Rabbi Shai Shacknai Memorial Prize, the German Ernst Jung Prize for Medicine, and, very recently, the French Léopold Griffuel Prize for cancer research. Last year the Netherlands Organisation for Scientific Research (NWO) awarded him a grant of EUR 2 million to support his work on generating intestinal tissue from stem cells.
Professor Clevers is a member of the Royal Netherlands Academy of Arts and Sciences and the American Association for Cancer Research. In 2005 he was made a Chevalier in the Ordre national de la Légion d’honneur, one of the highest French distinctions.

Laudatio
— English
— Dutch

Article
— Interview with Hans Clevers in Akademie Nieuws (Dutch)

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Professor Ralph Steinman was awarded the Dr A.H. Heineken Prize for Medicine 2010 for his discovery of the drendritic cell and its role in the immune response.
When pathogenic bacteria or viruses enter our bodies, our killer T cells rush out to attack these antigens while our B cells produce antibodies. For a long time, however, we did not know how this immune response got under way. Then, in 1973, Ralph Steinman and cellular biologist Zanvil Cohn discovered an entirely new kind of cell: the dendritic cell, so called because of its tree-like structure (Greek, dendron, tree). Dendritic cells are found where antigens are most likely to enter the body, for example in the skin and the mucous membranes of the nose, lungs and intestines. This small but powerful group of cells act as sentinels; as soon as they detect antigens in the body, they destroy them and show the broken fragments to other cells, which recognise them for what they are and spring into action. Dendritic cells are so sensitive that they register precisely what is happening in the organs in which they reside. They then conduct the T cell and B cell response, determining whether it should be increased, reduced or modified. After all, although cells that threaten the body must be repulsed, the immune response system should not react to something harmless, and especially not to the body’s own tissue or, for example, a foetus inside a pregnant woman. Since Steinman’s discovery of dendritic cells, their crucial role as conductors of the immune system has become clearer. This insight is extremely important in medical research, for example in combating infectious diseases, cancer, auto-immune diseases, allergies, and the rejection of organ transplants.

Key publications
Steinman R.M. & Cohn Z.A. 1973. ‘Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution’. In: Journal of Experimental Medicine 137: 1142-1162
Steinman R.M. & Cohn, Z.A. 1974. ‘Identification of a novel cell type in peripheral lymphoid organs of mice. II. Functional properties in vitro’. In:Journal of Experimental Medicine 139: 380-397
Steinman R.M., Lustig D.S. & Cohn Z.A. 1974. ‘Identification of a novel cell type in peripheral lymphoid organs of mice III. Functional properties in vivo.’ In: Journal of Experimental Medicine 139: 1431-1445
Steinman R.M., Gutchinov B., Witmer M.D. & Nussenzweig M.C. 1978. ‘Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice.’ In:Journal of Experimental Medicine 157: 613-627, 1983
Nchinda G., Kuroiwa J., Oks M., Trumpfheller C., Park C.G., Huang Y., Hannaman D., Schlesinger S.J., Minezina O., Nussenzweig M.C., Uberla K. & Steinman R.M. 2008. ‘The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells.’ In: Journal of Clinical Investigation 118: 1427-1436

Biography
Ralph Marvin Steinman was born in Montreal in 1943 and received his M.D. from Harvard Medical School in 1968. After completing an internship and residency at Massachusetts General Hospital, he joined The Rockefeller University in 1970 as a postdoctoral fellow in the Laboratory of Cellular Physiology and Immunology, where he began the research that led to the discovery of dendritic cells. In 1988 Steinman was appointed professor at The Rockefeller University. Ten years later he was named Director of the Christopher H. Browne Center for Immunology and Immune Diseases , where he is now – almost thirty years after his discovery – studying how dendritic cells can be used for therapeutic purposes, for example to develop vaccines for tumours and the HIV virus. Steinman has published numerous frequently-cited articles in prominent journals, evidence of his status as one of the most prestigious medical researchers in the world. Among other awards and honours, he is a recipient of the Albert Lasker Basic Medical Research Award and the Mayor’s Award for Excellence in Science and Technology (New York City). In 2011 he won the Nobel Prize in Physiology or Medicine (together with Bruce A. Beutler and Jules A. Hoffmann).
Steinman passed away in September 2011.

Laudatio
— English
— Dutch

Article
— Interview with Ralph Steinman in Akademie Nieuws (Dutch)

Video

Richard Peto, University of Oxford, United Kingdom, was awarded the Dr A.H. Heineken Prize for Medicine 2008 for his pioneering work in the field of clinical epidemiology.
Richard Peto is one of the founders of meta-analysis, a mathematical method in which the outcomes of diverse medical studies are combined to produce a single answer in an objective and logical way. Meta-analysis is at the heart of evidence-based medicine, an approach in which practitioners can nowadays base many treatment decisions on appropriate randomised evidence. Peto also developed new statistical analysis techniques for prospective studies. With Richard Doll, he helped discover that tobacco is a cause of many illnesses other than lung cancer; that half of all smokers will die of it; that stopping smoking can help prevent premature death and that, if current patterns persist, smoking will kill one billion people this century. He and his colleagues at Oxford have conducted internationally influential studies of the treatment of early breast cancer, heart disease and stroke. Peto’s research has made a significant contribution to public health.

Examples of key publications
Peto, R., Pike, M.C., Armitage P. et al., Design and analysis of randomized trials requiring prolonged observations of each patient, II: analysis and examples. In: Br J Cancer 1977; 35: 1-39
Doll, R., Peto, R., The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. In: J Natl Cancer Inst 1981; 66; 1191-1308
Doll, R., Peto, R., Boreham, J., Sutherland, I., Mortality in relation to smoking: 50 years’ observations on male British doctors. In: BMJ 2004; 328; 1519-1528
Early Breast Cancer Trialists’ Collaborative Group, Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. In: The Lancet 2005; 365: 1687-1717.

Biography
Richard Peto (1943) studied natural sciences at Cambridge University. He obtained his MSc in statistics at the University of London in 1967, has been with the University of Oxford since 1969 and was appointed professor of Medical Statistics and Epidemiology there in 1992. He is, with Rory Collins, one of the two co-directors of the Clinical Trial Service Unit & Epidemiological Studies Unit, a recent recipient of the Queen’s Award for Higher and Further Education.
Peto was made a Fellow of the Royal Society in 1989 for his work on meta-analysis and received a knighthood in 1999 for his achievements in the fields of epidemiology and cancer prevention. He devotes much of his energy to advising and providing information on what he calls ‘avoidable death’.
Peto is among the twenty most cited medical researchers in the world and his list of publications runs to almost 500 titles. His previous awards include the Guy Silver Medal from the Royal Statistical Society (1986), La Médaille de la Ville de Paris (1994), and the European Award for Excellence in Stroke Research (1996). He has also been granted two honorary professorships in China, where he was one of the first Western researchers to help initiate and conduct large-scale epidemiological studies.

Laudatio
— English
— Dutch

Article
— Interview with Sir Richard Peto in Akademie Nieuws (Dutch)

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Professor Mary-Claire King was awarded the Dr A.H. Heineken Prize for Medicine 2006 for proving the existence of the first hereditary breast cancer gene.
It took sixteen years before Mary-Claire King was able to demonstrate in 1990 that a single gene – it would later be called BRCA1 – was responsible for a large number of breast and ovarian cancer cases. At the time, virtually the entire medical science community believed that breast cancer was caused by a number of different genes interacting with different environmental factors, and that the search for a unique ‘breast cancer gene’ was a hopeless cause. By using her knowledge of mathematics, however, King developed a new research approach that would also prove to be successful in the study of other illnesses.
King had already changed our view of evolution when she demonstrated, for her doctorate, that the DNA of human beings and chimpanzees is 99% identical.
In the early 1990s, she discovered a technique for identifying individuals by genetic material taken from the teeth. Her work has made it possible for more than fifty children who ‘disappeared’ during the Argentinean military dictatorship to be reunited with their families. Professor King is currently researching the genetic basis of human deafness and HIV.

Further reading
King, M.C., Wilson, A.C., Evolution at two levels in humans and chimpanzees, Science 188: 107-116, 1975
Hall, J.M., Lee, M.K., Morrow, J., Newman, B., Anderson, L.A., Huey, B., King, M.C., Linkage of early-onset familial breast cancer to chromosome 17q21, Science 250: 1684-1689, 1990
Ginther, C., Issel-Tarver, L., King, M.C., Identifying individuals by sequencing mitochondrial DNA from teeth, Nature Genetics 2: 135-138, 1992
King, M.C., Marks, J.H., Mandell, J.B., New York Breast Cancer Study Group, Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2, Science 302: 643-646, 2003

Biography
Born in Chicago in 1946, Mary-Claire King was 19 when she took a degree in mathematics, graduating cum laude. She went on to pursue her doctorate in genetics and epidemiology at the University of California, Berkeley.
King was caught up in the social movements of the turbulent 1960s and has remained politically engaged. She left her doctoral studies for a year in order to perform environmental research for the consumer advocate and future presidential candidate Ralph Nader. King was in Chile when President Salvador Allende was assassinated and some of her colleagues and students were killed in the military coup. That is in part why, at the request of Argentina, she dedicated herself wholly to helping in the genetic identification of family members who had disappeared during the dictatorship. The technique she developed has now become a standard method of identifying human remains. King is currently investigating congenital deafness through an Israeli-Palestinian partner project that she set up, providing further confirmation of her social awareness.
Mary-Claire King has received many honorary doctorates, awards and other marks of distinction throughout her career. Her students praise her talent as a teacher. King remained at Berkeley until 1995, when she accepted an appointment as the American Cancer Society Research Professor at the University of Washington in Seattle.

Laudatio
— English
— Dutch

Article
— Interview with Mary-Claire King in Akademie Nieuws (Dutch)

Video

Prof. Elizabeth H. Blackburn was awarded the Dr A.H. Heineken Prize for Medicine 2004 for identifying the structure of chromosome ends (telomeres) and discovering the enzyme telomerase.
Elizabeth Blackburn has been given the sobriquet ‘Queen of the Telomeres’ because virtually everything we know about the form and function of the ends of chromosomes began with her. Before Blackburn, all we knew was that telomeres (from the Greek for ‘end’ and ‘part’) became shorter with each cell division. They are hence regarded as a kind of clock which is in any event partly responsible for the natural ageing process. Since Blackburn proved that telomeres have a unique structure that protects genetic material, however, they have also been compared to the ends of shoelaces: they are a marker that ensures that a chromosome does not ‘unravel’. It was also Elizabeth Blackburn who identified what telomeres are made of: a short, simple DNA sequence repeated over and over again, the sequence being slightly different in each organism.
Blackburn’s research group made the spectacular discovery that, although telomeres become shorter during cell division – to the point that cells are no longer capable of dividing – they in fact also replicate, and do so in a way entirely different from the rest of the chromosomal DNA. Ordinary DNA makes an exact copy of itself using the enzyme DNA polymerase; a telomere, on the other hand, copies an RNA sequence, a process known as reverse transcription. It does so using an enzyme baptised telomerase, which has the effect of lengthening it. Telomerase has been found in some specialised cells and in stem cells. These cells are capable of ‘supplementing’ their telomeres and ‘rejuvenating’ themselves.
But although telomerase has been found to be crucial to normal cell growth, it also plays a role in the uncontrolled, menacing type of cell growth. Eighty to ninety percent of all cancer cells have lengthened telomeres and contain a relatively large quantity of telomerase. Blackburn has even said that cancer cells are ‘addicted to telomerase’, and found that reducing the quantity of telomerase is enough to kill off cancer cells within a few days. Is telomerase the source of eternal youth or is it a murder weapon? Researchers are in any event already working on new cancer medications based on Blackburn’s discoveries.

Further reading
Szostak, J.W., Blackburn, E.H., Cloning yeast telomeres on linear plasmid vectors, Cell 29: 245-55, 1982
Greider, C.W., Blackburn E.H., Identification of a specific telomere terminal transferase activity in Tetrahymena extracts, Cell 43: 405-413, 1985
Yu, G.-L., Bradley, J.D., Attardi, L.D., Blackburn, E.H., In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymenatelomerase RNAs, Nature 344: 126-132, 1990
Blackburn, E.H., Telomere states and cell fates, Nature 408: 53-56, 2000

Biography
Elizabeth H. Blackburn was born in Tasmania, Australia, in 1948. She studied biochemistry at the University of Melbourne and received her Ph.D. in molecular biology from Cambridge in the United Kingdom in 1975. She then moved to the United States, her present home. She became a U.S. citizen in September 2003.
From 1975 to 1977, Blackburn did her post-doctoral work at Yale University, where her research included the DNA structure of the telomeres of the Tetrahymena, a single-cell pond-dweller (and parasite). She continued her career on the West Coast, joining the Department of Molecular Biology at the University of California in San Francisco in 1993. She is currently a professor in the Department of Biochemistry and Biophysics, where she has her laboratory. Blackburn has been the recipient of many awards and marks of honour, including an honorary doctorate from Yale University, the California Scientist of the Year Award (1999) and the General Motors Cancer Research Foundation Alfred P. Sloane Award (2001). In 2009 she won the Nobel Prize in Physiology or Medicine, together with Carol W. Greider and Jack W. Szostak. She has taken on many executive positions (for example as the president of the American Society for Cell Biology) and has an even longer list of lectures, articles and contributions credited to her name.
After accepting President Bush’s invitation to join his Council on Bioethics in 2001, Blackburn regularly took part in the public debate on therapeutic cloning and stem cell research, which she – unlike the Bush administration – advocates. The unexpected news that the White House had not renewed her membership of the Council led to protests in the foreign and American media and to considerable discussion of the role of politics in science.

Laudatio
— English

Article
— Interview with Elizabeth Blackburn in Akademie Nieuws (Dutch)

Video