Biochemistry and Biophysics

Roger Y. Tsien has been awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2002 for his extraordinary and unique contribution to the development of a series of methods and techniques for measuring and visualising processes within and between cells.
Roger Tsien can attribute his greatest claim to fame in the scientific world to Aequorea victoria, a jellyfish which glows brightly in the dark. It does this this with the help of the ‘green fluorescent protein’ (GFP) molecule, which Tsien has been a leader in improving and exploiting. His laboratory has even managed to create mutants with other colours. Introducing GFP or its variants into a cell makes it possible to follow all kinds of biochemical processes within living cells ‘in real time’: they are literally made visible. Tsien’s molecules can be used to track the transmission of signals between cells, monitor intracellular acidity and follow the movement of sodium and calcium within cells. Measurements in cell organelles are now also possible using GFP. Tsien’s methods are widely used by researchers for other purposes, including searching for the factors involved in the creation of malignant cells. Tsien himself is responsible inter alia for laying bare a molecular mechanism involved in the synaptic adaptive capacity of the brain.

Further reading
The Green Fluorescent Protein. Annual Review of Biochemistry 67 (1998) 507-544. 
Griffin, B.A., Adams S.R. and Tsien R.Y., Specific Covalent labeling of Recombinant Protein Molecules Inside Live Cells. Science 281 (1998), 269. 
Baird G.S., Zacharias D.A. and Tsien R.Y., Biochemistry, mutagenesis, and oligomerization of dsRed, a red fluorescent protein from coral. Proc.Natl.Acad.Sci. 97 (2000) 11984-11989. 
Zacharias D.A., Baird G.S. and Tsien R.Y., Recent advances in technology for measuring and manipulating cell signals. Current Opinion in Neurobiology 10 (2000) 416-421. 
Honda A., Adams S.R., Sawyer C.L., Lev-Ram V., Dostmann W.R.G. and Tsien R.Y., Spatiotemporal dynamics of guanosine 3′,5′-cyclic monophosphate revealed by a genetically encoded, fluorescent indicator. Proc.Natl.Acad.Sci.USA 98 (2001) 2437.

Biography
Roger Y. Tsien was born in New York in 1952. He studied chemistry and physics at Harvard College, graduating summa cum laude in 1972, following which he joined the Physiological Laboratory at Cambridge University in the UK with the aid of a Marshall scholarship. After obtaining his Ph.D. there in 1977, Tsien remained as a researcher in Cambridge until 1981. He then returned to America to take up a post at Berkeley, where he ultimately became a professor in the Physiology & Anatomy faculty. Since 1989 he has been attached to the University of California in San Diego, as Professor of Pharmacology and Professor of Chemistry and Biochemistry, and is also an investigator for the Howard Hughes Medical Institute. Tsien has been receiving prizes for his work since as far back as 1968, including the W. Alden Spencer Award in Neurobiology from Columbia University (1991) and the Pearse Prize from the Royal Microscopical Society (2000). In 2008 he won the Nobel Prize in Chemistry, together with Osamu Shimomura and Martin Chalfie. Since 1998 he has been a member of the National Academy of Sciences of the United States. Tsien died 24 August 2016.

James E. Rothman was awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2000 for clarifying the mechanism of intracellular membrane fusion.
He made the historic discovery that the cell contains very small membrane-enveloped vesicles that carry a large variety of proteins between different compartments in the cytoplasm. This delivery process, which involves vesicle flow and membrane fusion, is vital for the growth and division of every cell. How this process comes about was a great mystery, and one of the great unsolved questions of biochemistry and cell biology. James Rothman discovered the molecular principles of intracellular membrane fusion and demonstrated that the specificity of fusion was dictated by the pairing of SNARE proteins between membranes. This historic discovery provided a single unified principle for understanding important physiological processes, including the release of insulin into the blood, communication between nerve cells in the brain and the entry of viruses like HIV (the AIDS virus) to infect cells. Defects in the control of these pathways are important in diabetes and most likely also in certain cancers. Currently a major effort is under way to develop a new generation of drugs to control AIDS by blocking the membrane fusion process.

Further reading
Thomas H. Söllner, Sidney W. Whiteheart, Michael Brunner, Hedlye Erdjument-Bromage, Scott Geromanos, Paul Tempst & James E. Rothman: ‘SNAP receptors implicated in vesicle targeting and fusion’, Nature 362, 318 (1993);
Walter Nickel, Thomas Weber, James A. McNew, Francesco Parlati, Thomas H. Söllner & James E. Rothman: ‘Content mixing and membrane integrity during membrane fusion driven by pairing of isolated v-SNAREs and t-SNAREs’, PNAS, 96, (22), 12571 (1999);
B. Brugger, W. Nickel, T. Weber, F. Parlati, J.A. McNew, J.E. Rothman, T. H. Söllner: ‘Putative fusogenic activity of NSE is restricted to a lipid mixture whose coalescence is also triggered by other factors’, EMBO Journal, 19 (6), 1272 (2000).

Biography
James Rothman was born in Haverhill, Massachusetts, USA, in 1950 and is an American citizen. He has a Ph.D. in Biological Chemistry (Harvard Medical School), and has worked at the Sloan-Kettering Institute in New York since 1991. In that same year he was appointed Chairman of the Programme in Cellular Biochemistry and Biophysics at the Memorial Sloan-Kettering Cancer Center, where he holds the Paul A. Marks Chair. Dr Rothman has also been vice-chairman of the Sloan Kettering Institute since 1994. Amongst his other honours, Dr Rothman has received the Gairdner Foundation International Award (1996), the King Faisal International Prize in Science (1996) and the Lounsbery Award of the National Academy of Sciences (1997). In 2013 he won the Nobel Prize in Physiology or Medicine (together with Randy W. Schekman and Thomas C. Südhof).

Article
— Interview with James Rothman in Akademie Nieuws (Dutch)

Video

Anthony Pawson was awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1998 for his discovery of the ‘SH2 domain’ in proteins involved in signal transduction in living cells, which has shed invaluable light on intercellular communication.
His work has yielded a better insight in the way in which cells communicate with neighbouring cells. It appears that there is a connection between interference in the transduction of external signals into a cell and diseases such as cancer, diabetes and cardiovascular diseases. Pawson’s discovery has changed our concept of signal transduction so fundamentally that it has opened up new areas for the development of medicines for these diseases.
Pawson’s work has provided a new perspective of the way in which signals move from outside a cell to its nucleus. This process involves proteins that recognise each other by certain protein domains, such as the SH2 Domain, and then bind themselves to each other. This mutual binding is disrupted if structural changes take place within the proteins, which in turn may result in the development of a tumor. The discovery has created new ways of addressing this chain of events.

Biography
Anthony J. Pawson (1952 – 2013) was Head of the Department of Molecular Biology and Cancer Research of the Samuel Lunenfeld Research Institute, Toronto, Canada. For a scientist of his age, Dr Pawson has published an extraordinarily large number of articles in prestigious international journals. His influence is therefore considerable. Not only in the fields of biochemistry, biophysics and genetics, through which research in the field of intercellular communication has made great strides, but also in the world of medical science there is tremendous interest in the theories that are being developed on the basis of Dr Pawson’s revolutionary concept.
Dr Pawson’s more recent work has demonstrated the significance of proteins with SH2 domains for the development of mammal cells. In addition, by combining genetic experiments with flies, worms and mice, he has sought to clarify the molecular mechanisms that underlie signal transduction through conduction by way of axons in the central nervous system. Dr Pawson’s research therefore remains highly innovative, which promises further insights.

Paul M. Nurse was awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1996 for his exceptional scientific research, which forms the basis of our current knowledge on the regulation of the division of eukaryotic cells and the molecular components and mechanisms involved.
For a researcher of his age, Dr Nurse can boast an exceptionally large number of publications in prominent international scientific journals. Consequently, he has had considerable influence on other scientists, and not only in the field of the cell division cycle, where research has expanded enormously and great progress has been made in fathoming the cell division mechanism. The results of his research have also provided the pieces so that in other fields, such as oncology and DNA repair, various components could be fitted together to complete the puzzle. This has resulted in considerable insight into the transformation of healthy cells into harmful cells.
Pioneer research in the seventies into the simple eukaryotic yeast cell, Schizosaccharomyces Pombe (S. Pombe), led to the discovery of the so‑called cdc2‑gene whose protein production plays an important part in the G1 and G2/M stages of cell division. In subsequent years, Dr Nurse discovered large numbers of genes and proteins/enzymes which carry out a regulatory function during the various stages of cell division.
Dr Nurse is to be strongly commended for his application of the results of this relatively isolated research into S. Pombe to higher mammals and, subsequently, to humans. By means of excellent recombinant DNA research, Dr. Nurse demonstrated the irrefutable existence of a human variant of cdc2, and that the cell division cycle of all things from yeast to humans, as well as the necessary proteins and genes, show great similarities. In the late eighties, the human variant, cdkl, was isolated.

Biography
Paul Maxime Nurse was born in the United Kingdom in 1949 and obtained the B.Sc. degree from the University of Birmingham in Biological Sciences. In 1973 he received the Ph.D. degree from the University of East Anglia in Cell Biology/Biochemistry. He was Director of Laboratory Research at the Imperial Cancer Research Fund (ICRF) in London. Since 2003 he is president of The Rockefeller University in New York, USA. Dr Nurse is a fellow of the Royal Society, a member of Academia Europaea and a foreign associate of the US National Academy of Sciences. He has won many prizes and awards for his scientific work and has given numerous award lectures. In 2001 he won the Nobel Prize in Medicine, together with Leland H. Hartwell and Tim Hunt.

Michael J. Berridge has been awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1994 for his contribution to the study of cellular signal mechanisms and the role of inositol trisphosphate in them.

Biography
Michael John Berridge was born in Gatooma, Rhodesia, in 1938 and obtained the B.Sc. degree from the University College of Rhodesia and Nyasaland in Salisbury. In 1965 he received the Ph.D. degree from the University of Cambridge, and then spent four years as a postdoctoral fellow at the University of Virginia and at Case Western Reserve University in the USA. In 1969 he returned to Cambridge where he was appointed to a scientific position in the Invertebrate Chemistry and Physiology Unit of the Department of Zoology, now Laboratory of Molecular Signalling. In 1994 Berridge was made honorary professor. He is working as an Emeritus Babraham Fellow at the Babraham Institute.
Professor Berridge is a fellow of the Royal Society and has won many prizes and awards for his scientific work. These include the Gairdner Foundation International Award, the Albert Lasker Basic Medical Research Award and the CIBA-GEIGY/DREW Award in Biomedical Research. He has given numerous award lectures, such as the 16th FEBS Ferdinand Springer Lecture and the Inaugural Albert L. Lehninger Lecture. He sits on the editorial boards of many prestigious scientific journals.
Professor Berridge passed away in February 2020.

Piet Borst received the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1992 in recognition of his extraordinary record of scientific achievement in the fields of biochemistry and molecular biology.
What distinguishes Borst is his catholicity: he has made significant contributions to scientific research in several different fields. In the early stages of his career, Borst became interested in the metabolism of mitochondria. The malate-aspartate cycle, or ‘Borst cycle’, owes its name to the laureate, who discovered it is the principal route for the oxidation of extra-mitochondrial NADH in animal tissue. His studies on the biogenesis of mitochondria led to the discovery and characterisation of circular mitochondrial DNA in animal cells and yeast, and to important insights into the way this DNA is replicated. He was instrumental in mapping the genes in and the transcription of yeast mitochondrial DNA, besides its physical and genetic characteristics. One of the most widely used methods in molecular biology agarose gel electrophoresis of DNA – grew out of this research. More recently Professor Borst has devoted himself to the study of trypanosomes. These unicellular parasites cause sleeping sickness, which is often fatal. His work on the antigenic variation of trypanosomes led to several important findings, including discontinuous RNA synthesis and trans-splicing (the first example of pre-RNA splicing in protozoa), and the growth and contraction of trypanosome telomeres. He also discovered unique specialised organelles, the glycosomes. At the Netherlands Cancer Institute Borst began working on genes involved in the multidrug resistance of cancer cells and on the structure of amplified DNA. The laureate is not only an outstanding scientist, but also an excellent administrator, a gifted speaker, and both an inspired and inspiring teacher.

Biography
Piet Borst was born in Amsterdam in 1934. He studied medicine at the University of Amsterdam, where he received a PhD in biochemistry in 1961 and the MD degree in 1963, before spending two years as a research fellow at New York University. In 1965 he was made associate and in 1969 full professor of physiological chemistry at the University of Amsterdam, where he subsequently held the chair of biochemistry and molecular biology since 1974. In 1983 he was appointed research director of the Netherlands Cancer Institute in Amsterdam, while retaining a part-time university professorship of clinical biochemistry. Professor Borst is a member of the Royal Netherlands Academy of Arts and Sciences and of the Academia Europaea, a foreign member of the Royal Society, London, a foreign associate of the National Academy of Sciences, USA, and a foreign honorary member of the American Academy of Arts and Sciences, USA. He has received various honours and prizes for his scientific work. He is a member of the European Molecular Biology Organisation, or EMBO; he sat on the EMBO’s council from 1978 to 1984 and chaired its Scientific Advisory Committee from 1987 to 1991. He served and serves on the Scientific Advisory Committees of several European research institutes and he has chaired the juries of the Jeantet Prize (Europe) and of the Sloan General Motors Prize (USA). Since 1983, professor Borst writes a column for the scientific supplement of the Dutch paper NRC-Handelsblad.

Philip Leder received the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1990 in recognition of his pioneering research in the field of molecular biology, in particular immunology and cancer research.
In 1968 attention was focussed on Professor Lederfor work carried out in Professor M.N. Nirenberg’s laboratory which contributed to the deciphering of the genetic code. 
In 1978 and 1979 Professor Leder made a number of fundamental contributions to the knowledge and structure of genes in higher organisms. His discovery of the base sequence of a complete mammalian gene (the gene for betaglobin) enabled him to determine its organisation in detail, including its associated control signals. His research into the structure of genes which carry the code for antibody molecules was of pioneering significance. The main focus of inquiry was the question of how the enormous diversity of antibody molecules formed by a single individual arises. Leder’s work on antibody genes was later extended to research into Burkitt’s lymphoma, a tumour of antibody-producing cells, which involves the oncogene c-myc. This was crucial in understanding the origin of this type of tumour. In his recent work he has used transgenic mice carrying a single activated oncogene to determine how many genetic mutations are necessary for the development of a cancer cell. What is striking in his research is his multi-faceted approach to the problem, such as the study of specific growth signals, growth factors, etc. 
Professor Leder is one of the formost researchers in the oncogene field. Moreover, he combines his outstanding qualities as a scientist with exceptional gifts as a speaker.

Biography
Philip Leder was born in 1934 in Washington D.C. He received his B.A. from Harvard College in 1956 and his M.D. from Harvard Medical School in 1960. He holds honorary doctorates from Yale University, Mount Sinai Medical Center, New York and the University of Guelph, Ontario. 
From 1968 to 1973 he headed the Biochemistry Department of the Graduate Program of the Foundation for Advanced Education in the Sciences at the National Institute of Health in Bethesda, Maryland. In 1972 Professor Lederwas appointed director of the Laboratory for Molecular Genetics at the same institution and remained in that post until 1980. In 1980 he returned to Harvard Medical School as Professor of Genetics, occupying the John Emory Andrus Chair. In 1986 Professor Leder became a senior researcher at the Howard Hughes Medical Institute. 
He has been awarded various honours and prizes for his scientific work. 
Professor Leder is a member of the National Academy of Sciences, the American Academy of Arts and Sciences and the Institute of Medicine. He is a member of the board of a large number of scientific institutions in the United States.
Professor Leder passed away in February 2020.

Thomas R. Cech received the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1988 for one of the most sensational discoveries in biochemistry in the last few years by showing that RNA can act as an enzyme.
Up till then the ‘dogma’, that all biological catalysts are proteins, had not been questioned. Cech and his co-workers demonstrated that the large ribosomal RNA precursor of Tetrahymena thermophilia has the capacity of self-splicing or self-processing. In the complete absence of a protein enzyme, an intervening sequence (IVS or intron) is removed and the remaining RNA pieces are ligated correctly. The only requirement for this reaction is the presence of guanosine (or a derivative thereof, like for instance GMP) and magnesium ions. Cech and his colleagues were able to clarify the mechanistic details of this reaction.
The finding that RNA can act as an enzyme (also called ribozyme) active in breaking and making internucleotide bonds in present-day biological systems, raises the question whether these properties may have played a role in the prebiotic replication and evolution of RNA molecules. Since the substrate oligonucleotides are aligned by a complementary sequence in the IVS RNA itself, the polymerization reaction fulfils one of the requirements of a primitive autocatalytic replication mechanism. RNA has the qualities which are required for a hypercycle mechanism.
About twenty years ago Francis Crick remarked: ‘RNA is a molecule which desperately tries to be a protein.’ Thomas Cech demonstrated that RNA indeed is able to behave like a protein in that it has enzymatic activity. Thus it is possible that RNA was the primordial prebiotic molecule and that proteins and DNA evolved subsequently.

About the laureate
Thomas R. Cech was born in Chicago on December 8, 1947. He received his B.A. degree in chemistry from Grinnell College and his Ph.D. degree in chemistry from the University of California, Berkeley. His postdoctoral work in biology was conducted at the Massachusetts Institute of Technology. Since 2000, Thomas Cech has been President of the Howard Hughes Medical Institute (Chevy Chase, Maryland, USA). He still maintains his laboratory at the University of Colorado in Boulder, USA, where he is Distinguished Professor in the Department of Chemistry and Biochemistry. He was elected to the National Academy of Sciences in 1987 and received the Nobel Prize in Chemistry in 1989, together with Sidney Altman.

Bela Julesz and Werner E. Reichardt received the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1985. Both scientists performed pioneering research on the perception of depth and motion.
Julesz discovered that depth could be perceived by means of random patterns generated by a computer, which by its own don’t present anything identifiable. Does one look at the patterns by means of a stereoscope then all at once an object may dissolve from the background, creating a threedimensional effect. This offers e.g. possibilities for improving the research on eye-disturbances.
Reichardt studied by means of a common housefly the optical processing of motion and patterns. In the laboratory he constructed a kind of perfected home-trainer for the fly, by which he was able to take various measurements, and to formulate a general model for motion-perception. The research of both scientists affected decisively our conception on visual information-processing.

Biography
This was the first time that the award has been given to two scientists at the same time. Dr Julesz, of Hungarian origin, worked at the Bell Laboratories at Murray Hill, New Jersey, as a Head of the Department on Visual Perception Research. Professor Reichardt was Director of the Max-Planck-Institut für Biologische Kybernetik at Tübingen.
Professor Reichardt passed away in 1992. Dr Julesz died on 31 December 2003.

Werner E. Reichardt and Bela Julesz received the Dr H.P. Heineken Prize for Biochemistry and Biophysics 1985. Both scientists performed pioneering research on the perception of depth and motion.
Julesz discovered that depth could be perceived by means of random patterns generated by a computer, which by its own don’t present anything identifiable. Does one look at the patterns by means of a stereoscope then all at once an object may dissolve from the background, creating a threedimensional effect. This offers e.g. possibilities for improving the research on eye-disturbances.
Reichardt studied by means of a common housefly the optical processing of motion and patterns. In the laboratory he constructed a kind of perfected home-trainer for the fly, by which he was able to take various measurements, and to formulate a general model for motion-perception. The research of both scientists affected decisively our conception on visual information-processing.

Biography
This was the first time that the award has been given to two scientists at the same time. Dr Julesz, of Hungarian origin, worked at the Bell Laboratories at Murray Hill, New Jersey, as a Head of the Department on Visual Perception Research. Professor Reichardt was Director of the Max-Planck-Institut für Biologische Kybernetik at Tübingen.
Professor Reichardt passed away in 1992. Dr Julesz died on 31 December 2003.