Biochemistry and Biophysics

Carolyn Bertozzi, professor of Chemistry and, by courtesy, Chemical & Systems Biology at Stanford University, will be awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2022. The award honours Bertozzi’s ground-breaking research into communication between cells and methods of influencing this communication.

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 H.P. Heineken Prize for Biochemistry and Biophysics include Bruce Stillman (2020), Xiaowei Zhuang (2018) and Jennifer Doudna (2016). The award was established in 1964 by Alfred H. Heineken.

About the study
Our cells communicate with each other through molecules on the cell surface. Sugar molecules, also known as glycans, play an important role in this process. Bertozzi is developing chemical methods to study and influence the cell surface. Immune cells, for example, can tell from these sugars whether a cell is healthy or diseased. Amongst other things, her research shows that cancer cells fool immune cells by presenting a specific sugar molecule on the cell surface. With techniques from her lab, these sugar molecules can be ‘mowed down’, making immune cells recognise the cancer cells as dangerous and attack them. This is a major breakthrough in the treatment of cancer through immunotherapy that is currently being tested in patients.

Recent development
Recently, Bertozzi’s group discovered a new strategy to attack harmful extracellular molecules that cause disease. Conventional drugs for this often consist of monoclonal antibodies, which block harmful molecules by binding to them. But with some harmful molecules, this does not work. That is why Bertozzi and colleagues developed a way to not just block these molecules, but to ensure that they are taken into a cell and completely broken down there.

Jury praises Bertozzi’s role as founder of a new field
Bertozzi has developed more techniques to affect the cell surface and the inside of the cell, in living animals, grouped together under the name ‘bioorthogonal chemistry’. Bioorthogonal chemistry, founded by Bertozzi, has developed into a major field of study. Laboratories all over the world use these techniques to study and influence interactions between cells. The jury, chaired by Albert Heck, professor of chemistry and pharmaceutical sciences at Utrecht University, calls this concept one of the few truly transformative developments at the interface of chemical and life sciences. Bertozzi bridges the gap between chemistry and biology as well as between the laboratory and the patient. This proves her great contribution to translational research, in which she is a pioneer in the translation of results from fundamental research to practical application.

Role model for LGBTQ+ in science
In addition to her work as a brilliant chemist, the jury has praised Bertozzi’s activities regarding education for science and society, calling her an inspiring teacher, a successful entrepreneur, and a tireless advocate for the importance of science in everyday life as well as diversity in science. In particular her support of women and LGBTQ+ scientists. In addition, her research results are finding their way into medical applications.

About Carolyn Bertozzi
Carolyn Bertozzi (Boston, 1966) studied chemistry at Harvard University in the United States. She received her Ph.D., also in chemistry, from the University of California (UC) Berkeley in 1993. In 2002, she was appointed professor of Chemistry and Molecular Cell Biology there. In 2015, she moved from UC Berkeley to Stanford University and became professor of Chemistry and, by courtesy, of Chemical & Systems Biology. Her scientific work forms the basis of more than fifty patents and she is co-founder of several biotech companies, where her research results find their way into medical applications. In addition to the Dr H.P. Heineken Prize for Biochemistry and Biophysics, awards Bertozzi has received include the Wolf Prize, the Nagoya Medal, and the Solvay Prize.

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The Royal Netherlands Academy of Arts and Sciences has awarded the 2020 Dr H.P. Heineken Prize for Biochemistry and Biophysics to Bruce Stillman, President of the Cold Spring Harbor Laboratory in the state of New York. Stillman is receiving the prize for his ground-breaking research on the way DNA is copied in eukaryotic cells, a process of fundamental importance to life on earth.

Stillman discovered various proteins that are involved in DNA replication
Bruce Stillman started to become interested in DNA replication when doing his PhD research on how the DNA of adenoviruses is copied. He later switched his focus from adenoviruses to the polyomavirus simian virus 40 (SV40), a DNA virus with the potential for causing tumours, and he ultimately used a yeast as the model system.

Stillman discovered numerous important factors that are involved in DNA replication in eukaryotic cells. These cells have a nucleus. Virtually all multicellular organisms — such as plants, animals, and humans — are eukaryotes. Stillman co-discovered the RPA protein (Replication Protein A), which binds to a strand of DNA to prevent it from winding back on itself so that the enzyme polymerase can copy the strand of DNA. He also discovered Replication Factor C and the CAF1 molecule that helps packaging proteins to bind around the DNA that has just been copied.

In his later research Stillman focused on the start of replication: where on the DNA does the copying process start and which protein molecules are involved? He discovered one of the binding factors, ABF-1, that binds at locations where copying starts. He also discovered the crucial molecular complex — the Origin Recognition Complex (ORC) — that determines the exact starting point, and unravelled how this complex ensures that the replication process is initiated in a controlled manner.

Stillman’s research has led to important insights that allow us to understand how our hereditary material is copied, and how this relates to many other processes within the cell. He opened an entirely new and important field of research. His research contributes to a better understanding of the origin of mutations that can lead to hereditary conditions such as cancer.

About the laureate
Bruce William Stillman was born in Melbourne, Australia in 1953. He studied at the University of Sydney and earned his PhD in 1979 at the John Curtin School of Medical Research at the Australian National University for his research into replication of the adenovirus DNA. He then continued his career in the United States, where he started as a postdoctoral fellow at the Cold Spring Harbor Laboratory. Stillman was appointed professor in 1985. He became the director of the Cold Spring Harbor Laboratory in 1994 and nine years later its President, positions he still holds today.

Stillman is a member of the American National Academy of Science, the American Academy of Arts and Sciences, a fellow of the Royal Society in London, a corresponding member of the Australian Academy of Science and a member of the European Molecular Biology Organization. He has received numerous awards for his work, including the Alfred P. Sloan Prize (2004), the Louisa Gross Horwitz Prize (2005), the Herbert Tabor Research Award (2014), and last year the Canada Gairdner International Award.

The Royal Netherlands Academy of Arts and Sciences has awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2018 to Xiaowei Zhuang, Professor of Physics, Chemistry and Chemical Biology at Harvard University in Cambridge (USA).

Examining the behaviour of molecules in living cells
Xiaowei Zhuang received the Dr H.P. Heineken Prize for Biochemistry and Biophysics for her groundbreaking work on developing high-resolution imaging methods and their use in investigating a variety of fundamental biological problems.
Xiaowei Zhuang uses revolutionary imaging methods with single-molecule sensitivity to visualise what happens deep inside living cells. Thanks to the pioneering work of Zhuang and her team, it is now possible to visualise and track the behaviour of virions, RNA molecules and cytoskeleton filaments in living cells.
Her work builds on her own invention, STochastic Optical Reconstruction Microscopy (STORM), one of the first and most popular methods of ‘super-resolution’ imaging, which overcomes the diffraction limit of light to produce much sharper images than possible in conventional light microscopy and on a vast scale.
STORM uses fluorescent dyes that are activated at different times, making it possible to localise individual molecules and thus generate images of hitherto undreamed-of clarity.
Zhuang’s paper announcing her invention of STORM in 2006 was a milestone in the development of super-resolution microscopy. Zhuang herself is pioneering the application of such methods and using them to seek answers to longstanding, fundamental questions about the machinery of biological cells.

Researcher
Xiaowei Zhuang was born in Rugao (China) in 1972. She studied in China for several years but moved to the United States after receiving her Bachelor’s in Physics in 1991. She obtained her PhD from the University of California in Berkeley in 1996 and conducted her thesis research on non-linear optical studies of liquid crystals and polymers under the supervision of Dr Yuen-Ron Shen.
Zhuang continued her career as a Chodorow Postdoctoral Fellow in the laboratory of Dr Steven Chu at Stanford University. She arrived at Harvard University in Cambridge in 2001 and accepted a position there in 2005 as a Howard Hughes Medical Institute Investigator.
In 2014, Zhuang was appointed David B. Arnold Professor of Science at Harvard University and a year later became Director of the university’s Center for Advanced Imaging.
Zhuang is a member of the US National Academy of Sciences and the American Academy of Arts and Sciences. She has received many honours and awards, including the Sackler International Prize in Biophysics (2011) and the Lennart Nilsson Award (2017). In 2017, she was awarded an honorary doctorate by Delft University of Technology.

Article
— Interview with Xiaowei Zhuang in De Groene Amsterdammer (Dutch)

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The Royal Netherlands Academy of Arts and Sciences has awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2016 to Jennifer Doudna, Professor of Biomedical Sciences at the University of California in Berkeley (United States).

Pioneering research laying the foundations for revolutions in modern biochemistry 
Jennifer Doudna received the Dr H.P. Heineken Prize for Biochemistry and Biophysics for her pioneering research into the structure and functioning of RNA molecules and RNA protein complexes.
From the beginning of her career, Jennifer Doudna knew that knowledge of the structure of RNA molecules was essential in order to understand their catalytic effect. She therefore started analysing crystal structures of RNA molecules right at the outset of her studies.
At first, these were relatively simple molecules. However, in the mid-1990s, she made a daring but successful attempt to crystallise and analyse a much larger RNA molecule: the Tetrahymena ribozyme P4-P6 domain. For the first time, researchers learnt how a long, complex RNA strand folds itself into functional bends so as to interact with surrounding molecules.
Doudna is still a leading researcher in the rapidly expanding research field dealing with the functioning of RNA molecules and RNA protein complexes. Her work created the foundations for exciting developments at the forefront of biochemistry: RNA interference and CRISPR, a bacterial system of defence against invading DNA that can now be used to edit the DNA code of living organisms with the greatest possible precision.

Researcher
Jennifer Doudna was born in 1964 in Hawaii (US). She studied at Pomona College in Claremont, California, but after gaining a bachelor degree in chemistry, she relocated to Harvard University in Cambridge (Massachusetts). Under the supervision of Jack Szostak (who was later to win both the Dr H.P. Heineken Prize for Biochemistry and Biophysics (2008) and a Nobel Prize in Physiology or Medicine (2009)), she was awarded a doctorate in 1989 for research into ribosomes, DNA-creating structures at the centre of a cell.
In that same year, Doudna continued her research at the University of Colorado (in Boulder) together with Thomas Cech, who later also won both the Dr H.P. Heineken Prize for Biochemistry and Biophysics (1988) and a Nobel Prize in Chemistry (1989). In 1994, she was appointed assistant professor at Yale University. Three years later, she became an investigator at the prestigious Howard Hughes Medical Institute.
In 2002, Doudna was appointed Professor of Biochemistry and Molecular Biology at the University of California in Berkeley, where she still occupies a chair.
Jennifer Doudna is a member of the American National Academy of Sciences. She has been awarded many prizes, including the Paul Janssen Award for Biomedical Research in 2014, the Breakthrough Prize in Life Sciences in 2015 and in 2016 the L’Oréal-UNESCO For Women in Science Award and the Canada Gairdner International Award.
In 2020, Jennifer Doudna has been awarded the Nobel Prize in Chemistry, together with Emmanuelle Charpentier.

Article
— Interview with Jennifer Doudna in De Groene Amsterdammer (Dutch)

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The Royal Netherlands Academy of Arts and Sciences (KNAW) has awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2014 to Christopher Dobson, John Humphrey Plummer Professor of Chemical and Structural Biology, University of Cambridge (United Kingdom).
Professor Dobson received the prize for uncovering the manner in which proteins in the human body sometimes misfold themselves and how that process may lead to age-related diseases, including Alzheimer’s, Parkinson’s and diabetes.

Researcher
Christopher M. Dobson was born in the United Kingdom on 8 October 1949. He studied at the University of Oxford and in 1976 received his PhD there. One year later he left Oxford for the USA to do research at Harvard University and the Massachusetts Institute of Technology in Cambridge. In 1980 Dobson returned to Oxford, where he became Professor of Chemistry in 1996. Two years later he was appointed Director of the Oxford Centre for Molecular Sciences. In 2001, Dobson once again left Oxford for Cambridge, only this time it was Cambridge in the UK. He has served as the John Humphrey Plummer Professor of Chemical and Structural Biology at the University of Cambridge ever since.
Dobson has authored or co-authored over 650 published research and review papers, more than 30 of which were published in the prestigious journals Science and Nature. In addition to his duties as a highly productive and influential researcher, Dobson has served as Master of Cambridge’s age-old St John’s College since 2007.
Dobson has received numerous awards and decorations. In 2009 he received the Royal Medal of the Royal Society in London. He is a foreign member of the US National Academy of Sciences and the American Academy of Arts and Sciences. He has earned honorary doctorates from five universities in Belgium, Sweden, Italy and the United Kingdom.
Dobson passed away in September 2019.

Research
Chris Dobson has been studying the way in which biological molecules behave for many years, both in laboratories and test tubes and in the real world of the human body. His work has helped show how molecular building blocks assemble themselves into chains, and how these chains fold into complex structures.
Elaborately folded proteins, made up of hundreds of amino acids, together make up the smart machinery of every living cell. Sometimes, however, things end up less well: a misfolded protein may snag other proteins, sticking to them in clumps that can do serious damage to vital organs.
With his group at the University of Cambridge, Dobson has made great strides in unravelling how, as we grow older, such clumps may begin to appear more often. Small at first, they may spread to other organs. Ultimately, as more normal proteins get tangled up, the clump gets stuck in some organ’s tissue. There it may lead, directly or indirectly, to such serious ailments as Alzheimer’s Disease, Parkinson’s Disease or type-2 diabetes.
Years ago, researchers saw ‘amyloid plaques’ in brain tissue as a specific and unique cause of Alzheimer’s. Thanks in part to Dobson, many people now recognise that these plaques are but one example of misfolded proteins causing problems. In fact, Dobson suggests that most human proteins are capable of misfolding and that when we get older, they may affect many of our organs, resulting in numerous types of disease.
Dobson’s strength is that he has consistently approached complex problems such as protein folding through multiple disciplines. He has applied a range of techniques, including NMR, spectroscopy, molecular biology and computer modelling. With his original, creative and innovative work, he has managed to bridge the gap between our knowledge of molecular behaviour in test tubes and our knowledge of the ‘real world’ of living cells.
Dobson’s work is not finished. He has widened his research interests to include the self-assembly of molecules in wholly new fields such as materials science and nanotechnology.

More information
— Personal page on website University of Cambridge

Article
— Interview with Christopher Dobson in De Groene Amsterdammer (Dutch)

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Titia de Lange has been awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2012 for her research on telomeres, the protective elements located at the tips of chromosomes, which play a crucial role in ageing and cancer.
The biochemical machinery of human cells is designed to see breaks in the DNA ribbon as “defects” and to glue the loose ends together again. Fortunately, that machinery ignores the chromosome ends. Thanks to Titia de Lange and her research group, we now understand why.
De Lange was the first to suggest that telomeres are shielded from the cell machinery by a protein complex. Her ideas turned out to be correct. She played a major role in identifying the protein complex that protects the telomeres – a shield that she has named the ‘shelterin complex’.
De Lange and her group identified the first two proteins within the complex, Telomeric Repeat binding Factor (TRF) 1 and 2. She showed that TRF2 suppresses the cell’s repair system at the chromosome ends; if this protein is absent, the cell will ‘repair’ the telomeres and glue together chromosomes by mistake. De Lange showed that other repair processes are blocked by additional shelterin components.
De Lange also showed how shelterin prevents the activation of a surveillance system that monitors chromosomes for damage. The purpose of this alarm system is to stop the cell division cycle when chromosomes are broken. When shelterin is not working properly, the telomeres set off a false alarm, resulting in cell cycle arrest or cell death.
Together with her collaborator Jack Griffith, De Lange found that telomeres are arranged into lasso-like loops that hide the chromosome end. The cell’s repair and alarm systems therefore ignore the ends. They showed that the shelterin protein TRF2 helps in forming these loops.
Telomeres play a major role in healthy and sick cells. De Lange’s important and original research will therefore have implications for health care.

Further reading
Loayza, D., and de Lange, T. (2003). POT1 as a terminal transducer of TRF1 telomere length control. Nature 424, 1013-1018.
van Steensel, B., Smogorzewska, A., and de Lange, T. (1998). TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401-413.
Smogorzewska, A., van Steensel, B., Bianchi, A., Schnapp,,G., Schaefer, M. R., Oelmann, S., and de Lange, T. (2000) Control of human telomere length by TRF1 and TRF2. Mol. Cell Biol. 20: 1659-1668.
de Lange, T. (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19, 2100-2110.
Lazzerini Denchi, E., and de Lange, T. (2007). Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448, 1068-1071.

Biography
Titia de Lange was born in Rotterdam, the Netherlands in 1955. She studied at the University of Amsterdam and obtained her PhD at the Netherlands Cancer Institute in Amsterdam, studying under Professor Piet Borst.
She was a postdoctoral fellow in the laboratory of Nobel laureate Harold Varmus at the University of California, San Francisco (UCSF). In 1990 she went to the Rockefeller University in New York. She was appointed professor there in 1997 and since 2011 has been the director of the university’s Anderson Center for Cancer Research.
Titia de Lange has received many other prizes and distinctions during her career. She is the recipient of the 2011 Vilcek Prize in Biomedical Science, the 2010 AACR Clowes Memorial Award, and the 2008 Massachusetts General Hospital Cancer Center Prize. In 2003, the University of Utrecht awarded her an honorary doctorate.
She is a member of the Royal Netherlands Academy of Arts and Sciences, the European Molecular Biology Organization (EMBO), the American Academy of Arts and Sciences, and the United States National Academy of Sciences.

Laudatio
— English
— Dutch

Article
— Interview with Titia de Lange in Akademie Nieuws ( Dutch)

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Professor Franz-Ulrich Hartl was awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2010 for his contribution to the discovery of the role of ‘chaperones’ in protein folding.
Proteins can only guide cellular processes after they have become three-dimensional in shape. One of the key questions in biochemistry is how an amino acid chain folds itself into a three-dimensional shape, thereby becoming a protein, and how the resulting protein avoids becoming unfolded again and losing its function. It is because of Franz-Ulrich Hartl that we now understand the significance of chaperone molecules in this process. Chaperones are proteins that help other proteins fold themselves into the proper shape and remain that way. It was long assumed that proteins acquired their shape through a process of self-assembly, but Hartldiscovered that many of the thousands of different proteins in cellular fluid in fact depend on chaperones to guide them. He developed a series of ingenious experiments, both in vitro and in vivo, to explain in detail how chaperone-assisted protein folding works. In the first half of the 1990s, his publications in Nature led to a drastic overhaul of the basic principles of protein biogenesis, the fast-growing discipline that investigates protein formation.
Understanding the process of protein folding and unfolding has major implications. For example, a disruption in the folding mechanism leads to neurodegenerative diseases such as Parkinson’s and Huntington’s. Hartl and his research group are attempting to decipher these mechanisms. Ultimately, they hope to use the power of chaperones to combat disease and to assemble proteins in biotechnology.

Key publications
Cheng M.Y., Hartl F.U., Martin J., et al. 1989. ‘Mitochondrial heat-shock protein HSP60 is essential for assembly of proteins imported into yeast mitochondria.’ In: Nature 337: 620-625
Hartl F.U. 1996. ‘Molecular chaperones in cellular protein folding.’ In: Nature 381: 571-580
Hartl F.U. & Hayer-Hartl M. 2002. ‘Molecular chaperones in the cytosol: from nascent chain to folded protein.’ In: Science 295: 1852-1858
Tang Y.C., Chang H.C., Roeben A., et al. 2006. ‘Structural features of the GroEL-GroES nano-cage required for rapid folding of encapsulated protein.’ In: Cell 125: 903-914
Liu C.M., Young A.L., Starling-Windhof A., et al. 2010. ‘Coupled chaperone action in folding and assembly of hexadecameric Rubisco.’ In: Nature 463: 197-202

Biography
Franz-Ulrich Hartl was born in 1957 in Essen, Germany. He studied medicine at Heidelberg University, graduating summa cum laude in 1985. He also received his doctoral degree there for his dissertation on the role of hormones in the rat liver. In 1990, Hartl obtained his Dr. Med. Habil. from the University of Munich for his dissertation on protein assembly processes. Hartl went to the United States in 1989 as a postdoctoral fellow at the University of California (UCLA). In 1991, he moved to the Graduate School of Medical Sciences at Cornell University, where he worked as an instructor and researcher. From 1994 to 1997, he also worked as an associate investigator at the prestigious Howard Hughes Medical Institute for biomedical research. Hartl returned to Europe in 1997 after accepting an appointment as professor of physiological chemistry and managing director of the Max Planck Institute for Biochemistry in Martinsried, Germany.
Hartl has won many international awards and honours and is a member of the German Academy of Sciences, a foreign honorary member of the American Academy of Arts and Sciences and an honorary member of the Japanese Biochemical Society.

Laudatio:
— English
— Dutch

Article:
— Interview with Frans-Ulrich Hartl in Akademie Nieuws (Dutch)

Video

Video interview with Franz-Ulrich Hartl

Jack W. Szostak was awarded the Dr H.P. Heineken Prize for Biochemistry and Biophysics 2008 for his highly original insights into the fundamental processes of life.

Examples of key publications
Szostak, J.W, Blackburn, E.H., Cloning yeast telomeres on linear plasmid vectors. In: Cell1982; 29: 245-55
Szostak, J.W., Orr-Weaver, T.L., Rothstein, R.J., Stahl, F.J., The double-strand-break repair model for recombination. In: Cell 1983; 33: 25-35
Murray, A.W., Szostak , J.W., Construction of artificial chromosomes in yeast. In: Nature1983; 305: 189-193
Roberts, R.W., Szostak, J.W., RNA-peptide fusions for the in vitro selection of peptides and proteins. In: Proc. Natl. Acad. Sci. USA 1997; 94: 12297-12302
Seelig, B., Szostak, J.W., Selection and evolution of enzymes from a partially randomized non-catalytic scaffold. In: Nature 2007; 448: 828-831

Biography
Jack Szostak (1952) was only nineteen when he was awarded his B.S. in cell biology at McGill University in Montreal, Canada. He obtained his PhD in biochemistry at Cornell University (Ithaca, New York, USA), where he worked as a research assistant until 1979. He then moved to Harvard Medical School, where he has been a professor with the Department of Genetics since 1988. In that same year, he accepted an appointment with the Department of Molecular Biology at Boston’s Massachusetts General Hospital, where he became an Alex Rich Distinguished Investigator in 2000. In 1998, Szostak became an Investigator at the Howard Hughes Medical Institute at Massachusetts General Hospital.
Szostak has been granted numerous patents and is a member of several American academies and the American Association for the Advancement of Science (AAAS). His previous awards include the 2006 Albert Lasker Award for Basic Medical Research (together with Elizabeth Blackburn and others). In 2009 he won the Nobel Prize in Physiology or Medicine (together with Elizabeth Blackburn and Carol Greider). Szostak is praised on all sides for his versatility and originality.

Laudatio
— English
— Dutch

Article
— Interview with Jack Szostak in Akademie Nieuws (Dutch)

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