Robert Williamson (geneticist)

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Robert Williamson

AC FAA FRA
Born1938 (age 85–86)
Cleveland, Ohio, USA
Alma mater University College London
Awards Officer of the Order of Australia (2004)
Scientific career
Fields Human Genetics; Molecular genetics
Institutions Murdoch Children's Research Institute, University of Melbourne
Website www.rch.org.au/alumni/alumni_profiles/Williamson,_Bob_________AO/

Robert Williamson AO FAA (born 1938) is a retired British-Australian molecular biologist who specialised in the mapping, gene identification, and diagnosis of human genetic disorders.

Contents

Career

Williamson was born in Cleveland, Ohio, to Scottish parents. He was educated at the Bronx High School of Science in New York and then Wandsworth School in South London after his parents returned to the UK, before studying at University College London. [1] From 1963 he was lecturer, then senior lecturer, in developmental biology at the University of Glasgow. From 1976 he was Professor and head of Molecular Genetics and Biochemistry at St Mary's Hospital Medical School, University of London. [2]

He emigrated to Melbourne, Australia in 1995 to be Director of the Murdoch Children's Research Institute (then the Murdoch Institute) and Professor of Medical Genetics at the University of Melbourne. He edited several books on genetic engineering and on the ethics of the new genetic sciences.

Since his retirement in 2004, Williamson has been the Secretary for Science Policy at the Australian Academy of Science and an Honorary Senior Principal Fellow (Professor) at the University of Melbourne.

Research

Williamson began his career working on haemoglobin synthesis in reticulocytes (immature red blood cells) and thalassaemias (inherited blood disorders). As a lecturer at the University of Glasgow, he studied human gene organisation and expression. In 1970, he was the solo author of a paper that provided the dual discovery of the origin of cell-free DNA and the nucleosome organisation of DNA in chromosomes, including the first description of the "nucleosome ladder". [3] Decades later, the geneticists Steven Henikoff and George Church hailed Williamson's report as “a remarkably prescient paper,” adding: “The simultaneous discovery of the nucleosome ladder and the origin of [cell-free] cfDNA in 1970 was thus correctly interpreted by Williamson, respectively 3 years and nearly 3 decades before the biological significance of nucleosomes and the clinical utility of cfDNA were appreciated.” [4]

Williamson chose not to follow up on those results, turning his attention to messenger RNA and then the study of globin genes and the thalassaemias. In 1974, Williamson's group demonstrated that severe alpha-thalassaemia is due to a deletion in the alpha globin gene, [5] and subsequently that delta-beta thalassaemia was attributed to a deletion in the beta globin gene. [6] From his new position at St. Mary's Hospital Medical School, Williamson's group went on to clone the human alpha-, beta- and gamma-globin genes from cDNAs, and used them to deduce their genomic structures.

By 1980, Williamson and colleagues began applying the discovery of DNA markers called restriction fragment length polymorphisms to perform linkage mapping to locate the position of important human disease genes. In 1982, working with Kay Davies, Williamson's group narrowed down the location of the X-linked Duchenne muscular dystrophy gene. [7] Williamson is best known for his research on the genetics of cystic fibrosis. In 1985, Williamson lead one of three teams that independently mapped the gene mutated in cystic fibrosis to chromosome 7, [8] sparking an intense international race to identify the gene. His group came close to isolating the defective gene, reporting a strong candidate in 1987, [9] only to be scooped by Lap-Chee Tsui, Francis Collins and colleagues in 1989. [10]

Throughout the 1980s, Williamson and colleagues pursued the use of random DNA markers to map mutated genes responsible for several other major genetic disorders, including myotonic dystrophy, Friedreich's ataxias, coronary artery disease, craniofacial abnormalities, and Alzheimer's disease. In 1988, Williamson's group also developed the first method for genetic testing using cheek buccal epithelial cells obtained by a simple mouthwash. [11] In 1991, John Hardy, a lecturer in Williamson's department, identified the first mutation associated with Alzheimer's disease in the gene encoding the amyloid precursor protein (APP). [12]

Williamson was an early proponent of human gene therapy, writing presciently in 1982: "Gene therapy is not yet possible, but may become feasible soon, particularly for well understood gene defects. Although treatment of a patient raises no ethical problems once it can be done well, changing the genes of an early embryo is more difficult, controversial and unlikely to be required clinically." [13] Following the discovery of the CF gene in 1989, he turned his attention to developing strategies for gene therapy for CF patients in his final years at St. Mary's, including a non-viral proof-of-concept study in the inaugural issue of Nature Medicine. [14]

Williamson recruited and mentored many leading molecular geneticists during his two decades at St. Mary's Hospital, including Royal Society Fellows Dame Kay Davies, Stephen D. M. Brown, Gillian Bates and John Hardy. Davies recalled: “With Bob, nothing was impossible; he always knew someone in the field who would be able to help whenever we needed a new technique or vector for cloning. He taught me how much more successful you could be as a scientist if you were collaborative and had an extensive network of basic and clinical scientists.” [15] Hardy acknowledged that the “first 13 grant applications I wrote were unsuccessful and without the continuing support of Bob, our efforts would have foundered.” [16]

In 1995, Williamson moved from London to Melbourne, Australia, to become Director of the Murdoch Children's Research Institute, taking over from David Danks, [17] a clinical geneticist who had trained with Victor A. McKusick. Williamson directed a broad research portfolio on a range of molecular genetics technologies, such as preimplantation genetic diagnosis [18] used in conjunction with in vitro fertilisation and Friedreich's ataxia [19] He established training for genetic counsellors and public health paediatricians [20] and continued working at the interface of ethics genetics, with a particular interest in Aboriginal genomics. [21] Williamson successfully broadened the orientation of the Murdoch Institute, growing it to some 600 staff by the time he retired in 2005, pursuing research on ethics, public health, and genetics of complex diseases.

Williamson has published more than 400 scientific papers. [22] He is an eloquent commentator and prominent evangelist for the societal benefits of genetic testing, from proposing community-wide carrier screening for cystic fibrosis [23] to universal DNA testing. [24]

Honours and awards

In 1994, he was awarded the King Faisal International Prize in Medicine, together with W. French Anderson, for medical applications of molecular genetics. [25]

In 1997, he received an Honorary MD degree from the University of Turku, Finland.

He was elected to the Royal Society in 1999. [22] He is also a Fellow of the Royal College of Physicians, the Royal College of Pathologists and the Australian Academy of Science (2001).

In 2004, he was appointed an Officer of the Order of Australia (AO).

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical field

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">Thalassemia</span> Medical condition

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time.

<span class="mw-page-title-main">Molecular genetics</span> Scientific study of genes at the molecular level

Molecular genetics is a branch of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the structure and/or function of genes in an organism's genome using genetic screens. 

A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens can provide important information on gene function as well as the molecular events that underlie a biological process or pathway. While genome projects have identified an extensive inventory of genes in many different organisms, genetic screens can provide valuable insight as to how those genes function.

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutation is not always harmful, the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

<span class="mw-page-title-main">Copy number variation</span> Repeated DNA variation between individuals

Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of duplication or deletion event that affects a considerable number of base pairs. Approximately two-thirds of the entire human genome may be composed of repeats and 4.8–9.5% of the human genome can be classified as copy number variations. In mammals, copy number variations play an important role in generating necessary variation in the population as well as disease phenotype.

An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.

<span class="mw-page-title-main">Alpha-thalassemia</span> Thalassemia involving the genes HBA1and HBA2 hemoglobin genes

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">Beta thalassemia</span> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Chromosome conformation capture</span>

Chromosome conformation capture techniques are a set of molecular biology methods used to analyze the spatial organization of chromatin in a cell. These methods quantify the number of interactions between genomic loci that are nearby in 3-D space, but may be separated by many nucleotides in the linear genome. Such interactions may result from biological functions, such as promoter-enhancer interactions, or from random polymer looping, where undirected physical motion of chromatin causes loci to collide. Interaction frequencies may be analyzed directly, or they may be converted to distances and used to reconstruct 3-D structures.

<span class="mw-page-title-main">Hemoglobin subunit zeta</span> Mammalian protein found in Homo sapiens

Hemoglobin subunit zeta is a protein that in humans is encoded by the HBZ gene.

<span class="mw-page-title-main">HBAP1</span> Pseudogene in the species Homo sapiens

Hemoglobin, alpha pseudogene 1, also known as HBAP1, is a human gene.

<span class="mw-page-title-main">1000 Genomes Project</span> International research effort on genetic variation

The 1000 Genomes Project, taken place from January 2008 to 2015, was an international research effort to establish the most detailed catalogue of human genetic variation at the time. Scientists planned to sequence the genomes of at least one thousand anonymous healthy participants from a number of different ethnic groups within the following three years, using advancements in newly developed technologies. In 2010, the project finished its pilot phase, which was described in detail in a publication in the journal Nature. In 2012, the sequencing of 1092 genomes was announced in a Nature publication. In 2015, two papers in Nature reported results and the completion of the project and opportunities for future research.

Douglas Roland Higgs FRS is a Professor of Molecular Haematology at the Weatherall Institute of Molecular Medicine, at the University of Oxford. He is known for his work on the regulation of alpha-globin and the genetics of alpha-thalassemia. He is currently working in understanding the mechanisms by which any mammalian gene is switched on and off during differentiation and development.

The history of genetics can be represented on a timeline of events from the earliest work in the 1850s, to the DNA era starting in the 1940s, and the genomics era beginning in the 1970s.

Johanna Rommens is a Canadian geneticist who was on the research team which identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later discovered the gene responsible for Shwachman-Diamond syndrome, a rare genetic disorder that causes pancreatic and hematologic problems. She is a Senior Scientist Emeritus at SickKids Research Institute and a professor in the Department of Molecular Genetics at the University of Toronto.

Haig H. Kazazian, Jr. was a professor in the Department of Genetic Medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland. Kazazian was an elected member of the National Academy of Sciences and the American Academy of Arts and Sciences.

References

  1. ↑ Who's Who 2019. A & C Black, London. 2018. ISBN   978-1-472-94758-1.
  2. ↑ "Professor Bob Williamson". Murdoch Children's Research Institute. Retrieved 15 August 2018.
  3. ↑ Williamson, R. Properties of rapidly labelled deoxyribonucleic acid fragments isolated from the cytoplasm of primary cultures of embryonic mouse liver cells. J. Mol. Biol. 51, 157-160 (1970). https://doi.org/10.1016/0022-2836(70)90277-9
  4. ↑ Henikoff, S. & Church, G.M. Simultaneous Discovery of Cell-Free DNA and the Nucleosome Ladder. Genetics 209, 27-29 (2018). https://doi.org/10.1534/genetics.118.300775
  5. ↑ Ottolenghi, S. et al. Gene deletion as the cause of α thalassaemia: The severe form of α thalassaemia is caused by a haemoglobin gene deletion. Nature 251, 389-392 (1974). https://doi.org/10.1038/251389a0
  6. ↑ Ottolenghi, S. et al. δβ-Thalassemia is due to a gene deletion. Cell 9, 71-80 (1976). https://doi.org/10.1038/251389a0
  7. ↑ Murray, J.M. et al. Linkage relationship of a cloned DNA sequence on the short arm of the X chromosome to Duchenne muscular dystrophy. Nature 300, 69-71 (1982). https://doi.org/10.1038/300069a0
  8. ↑ Wainwright, B.J. et al. Localization of cystic fibrosis locus to human chromosome 7cen–q22. Nature 318, 384-385 (1985). https://doi.org/10.1038/318384a0
  9. ↑ Estivill, X. et al. A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. Nature 326, 840-846 (1987). https://doi.org/10.1038/326840a0
  10. ↑ Kevin Davies. The search for the cystic fibrosis gene. New Scientist 20 October 1989. https://www.newscientist.com/article/mg12416873-900/
  11. ↑ Lench, N. et al. Simple non-invasive method to obtain DNA for gene analysis. Lancet 331, 1356-1368 (1988). https://doi.org/10.1016/S0140-6736(88)92178-2
  12. ↑ Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706 (1991). https://doi.org/10.1038/349704a0
  13. ↑ Williamson, B. Nature 298, 416-418 (1982). https://doi.org/10.1038/298416a0
  14. ↑ Caplen, N.J. et al. Nature Medicine 1, 39-46 (1995).
  15. ↑ Davies, K.E. The Long Journey from Diagnosis to Therapy. Ann. Rev. Genomics & Human Genet. 21, 1-13 (2020). https://doi.org/10.1146/annurev-genom-112019-083518
  16. ↑ Hardy, J. The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis”. FEBS Journal 284, 1040-1044 (2017). https://doi.org/10.1111/febs.14004
  17. ↑ Choo, K.H.A. "David M. Danks, M.D., A.O. (June 4, 1931–July 8, 2003): Founder, Murdoch Childrens Research Institute". American Journal of Human Genetics 73: 981–985 (2003). doi:10.1086/379383.
  18. ↑ Wilton, L., Williamson, R., McBain J., Edgar, D., and Voullaire, L. “Birth of a Healthy Infant after Preimplantation Confirmation of Euploidy by Comparative Genomic Hybridisation” N. Engl. J. Med, 345:1537-1541 (2001).
  19. ↑ Delatycki, M.B., Williamson, R. and Forrest, S.M. “Friedreich Ataxia; an overview.” J. Med. Genet. 37:1-8 (2000).
  20. ↑ Collins, V., Halliday, J., Kahler, S., and Williamson, R. “Parents’ Experience with Genetic Counseling After the Birth of a Baby with a Genetic Disorder: An Exploratory Study.” J. Genet. Coun. 10:53-72 (2001).
  21. ↑ Dodson, M. and Williamson, R. “Indigenous People and the Morality of the Human Genome Diversity Project.” J. Med. Ethics 25:204-208 (1999).
  22. 1 2 "Robert Williamson". Royal Society. 12 August 2015. Retrieved 12 August 2018.
  23. ↑ Williamson, R. Universal community carrier screening for cystic fibrosis? Nature Genetics 3, 195-201 (1993). https://doi.org/10.1038/ng0393-195
  24. ↑ Williamson, R. & Duncan, R. DNA testing for all. Nature 418, 585-586 (2002). https://doi.org/10.1038/418585a
  25. ↑ "Professor Robert Williamson". King Faisal Prize. 10 October 2012. Retrieved 12 August 2018.
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