Robert Andrew Holt

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Robert Holt, (born July 22, 1968 in New Westminster, BC, Canada) is a genomic scientist and immunogeneticist. He is currently a Distinguished Scientific at the BC Cancer Research Centre, where he is also Co-Director of the BC Cancer Immunotherapy program (in Vancouver, Canada). He is also appointed as Professor of Medical Genetics at the University of British Columbia and Professor of Molecular Biology & Biochemistry at Simon Fraser University. Through international consortia, he has had made several significant contributions to science (e.g. The Cancer Genome Atlas, The Human Microbiome Project, Cancer Research UK Grand Challenges). After initial sequencing of the Drosophila [1] and human genomes [2] was co-PI on the NIH program to sequence the rat genome, [3] and was also a PI on the international effort to sequence the malaria mosquito genome, [4] which involved >30 principal scientists from 11 different countries. With his publications exceeding over 200 and his citations being recorded approximately 70,000 times, Holt earned a position in the top 1% of Web of Science cited researchers by Clarivate Analytics in 2018 and 2019.

Contents

Education

After earning an undergraduate degree (BSc) in General Science from the University of British Columbia in 1992, he studied neuroscience and pharmacology under the supervision of Drs. Ian L. Martin and Alan N. Bateson at the University of Alberta and graduated with a PhD in Pharmacology in 1998. His thesis focused on the molecular characterization of GABA-A receptors. He undertook postdoctoral research at the State University of New York in Albany with Dr. Caro-Beth Stewart, where he used rapid DNA sequencing techniques to study molecular evolution in primates.

Career

Throughout his undergraduate and graduate studies, for several months each year, he worked in the silviculture industry in northern British Columbia. After his brief postdoctoral research program he joined Dr. Craig Venter's team at Celera Genomics, as the production manager for DNA sequencing operations. He was a leading figure actualizing industrial-scale molecular biology and established, at the time, the world's largest DNA sequencing center. Upon his return to Canada, he joined the Michael Smith Genome Sciences Centre (GSC), a world-leading genome center with >300 personnel, at the BC Cancer Research Centre. He served as Head of Sequencing and co-Director (with Dr. Marco Marra) of the Genome Canada Innovation Network GSC node from 2005 to 2016. Together with Medical Director A. Karsan, he established the first College of American Pathologists-accredited clinical next generation sequencing (NGS) platform in Canada.

He joined the faculty of the University of British Columbia in 2003 where he is now a Professor in the Department of Medical Genetics, a Faculty Member of the Genome Science and Technology program, the Interdisciplinary Oncology Graduate Program, the Genetics Graduate Program and the Health Brain Research Centre. He is also a Professor in the Molecular Biology and Biochemistry Department at Simon Fraser University.

Moreover, together with Dr. Brad Nelson, he is currently Scientific Co-Director of the BC Cancer Immunotherapy program. With Dr. John Bell (Univ. of Ottawa) and others he launched BioCanRx, a Networks of Centres of Excellence program focused on cancer biotherapeutics. He serves as overall PI for a team of basic and clinical scientists in BC and Ontario that has established domestic CAR-T manufacturing capacity and launched the first investigator-initiated, self-sponsored CAR-T clinical trial in Canada "CLIC-01" laying the groundwork for new CAR-T innovations in Canada.

Research

His lab described the link between an emerging pathogen, Fusobacterium nucleatum (Fn), and colorectal cancer. [5] This finding (named by TIME magazine as one of the top 10 medical breakthroughs for 2011) has been extensively replicated and its significance has gained a global renown. He leads one of six work-packages in a newly awarded Cancer Research UK Grand Challenges grant where their international team will interrogate Fn biology comprehensively in global cohorts and model systems.

His group pioneered decoding immune repertoire by deep sequencing, [6] opening a fast-developing field [7] [8] encompassing numerous biotechnology companies, holding international meetings and establishing a scientific society mainly focused on this methodology. Their work also profiled T-lymphocyte antigens, as well. [9] They led the way to develop an NGS assembly algorithm [10] and succeeded in extracting Human Leukocyte Antigen (HLA) types from NGS data sets. [11] These methods have been utilized by themselves and by the community in recent high impact studies. [12] [13] They were also the first to show that the anti-cancer immune response is linked to mutational antigen (neoantigen) load. [14] Neoantigens are now being thoroughly scrutinized as targets for cancer immunotherapy and are implicated in the achievements of the new blockbuster checkpoint blockade therapies.

Related Research Articles

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In immunology, an antigen (Ag) is a molecule or molecular structure that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. The term antigen originally referred to a substance that is an antibody generator. Antigens can be proteins, peptides, polysaccharides, lipids, nucleic acids, or other biomolecules.

Antibody Immune system protein

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

Bioinformatics Computational analysis of large, complex sets of biological data

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Leroy Hood American biologist

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Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.

An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The part of an antibody that binds to the epitope is called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized are also epitopes.

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SSX2

Protein SSX2 is a protein that in humans is encoded by the SSX2 gene.

ZRF1

DnaJ homolog subfamily C member 2 is a protein that in humans is encoded by the DNAJC2 gene.

ZNF366

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STEAP1

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Duplex sequencing

Duplex sequencing is a library preparation and analysis method for next-generation sequencing (NGS) platforms that employs random tagging of double-stranded DNA to detect mutations with higher accuracy and lower error rates.

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Tumor mutational burden

Tumour mutational burden is a genetic characteristic of tumorous tissue that can be informative to cancer research and treatment. It is defined as the number of non-inherited mutations per million bases (Mb) of investigated genomic sequence, and its measurement has been enabled by next generation sequencing. TMB has shown potential as a predictive biomarker with several applications, including associations reported between different TMB levels and patient response to immune checkpoint inhibitor (ICI) therapy in a variety of cancers.

References

  1. ↑ Adams, MD, Celniker SE, Holt, RA, et al., The genome sequence of Drosophila melanogaster. Science, 2000. 287: 2185 Breakthrough of the Year (Science 290:2255).
  2. ↑ Venter, JC, Adams, MD, Meyers, EW, Li, PW, Mural, RJ, Sutton, GG, Smith, HO, Yandell, M, Evans, CA, Holt, RA, et al., The sequence of the human genome. Science, 2001. 291:1304
  3. ↑ The Rat Genome Sequencing Project Consortium.. Nature, 2004. 428:493
  4. ↑ Holt, RA, et al., The genome sequence of the malaria mosquito Anopheles gambiae. Science, 2002. 298:129
  5. ↑ Castellarin M et al., F.nucleatum infection is prevalent in human colorectal carcinoma. Genome Res, 2012. 22:299
  6. ↑ Freeman JD et al.,. Profiling the T-cell receptor beta-chain repertoire by massively parallel sequencing. Genome Res, 2009. 19:1817
  7. ↑ Keener, AB, A sense of immunity: scientists are detailing the immune system as never before. Nat Med, 2015. 21:3-8.
  8. ↑ Holt, RA, Interpreting the T cell repertoire. Nat Biotechnol. 2017. 35:829
  9. ↑ Sharma G et al., Rapid selection and identification of functional CD8+ T cell epitopes from large peptide-coding libraries. Nat Comm, 2019. 10:4553
  10. ↑ Warren RL et al., Assembling millions of short DNA sequences using SSAKE. Bioinformatics, 2007. 23:500
  11. ↑ Warren RL et al., Derivation of HLA types from shotgun sequence datasets. Genome Med, 2012. 4(12): p. 95.
  12. ↑ Zhang AW et al., Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer. Cell. 2018. 173:1755
  13. ↑ Thorsson V, et al., The Immune Landscape of Cancer. Immunity. 2018 48(4): p. 812-830
  14. ↑ Brown SD et al., Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res, 2014. 24:743-50.
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