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Joseph Noozhumurry (Jose) Varghese

Biography

Joseph Noozhumurry Varghese was born in Nairobi, Kenya on 13 March 1949 of parents from Travancore and Cochin in India. His father, Noozhumurry (George) Varghese and mother, Annamma Varghese were teachers in Kenya and George was a High School Principal. Jose’s early schooling was at Usin Gishu Primary School, Eldoret, Kenya.

The family migrated to Newcastle, NSW, Australia in February 1964, and Jose continued his secondary schooling at Newcastle Boys High School. In 1965, his father was appointed as a Senior Lecturer in Education at the University of Queensland in Brisbane. Jose remained in Newcastle to finish his NSW Leaving Certificate with Honours in Physics and Applied Mathematics in 1965.

He moved to the University of Queensland in 1966 to commence an Honours Stream in Physics and Mathematics at the St Lucia Campus under a Commonwealth Undergraduate Scholarship. He obtained his BSc in 1968 majoring in Physics and Mathematics and in 1969 obtained postgraduate Honours in Theoretical Physics with his thesis entitled ‘Electron-electron interactions at relativistic energies’.

In 1970, he was awarded a Commonwealth Postgraduate Scholarship for a PhD in Physics at the University of Western Australia at Nedlands, Perth. He joined Dr Ted Maslen’s X-ray Crystallography Group and carried out research probing the coupling of charge density and thermal motion in molecules by X-ray diffraction. He submitted his PhD Thesis in 1973 entitled ‘Charge density and thermal motion in molecular crystals’ which laid the foundations of extracting the net electric charge on individual atoms in complex molecules using combined X-ray and neutron diffraction.

In 1974, after tutoring at the Physics Department of the University of Queensland, he obtained an ARC Postdoctoral Fellowship to work with Drs Allan White, Graham Chandler and Ted Maslen at the Crystallography Centre, University of Western Australia, on investigating the spin-orbital coupling of transition metal in organic complexes and fundamental studies of obtaining quantum mechanical solutions to the three body problem of the hydrogen ion (H2+) and extending it to larger systems.

In 1977, Jose was awarded a Science Research Council (UK) Postdoctoral Fellowship to study spin transfer in transition metal complexes using polarised neutron scattering at the School of Molecular Sciences, University of Sussex in England. He worked at the experimental nuclear reactors at the Rutherford Laboratories at Oxford, England and at the Institut Laue-Langevin (ILL), Grenoble, France. During this period Jose carried out seminal theoretical and experimental studies of spin transfer in transition metal complexes.

In 1980, he was invited to take up a CSIRO Postdoctoral Fellowship in Dr Peter Colman‘s laboratory in Parkville, Victoria initially to work with Peter on the X-ray structure of the tymovirus Erisimum latent virus. In 1981, he commenced his long and outstanding collaboration with Peter Colman on the determination of the 3D structure of influenza virus neuraminidase. This research culminated in the development of Relenza® by CSIRO and the Victorian College of Pharmacy funded by the Australian biotechnology company Biota Holdings Limited. The ‘flu work involved the following:

  • the determination of the 3D structures of two N2 neuraminidase molecules of human influenza Type A viruses isolated 10 years apart (1957 and 1967) employing novel mathematical techniques of combining the data of two crystal systems with different strains of the virus. The work carried out with Peter Colman was published in back-to-back articles in the 11 May 1983 issue of the prestigious journal Nature with a hand drawing by Varghese of the neuraminidase molecule on the front cover
  • the determination of the structure of sialic acid complexed with influenza virus N2 neuraminidase that was used in the design of the anti-influenza virus drug Relenza
  • the determination of the structures of complexes of N2 neuraminidase and potential neuraminidase inhibitors leading to the design and development of zanamavir, now marketed as Relenza®
  • the subsequent development of Tamiflu® by the US-based company Gilead Sciences and Roche was also based on this CSIRO research.

During the period 1981-90, Jose Varghese was involved also (with Peter Colman) in the determination of the first structure of a viral antigen/antibody complex, and the development of the ‘hand-shake’ model of antibody-antigen interaction. This was published in Nature in 1987 and again made the cover.

Varghese was also involved in the determination of the structure of phaseolin, the first of several seed storage proteins solved (with Mike Lawrence, Peter Colman, Eikichi Suzuki and Peter Tulloch) and with Dr Steven Wilkins developed the theory of ‘Statistical Geometry’ to process noisy images using Bayesian Statistics. This was the forerunner to the maximum entropy methods now used widely in data analysis.

In 1990, Jose was seconded to the newly formed Biomolecular Research Institute, a joint initiative between the CSIRO and the Victorian Government’s Strategic Research Foundation, and remained there until its closure in December 2000. The BRI was co-located with the CSIRO Division of Biomolecular Engineering at 343 Royal Parade, Parkville. During this decade he:

  • continued discoveries and authorship of seminal scientific papers in the field of influenza research, culminating in determining the structural basis for drug resistance in influenza and predicting the emergence of drug resistance strains which recently has been verified
  • determined the structure of several plant hydrolyses and designed thermo-stable mutations to improve the malting quality of barley for the brewing and feed stock industries with Professor Geoff Fincher of the University of Adelaide.
  • assembled and led a multi-disciplinary team from the Ludwig Institute, CSIRO and BRI to successfully purify, crystallise and solve the structure of the extracellular region of the Interleukin-6 receptor and initiated a drug discovery program with the Ludwig against a variety of human diseases that has generated several patents
  • led the construction of mono-capillary optics for laboratory X-ray sources (with the University of Melbourne) which increased the brilliance by two orders of magnitude. This enabled CSIRO to collect X-ray data that normally required synchrotron sources
  • led a team that constructed the Caduceus and Democretos Beowulf clusters to simulate proteins at a high-level of theory, and carry out novel methods of in silico screening of molecules binding onto a protein surface for drug design.

In 2001, he returned to CSIRO (now the Division of Food and Nutritional Sciences) where he was engaged in the several structural biology programs. In the period 2001-09, he has:

  • assembled and led multidisciplinary teams of scientists in structural biology, virology, cell culture, mass-spectrometry, molecular biology and protein chemistry to pursue various projects in developing inhibitors of viral replication (ortho- and paramyxo viruses) and parasite infection
  • initiated a major program in neuro-degenerative diseases with CSIRO P-Health in collaboration with Professor Colin Masters of Neuroscience Australia. In this program cell based assays for inhibition of amylogenesis and oxidative damage were developed, along with X-ray Absorption Spectroscopy to study REDOX reaction of beta-amyloid and metals. By 2009, he was leading six projects in this area with the aim of developing intervention and diagnostic agents for preventing the onset of Alzheimer’s disease
  • initiated a program of structure determination of integral membrane proteins using novel surfactant technology and combining X-ray and electron diffraction methodologies. This project (on muscarinic receptors in schizophrenia) was in collaboration with Professor Dean of the Mental Health Research Institute.

Highlights

He was a Principal Investigator in a successful bid in the Australian Research Council’s Centre of Excellence in Coherent X-ray Science, which he is partnering with Steve Wilkins of CSIRO Material Science and Engineering. This work was initially within the CSIRO Emerging Science Area of Synchrotron Science to develop non-crystalline structure methods for imaging parasite infected cells and for the determination of membrane protein structures and other novel synchrotron derived methodologies.

He successfully obtained an NIH grant with Dr Jenny Breshkin for the study of drug resistance in influenza virus infections.

Since the late 1990s, Jose has lobbied both State and Federal Governments for funding of the Australian Synchrotron. He was a principal author in presenting the scientific and business case (from a biophysics perspective for the construction of an Australian Synchrotron) to the Victorian Government which resulted in the commitment of the Victorian Government to building the Synchrotron in Melbourne.

Following the successful funding for the storage ring, Varghese helped obtain funding for the beamlines from various other State Governments, CSIRO, other Research Alliances and the Federal Government. He was closely involved in the design of the proposed ring and led the design and construction of two MX beamlines. Both beamlines are close to meeting design specifications.

In addition, he was involved in developing the successful business case for the Victorian Large Scale Computing Initiative led by Melbourne University, and initiated one of the seed projects on the simulation of the REDOX chemistry of Amyloid beta in Alzheimer’s Disease.

Varghese is an named inventor on the following seven International patents covering: influenza virus neuraminidase inhibitors, nutritional enhancement through engineering plant storage proteins, plant genetic engineering for improved industrial performance, interleukin six receptor inhibitors for AIDS, and a novel class of binding proteins for diagnostic and therapeutic applications.

In addition, he has over 92 refereed scientific papers including four articles in Nature, three of which appeared in the front cover. His lifetime citations number up to February 2008 was over 4 600.

Selected invited plenary and public lectures

2008

Redox Chemistry of Amyloid-beta, EFMC International Symposium on Medicinal Chemistry, Vienna, Austria

2007

Analysis of metal ion toxicity in Alzheimer’s Disease by X-ray studies of Amyloid Beta and copper ion interactions, 6th AFMC International Medicinal Chemistry Symposium, Istanbul, Turkey

2006

Biology and Synchrotron Science, Australian Academy of Sciences – Reece Lecture, Clayton, Victoria

2006

Avian Influenza viruses and emerging pandemics, Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand

2004

Influenza virus pandemics, Sune Bergström Lecture, AstraZeneca Foundation, Bangalore, India

2003

The Development of anti-influenza drugs, 50th Anniversary of the Tokyo Medical and Dental University, Tokyo Japan

2003

Modulation of Interleukin-6 Signalling Using the Structure of the Extracellular Complex, AIMECS03, Kyoto, Japan

1999

Designing drugs for Influenza, The Biology of Drug Discovery, Whitehead Symposium XVII, Boston, USA

Professional appointments

2009 –

Project Stream Leader Alzheimer’s and Mental Disorders in P-Health

2008 – 09

Acting Theme Leader of P-Health Neurodegenerative Diseases

2005 – 07

Project leader Neurodegenerative Diseases in P-Health. Project leader in ESI-Synchrotron Science. Theme Leader of CSIRO MXDP Synchrotron Science

2001 – 05

Head, Structural Biology Program CSIRO Health Sciences and Nutrition initiated projects in inflammation and neurodegenerative diseases, cluster computing

1990 – 2000

Biomolecular Research Institute, Chief Research Scientist in Protein Structure Group on drug Resistance, Cytokines, Plant Glucanases, Protein Thermostability and design of X-ray optics

1984 – 90

Principal Research Scientist, CSIRO Biomolecular Engineering Development of Relenza®, structural studies of antibody-antigen complexes, plant storage proteins and plant viruses

1980 – 84

Post Doctoral Fellow, CSIRO Protein Chemistry. Structural Biology – Determined structure of Influenza Virus Neuraminidase

1978 – 80

Lecturer & SRC Fellow, School of Molecular Sciences, University of Sussex, UK. Polarized neutron scattering and spin transfer

1974 – 77

ARC Post Doctoral Fellow, Crystallography Centre, University of Western Australia. Charge distributions in transition metal complexes

Recent board and committee memberships

2010

Chair of the Local Organising Committee for the Biology and Synchrotron Research 2010 International Meeting, Melbourne

2009 –

President of the Society of Crystallographers in Australia and New Zealand

2007 – 09

Vice-President of the Society of Crystallographers in Australia and New Zealand

2006 – 09

CSIRO Coordinator of Synchrotron Science

2005 – 09

Australian Academy of Science Crystallography Council Member

2004 – 09

Member of the Executive of the ARC Centre of Excellence in Coherent X-ray Science

2003 – 09

Chair of the Australian Synchrotron PX Beamlines Advisory Panel

2003 – 08

Member of the National Synchrotron Scientific Advisory Committee (appointed by the Premier of Victoria)

1998 – 08

Member of the Policy and Review Board of the Australian Synchrotron Research Program

Source

  • Varghese JN, 2009, Personal communication.