Professor Philip Lawley
Distinguished ICR scientist Professor Philip Lawley died recently at the age of 84. His former ICR colleague Dr Stan Venitt, Emeritus Reader in Cancer Studies, reflects on an accomplished and dedicated man who gave the world the first convincing evidence that DNA damage was the basic cause of cancer.
In the 1960s, Professor Philip Lawley and his colleague Professor Peter Brookes were the first to show that DNA was the target for chemicals that cause cancer.
This was a major advance when proteins were thought to be the prime site of attack by carcinogens, and provided a secure foundation for the now universally accepted idea that cancer is a genetic disease.
Philip Lawley joined the Chester Beatty Research Institute (CBRI) - now The Institute of Cancer Research (ICR) - in Chelsea in 1953 (the year when Watson and Crick revealed the double-helical structure of DNA) to work on the chemistry of carcinogenic and mutagenic alkylating anti-tumour drugs such as nitrogen mustard.
Lawley’s findings challenge conventional wisdom
In 1957, using physicochemical methods, he showed that positively charged atoms in alkylating agents could react with negatively charged atoms in DNA bases (the ‘letters’ that spell out the genetic code) to form chemically stable entities known as DNA adducts. DNA adducts cause mispairing during DNA replication which leads to mutation. At the time, scientists believed carcinogens reacted weakly and reversibly with DNA.
Plan for radioactive mustard gas experiments in central London provoke alarm
By the late 1950s Lawley had joined forces with another chemist, Peter Brookes. They realized that a more sensitive method was needed to detect DNA adducts at the levels expected in living organisms. At this time the state-owned Radiochemical Centre in Amersham was producing radiolabelled mustard gas. This mutagenic and carcinogenic difunctional alkylating agent was used as a chemical weapon in the 1914-18 war, and is the archetype of anti-tumour drugs such as chlorambucil and melphalan which were developed in the CBRI. The idea of handling even small amounts of radiolabelled mustard gas in Chelsea provoked alarm and so Lawley and Brookes moved from the Chelsea laboratories to the CBRI’s Pollards Wood Research Station in Buckinghamshire to further their studies.
Brookes and Lawley’s first seminal paper describes DNA binding with carcinogens in vitro and in vivo
The Pollards Wood laboratories were set in 60 acres of woodland near Little Chalfont, Buckinghamshire, close to the Radiochemical Centre. It was in these leafy and peaceful surroundings that Lawley and Brookes produced their seminal work on the binding of mutagens and carcinogens to DNA. In 1960, they reported, in the Biochemical Journal, that mustard gas formed an adduct with guanine in DNA, in viruses, bacteria, cultured mouse cancer cells and cancers in mice. They showed that it cross-linked the complementary strands of the DNA helix and blocked DNA replication and cell division, explaining the extraordinary cytotoxicity of mustard gas. They demonstrated that bacteria resistant to mustard gas enzymatically removed the crosslinked DNA adducts, but sensitive bacteria did not. This was the first convincing evidence for the repair of DNA adducts in a living organism. It is now clear, 50 years on, that many of the genes mutated in human cancer are involved in DNA repair.
Second classic paper shows amount of DNA binding is proportional to carcinogenicity
In a second landmark paper 1964 Lawley and Brookes reported in Nature a quantitative relationship between carcinogenicity and DNA binding, using polycyclic aromatic hydrocarbons (PAHs). These ubiquitous products of incomplete combustion (found, for example, in tobacco smoke) are chemically inert, but many are potent carcinogens following their metabolic activation. Brookes and Lawley, using a series of radiolabelled PAHs, observed that the carcinogenic potency of the PAHs in mouse skin was positively correlated with the degree of DNA binding, but not with binding to protein or RNA. This seminal discovery overturned the prevailing view that proteins were the critical cellular targets for carcinogens and changed the course of cancer research.
Lawley made further advances in unravelling the fine detail of how carcinogens react with DNA. He showed how potent alkylating mutagens induced point mutations by reacting with those atoms in DNA that determine base-pairing during DNA replication. Point mutations are now known to occur frequently in a variety of human cancer genes. He discovered the O6-methylguanine-DNA methyltransferase repair system that selectively removes such modified DNA bases.
Outwardly shy, Lawley was a man of piercing intellect and wry wit
Philip Lawley was born in July 1927 in Abbots Bromley in Staffordshire to parents who were teachers. His father had suffered mustard gas attack in the First World War. Lawley obtained a degree in Chemistry in 1949 at University College, Oxford and a PhD at Nottingham University in 1953.
Beneath his rather shy exterior Philip Lawley was a kind man of piercing intellect, deep scholarship, prodigious memory, wry wit, liberal views and iron-clad integrity. He did not follow scientific fashion and was happiest working at the bench, usually with one or two colleagues. He wrote concisely and elegantly, in long-hand, standing at tables piled with papers, moving from table to table until his manuscript was completed. He took great pleasure in conversation and often engaged in protracted and sometimes heated debate with whoever happened to be around – usually with a scientific colleague, but occasionally with an innocent bystander - sometimes losing track of time. His conversations were enriched by his interests in jazz, painting, reading, dogs, and old trams.
ICR laboratory named in Brookes and Lawley’s honour
He was awarded a DSc in 1975 and became Professor of Chemical Carcinogenesis in the University of London in 1983. He received the European Environmental Mutagen Society Award in 1987 and was made a Fellow of the United Kingdom Environmental Mutagen Society in 1990 and an Associate Member of the ICR in 2002. In January 2003 the ICR honoured the achievements of Brookes and Lawley by naming a £21 million laboratory after them. This is located at the ICR’s Sutton site.
Philip Lawley officially retired in 1992, but continued to work in the laboratories at Sutton, at the bench, for many more years, enriching the lives of those who worked with him and alongside him, with his knowledge, congenial company and wit.
He was a devoted family man, and is survived by Pauline, his wife, his daughter Fiona, his sons Guy and Hugh, and grandchildren Beatrix, Baxter, Xabier and Valentin.
Professor Phillip D. Lawley, scientist, born 4th July, 1927; died 18th December 2011