Professor Beverly Griffin

Born 23rd January, 1930 (Delhi, Louisiana) - Died 13th June, 2016

Griffin earned two doctorates in chemistry in an era when it was rare for women to pursue a scientific career. She is best known for her pioneering work on the molecular biology of two viruses that cause cancer - the polyomavirus and Epstein Barr Virus (EBV). From the 1980s she was devoted to understanding how in one setting EBV could cause glandular fever, a largely harmless disease, and yet in another Burkitt's Lymphoma, a major killer of children in Central Africa. She also spearheaded efforts to improve the diagnosis and treatment of the cancer and was a tireless campaigner for raising awareness of the plight of children with the disease in Africa.

Beverly Griffin (Photo credit: Richard Adeney)

Family

Beverly (Smith) Griffin was the oldest of three children. Her father, Solon Edgar Smith, was a self-employed businessman and ran a food shop. A highly respected and helpful citizen, Griffin’s father built the family’s large beautiful house. Her mother, Nina Lee Gilliland, was a full-time mother and housewife. Griffin grew up in Delhi, a small town in the heart of the American southern state of Louisiana. The town became the centre of a large natural gas boom during Griffin’s childhood. Griffin never lost her gentle Southern accent despite moving to England when she was 25 years old.

Griffin married three times. She first married when she was very young, but the marriage did not last long. Her second husband was Ross Dougall, a doctor who practised as a General Practitioner in London, with whom she remained good friends after their separation. Griffin met her third husband, Tomas Lindahl, a Swedish born biochemist, in 1979. They first met at a scientific meeting in Colorado during which they found they had common research interests around DNA and the Epstein Barr Virus (EBV).

Lindahl had two children by a previous marriage and had only just taken up a position in Gothenburg when they met. By 1981, however, it was clear they wanted to spend the rest of their lives with each other so Lindahl joined Griffin in London. The two of them shared a laboratory for a short time at the Imperial Cancer Research Fund (ICRF) before Lindahl became director of the ICRF’s Clare Hall Laboratories.

In addition to their overlapping scientific interests, Griffin and Lindahl shared a passion for music and art. Sadly, Griffin was too ill to celebrate with Lindahl when, in 2015, he went to Stockholm to receive his Nobel Prize for his breakthrough research on DNA repair.

Click here for more pictures from the life of Beverly Griffin

Education

Griffin attended her local school in Louisiana and then in 1947 won a scholarship to attend Baylor University. This was a remarkable achievement for a girl in these years and was highly unusual for her school. By 1951 she had completed a science degree with ‘magna cum laude’. She then did a master’s degree and a doctorate at the University of Virginia under the supervision of Alfred Burger. Her thesis, submitted in 1955, focused on medicinal chemistry and antispasmodics.

Following her doctorate, Griffin secured a Marshall Scholarship from the British Government to study in England. Coming from a small town in Louisiana this was a major step for Griffin, but her father encouraged her to pursue the exciting opportunity. She landed up in the laboratory of Alexander (later Lord) Todd, a chemist at Cambridge University. Two years after Griffin’s arrival, in 1957, Todd gained the Nobel Prize for his research on the structure and synthesis of nucleotides, the building blocks of DNA and RNA, and nucleotide coenzymes. Griffin completed a second doctorate under Todd in 1958, during which she conducted research on nucleic acid chemistry and worked in close collaboration with Colin Reese and Dan Brown, two outstanding members of Todd’s laboratory.

Career

After Cambridge, Griffin returned to the US where she spent three years as an assistant professor at Mount Holyoke College in Massachusetts. She then went back to Cambridge in 1962, where she became a fellow of Girton College and a senior research associate in the Department of Chemistry. In 1968 she moved down the road to the Laboratory of Molecular Biology in Cambridge. There she worked as a postgraduate researcher with Fred Sanger. He had won the Nobel Prize ten years before for working out the full sequence of amino acids in insulin. Griffin enthusiastically joined in Sanger’s efforts for four years to help him develop a method to sequence nucleic acids.

In 1972 Griffin was appointed the head of nucleic acids research at the Imperial Cancer Research Fund (ICRF) Laboratories in London, where she remained for 16 years. She then became the professor of virology at the Royal Postgraduate Medical School (RPMS) at Hammersmith Hospital. This was a major achievement as she was the first woman to be appointed professor at the Hospital, which became part of Imperial College of Medicine in 1997. Griffin spearheaded the establishment of a strong molecularly based virological unit within the RPMS. While Griffin retired in 1995, she continued to play an active role in research at Imperial College until she was incapacitated by poor health in the aftermath of a series of stroke in the last years of her life. After her retirement, her department was headed up by Profesor Martin Allday, one of her colleagues, who continued the EBV programme of research set up by Griffin until his death from cancer in 2017.

Achievements

Griffin first made her mark by determining the complete DNA sequence of the polyoma virus, a virus that causes cancer in animals. It was one of two small DNA viruses, the other one being SV40, then being intensively studied at the ICRF and elsewhere for determining how DNA can be expressed. Until then most of the knowledge about this process was from simple bacterial systems. By studying DNA tumour viruses, like the polyoma virus, Griffin and her colleagues hoped to see if gene expression was similar in the eukaryote, an organism with a complex cell or cells in which the genetic material is organised into a membrane-bound nucleus. Small DNA tumour viruses have the advantage that they have small circular genomes with only a very limited number of genes so are easy to isolate from the large mammalian chromosomes in which they hide and replicate.

Using the early painstaking and time-consuming DNA sequencing technique she learned from Sanger, Griffin managed to sequence the polyoma virus with her team at the ICRF. It was one of the longest tracts of eukaryotic DNA ever sequenced - 5,293 base pairs, and the second complete DNA virus structure to be worked out up to that time. Work on the virus had begun in the early 1970s and the final sequence was published in 1979. Griffin and her team not only managed to complete the sequence of the virus, they also worked out the structures of its transcripts and the proteins it encoded. In addition, they demonstrated for the first time that the same piece of DNA could make two or more different messenger RNAs and proteins.(Soeda et al, 1979; London Research Institute, 2014) Griffin subsequently helped show that the polyoma virus could be adopted as a tool for delivering gene therapy.(Krauzewicz, et al)

Alongside working on the polyoma virus, Griffin began hunting for a way to sequence the large DNA of the Epstein-Barr virus (EBV). It was the first virus shown to cause human cancer. The virus was first connected with Burkitt’s lymphoma (BL) in the 1960s. This is a highly aggressive form of B-cell non-Hodgkin’s lymphoma. BL is the fastest-growing of all human cancers and has three different subtypes: endemic, sporadic and immunodeficiency related. Endemic BL is most prevalent in regions where malaria is widespread, including equatorial Africa, Brazil and Papua New Guinea. In these places BL targets otherwise healthy children aged between 2-14 years old. It accounts for 30-50% of all childhood cancers per 100,000 children per year. Sporadic BL is mostly seen in the US and Europe. Its incidence in adults and children in the US is 3 cases in a million and in Europe 2.2 cases in a million. The immuno-deficient variant of BL is primarily found in patients with HIV and other immunodeficiency disorders.(Magrath)

Relatively little was known about the EBV when Griffin first began working on it. In part this reflected the fact that scientists could access only minute quantities of its DNA. Armed with a new technique for genetic engineering, developed in the early 1970s, Griffin poured her energies into cloning the DNA of the virtus. This she did with Lindahl and others. By 1979 they were able to announce to a meeting at Cold Spring Harbor that they had managed to clone several large fragments derived from an EBV stain known as B95-8. Two years later they had produced a complete library of overlapping genomic clones from the strain.(Arrand, Rymo, Griffin) This was a major breakthrough. Importantly it opened up the path for sequencing the genome of the EBV, a task completed by a team in Sanger's department in Cambridge in 1984. Click here for more about Sanger’s sequencing of the EBV.

Thereafter, Griffin devoted her life to EBV – looking at why in one setting (as in Britain) it can cause glandular fever, which is largely harmless, while in another (Central Africa) it leads to the deadly scourge of BL. She suspected a number of factors could play a role, including malaria, diet, socio-economic conditions suppressing the immune system and genetics. To investigate these issues she launched a major collaboration with the Ministry of Health in Malawi and Elizabeth Molyneux from Alder Hey Children’s Hospital in Liverpool. By 1987 Griffin and her collaborators had secured three years worth of funding from the ICRF to investigate the immunology of BL and drug treatment in BL patients referred to Kamazu Central Hospital for the Northern and Central region of the country.

Undertaking such a venture was highly ambitious in a country with poor communication and transport networks. The operation involved completing questionnaires about the nutrition, medical, obstetric and social history of each patient and identifying any plants that they might have been exposed to which might have promoted EBV growth. It also involved taking blood samples and tumour biopsies from patients in hospital, who were then followed-up in their homes. This was not easy because the patients usually lived far away and could not be contacted by telephone. Everything collected had to be transported to London for analysis.

In addition to the difficulties in Malawi, Griffin struggled to get funding to continue the project. A letter between Griffin and a colleague in 1993 commented ‘We are coming to the point where we shall have to abandon BL soon, however, if we don’t find external funding, and after many efforts I despair of the UK!’ She came to the conclusion it might only be possible to proceed by asking for money from private sources. (Unpublished letter from Griffin to Magrath)

Griffin’s efforts in the area were not purely academic. She worked tirelessly to raise funds for setting up treatment centres in Malawi. This was an uphill struggle in a country severely strapped for resources. Most BL tumours respond well to two or three courses of standard cheap anti-cancer drugs. Such treatment, however, has to be given by drip in a hospital for prolonged periods necessitating frequent admissions. This poses significant problems in Malawi which has very few hospitals. Patients therefore have to travel very long distances. Not surprisingly many patients could not make the journey or follow-up visits. Those who fail to complete their course of treatment run the risk developing drug resistance. Frustrated by the fact few people, including doctors, grasped these problems Griffin campaigned widely to raise greater awareness about BL. To this end she sponsored and helped write the script for the documentary ‘Surviving Burkitt's Lymphoma’, a highly moving film that follows the footsteps of a British mother’s journey to Malawi to understand the disease that took her own son’s life. The film can be viewed here.

This profile was written by Lara Marks in May 2018 with generous input from Tomas Lindahl. Photo credit: Richard Adeney.

References

J R Arrand, L. Rymo, J E Walsh, E Bjorck, T Lindahl and B E Griffin, ‘Molecular cloning of the complete Epstein-Barr virus genome as a set of overlapping restriction endonuclease fragments’, Nucleic Acids Research, 9/13 (1981), 2999-2014.

Beverly Griffin unpublished letter to Ian Magrath, 6 Aug 1993, Griffin’s papers, Imperial College.

London Research Institute, Scientific Report, 2014.

N Krauzewicz, K Stokrova, C Jenkins, M Elliott, CF Higgns, BE Griffin, ‘Virus-like gene transfer to cell nuclei mediated by polyoma virus pseudocapsids’, Gene Therapy, 7 (2000), 2122-31.

I Magrath, ‘Epidemiology: Clues to the pathogenesis of Burkitt lymphoma’, British Journal Haematology, 156/6 (2010),744-56.

E Soeda, JR Arrand, N Smolar, JE Walsh, BE Griffin, ‘Coding potential and regulatory signals of the polyoma virus genome’, Nature, 283 (1980) 445-53.

Beverly Griffin: timeline of key events