[ She determined the roles of several of the genes in HIV. These findings have been significant in studying and understanding different characteristics of HIV and Human T-lymphotropic virus (HTLV).]
At the NIH, Fisher developed approaches that allowed the successful introduction of exogenous DNA onto human blood cells. Two methods, protoplast fusion and electroporation, proved successful and allowed Fisher to test whether molecular clones isolated from HIV-infected cultures could generate infectious retrovirus upon transfection.
Fisher showed in 1985 that molecular clones of HIV, contained within approximately 18kb of contiguous proviral DNA, were biologically active and generated cytopathic virus when introduced into primary human T-cells. This established that products of the viral genome itself, rather than a cofactor or contaminant, were capable of killing human T cells and were therefore potentially capable of mediating the immunosuppressive effect of HIV. It provided the basis for dissecting the molecular function of each of the viral genes and for developing DNA-based diagnostic tests for HIV infection.
Over the following four years, Fisher showed that the transactivator gene ''tat'' was essential for virus replication, that truncation of the 3' open reading frame
In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
(ORF) disrupts virus cytopathogenicity, and that ''sor'' (now called ''vif)'' is required for efficient cell to cell transmission of HIV virus. With clinical collaboration from the Walter Reed National Military Medical Center
The Walter Reed National Military Medical Center (WRNMMC), formerly known as the National Naval Medical Center and colloquially referred to as the Bethesda Naval Hospital, Walter Reed, or Navy Med, is a United States' tri-service military medi ...
Fisher showed that patient antisera displayed type-specific neutralising properties and that multiple HIV isolates derived from a single patient were biologically diverse and contained replication-competent as well as replication-incompetent cytopathic variants.
Human T cell development
Fisher moved from the US to the UK in 1987 to study human T cell development. She established the first human thymus organ cultures in 1990, based on studies pioneered by Owen and Jenkinson in the mouse. This refinement allowed cell-fate to be mapped ''in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' and provided a system in which potential factors that shape the human T cell repertoire could be experimentally tested. She spent a further 3 years training in mouse genetics, transgenic and knockout technologies at the Institut de génétique et de biologie moléculaire et cellulaire (IGBMC) Strasbourg, before being invited by the Medical Research Council to establish a research team with her partner Matthias Merkenschlager at what was then the Clinical Sciences Centre (CSC). Fisher joined the CSC in 1993, and subsequently became its director in 2008. At the CSC her work has focused on understanding gene regulation during cell commitment. In January 2017, the CSC was renamed the MRC London Institute of Medical Sciences (MRC LMS).
Epigenetics and chromatin
In 1997, Fisher's group published an important paper[ on the DNA-binding factor Ikaros, that at the time was presumed to be a transcriptional activator. Fisher's group showed that Ikaros proteins unexpectedly localised to percentric heterochromatin in cycling lymphocytes in association with transcriptionally silent genes. This provided some of the first evidence that where a gene is located inside the nucleus may be relevant for its expression. The development of three dimensional (3D) immuno-FISH techniques by Fisher's team, in which the protein structure and the nuclear architecture of a sample remains preserved, was critical for revealing the spatial distribution of chromosomes and the genes within the nucleus. In the last 15 years, analogous approaches have been widely used to interrogate the relationship between gene function and nuclear organisation. For example, studies showed that Ikaros- target genes in T and B cells were recruited to pericentric heterochromatin domains only when gene silencing was inherited by daughter cells. This study, together with others, established that the nuclear location, physical compaction and local chromatin environment of many genes was important for maintaining heritable silencing. Subsequent studies to characterise the differences between transient and heritable/permanent silencing revealed that several silent genes that were assumed to replicate late during synthesis phase (S-phase) of the cell cycle (based on Fluorescence in situ hybridisation (FISH) detection of doublet signals), actually replicated much earlier (based on quantitative increases in DNA content). This discovery in 2003, led Fisher and Merkenschlager to hypothesis that – rather than altering the time of DNA replication – heritable gene silencing could retard chromatid separation and resolution. From this viewpoint they began a series of studies that have subsequently shown the involvement of cohesin complexes in gene regulation and in 2002, Fisher was awarded the ]EMBO Gold Medal
The EMBO Gold Medal is an annual award of the European Molecular Biology Organization (EMBO) given to young scientists for outstanding contributions to the life sciences in Europe. Laureates receive a medal and €10,000 and are invited to rec ...
in recognition of her early work on HIV, and the role of nuclear organisation in gene regulation.
Since 2003, Fisher has been studying gene regulation in embryonic stem cell
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...
s (ES), as a model for understanding pluripotency, lineage commitment and lineage restriction. In 2006, she showed that the promoters of many lineage-specifying genes in ES cells were simultaneously enriched for modified histones thought to mark either active genes (such as acetylation of H3K9, di- and tri-methylation of H3K4), or repressed domains ( such as tri-methylation of H3K27). This discovery ran contrary to the prevailing dogma of the time: that chromatin markers of actively transcribed and inactive domains were mutually exclusive. The study was published in 2006, contemporaneously with similar reports from several US-based groups. suggesting that important developmental regulator genes might be poised for transcription in ES cells, yet repressed by the activity of Polycomb Repressor Complexes (PRCs).
Awards and honours
Fisher was elected a member of the European Molecular Biology Organization
The European Molecular Biology Organization (EMBO) is a professional, non-profit organization of more than 1,800 life scientists. Its goal is to promote research in life science and enable international exchange between scientists. It co-funds cour ...
(EMBO) in 2001 and awarded the EMBO Gold Medal
The EMBO Gold Medal is an annual award of the European Molecular Biology Organization (EMBO) given to young scientists for outstanding contributions to the life sciences in Europe. Laureates receive a medal and €10,000 and are invited to rec ...
in 2002 in recognition of her work on nuclear organisation and gene expression, as well as for her research on the molecular characterisation of the HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
.
In 2014, she was elected a Fellow
A fellow is a concept whose exact meaning depends on context.
In learned or professional societies, it refers to a privileged member who is specially elected in recognition of their work and achievements.
Within the context of higher education ...
of the Royal Society
The Royal Society, formally The Royal Society of London for Improving Natural Knowledge, is a learned society and the United Kingdom's national academy of sciences. The society fulfils a number of roles: promoting science and its benefits, re ...
. Her nomination reads:
In 2003 she was elected a Fellow of the Academy of Medical Sciences
Fellowship of the Academy of Medical Sciences (FMedSci) is an award for medical scientists who are judged by the UK Academy of Medical Sciences for the "excellence of their science, their contribution to medicine and society and the range of th ...
(FMedSci) for excellence in her contributions to medicine and society.[ Fisher organises and participates in a range of public engagement projects and events, and in recognition of this work she received an 'Outstanding Women in Science Award for communication in Science, Engineering Technology (SET) award in March 2010. Fisher was awarded the ]Helmholtz Association of German Research Centres
The Helmholtz Association of German Research Centres (german: Helmholtz-Gemeinschaft Deutscher Forschungszentren) is the largest scientific organisation in Germany. It is a union of 18 scientific-technical and biological-medical research centers. ...
International Fellow award in 2015.[
Fisher was appointed ]Dame Commander of the Order of the British Empire
The Most Excellent Order of the British Empire is a British order of chivalry, rewarding contributions to the arts and sciences, work with charitable and welfare organisations,
and public service outside the civil service. It was established o ...
(DBE) in the 2017 New Year Honours
The 2017 New Year Honours are appointments by some of the 16 Commonwealth realms to various orders and honours to recognise and reward good works by citizens of those countries. The New Year Honours were awarded as part of the New Year celebrati ...
for services to medical research and the public understanding of science.
In January 2023, Fisher was elected as the Whitley Chair and Fellow in Biochemistry at Trinity College, Oxford
(That which you wish to be secret, tell to nobody)
, named_for = The Holy Trinity
, established =
, sister_college = Churchill College, Cambridge
, president = Dame Hilary Boulding
, location = Broad Street, Oxford OX1 3BH
, coordinates ...
.
References
{{DEFAULTSORT:Fisher, Amanda
20th-century British biologists
21st-century British biologists
Alumni of the University of Birmingham
British women biologists
Dames Commander of the Order of the British Empire
Fellows of the Academy of Medical Sciences (United Kingdom)
Fellows of the Royal Society
Female Fellows of the Royal Society
Living people
Members of the European Molecular Biology Organization
Place of birth missing (living people)
Year of birth missing (living people)
British expatriate academics in the United States