Sir Adrian Bird | |
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Born | Adrian Peter Bird 3 July 1947 [1] Rowley Regis, Staffordshire, England [2] |
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Spouse | [1] |
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Scientific career | |
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Thesis | The cytology and biochemistry of DNA amplification in the ovary of Xenopus laevis (1972) |
Doctoral advisor | Max Birnstiel [13] [14] [15] |
Doctoral students | Rob Klose [16] |
Website | birdlab |
Sir Adrian Peter Bird, CBE , FRS , FRSE , FMedSci (born 3 July 1947) is a British geneticist and Buchanan Professor of Genetics at the University of Edinburgh. Bird has spent much of his academic career in Edinburgh, from receiving his PhD in 1970 to working at the MRC Mammalian Genome Unit and later serving as director of the Wellcome Trust Centre for Cell Biology. His research focuses on understanding DNA methylation and CpG islands, and their role in diseases such as Rett syndrome. [17]
Bird was born in Rowley Regis near Wolverhampton, England, but from age 4 lived in the town of Kidderminster, near Birmingham. [18] He attended a grammar school in Hartlebury, achieving grades CCD for his A-level results. Whilst at school, Bird played cricket and hockey for a local team. [18] Bird received his PhD [13] from the University of Edinburgh in 1970 for research supervised by Max Birnstiel, [13] following undergraduate study of Biochemistry at the University of Sussex. [12]
Following his PhD, Bird went on to postdoctoral research positions, first at Yale University with Joseph G. Gall, and then at the University of Zurich before returning to Edinburgh in 1975 to work at the MRC Mammalian Genome Unit, where he would stay for 11 years. [19] [20] It was here that Bird, along with Edwin Southern, mapped the methylation status of CpG dinucleotides along ribosomal RNA in the African clawed frog. [19] [21] From 1987 to 1990 Bird continued his research at the Research Institute of Molecular Pathology in Vienna.
In 1990, Adrian Bird became Buchanan Professor of Genetics at the University of Edinburgh. He helped create the Wellcome Trust Centre for Cell Biology, also in Edinburgh, and served as its director from 1999 until 2011, when he was succeeded by David Tollervey. [22] From 2000 to 2010, he was also a governor of the Wellcome Trust, serving as deputy chairman during the latter three years. [22] [23]
Bird is a trustee of the charitable organisation Cancer Research UK and of the Rett Syndrome Research Trust. [22] [24] He also serves as a Governance Board Member of the Edinburgh Cancer Research Centre. [25]
Bird's research has focused on CpG islands and their associated binding-factor MeCP2. [26] He led the team which first identified CpG islands—originally named "HpaII tiny fragments" [19] —in vertebrate genomes. These are short genomic regions with a high density of CpG dinucleotides, and are commonly found in an unmethylated state within or nearby to an active gene's promoter.
Bird's group discovered that the MeCP2 protein binds specifically to methylated CpG sites, and further that disruption of this interaction causes the autism spectrum disorder Rett syndrome. The Bird lab also implicated nuclear receptor co-repressor 1 as an important binding partner in the MeCP2/methyl-CpG interaction. [26]
In 2007, the Bird laboratory published a paper in the journal Science [27] describing a proof-of-principle that the murine equivalent of Rett syndrome could be successfully reversed in laboratory mice. [28] This was accomplished by reintroducing a functional MeCP2 gene and proved successful even when the condition was at an advanced stage, hinting at the possibility of a gene therapy approach to curing the human disease in the future. [28] [29]
Bird was elected a Fellow of the Royal Society (FRS) in 1989, his nomination read:
Adrian Bird is the leading authority on DNA methylation in animal cells. He demonstrated a rolling circle mechanism for ribosomal gene amplification. He showed that DNA methylation sites can be mapped using restriction enzymes and thus showed semi-conservative copying of methylation patterns. He showed convincingly that the doublet CpG is a source of mutation in vertebrates which led to the use of 'GpG' restriction enzymes to detect polymorphisms linked to genetic diseases. He discovered unmethylated 'HTF' islands at the 5i ends of housekeeping genes. This discovery has allowed new strategies for mapping and identifying genes and it has allowed Bird to propose that the unmethylated HTF islands identify DNA sequences to be kept constantly available within the nucleus. [30]
Bird was awarded the Gabor Medal in 1999 "in recognition of his pioneering work in the study of global mechanisms by which transcription of the mammalian genome is regulated and for his exploration into the molecular basis of fundamental biological mechanisms, particularly his development of ways of analysing methylation patterns of eukaryotic DNA using endonucleases and the discovery of and continued research into a new class of DNA sequences found in all vertebrates". [31] He received the Louis-Jeantet Prize for Medicine in the same year, [23] and was made a Commander of the Order of the British Empire in the Queen's Birthday Honours in 2005.
In 2011, he was a recipient of the Gairdner Foundation International Award, "for his pioneering discoveries on DNA methylation and its role in gene expression." [32] The following year Bird won the 2012 GlaxoSmithKline Prize. [22] In 2013, he was named a Thomson Reuters Citation Laureate and received the 2013 BBVA Foundation Frontiers of Knowledge Award in Biomedicine "for his discoveries in the field of epigenetics". [20] [33]
In 2013, Bird was tipped as a potential winner of the Nobel Prize in Physiology or Medicine for "fundamental discoveries concerning DNA methylation and gene expression" [34] though the prize later went to James Rothman, Randy Schekman and Thomas C. Südhof.
He was knighted in the 2014 New Year Honours for services to science. [35] [36] [37]
In 2016, he was elected as a foreign associate of the National Academy of Sciences [38] and received the Shaw Prize together with Huda Y. Zoghbi. [39] In 2017 he received the Charles Rudolphe Brupbacher Prize. [40]
He was awarded the Buchanan Medal of the Royal Society in 2018 for his medical discoveries, [41] and elected a Fellow of the Academy of Medical Sciences (FMedSci) in 2001. [42] In 2020 he was awarded the Brain Prize. [43]
Adrian Bird is married to fellow geneticist Cathy Abbott and has four children. [18] [19] At age 66, Bird was quoted as having no plans to retire, saying "we [the research group] are still funded well and our work is still published in journals and as long as that continues, so will I." [18]
In biology, epigenetics are stable heritable traits that cannot be explained by changes in DNA sequence, and the study of a type of stable change in cell function that does not involve a change to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance.. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.
Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often have slower growth, difficulty walking, and a smaller head size. Complications of Rett syndrome can include seizures, scoliosis, and sleeping problems. The severity of the condition is variable.
5-Methylcytosine is a methylated form of the DNA base cytosine (C) that regulates gene transcription and takes several other biological roles. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered. 5-Methylcytosine is incorporated in the nucleoside 5-methylcytidine.
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.
MECP2 is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MECP2 protein is likely to be involved in turning off several other genes. This prevents the genes from making proteins when they are not needed. Recent work has shown that MECP2 can also activate other genes. The MECP2 gene is located on the long (q) arm of the X chromosome in band 28 ("Xq28"), from base pair 152,808,110 to base pair 152,878,611.
Methylation specific oligonucleotide microarray, also known as MSO microarray, was developed as a technique to map epigenetic methylation changes in DNA of cancer cells.
Methyl-CpG-binding domain protein 1 is a protein that in humans is encoded by the MBD1 gene. The protein encoded by MBD1 binds to methylated sequences in DNA, and thereby influences transcription. It binds to a variety of methylated sequences, and appears to mediate repression of gene expression. It has been shown to play a role in chromatin modification through interaction with the histone H3K9 methyltransferase SETDB1. H3K9me3 is a repressive modification.
DNA (cytosine-5)-methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.
Methylated DNA immunoprecipitation is a large-scale purification technique in molecular biology that is used to enrich for methylated DNA sequences. It consists of isolating methylated DNA fragments via an antibody raised against 5-methylcytosine (5mC). This technique was first described by Weber M. et al. in 2005 and has helped pave the way for viable methylome-level assessment efforts, as the purified fraction of methylated DNA can be input to high-throughput DNA detection methods such as high-resolution DNA microarrays (MeDIP-chip) or next-generation sequencing (MeDIP-seq). Nonetheless, understanding of the methylome remains rudimentary; its study is complicated by the fact that, like other epigenetic properties, patterns vary from cell-type to cell-type.
Combined Bisulfite Restriction Analysis is a molecular biology technique that allows for the sensitive quantification of DNA methylation levels at a specific genomic locus on a DNA sequence in a small sample of genomic DNA. The technique is a variation of bisulfite sequencing, and combines bisulfite conversion based polymerase chain reaction with restriction digestion. Originally developed to reliably handle minute amounts of genomic DNA from microdissected paraffin-embedded tissue samples, the technique has since seen widespread usage in cancer research and epigenetics studies.
Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.
Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation. Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation in how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression. Mechanisms such as cytosine regulation and post-translational modifications of histones. Of the 215 genes contributing, to some extent in ASD, 42 have been found to be involved in epigenetic modification of gene expression. Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye contact and limitations in social situations, as well as verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions. Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities, initiating and sustaining relationships, and maintaining jobs.
Differentially methylated regions (DMRs) are genomic regions with different DNA methylation status across different biological samples and regarded as possible functional regions involved in gene transcriptional regulation. The biological samples can be different cells/tissues within the same individual, the same cell/tissue at different times, cells/tissues from different individuals, even different alleles in the same cell.
Epigenetics of depression is the study of how epigenetics contribute to depression.
Robin Campbell Allshire is Professor of Chromosome Biology at University of Edinburgh and a Wellcome Trust Principal Research Fellow. His research group at the Wellcome Trust Centre for Cell Biology focuses on the epigenetic mechanisms governing the assembly of specialised domains of chromatin and their transmission through cell division.
CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.
Rob Klose is a Canadian researcher and Professor of Genetics at the Department of Biochemistry, University of Oxford. His research investigates how chromatin-based and epigenetic mechanisms contribute to the ways in which gene expression is regulated.
Professor Susan J. Clark is an Australian biomedical researcher in epigenetics of development and cancer. She was elected a Fellow of the Australian Academy of Science in 2015, and is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and Research Director and Head of Genomics and Epigenetics Division at the Garvan Institute of Medical Research. Clark developed the first method for bisulphite sequencing for DNA methylation analysis and used it to establish that the methylation machinery of mammalian cells is capable of both maintenance and de novo methylation at CpNpG sites and showed is inheritable. Clark's research has advanced understanding of the role of DNA methylation, non-coding RNA and microRNA in embryogenesis, reprogramming, stem cell development and cancer and has led to the identification of epigenomic biomarkers in cancer. Clark is a founding member of the International Human Epigenome Consortium (IHEC) and President of the Australian Epigenetics Alliance (AEpiA).