Laboratory of Mammalian Molecular Embryology
Department of Biology and Biochemistry, University of Bath, England
[June 2023]
n June 27th, Tony addressed the European Society of Human Reproduction and Embryology (ESHRE) in Copenhagen. His talk covered some of our recent work on the initiation of transcription in mouse and human embryos. For more information, please contact Tony at <perry135@aol.com>.
[February 2023]
How and when embryonic gene activity begins following fertilization are unknown. In a paper just published in Cell Reports (https://doi.org/10.1016/j.celrep.2023.112023), we report a high-resolution time-course that reveals a transcription programme initiating within four hours of fertilization in mouse one-cell embryos. We refer to this programme as immediate embryonic genome activation, or iEGA. The iEGA programme predicts embryonic and cancer-associated pathway expression: regulators predicted by iEGA are also predicted by gene expression in human one-cell embryos, and inhibiting them in the mouse quickly blocks transcription and embryonic development. We hope that parallels between embryos and cancer could in the future be exploited to close gaps in our understanding of both.
[October 2022]
In an Opinion piece just published in Trends in Cell Biology 'The initiation of mammalian embryonic transcription: to begin at the beginning': https://doi.org/10.1016/j.tcb.2022.08.008), Tony describes a model to account for the onset of embryonic transcription based on the lab's work on human one-cell embryos. The initiation of gene activity in embryos has parallels to cancer, and the model proposes that the origin of many cancers is epigenetic and recapitulates the initiation of embryogenesis by fertilisation.
https://www.bath.ac.uk/announcements/do-human-embryos-and-cancer-share-the-same-starting-fuse/
https://www.eurekalert.org/news-releases/966658
[April 2022]
Tony has been appointed to the Scientific and Clinical Advances Advisory Committee, which considers advances in science and clinical practice relevant to the Human Fertilisation and Embryology Authority (HFEA). The position entails informing the HFEA to help it shape policy in rapidly advancing areas. This is a key period for considering the application to humans of emerging technologies including genome editing, the production of sperm and eggs in the lab, and the development of embryos in cell culture systems, and Tony feels it's an honour to be asked to contribute at this time. More information can be found at:
[December 21st, 2021]
Our latest work, published in Cell Stem Cell, reports that embryonic genome activation begins at the one-cell stage in human embryos.
This is days sooner than had been thought and means that transcription occurs soon after fertilisation. The finding, made with collaborators Giles Yeo and Brian Lam at Cambridge University, and Tex VerMilyea at Ovation Fertility in Texas, indicates that the genes are normally spliced and are expressed from canonical promotors. Many of the genes match processes known to occur in early embryos, but some are unknown and may reveal new pathways. Analysis of active promoters predicts that expression is by transcription factors that are often associated with cancer, providing an implicit link between carcinogenesis and embryogenesis that may open new avenues to disease prevention.
Asami, M., Lam, B., Ma, M.K., Rainbow, K., Braun, S., VerMilyea, M.D., Yeo, G.S.H. and Perry, A.C.F. (2021). Human embryonic genome activation initiates at the one-cell stage. Cell Stem Cell : https://authors.elsevier.com/sd/article/S1934-5909(21)00484-7
[June 21st , 2021]
'Discovery of new imprinted genes '
Experiments to develop nuclear transfer cloning in the Perry lab have lead to the identification of many new imprinted genes. Imprinted genes are switched on (expressed) in a programmed way mainly from one parental copy (allele) during development (and sometimes into adulthood). There are about 150 known imprinted genes in the mouse, and disrupting the delicate balance of imprinted gene expression can result in catastrophic developmental failure or disease. With colleagues in Vienna, the lab determined which genes exhibited parentally-biased expression in mouse embryos at the blastocyst stage, about four days after fertilisation. Some of these genes were linked to the classical epigenetic mark, DNA methylation, but most were associated with a particular type of histone methylation. As well as known imprinted genes, we identified 71 new stringently-attributed imprinted genes, called nBiX. We found that the imprinted status of nBiX genes was lost soon after embryo implantation into the uterus: at this time, both parental gene copies were expressed (or not expressed) equivalently. This greatly extends a catalogue of imprinted genes, and because many imprinted genes in the mouse are also imprinted in humans, it may help to diagnose, treat or prevent disease. It also opens new doors to understanding clinical Lamarckism: how disease traits acquired by parents (such as substantial weight gain) are passed to their offspring.
Santini et al., Nat.Commun. 2021 https://doi.org/10.1038/s41467-021-23510-4
[May 25th, 2020] 'Nanodevices show how cells change with time, by tracking from the inside'
BIOSENSORS
Detecting intracellular mechanics
In the 1966 sci-fi film, 'The Fantastic Voyage', a submarine and its are crew shrunk to microscopic size to journey through a body. Work published in Nature Materials, by Bath team lead by Professor Tony Perry with physicists lead by Prof. José Antonio Plaza in Barcelona, describes an 'Even More Fantastic Voyage'. The group made minute devices not only small enough to fit inside a body, but inside a single living mammalian cell. The group injected each device with a sperm into a mouse egg, so that a new embryo formed and development started with the device inside. They then filmed a day of the journey the devices took inside the embryo as it developed. Each journey told an amazing and unprecedented story, showing for the first time from within how physical forces and pressure of a cell change. Sometimes the devices were pitched and twisted by forces in the cell interior even greater than those inside muscle cells. At other times, the devices moved very little, showing that the embryo interior was calm. The changes occurred in the same order in each cell, as if it were made of smart matter whose properties changed as with each season of development. This work adds to an emerging picture of biology suggesting that material inside living cells is not the equivalent of the nuts and bolts that make a car, but transforms its properties in step with cell changes. These findings speak to how cells age and processes of aging and disease, and provide technological keys to unlocking other dynamic changes within cells.
Duch et al., Nat Mater. 2020
https://doi.org/10.1038/s41563-020-0685-9
[October 22nd, 2019] Visit to the university of Warwick. Tony proposed the motion (together with Prof. Christine Watson, Cambridge U.) that 'This House Supports the Creation of Genetically Modified Human Babies' at the Warwick University Debating Union. It was nice to meet the folks there who were excellent hosts during what was an interesting and enjoyable evening.
[August 21st, 2018] Tony was pleased to meet presenters for a BBC Radio 1 Stories, "DNA+: Beauty", BBC iPlayer programme, out on 21.08.18, although he was talking about preventing disease, not beauty:
https://www.bbc.co.uk/iplayer/episode/p06gx2kf/radio-1-stories-dna-beauty#
[19th Dec 2017] University nominated for animal research openness award
We contributed for the nomination to ‘Media Engagement’ award at the recent Understanding Animal Research (UAR) Openness Awards.
The annual awards recognise best practice in openness around animal research from signatories of the Concordat on Openness on Animal Research.
The University was nominated for its media work around a discovery by Dr Tony Perry and his team.
The story was the focus of major international media attention. Working with the University press office Dr Perry and colleagues held a press conference at the Science Media Centre in London, and then participated in numerous radio, TV and print media interviews over several days. TV cameras were also permitted into the University’s animal research facility and Dr Perry’s labs to film where and how the work took place. http://reut.rs/2kmIkly
Dr Perry said: “We wanted to communicate our ground-breaking research to the public and knew it was really important to be clear the research took place in mice. This not only gave people an accurate picture of the story, but let them know animal research was necessary for this type of science.
“It’s great to have been nominated for the award and see Bath demonstrating commitment to the Concordat on Openness on Animal Research.”
http://www.bath.ac.uk/news/2017/12/19/animal-openness-award/
[9th Nov 2017]
Humans 2.0: the lab contributes to a review on mitochondrial replacement therapy in November’s issue of Nature Biotechnology
https://www.nature.com/articles/nbt.3997
https://www.nature.com/articles/nbt.4019
[TEDx Talk]
Tony's talk can be seen bellow now!
https://www.youtube.com/watch?v=0HsFA5350Rw
[30th Sep 2016]
On Sept 30, the Nuffield Council on Bioethics Working Group on Genome Editing, of which Tony was a member, published its Platform Report, which can be found at
http://nuffieldbioethics.org/project/genome-editing/
[13th Sep 2016]
We have developed a method of injecting mouse parthenogenotes with sperm that allows them to become healthy offsprings with a success rate of up to 24 per cent of its control. This compares to a rate of zero per cent for parthenogenotes or about two per cent for nuclear transfer cloning.
Mice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes
Nat. Commun. 7:12676 doi:10.1038/ncomms12676
[21 June 2016]
Tony join the reconvened Human Fertilisation & Embryology Authority (HFEA) panel to consider the safety and efficacy of mitochondrial donation technique
[23rd May 2016]: Why? When? Who? Report of workshop on genome editing and public dialogue now published
(Nuffield Council on Bioethics) http://nuffieldbioethics.org/news/2016/why-when-who-
report-of-workshop-on-genome/
[18th Feb 2016]: Crazy for CRISPR: Tony talks to the Naked Scientist
www.thenakedscientists.com/HTML/podcasts/genetics/show/20160214/
[9 Dec 2015]
The 2015 anuual conference of the Progress Educational Trust (PET)
From Three-Person IVF to Genome Editing: The Science and Ethics of Engineering the Embryo
Tony contributes to the meeting as a speaker
"Festive Christmas Presents and Genomic CrispCas Presence: The Strategic Application of Scissors and Tape"
An account of the conference may be found bellow.
"www.progress.org.uk/conference2015"
[12 May 2015]
CRISPR germline engineering—the community speaks
Tony contributes to a potpourri of comments by the scientific community on germline engineering in May's Nature Biotechnology.
Nature Biotechnology 33, 478–486, (2015)
http://www.nature.com/nbt/journal/v33/n5/full/nbt.3227.html?WT.ec_id=NBT-201505
[10 May 2015]
Crispr: is it a good idea to ‘upgrade’ our DNA?
The lab's work on genome editing features prominently in a nice piece by Zoë Corbyn in the UK Observer.
[28 Apr 2015]
Council hosts scoping workshop on genome editing
On 22 April, Tony gave the lead-off presentation at the Nuffield Council on Bioethics workshop to identify the main issues raised by advances in genome editing. An account of the workshop may be found bellow.
"Nuffield Council on Bioethics"
http://nuffieldbioethics.org/news/2015/council-hosts-scoping-workshop-on-genome-editing/
[23 Dec 2014]
Asymmetric parental genome engineering by Cas9 during mouse meiotic exit
Mammalian genomes can be edited by injecting pronuclear embryos with Cas9 cRNA and guide RNA (gRNA) but it is unknown whether editing can also occur during the onset of embryonic development, prior to pronuclear embryogenesis. We here report Cas9-mediated editing during sperm-induced meiotic exit and the initiation of development. Injection of unfertilized, mouse metaphase II (mII) oocytes with Cas9 cRNA, gRNA and sperm enabled efficient editing of transgenic and native alleles. Pre-loading oocytes with Cas9 increased sensitivity to gRNA ~100-fold. Paternal allelic editing occurred as an early event: single embryo genome analysis revealed editing within 3 h of sperm injection, coinciding with sperm chromatin decondensation during the gamete-to-embryo transition but prior to pronucleus formation. Maternal alleles underwent editing after the first round of DNA replication, resulting in mosaicism. Asymmetric editing of maternal and paternal alleles suggests a novel strategy for discriminatory targeting of parental genomes.
[9 Aug 2013]
A caffeine fix for human nuclear transfer?
The August issue of Nature Biotechnology contains a News and Views commentary by Tony (1) on a recent report (2) of human cloning to generate nuclear transfer embryonic stem (ntES) cells. The long-anticipated success in human ntES cell generation rests on meiotic stabilization of occytes by caffeine prior to nuclear transfer, but the mechanisms remain arcane and the report really serves to highlight unknowns in the protocol. Tony's News and Views suggests what some of the unknowns might be and where there are addressable gaps relative to what is known about meiotic and epigenetic regulation in the embryos of model species such as the mouse. Although working with human oocytes and early embryos is fraught, it also presents a range of phenotypes not available to those working on animal models.
1.Perry, A.C.F. (2013). A caffeine fix for human nuclear transfer? Nature Biotechnol. 31, 717–719.
2.Tachibana, M. et al. (2013). Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 1228–1238.
[14 June 2012]
SCID pigs are here
The June 14, 2012 issue of Cell Stem Cell reports part of a long-standing collaboration between the laboratory of Dr Akira Onishi and the Perry lab (Suzuki et al., Cell Stem Cell 10, 753-758 [2012]). The paper reports the generation of severe combined immunodeficiency (SCID) pigs. SCID mice are well-established as models with which to analyse the behaviour of cancer and stem cells. Trouble is, some of the many biological differences between mice and humans are pretty much deal-breakers in the context of human pre-clinical comparisons; for instance, lab mice live for only two years, so they are of limited use for essential longer-term evaluation of stem cell transplantation therapies. By contrast, pigs are physiologically more akin to humans and live long enough (~10 years) to test better the efficacy of (for example) transplanted stem cells. The SCID pigs are the latest of several sophisticated approaches to genome manipulation Dr Onishi is taking to harness the biology of pigs in the development of human (and perhaps pig!) clinical strategies. In March, 2012, Tony became the first Westerner to visit the SCID pigs, in Tsukuba, Japan, when he took the picture shown of Dr Onishi.
[10 November 2011]
Yuami, England's first cloned mouse
The laboratory is pleased to announce the birth of England's first cloned mouse, Yuami (Japanese for 'taking a bath'). Yuami was one of two mice cloned by Dr Toru Suzuki from cumulus cell nuclei and was born on July 4th, 2011. Yuami was associated with placentomegally, which is characteristic of mouse clones, and is healthy and fertile. Yuami is believed to be the first adult cloned from an adult of any species in England.
PhICSI: injecting sperm into a one cell mouse embryo
Suzuki et al., Nat. Commun (2016)
PhICSI embryo
Founder (F0, left) and F1 offspring produced by Cas9-mediated mII editing of the Tyr locus. Editing to produce founders was performed in C57BL/6. Yellow arrow, mosaic; red arrows, apparently non-mosaic mutants. The F1 litter was produced by crossing a black coat-colour female founder with a CD1 male; the founder carried a germline Tyr mutation confirmed by sequencing, to produce white coat-colour pups (indicated with red arrows in F1, right).
Suzuki T, Asami M & Perry ACF. Scientific Reports (2014)