Staff Profile

Personal Biography

Research Biography

1. improving the treatment and understanding of infertility
2. extending the scope of reproductive technologies to prevent transmission of disease. 

Research Areas

Regulation of chromosome segregation during mammalian oogenesis

Meiosis generates haploid gametes from diploid germ cells and is essential for sexual reproduction.  It involves two rounds of chromosome segregation without an intervening round of DNA replication. The first meiotic division (meiosis I) involves segregation of recombined homologous chromosomes, which have previously established physical linkages (chiasmata) during meiotic recombination to form bivalent chromosomes.  Dissolution of cohesion between chromosome arms during anaphase of meiosis I converts bivalents to dyad chromosomes. Dyads consist of two chromatids (at least one recombinant) linked together by cohesion at the centromeres (see Box).  Dissolution of centromeric cohesion during anaphase of meiosis II results in segregation of chromatids enabling one copy of each to be inherited by the gamete. 

Female meiosis is co-ordinated with the protracted process of oogenesis. Homologous chromosomes recombine in utero but are not resolved until just before ovulation, and meiosis is not finally completed until after fertilisation. The female meiotic divisions are highly asymmetric resulting in the formation of a large oocyte and two tiny, inviable polar bodies.  This is a notoriously error-prone process, frequently resulting in too few or too many chromosomes being retained in the oocyte.   For reasons that have remained unclear, the risk of error increases greatly as women get older.  This results in a dramatic decline in fertility and an increased risk of miscarriage and birth defects from the around the age of 35 years.   

We are interested in understanding the molecular links between female ageing and the fidelity of chromosome segregation during the meiotic divisions.  We are investigating how the protracted process of female oogenesis affects the unique chromosome structure required for accurate segregation during meiosis (see Box).  We use mouse oocytes to elucidate basic mechanisms and we use human oocytes to test the clinical significance of our findings.

This research programme is funded by the MRC.

Development of techniques to prevent transmission of mitochondrial DNA disease.

Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause a range of serious, debilitating and fatal diseases. This area of research aims to develop techniques to uncouple the inheritance of nuclear DNA and mtDNA, thereby reducing the risk of an affected woman transmitting mutated mtDNA to her child.  In the context of clinical treatment, this could be accomplished by transplanting the nuclear DNA from the egg of an affected woman to an enucleated egg from an unaffected donor.  In principle, nuclear DNA can be transferred either before (Spindle transfer) of after (Pronuclear transfer). 

Diagram shows the two approaches to nuclear genome transplantation currently being developed to reduce the risk of mtDNA disease. Pronuclear transfer is performed after the egg is fertilised and Spindle transfer is performed before fertilisation.

Proof of concept studies indicate that transplantation of the nuclear genome either before or after fertilisation provides a feasible option for reducing the risk of transmitting mtDNA disease. However, the potential of either approach as future treatments will depend on whether manipulated embryos are capable of undergoing normal development to a stage where they would be capable of implanting in the uterus. Our current research efforts are therefore focussed on optimising procedures to maximise development to the blastocyst stage in vitro, and to perform a range of tests to determine whether those blastocysts are comparable to unmanipulated embryos.

This research programme is funded by the Wellcome Trust and is a collaboration with Professors Doug Turnbull and Alison Murdoch.

Patents

US/2010/0291664 A1 Laboratory Apparatus with Incubator Mary Herbert, Jeanette Fenwick, Steve Harbottle, James Walker (Publication date: Nov 2010)

B.Solano, D.Wood, M.Herbert (2006) “Electro-mechanical actuator device and apparatus incorporating such device” (WO 2007138266, GB 2452176, US 2010058899, EP 2032849)

Current Lab Members  (Research)

Lisa Lister (RA) 

Lucia Arizzi (RA)

Mahdi Lamb (RA)

Raveen Sandher (Clinical Fellow)

Jessica Richardson (MRes/PhD student)

Randy Ballesteros (PhD student)

Daniel Cooney (PhD student)  

Hannah O'Keefe (technician)

Current Lab Members  (Clinical)

Sam Byerley (Lab Manager)

Louise Hyslop (Lab Manager)

Emma Dunkley (Senior Embryologist)

Alison Lamont (Senior Embryologist)

Ella Clapham (Senior Embryologist) 

Lynne Novak (Senior Embryologist)

David Cullen (Senior Embryologist)

Zoe Brame ( Embryologist)

Danielle Mayhew (Trainee Embryologist)

Simon Cassley (Senior Technologist)

Sharon Parker (Senior Technologist)

Jeanine Watt (Technologist)

Kathryn Rogers (Technologist)

Louise Needham (Technologist)

Christine Wallace-Lee (Technologist)

Rez Prathalingam (Quality Manager)

• Herbert M, Turnbull D. Progress in mitochondrial replacement therapies. Nature Reviews Molecular Cell Biology 2018, 19(2), 71-72.
• Rattani A, Ballesteros Mejia R, Roberts K, Roig MB, Godwin J, Hopkins M, Eguren M, Sanchez-Pulido L, Okaz E, Ogushi S, Wolna M, Metson J, Pendas AM, Malumbres M, Novak B, Herbert M, Nasmyth K. APC/C^Cdh1 Enables Removal of Shugoshin-2 from the Arms of Bivalent Chromosomes by Moderating Cyclin-Dependent Kinase Activity. Current Biology 2017, 27(10), 1462-1476.
• Herbert M, Toth A. How Meiosis Creates the Single-Copy Genome. Developmental Cell 2017, 40(1), 3-4.
• Herbert M, Turnbull D. Mitochondrial donation - Clearing the final regulatory hurdle in the United Kingdom. New England Journal of Medicine 2017, 376(2), 171-173.
• Craven L, Herbert M, Murdoch A, Murphy J, Davies JL, Turnbull DM. Research into Policy: A Brief History of Mitochondrial Donation. Stem Cells 2016, 34(2), 265-267.
• Hyslop LA, Blakeley P, Craven L, Richardson J, Fogarty NME, Fragouli E, Lamb M, Wamaitha SE, Prathalingam N, Zhang Q, O'Keefe H, Takeda Y, Arizzi L, Alfarawati S, Tuppen H, Irving L, Kalleas D, Choudhary M, Wells D, Murdoch AP, Turnbull DM, Niakan KK, Herbert M. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 2016, 534(7607), 383-386.
• Richardson J, Irving L, Hyslop LA, Choudhary M, Murdoch A, Turnbull DM, Herbert M. Assisted Reproductive Technologies to Prevent Transmission of Mitochondrial DNA Disease. Stem Cells 2015, 33(3), 639-645.
• Panagiotopoulou N, Ghuman N, Sandher R, Herbert M, Stewart JA. Barriers and facilitators towards fertility preservation care for cancer patients: A meta-synthesis. European Journal of Cancer Care 2018, 27(1), e12428.
• Pyle A, Hudson G, Wilson IJ, Coxhead J, Smertenko T, Herbert M, Santibanez-Koref M, Chinnery PF. Extreme-Depth Re-sequencing of Mitochondrial DNA Finds No Evidence of Paternal Transmission in Humans. PLoS Genetics 2015, 11(5), e1005040.
• Herbert M, Kalleas D, Cooney D, Lamb M, Lister L. Meiosis and Maternal Aging: Insights from Aneuploid Oocytes and Trisomy Births. Cold Spring Harbor Perspectives in Biology 2015, 7(4).
• Gorman GS, Grady JP, Ng Y, Schaefer AM, McNally RJ, Chinnery PF, Man PY, Herbert M, Taylor RW, McFarland R, Turnbull DM. Mitochondrial Donation: How Many Women Could Benefit?. New England Journal of Medicine 2015, 372(9), 885-887.
• Herbert M, Turnbull D. Mitochondrial replacement to prevent the transmission of mitochondrial DNA disease. EMBO Reports 2015, 16(5), 539-540.
• Hyslop L, Irving L, Richardson J, Craven L, Choudhary M, Murdoch A, Turnbull D, Herbert M. Towards therapeutic application of IVF-based techniques to prevent transmission of mtDNA disease. In: 31st ESHRE Annual Meeting. 2015, Lisbon, Portugal: Oxford University Press.
• Byerley SK, Blakely EW, Alston CL, Turnbull DM, Stewart JA, McFarland R, Taylor RW, Herbert M. PGD to prevent mitochondrial disease: embryological aspects. In: 13th Annual Preimplantation Genetic Diagnosis International Society (PGDIS) Meeting. 2014, Canterbury, UK: Springer.
• Craven L, Irving L, Alston CL, Watson EL, Byerley S, McFarland R, Stewart JA, Taylor RW, Herbert M, Turnbull DM. Preimplantation genetic diagnosis for mitochondrial DNA disease. In: 13th Annual Preimplantation Genetic Diagnosis International Society (PGDIS) Meeting. 2014, Canterbury, UK: Springer.
• Sandher RK, Pickard R, Herbert M. Spermatogonial stem cells: a route to preserving fertiltiy. In: Society of Academic and Research Surgery Annual Meeting. 2014, Cambridge, UK: John Wiley & Sons, Inc.
• Chinnery PF, Craven L, Mitalipov S, Stewart JB, Herbert M, Turnbull DM. The Challenges of Mitochondrial Replacement. PLoS Genetics 2014, 10(4), e1004315.
• Greggains GD, Lister LM, Tuppen HAL, Zhang Q, Needham LH, Prathalingam N, Hyslop LA, Craven L, Polanski Z, Murdoch AP, Turnbull DM, Herbert M. Therapeutic potential of somatic cell nuclear transfer for degenerative disease caused by mitochondrial DNA mutations. Scientific Reports 2014, 4, 3844.
• Higgins JMG, Herbert M. Nucleosome Assembly Proteins Get SET to Defeat the Guardian of Chromosome Cohesion. PLoS Genetics 2013, 9, e1003829.
• Hyslop L, Prathalingam N, Nowak L, Fenwick J, Harbottle S, Byerley S, Rhodes J, Watson B, Henderson R, Murdoch A, Herbert M. A Novel Isolator-Based System Promotes Viability of Human Embryos during Laboratory Processing. PLoS ONE 2012, 7(2), e31010.
• Craven L, Irving L, Herbert M, Turnbull D. Development of the Pronuclear Transfer Technique to Prevent Transmission of Mitochondrial DNA Disease in Humans. In: United Kingdom Neuromuscular Translational Research Conference. 2012, Newcastle upon Tyne: Elsevier.
• Craven L, Irving L, Herbert M, Turnbull D. Development of the Pronuclear Transfer Technique to Prevent Transmission of Mitochondrial DNA Disease in Humans. In: UK Neuromuscular Translational Research Conference. 2012, Newcastle upon Tyne, UK: Elsevier.
• Choudhary M, Nesbitt M, Burgess L, Hyslop L, Herbert M, Murdoch A. Egg Sharing for Research: A Successful Outcome for Patients and Researchers. Cell Stem Cell 2012, 10(3), 239-240.
• Prathalingam N, Ferguson L, Young L, Lietz G, Oldershaw R, Healy L, Craig A, Lister H, Binaykia R, Sheth R, Murdoch A, Herbert M. Production and validation of a good manufacturing practice grade human fibroblast line for supporting human embryonic stem cell derivation and culture. Stem Cell Research and Therapy 2012, 3(2), 12.
• Irving L, Alston C, Craven L, Herbert M, Turnbull DM. Analysis of mitochondrial DNA mutant loads in oocytes & preimplantation embryos for the 14709T > C & 14487T > C mtDNA mutations by pyrosequencing. In: United Kingdom Neuromuscular Translational Research Conference. 2011, London, UK: Elsevier.
• Irving L, Craven L, Herbert M, Turnbull DM. Manipulation of human abnormally fertilized pronuclear stage zygotes following vitrification. In: United Kingdom Neuromuscular Translational Research Conference. 2011, London, UK: Elsevier.
• Craven L, Elson JL, Irving L, Tuppen HA, Lister LM, Greggains GD, Byerley S, Murdoch AP, Herbert M, Turnbull D. Mitochondrial DNA disease: new options for prevention. Human Molecular Genetics 2011, 20(R2), R168-R174.
• Lister LM, Kouznetsova A, Hyslop LA, Kalleas D, Pace SL, Barel JC, Nathan A, Floros V, Adelfalk C, Watanabe Y, Jessberger R, Kirkwood TB, Hoog C, Herbert M. Age-Related Meiotic Segregation Errors in Mammalian Oocytes Are Preceded by Depletion of Cohesin and Sgo2. Current Biology 2010, 20(17), 1511-1521.
• Santos F, Hyslop L, Stojkovic P, Leary C, Murdoch A, Reik W, Stojkovic M, Herbert M, Dean W. Evaluation of epigenetic marks in human embryos derived from IVF and ICSI. Human Reproduction 2010, 25(9), 2387-2395.
• Herbert M, Fenwick J, Harbottle S, Walker J. Laboratory Apparatus with Incubator. UK: NHS Innovations, 2010/0291664, 18/11/2010.
• Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 2010, 465(7294), 82-85.
• Kouznetsova A, Lister L, Nordenskjold M, Herbert M, Hoog C. Bi-orientation of achiasmatic chromosomes in meiosis I oocytes contributes to aneuploidy in mice. Nature Genetics 2007, 39(8), 966-968.
• Brown D, Herbert M, Lamb V, Chinnery PF, Taylor R, Lightowlers R, Craven L, Cree L, Gardner JL, Turnbull DM. Transmission of mitochondrial DNA disorders: possibilities for the future. Lancet 2006, 368(9529), 87-89.
• Homer HA, McDougall A, Levasseur M, Murdoch AP, Herbert M. Mad2 is required for inhibiting securin and cyclin B degradation following spindle depolymerisation in meiosis I mouse oocytes. Reproduction 2005, 130(6), 829-843.
• Homer HA, McDougall A, Levasseur M, Yallop K, Murdoch AP, Herbert M. Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes and Development 2005, 19(2), 202-207.
• Homer HA, McDougall A, Levasseur M, Herbert M. Restaging the spindle assembly checkpoint in female mammalian meiosis I. Cell Cycle 2005, 4(5), 650-653.
• Herbert M, Levasseur M, Homer H, Yallop K, Murdoch A, McDougall A. Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nature Cell Biology 2003, 5(11), 1023-1025.
• Fenwick J, Platteau P, Murdoch AP, Herbert M. Time from insemination to first cleavage predicts developmental competence of human preimplantation embryos in vitro. Human Reproduction 2002, 17(2), 407-412.
• Griffiths TA, Murdoch AP, Herbert M. Embryonic development in vitro is compromised by the ICSI procedure. Human Reproduction 2000, 15(7), 1592-1596.
• Herbert M, Morgan J, Levasseur M, Murdoch AP, McDougall A. A non-degradable form of cyclin can be used to induce arrest at the first meiotic metaphase in human oocytes. In: ESHRE campus workshop 'ART in the year 2000'. 1999, Hamburg-Norderstedt, Germany: Oxford University Press.
• Evbuomwan IO, Fenwick JD, Shiels R, Herbert M, Murdoch AP. Severe ovarian hyperstimulation syndrome following salvage of empty follicle syndrome. Human Reproduction 1999, 14(7), 1707-1709.
• Clouston,H.J., Fenwick,J., Webb,A.L., Herbert,M. Murdoch,A.P., Wolstenholme,J. Detection of mosaic and non-mosaic chromosome abnormalities in 6-8 day old human blastocysts. Human Genetics 1997, 101, 30-36.