Activation of human ovarian follicles and derivation of competent oocytes

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

Women are born with a store of eggs that must last them throughout their reproductive life. These eggs are in the ovary at an immature stage within protective sac like structures (follicles) and held in a resting state until they are activated to grow. This process of activation is the most important factor that determines a womans reproductive lifespan and when she will enter menopause. However, almost nothing is known about how this process is regulated in humans although its disruption can lead to Premature Ovarian Failure (POF), infertility and associated female health problems.
This study is looking at how activation is regulated and how it can be manipulated to alter the number and quality of eggs that develop to the stage where they can be fertilised. We are now able to tackle this problem in human tissue by using a novel culture system that we have developed that supports activation of follicles outside the body. Using this we will investigate the role of two mechanisms (PTEN and mTORC1) that have been shown to affect the rate of follicle activation in mice by adding factors that disrupt (inhibit/stimulate) them. Oocyte development and function can then be tested after these manipulations. The results obtained could lead to improved treatments for POF, infertility as well as development of methods to regulate female fertility.

Technical Summary

Women are born with a fixed population of germ cells that must last them throughout their reproductive lifespan. These germ cells are contained within resting primordial follicles that are activated to grow throughout life. The depletion of this population leads to reproductive ageing and this can occur prematurely leading to infertility. Some follicles from this quiescent population are being continuously activated whilst the rest remain dormant, indicating that quiescence is the default pathway. How this complex process of activation is regulated is unknown although it is a fundamental aspect of ovarian biology and has considerable practical importance as it underpins future improvements in the success of Assisted Reproductive Techniques (ART) i.e. the availability of high quality oocytes suitable for fertilisation as well as being a potential target for fertility regulation. Recent studies using tissue specific knock out mouse models have demonstrated the importance of the phosphatidylinositol-3?-kinase (PI3-K) signalling pathway in this process. PTEN (phosphatase and tensin homolog deleted on chromosome 10) has been shown to suppress whilst mTORC1 (mammalian target of rapamycin complex1) promotes follicle activation. In this proposal we will manipulate PTEN and mTORC1 signalling by using well defined inhibitors/activators in a continuum of in vitro methods to study human oocyte development from the most immature stage to fully grown oocytes. This model system represents a major advance in our ability to investigate the regulation of quiescence and activation of human primordial follicles and subsequent oocyte development. We will test the hypothesis that PTEN and mTORC1 regulate human primordial follicle quiescence/activation and demonstrate the efficacy and safety of this model for deriving mature oocytes capable of being fertilised. This proposal will significantly advance our knowledge of the initiation of follicle growth and how it underpins oocyte quality right through to fertilisation.

Publications

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Albertini DF (2016) Deconstructing the winding path to the recapitulation of mammalian oogenesis ex vivo. in Proceedings of the National Academy of Sciences of the United States of America

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Anderson RA (2018) Being a good egg in the 21st century. in British medical bulletin

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Ding CC (2010) Activin A inhibits activation of human primordial follicles in vitro. in Journal of assisted reproduction and genetics

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Du Q (2010) Human oocytes express ATP-sensitive K(+) channels. in Human reproduction (Oxford, England)

 
Description Knowledge Transfer Scheme
Amount £12,000 (GBP)
Funding ID 9bM-11/0637 
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 06/2012 
End 12/2012
 
Description MRC Project Grant
Amount £750,000 (GBP)
Funding ID MR/R003246/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2020
 
Description MRC project Grant: G1002118 (with Norah Spears)
Amount £650,000 (GBP)
Funding ID G1002118 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2011 
End 02/2015
 
Description Project Grant
Amount £250,000 (GBP)
Funding ID MR/L00299X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2013 
End 03/2016
 
Title Follicle Initiation in human 
Description We have further developed a human culture model to study the initiation of primordial follicles. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Facilitates understanding of basic mechanisms of oocyte development in humans thus reducing the need to use animal models for these processes. 
 
Description Bovine Oocyte Maturation 
Organisation Paragon Veterinary Group
Department Assisted Reproduction
Country United Kingdom 
Sector Academic/University 
PI Contribution We are testing a bovine oocyte maturation protocol that we have developed to determine whether it is commercially viable.
Collaborator Contribution Partners provide animal resources.
Impact We are producing a detailed protocol that may be marketed commercially. paragon Vets would have first option on this.
Start Year 2012
 
Description Germ line Stem Cells 
Organisation Vincent Reproductive Centre
Country United States 
Sector Hospitals 
PI Contribution We are using our human ovarian culture system developed using MRC funding to test the potential of germ line stem cells isolated from human ovaries.
Collaborator Contribution Partners have provided the germ line stem cells and are actively collaborating to assist us in the isolation of these cells in Edinburgh
Impact Preparation of manuscript
Start Year 2012
 
Description Molecular origin of non-disjunction in human meiotic and early mitotic divisions 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution Prof Richard Anderson and I have formed a collaboration with Prof Adele Marston in Cell Biology UOE who is an expert in the process of Meiosis. We are contributing through generating in vitro grown human oocytes that can be tested for meiotic errors.
Collaborator Contribution Prof Adele Marston
Impact Wellcome TRust Collaborative grant application
Start Year 2017
 
Title In vitro oocyte growth and maturation 
Description The patent covers the culture system used to support early stages of oocyte maturation which Prof Telfer and colleagues have developed. Using this system immature oocytes can be developed completely ex vivo to the stage where they have developed the competence to resume meiosis and potentially be fertilised. 
IP Reference WO2016046557 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact One impact is that this culture system can test ovarian tissue that has been cryopreserved before any transplantation.
 
Description Clinical Achievements of Reproductive Medicine: Karolinska Institute Postgraduate Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Presented two lectures to a postgraduate course at Karolinska Institute in Stockholm organised by Dr Kenny Rodriguez Wallberg. Talks were directly related to MRC awards, one on in vitro growth of human oocytes and the other on germ line stem cells. This resulted in discussion and further invitations to fertility group meeting in Stockholm later in the year.
Year(s) Of Engagement Activity 2015
 
Description Contributer to a Radio Four Programme: Rewinding the menopause 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Telfer, Professor Richard Anderson and Dr Marie McLaughlin participated in making a radio programme for Radio 4 with Dr Aarathi Prasad. Dr Prasad and BBC producers visited Telfer's laboratory and warched the ongoing work and conducted interviews. This led to increased interest in the work and approaches from other BBC programme makers as well as enquiries from members of the public.
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b0643vfl
 
Description Excemed Workshop for Clinicians and Embryologists (Helsinki) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a pre- ESHRE workshop to explore new research that would form the basis of next generation fertility treatments. Over 150 practitioners attended and the topic of Evelyn Telfer's presentation (germ line stem cells) sparked many questions and discussion afterwards. This has led to other invitations and interest in this area.
Year(s) Of Engagement Activity 2016
URL https://www.excemed.org/live-events/pre-eshre-advanced-course-embryology-ivf-today-it-possible-furth...
 
Description Independent article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact http://www.independent.co.uk/life-style/health-and-families/health-news/eggs-unlimited-an-extraordinary-tale-of-scientific-discovery-7624715.html
Interviewed by the Independent's Science writer (Steve Connor). Resulted in front page coverage in Independent on Easter saturday.

Several other newspapers took up this story which has resulted in many conference and workshop invitations.
Year(s) Of Engagement Activity 2009,2012
 
Description Invited Speaker ESHRE Annual conference Istanbul 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact ESHRE Annual conference Istanbul July 1st-4th 2012
http://www.eshre.eu/ESHRE/English/Annual-meeting/Istanbul-2012/page.aspx/1381

Interaction with a Spanish research group which has resulted in a post-doc coming to work in my lab.
Year(s) Of Engagement Activity 2012
 
Description Invited Speaker at Ovarian Club 2016 Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to speak on female germline stem cells and their potential clinical use. This presentation contributed to the ongoing debate surrounding female germline stem cells.
Year(s) Of Engagement Activity 2016
URL http://oc2016.cme-congresses.com/scientific-program.aspx
 
Description Lecture to ASRM post graduate course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 120 international participants.

Initiated a great deal of discussion and invited to participate in a strategy panel.
Year(s) Of Engagement Activity 2012
 
Description Named one of Porter's Magazine's Incredible Women of 2018 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Named as one of Porter's magazine in recognition of work on in vitro growth of human oocytes.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/news/2018/fertility-pioneer-receives-international-award
 
Description Nature Articles 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact http://www.nature.com/news/reproductive-biology-fertile-mind-1.11805

Contributed to preparation of news article.

Resulted in a great deal of contact regarding my research including some people who would like to fund raise for this research in general.
Year(s) Of Engagement Activity 2012
 
Description Newspaper article (Guardian) on first ovarian tissue transplantation in UK carried out by Ediburgh Team 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Media coverage of first ovarian transplant in U.K. that was carried out by the Edinburgh team. Newspaper article highlighted the collaborative nature of this work between basic science and clinical work. This led to more media interest and interest from the general public on the development of our in vitro system.
Year(s) Of Engagement Activity 2016
URL https://www.theguardian.com/science/2015/jun/10/woman-gives-birth-after-pioneering-ovarian-tissue-tr...
 
Description Podcast for Women in Science day 2015 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact I was interviewed by the University of Edinburgh Biology Society students for a special podcast for Women in Science day. The podcast led to interest from undergraduates and postgraduates and also invitations to speak at some of their events.
Year(s) Of Engagement Activity 2015
URL http://www.biology.ed.ac.uk/polopoly/podcasts/BIOPOD_OCT_2015_ALD.mp3
 
Description Prepubescent tissue freezing: it's not just for the boys : Nature Medicine Article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The development of our in vitro system to support human oocyte development was discussed in a Nature Medicine article on ovarian tissue freezing. Alison McCook Nature Medicine 19, 958-961 (2013) doi:10.1038/nm0813-958 Published online 06 August 2013 Corrected online 16 August 2013.

This has led to interest in our in vitro work and also how this can be combined to test tissue prior to transplantation.
Year(s) Of Engagement Activity 2013
URL http://www.nature.com/nm/journal/v19/n8/box/nm0813-958_BX1.htm
 
Description Press coverage including TV, Radio and newspaper interviews on culturing oocytes in vitro 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press coverage in the following: AGENCE FRANCE PRESSE, TOP SANTE, EURO NEWS, YAHOO ACTUALITIES, QUEST FRANCE, LE MONDE (France), YAHOO SINGAPORE (Singapore), DEUTSCHE WELLE, DPA, SUDDEUTSCHE ZEITUNG ONLINE, DEUTSCHE PRESSE-AGENTUR (Germany), RADIO NEW ZEALAND NEWS, THE PRESS (New Zealand), IRISH INDEPENDENT, IRISH DAILY MAIL, NEWSTALK, THE JOURNAL (Ireland), AFPBB (Japan), FOX NEWS.COM, NF NEWS, US NEWS AND WORLD REPORT, MED PAGE TODAY, FUTURISM, FORT MILL TIMES, QUARTZ, NEWSER, CNN, SMITHSONIAN, SCIENCE DAILY, SCIENCE, FORBES, NATIONAL GEOGRAPHIC, PARENTS.COM, USA TODAY, IFL SCIENCE (USA), DE TELEGRAAF, WEBLOG DOS JORNAL, NOS NIEUS, REFORMTORISCH DAGBLAD (Netherlands), PRESS TRUST OF INDIA, INDO-ASIAN NEWS SERVICE, HINDUSTAN TIMES, DOMAIN B, ASIAN AGE, HI INDIA, DECCAN CHRONICLE, TIMES OF INDIA (India), AGENCIA EFE, LAVOZDIGITAL, FARO DE VIGO, LA OPINION LA CORUNA, EL PAIS (Spain), DAGENS NYHETER (Sweden), IOL (South Africa), BD NEWS 24 (Bangladesh), POSTMEDIA BREAKING NEWS, CBC, THE SCIENTIST, MING PAO CANADA (Canada), PANAMA AMERICA ONLINE (Panama), TELE TRECE CANAL 13, LA TERCERA, EMOL.COM, DIARIO EL DIA (Chile), JORDAN NEWS AGENCY (Jordan), SPECIAL BROADCASTING SERVICE, NEWS.COM.AU (Australia), NANONEWSNET.RU (Russia), LA PRENSA (Argentina), TELESUR (Cuba), THE NEW VISION (Uganda), ACENTO (Dominican Republic), GALILEO, ANSA NEWS AGENCY, LA VERITA (Italy), NZZ INTERNATIONAL (Switzerland), SECONDS (Indonesia), THE HERALD (Ghana), FRONTERA, THE CHRONICLE OF TODAY (Mexico), NEWSWEEK POLSKA (Poland), GLOBO TV (Brazil), RADIO ROMANIA (Romania), MALAY MAIL (Malaysia), IAFRICA.COM, NIGERIAN TRIBUNE (Pan Africa), REAL TIME NEWS, CHINA TIMES, KENG SHUN DAILY NEWS, YAM NEWS, CENTRAL DAILY NEWS, LIBERTY TIMES, TAIWAN NEWS (Taiwan), SING TAO DAILY, AFP, MING BAO, ORIENTAL DAILY NEWS, SING TAO DAILY (Hong Kong), CD NEWS, WORKER CHINA, XINHUA, JIANGSU CHINA, 163.COM, CHINA SCIENCE AND TECHNOLOGY NET, SCIENCE NET, BUSINESS WEEK, SHENZHEN NEWS, CHINESE ACADEMY OF SCIENCES, CCTV, CREADERS.NET (China)
Prof Evelyn Telfer (Biological Sciences) leads study that grows human eggs in a laboratory, in a move that could lead to improved fertility treatments
Year(s) Of Engagement Activity 2018
 
Description Public Lecture Royal Infirmary Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Approx 80 members of the public (including school pupils) attended a public lecture given by me and Prof Richard Anderson. It sparked discussion and I had at least 10 people stay behind to ask questions. It was a thought provoking and stimulating evening.

No notable impact as yet (too early to say).
Year(s) Of Engagement Activity 2011
 
Description Radio Interview on Today Programme with John Humphries 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview on the morning programme Today with John Humphries to discuss our published work on growing human oocytes in vitro
Year(s) Of Engagement Activity 2018
 
Description Sunday Times article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Sunday Times Journalist (Sarah-Kate Templeton) contacted me to include our work in an article she was writing on Fertility Preservation.

Received interest in our work via e-mail contacts.
Year(s) Of Engagement Activity 2011
 
Description Talk to GRECOT ( French Study and Research Group about Ovarian and Testicular tissue Cryopreservation) Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to speak at Fertility Preservation Forum in Paris. mainly Clinicians and Scientists working on storing ovarian and testicular tissue. My presentation will deal with in vitro follicle development.
Year(s) Of Engagement Activity 2017
 
Description Teaching RCOG 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Group of obstetricians and other clinicians attended and asked questions. Some have asked to visit our lab.

Arranged lab visits
Year(s) Of Engagement Activity 2013
 
Description Training day for National Tissue Banking Services 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Presentation to inform Tissue Services how ovarain tissue may be utilised post thawing and to report on results of testing stored tissue.

N/A talk still to happen
Year(s) Of Engagement Activity 2012
 
Description University of Edinburgh Open days 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Schools
Results and Impact I present information about studying Biological Sciences at the University of Edinburgh.

I have been invited to speak at schools following these presentations. There is a particular interest from girls schools as a way to increase awareness and stimulate interest in career options in Science.
Year(s) Of Engagement Activity 2011,2012