08/H1010/28

North West Research Ethics Committee

St Mary's Hospital

Early Pregnancy Tissue Collection

Early Pregnancy Tissue Collection

Permission to publish contact details not yet received

Permission to publish contact details not yet received

Products of conception from women undergoing termination of pregnancy will be collected (i.e. developing organs and placenta, including the lining of the uterus (decidua)).

These tissues will be obtained with informed consent under guidelines issued by the Polkinghorne committee from women undergoing elective termination up to 20 weeks of pregnancy. Following termination of pregnancy, either by surgical or medical methods, the products of conception are normally disposed of by incineration. For women who give consent, there will be no intervention beyond routine clinical care.

Women will also have the opportunity to consent for the collection of limited biophysical data (height, weight, age, ethnicity, smoking status and parity) that will be anonymised for the researchers' use.

The material is acquired fresh and will be used fresh in culture experiments or processed for storage (e.g. for preparation of tissue sections on glass slide, protein, RNA or DNA) (details later). The material will underpin the research of the Hanley and Sibley groups, and their active collaborators.

The lead investigators are Professor Neil Hanley and Professor Colin Sibley. Professor Hanley, has experience of such collection from over 1,200 termination of pregnancy procedures from his prior research at the Centre for Human Development, Stem Cells & Regeneration, University of Southampton (Current ethics No. 296/00, Southampton and South-West Hants LREC; active until October 2010). Professor Sibley has experience of collecting placental material from terminations of pregnancy at St. Mary's Hospital, Manchester under ethics no. 03/CM/031 (Central Manchester Research Ethics Committee) active until April 2009.

We estimate gaining consent from 200 women per year (in Hanley's previous experience approximately 50% of eligible women give consent)

Nil

In general, the material will be used to study the physiology and biology of human fetal organ development and function. Specifically, the material will be used by (1) the laboratory research team of Professor Colin Sibley (placenta); (2) the laboratory research team of Professor Neil Hanley (other fetal tissues); and (in a small minority of circumstances) (3) their internal and external UK collaborators.

a) The aim of collecting early placental tissue is to facilitate research into understanding normal fetal growth and development and serious pregnancy complications, such as fetal growth restriction, pre-eclampsia, miscarriage and preterm delivery. The Maternal and Fetal Health Research Group (MFHRG) run by Professor Sibley is the largest pregnancy research group in Europe comprised of more than 50 researchers studying multiple aspects of pregnancy. Our success has been entirely dependent on acquiring clinical samples, such as those in this application, for our laboratory investigations. Our combined team of clinicians and basic research scientists, as well as our location in St Mary’s Hospital, facilitates translation of research findings from laboratory bench to bedside. The collection of normal early pregnancy samples would provide researchers with the optimal material for high-quality detailed research to enable greater understanding of how placental physiology in early gestation determines a successful outcome of pregnancy, which will ultimately benefit all pregnant women.

b) The relocation of the Hanley research group from Southampton to the School of Medicine at the University of Manchester brings with it an active internationally recognised research programme on early human development and stem cell biology. This already utilizes cells from the central nervous system, anterior pituitary, eye, stomach, pancreas, liver, kidney, adrenal gland, testis, ovary, external genitalia, heart, skin, lungs and bone. Results of the research from been widely published in scientific literature and further manuscripts are in preparation from these ongoing studies. Transferring / reacquiring ethical approval for this research programme is needed for Hanley’s recruitment to Manchester, thus fulfilling the aims of several research council and charity grants. The research has already informed clinical practice in paediatric endocrinology (understanding adrenal cortex function and sexual development with implications for therapy in congenital adrenal hyperplasia). Work on how pancreatic beta cells develop informs ambitious approaches of beta cell therapy / regeneration in patients with type 1 diabetes. Studying the liver has direct clinical relevance in predictive drug toxicology studies, whereby potentially dangerous drugs are identified and discarded prior to being given to human subjects (either volunteers or patients).

c) Other information:
i) Hanley’s research includes stem cell biology. Many developing human fetal organs have the potential to give rise to stem cells / progenitor cells that would be suitable for deposition in the UK Stem Cell Bank (e.g. neuroprogenitors)(currently such cells would be regarded as research-grade rather than clinical-grade). All accreditations for the UK Stem Cell Bank are in place and we would not be allowed to deviate from its code of practice.

ii) As part of the assessment of normal physiology, there is an increasing demand made by peer review for transplantation into rodent models as proof of function. For instance, assessment of human pancreatic beta cells is commonly considered incomplete without demonstrating an ability of the transplanted cells to restore normal blood glucose in diabetic laboratory mice. We propose to use the human fetal material in these types of rodent studies (with the appropriate home office licences). The experiments commonly last for a few weeks up to approximately two months.
Our interests do not include contraceptive development or cloning. All genetic analyses will remain totally anonymous (they are largely restricted to analysis of placental samples to determine gender, e.g. by karyogram, fluorescence in situ hybridization or PCR).

iii) The existence of our material collection and its associated data and protocols will be apparent from published peer-reviewed studies from the Sibley and Hanley groups. The current informed consent used by the Hanley group, reproduced here, indicates that women giving consent have no financial claim from the potential commercial use of the material or its derivatives (e.g. drug toxicology screening, stem cell therapy). Any future commercial development of intellectual property from our research would be considered under guidance from the University of Manchester Technology Transfer Office (and would require its own approval).

2) Access to the bank is restricted to medical research of potential benefit to understanding or treating cancer and other diseases. Current, ongoing ethically approved projects within the existing portfolio will be supported to completion.

3) Samples may be put to a wide range of uses including: extensive use of Immunohistochemistry, RNA, protein analysis and genetic analysis. Fresh cells may be grown to produce cancer cell lines. Use in animal models is considered unlikely but has not been ruled out. Use for therapeutic cloning and production of stem cells for therapeutic use, nonmedical appications (eg cosmetics) and reproductive research (including contraception) are excluded.

4) Applications will be made and assessed as follows:
Anyone wishing to access samples may approach the BioBank. The process is shown diagrammatically in the protocol. All new potential users must submit a valid research proposal. These will undergo peer review and prioritisation by a duly constituted Biobank steering committee.

Applications to the biobank will be processed according to written procedures. All applications to use stored samples must be documented, including those instances where permission to use the samples has not been granted. Priority will be given to:
*Peer reviewed research of high scientific merit intended to translate into early phase trials
*Goodness of fit with Oxford and National cancer research programmes and interests;
*Research led or endorsed by contributing coinvestigators, especially if undertaken within the Oxford Cancer Centre.

Samples may only be released if:
*The proposed research is covered by the scope of the donor consent covering the uses of the samples;
*The specific research plans have been approved by an appropriate Research Ethics Committee OR come under the REC approval for this protocol; and
*The requested samples are available.

Other considerations may include:
*Does the host institution support the research project? [relevant internal Committee approval is required for research within the establishment].
*Is the research sufficiently funded and otherwise resourced?
*Will the researcher’s organisation enter into a contract (e.g. Material Transfer Agreement) that governs the transfer and use of samples supplied?
*Is the specific project deemed to be of high priority in situations where there is competition for access to limited tissue resources?
*If the research is of a particularly sensitive nature, is the use appropriate and justified?
*Will the research render the samples depleted?
*For research undertaken by collaborators elsewhere, including Industry, is protection of the biobanks intellectual property and publication rights protected adequately?

Proposals will be submitted (in outline or full protocol) to the designated Steering Committee for peer review, prioritisation and approval. The Committee may coopt external review as appropriate. Only once full approval has been given may samples be released.

Supply of tissue or data outside the UK
We will only do this within ethically approved protocols that conform to regulations in force in the UK and overseas at the time of transfer. In this case expert advice would be sought on the legal and ethical implications.

5 Research Bio- Bank funding
The cost of operating the biobank will be met via the Centre’s research and Host Institution infrastructures. The biobank is not run for profit but may apply (or co-apply) for additional grant or commercial infrastructure and/or project funding. It may also seek to recover the actual operating costs of work required to acquire, process, store and supply samples and data.

Financial dealings related to the supply of samples and/or data will be managed via the University of Oxford central contracts office i.e. via the material transfer agreement.

6) Publication policy:
The biobank will operate an open communication policy that will:
• support and acknowledge donation;
• help maximise access for high quality collaborative research; and
• publicise research outputs arising from the Biobank.

The existence of the biobank will be communicated primarily via our existing national and international professional research networks, which embrace both academic and industry partnerships. The Centres research capability and resources (of which the biobank is a major part) are publicised widely via our regular reports to funding bodies and sponsors. Biobank details will be made easily available via the internet via web sites maintained internally and also via the web sites of our collaborative research organisations such as: CRUK; ECMC; BRC; NCRN and the like.

Researchers utilising the biobank do so on the understanding that they intend to publish the research findings in specialist peer reviewed scientific journals. Results may also be presented at scientific meetings and/or used for a thesis or other legitimate purpose. For collaborative research a designated biobank Investigator should be co-author, involved in reviewing drafts of the manuscripts, abstracts, press releases and any other publications. Authors should acknowledge the support of the biobank as appropriate and provide a copy of all publications.

The biobank will maintain a publication list updated annually.


7) Accountability of the bank to donors
Prospective donors will be given a copy of the written information sheet and signed consent form setting out the key policies with respect to donation. The Bank will not provide them routinely with information about the use, results or destruction of their samples. They will not benefit financially. They will retain no rights to their samples other than the ability to withdraw consent for future use of their samples or data. Any that have already been provided to research cannot be withdrawn.

Ethical approval is sought for research to be undertaken by the Hanley group and the Sibley group in conjunction with their chosen active research collaborators (either University of Manchester or UK-based).

All work undertaken will be biomedical, laboratory-based research predominantly centred on understanding normal human development during early gestation. The origins of a range of serious developmental and pregnancy disorders lie in early pregnancy, and therefore it is critical to understand how these processes are regulated in normal pregnancy for the future development of therapeutic or preventative strategies. In addition, research will include (and complement other studies of) stem cell biology. Because the acquired cells are human and primary, adult versions of which are difficult to obtain, the material, which would otherwise be discarded, will also be used to model adult human biology and for predictive toxicology research.

Understanding normal human development:
Samples from the tissue bank will be used in research studying the development and function of the fetal organs. This is most easily divided as (a) investigations of placenta and (b) studies of the organs within the developing body.

a) Placental research
Normal development of the placenta in early pregnancy is essential for successful pregnancy, and for optimal health and growth of the baby. Conversely, abnormal or inadequate development and function can have devastating consequences on the health of the baby. Many pregnancy complications, including miscarriage, intrauterine growth restriction (IUGR; where the baby is abnormally small), pre-eclampsia and premature labour, result from abnormal placental development in early pregnancy. It is therefore essential to determine how normal placental development and function in early pregnancy is regulated.

Our current research projects fall within the following themes:
i. Regulation of placental development
ii. Trophoblast invasion into the maternal decidua
iii. Nutrient transport across the placenta
iv. Early placental vascular function

i. Placental development
During the first trimester of pregnancy there is rapid branching growth of the placenta producing a large surface area for exchange of nutrients and gases between maternal and fetal blood. Failure of this growth results in a placenta that is unable to nourish the fetus: a hallmark of severe early onset IUGR, which demands premature delivery of a dangerously small baby and carries an elevated risk of stillbirth, neonatal death and long-term disability. Thus, understanding what and how hormones and growth factors regulate placental growth in early pregnancy is critical to determine how this process is impaired in IUGR.

ii. Trophoblast invasion into the maternal decidua
At the same time as placental development occurs, a further population of placental cells (the trophoblast) break away from the placenta and invade the decidua (the lining of the uterus). They migrate within the blood vessels of the decidua and alter blood vessel walls to create large dilated blood vessels allowing a high volume of maternal blood to the placenta. This is essential to provide the baby with sufficient oxygen and nutrients during later pregnancy. In pre-eclampsia and IUGR this does not occur, leading to compromised blood flow to the placenta and damage to the growing baby. The normal mechanisms are poorly understood. We will study what factors regulate this process.

iii. Nutrient transport across the placenta
Nutrients, such as amino acids, glucose and calcium, are critical for the growth of the baby and rely on highly specialised transporter systems across the placenta from the mother to the baby. Reduced transporter activity and insufficient nutrient transfer is apparent in the placenta from pregnancies complicated by IUGR. Determining whether this is a primary event in restricting fetal growth is critical for understanding the development of IUGR. Certain hormones, such as insulin and leptin, appear to stimulate nutrient uptake by the placenta, but little is understood about transfer to the fetus. Our work looks to identify regulators of nutrient transport systems for the future development of therapeutic measures to promote nutrient supply to the fetus.

iv. Early placental vascular function
A clinical feature of IUGR and pre-elampsia is reduced blood flow within the placenta, leading to reduced oxygen and nutrient supply to the fetus. In later pregnancy, this is due at least in part to altered contractile activity of the larger blood vessels that connect the umbilical cord vessels to the capillary network in the placenta. Our studies will focus on understanding the regulation of blood flow in the early placenta, in order to establish whether impaired blood flow is an early determinant of reduced fetal growth.

b) Researching development of the organs within the body
Understanding how the body’s organs normally develop is critical for discovering what goes wrong and why in congenital disorders (e.g. ‘hole-in-the-heart’ babies). In humans, early gestation is also remarkable for critical fetal organ function as well as development. Understanding this physiology / biology is important for understanding a range of human development disorders (e.g. congenital adrenal hyperplasia where female sexual differentiation is disrupted). Thus, our research aims to understand the molecular events that underlie normal human development in order to improve healthcare and develop new therapies for individuals when the process goes wrong. Our research on otherwise discarded material limits the use of laboratory animals in biomedical research. Furthermore, a number of critical developmental processes in humans are not adequately mirrored in commonly used laboratory animal models.
Broadly, Professor Hanley’s current research includes:

i) Studies of pancreatic beta cell development (Piper et al, J Endocrinol, 181, 11-23, 2004). Determining how the insulin-secreting beta cell normally develops is arguably the best way of working out how the cell might be regenerated in patients with type 1 diabetes, where there is currently a reliance on administering insulin by injection several times each day. Our work is unravelling the molecular pathway by which progenitor cells in the pancreas turn (differentiate) into the hormone-secreting beta cells.

ii) Studies of sexual differentiation. How the fetus completely assembles a male or female phenotype is critical as failure for this to occur compromises future reproductive ability / species survival. Our studies of the external genitalia during early development have demonstrated a hitherto unappreciated presence of male hormones (e.g. testosterone) during normal female development (Goto et al, J Clin Invest, 116, 953-960, 2006). Our ongoing research aims to work out the molecular basis of these events, which are relevant to paediatric endocrinology where babies are born relatively frequently with either under-developed male or virilized (i.e. over-exposed to male hormonal influences) female external genitalia.

iii) Studies of adrenal gland development and function. Our work has demonstrated a hitherto unappreciated early function of the human adrenal gland in making the hormone cortisol. This research has led to an improved appreciation of, and treatment potential for, the condition congenital adrenal hyperplasia.

These studies frequently rely on investigation of several organs at the same time as development is inter-linked. For instance, understanding how the adrenal gland and testis develop is inextricably linked to understanding the same process in the anterior pituitary as hormones from one gland regulate the other (Goto et al, J Clin Invest, 116, 953-960, 2006). Similarly, the molecular pathways and genes responsible for orchestrating development are frequently the same across numerous organ systems, thus prompting parallel investigation. For instance, the Hanley group has an interest in the role of the gene, SOX9, which regulates development in the eye, gut, nervous system, kidney, heart, skin and liver (Piper et al, Mech Dev, 116, 223-226, 2002; Piper Hanley et al, JBC in press). Hence, as at present, our ethical approval needs to cover research on all cell-types within the developing embryo / fetus. Nevertheless, the principle is always the same: understanding normal development gives insight and new therapeutic angles into what happens when development is abnormal.

c) Stem cell research
The Hanley group has an active stem cell research programme including human embryonic stem cells and human embryonic germ cells (Turnpenny et al, Stem Cells, 21, 598-609, 2003). The latter are derived from culturing the germ cells, obtained from the developing gonad (testis and ovary). These experiments are very similar to those described above and use methodology described below. The relevance to this application is that demands placed upon us, originally by a funding application to the US Government National Institutes of Health, and more latterly by the UK Stem Cell Bank, have shaped our current patient information sheet and consent form into its current LREC-approved format, e.g. sections on:
i. The potential therapeutic application of stem cell therapy (even though our cells would only be considered research-grade at present)
ii. Lack of financial incentive, ownership or influence by the woman giving consent
iii. Awareness that commercial development may arise from therapeutic applications

d) Modelling adult human biology and toxicology studies
The Hanley group has a programme of DTI (now TSB)-funded research that recognizes the privileged nature of this material as primary and human in origin. Adult human cell-types are difficult to acquire, yet human fetal cells are frequently very similar in their physiological profile (and commonly more similar than those from other species, e.g. rat or mouse). Thus, we have active programmes investigating human cell-types (e.g. liver, heart, neural) in predictive toxicology research with the goal of identifying potentially toxic putative drugs at an early stage of product development. Not only is this area of research exceedingly important for patient and volunteer safety, it is a source of huge wasted expense to the worldwide pharmaceutical industry.
Other research has identified that the developmental gene, SOX9, is critical for causing fibrosis in adult organs. This has given rise to a patent and a manuscript in press (Piper Hanley, JBC) indicating the potential role of altering SOX9 activity as a new therapy for fibrosis.

Favourable Opinion

not yet received