Human Developmental Biology Resource: support for Human Cell Atlas

Birth defects such as spina bifida or hole-in-the-heart affect one in every thirty pregnancies and arise when there is a problem in development of the fetus before birth. Even diseases of older children or adults can have their origins before birth. Researchers are increasingly finding faulty genes to be associated with such diseases, raising the possibility that genetic counselling and perhaps gene therapy might be offered in future. However, we need to understand how such genes function in the embryo and fetus, in order to move forward towards new methods of diagnosis and treatment. While research with animals can help in providing information on the origin of such diseases, there is ultimately no alternative to studying the processes in humans themselves.

The Human Developmental Biology Resource (HDBR) enables this research by providing scientists with access to material from human embryos and fetuses. The HDBR has approval from an Ethics Committee and from the Human Tissue Authority to collect, store and distribute human fetal material for research. The material is obtained, with informed consent of the mother, from unwanted pregnancies that are being terminated. Staff in the HDBR examine the fetal samples for stage of development and their chromosomes are tested to detect any abnormalities. The tissues are then either sent to researchers for immediate research, or else the samples are frozen or otherwise preserved for later distribution to researchers. Sample details are recorded on a secure database that is anonymized, so no results from the research can be linked back to the donating woman.

To date, over 400 different research projects have received fetal material from the HDBR, and this has led to over 240 scientific papers being published. Discoveries have included genes for bowel disorders, schizophrenia and severe eye defects. In this way, scientists are using HDBR material to learn how genes contribute to human development and how mutations (mistakes) in these genes may lead to birth defects or rare diseases.

Recently, the MRC allocated funds to pay for a new initiative: the Human Cell Atlas (HCA). In this research, the genes that are active in different organs and tissues of the human embryo and fetus will be identified, so that all the different types of cells within the organs can be recognized. Similarities and differences between fetal and adult organs will be especially studied. This information will be valuable in forming a basis for future research on how genes lead to birth defects and children's diseases. The HDBR will be the primary provider of human fetal material for this research, and the present application seeks additional funding to pay for the extra HDBR work that will be needed to support this HCA initiative.

The new research projects within the HCA initiative pose considerable challenges for the HDBR and its tissue supply-chain. As a result, the HDBR is requesting extra funding to pay for additional staff members and running costs, in order to deliver a larger-scale service than at present. The HDBR will increase its attendance at abortion clinics, so as to collect extra fetal samples for research. Staff will be trained in new specialist tissue handling procedures that are required for the exacting demands of the HCA research. Operating efficiency of the HDBR will be improved to ensure that every, valuable fetal sample is used as well as possible. Close working with the HCA research teams will be emphasised, to ensure that tissue supply is coordinated with project needs. Finally, the use of stored frozen tissue as an alternative to fresh samples will be explored, as frozen tissue is easier to supply than fresh tissue. In these ways, the HDBR will rise to the demands of the new HCA project and will continue to supply tissues of the highest standards to enable the best possible quality research.

The Human Developmental Biology Resource (HDBR) is an ethically-approved human fetal tissue bank that provides the national and international scientific community with embryonic and fetal samples (4 to 23 weeks gestation) for research. This stage range represents the period when congenital disorders arise and many diseases of childhood and adulthood originate. Fetal material is supplied to an average of 100 projects at any time, and has contributed to more than 240 research publications, including in Nature, Science and Cell.

The HDBR proposes to extend its service to supply human developmental material to projects within the MRC Human Cell Atlas (HCA) initiative. This new funding stream will support single cell gene expression and image analysis studies in embryonic and fetal tissues, for comparison with adult tissues. To supply projects under the MRC HCA initiative, the HDBR requires additional resource to meet several challenges. These include: greater tissue demand in terms of sample numbers per year, a larger range of specialist dissections to supply particular tissues/organs, and the ability to adapt tissue supply to specific project and funding milestones within the MRC HCA research portfolio.

To meet these challenges, the HDBR will: (i) attend additional clinics to substantially increase the number of samples collected; (ii) train new and existing staff in an extended range of specialist dissection procedures, where possible via collaborations with MRC HCA groups; (iii) improve operating efficiency by providing samples from each embryo/fetus to multiple projects, working closely with HCA groups to ensure tissue supply is coordinated with project needs, and exploring the use of archived frozen tissue as an alternative to fresh material. While meeting HCA project needs, the HDBR will also ensure that its existing and new non-HCA projects remain well provided for, and that the highest possible standard of fetal material supply is maintained.

The HDBR will have impact in the following ways:

Researchers funded under the MRC Human Cell Atlas (HCA) initiative. As described in the Academic Beneficiaries section, these research teams will benefit directly from HDBR's provision of hard-to-access human embryonic and fetal material. Supply of this material will enable the teams to generate single cell gene expression data for comparison with adult tissues of the same types. The data produced in the HCA study will then have impact on a number of groups, as follows.

Clinical Geneticists and Cancer Biologists. Single cell transcriptomic data are of considerable interest to both groups of professionals. Genetic variants are being increasingly linked to diseases, and the next step after this linkage phase will involve functional studies of gene expression and the effects of genetic variants. The HCA-derived data will have considerable impact in this research. Moreover, single cell RNAseq data have already contributed to understanding of cancers, as with the HDBR-supported study of kidney gene expression in normal and malignant tissues (Young et al, 2018, Science 361: 594-9). Further examples of this type can be expected arising from the HCA initiative.

Translational and Clinical Researchers. Development of stem-cell based therapies for congenital or other disorders rely on data from normal human development as the "gold standard" for assessing the accuracy of the cellular reagents being developed to replace/repair affected cells/tissues. Differences in tissue and organ development and/or prenatal function between human and animal models mean that human data are crucial. There will be long-term benefit to patients through development of therapies based on this knowledge.

Students and Lecturers: under- and post-graduate students doing projects in the HDBR or HCA laboratories will benefit from research training and specialized knowledge about human development. More generally, medical and biomedical students will benefit from access to the learning materials available via the HuDSeN website. There has been a progressive decline in embryology teaching on medical courses in recent decades, and the HDBR's provision of visually instructive images and models of human development help to provide much-needed student resource. Lecturers and other teachers will benefit from access to the learning materials for use in their courses.

HDBR staff will themselves benefit from the research knowledge and skills obtained from collaboration with HCA teams. They will also benefit from the public engagement activities they take part in as these require them to learn new skills and give them the opportunity to listen and respond to questions and discussion points from members of the public (adults and children). Career prospects for HDBR staff are greatly enhanced by authorship on publications arising from use of HDBR material, and we encourage such authorship where an HDBR staff member has made a significant contribution.

Members of the public: will benefit from the public engagement activities led by HDBR staff as well as the new exhibit developed for Life Science Centre. These will provide an opportunity to further their understanding and interest in human development and to discuss any concerns. A recent success for the HDBR was the provision of images to the Hong Kong Science Museum for its new "Distant relatives" exhibit in the Biodiversity Gallery (http://hk.science.museum/en_US/web/scm/pe/bdg/contents.html). The exhibition is part of the museum's response to the "United Nations Decade on Biodiversity", 2011-20, to raise public awareness about the importance of biodiversity conservation.