Human Developmental Biology Resource (HDBR): meeting new trends and challenges in developmental biobanking

Understanding how the embryo and fetus develop before birth is important, not only to properly appreciate our origins from the fertilised egg, but also to gain insight into the many diseases that arise before or around the time of birth. Some later childhood or adult diseases also have strong influences from the fetal period. Despite this, we understand rather little about human development and much more about the development of other animals, including the mouse, chicken, fish and even the fruit fly. This poor level of knowledge about human development is now being tackled through studies of tissues from embryos and fetuses, which are obtained after termination of pregnancy. The Human Developmental Biology Resource (HDBR) enables this vital research by providing scientists with access to material from these samples. The HDBR has ethical and Human Tissue Authority approval to collect, store and distribute human fetal material for research. The material is obtained, with informed consent, after the woman has received professional counselling and decided to terminate her pregnancy. The samples are assessed for developmental stage and tested to determine whether they are genetically normal. The tissues are then either immediately sent to researchers to either culture the tissue/cells or to extract the biological molecules, 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 link to the donating women exists. HDBR also provides a 'research service' where HDBR staff perform research work on the human material on behalf of scientists. To date, over 600 different research projects have received material from the HDBR, and this has led to nearly 400 scientific papers being published.

The goals for the next phase of HDBR work are several-fold. We will develop 'research clinics' in which women are invited to complete their pregnancy termination in hospital, rather than at home as is the current health service trend. This will ensure that the HDBR can continue to collect the earliest embryonic stages, which are vital for understanding how organs are first formed. We will also extend tissue collection into the later fetal and newborn periods, where research is urgently needed but samples are rarely available. We will work with scientists to ensure that even the smallest and most hard-to-access parts of the fetus are provided for research. We will extend our collection of abnormal samples, for example from pregnancies that are terminated because of Down Syndrome, or other serious fetal problems. We will establish a new part of the HDBR research service, called Spatial Transcriptomics, in which the expression of genes can be studied directly in the fetal tissues. We will also expand the HDBR Atlas, a publicly available web site where information can be obtained about human development.

The eventual aim of this research into human development is to better understand birth defects which occur in 3% of pregnancies and are responsible for 20% of infant deaths. This includes conditions like spina bifida, hole-in-the-heart, and cleft lip and palate which often pose life-long medical problems for the child, caring challenges for the family, and a considerable financial burden for the health service. While pregnancy termination can be an option, the ultimate goal is to learn how birth defects develop in the embryo and fetus, so that preventive measures can be offered. These might involve vital nutrients like folic acid, or stem cell transplants which hold great promise for future disease treatment. Researchers are increasingly finding disruptions of genes that are associated with such diseases, raising the possibility that genetic counselling and perhaps gene therapy might be offered in future. All of these medical advances will be made more achievable by an improved understanding of how the human embryo and fetus develop.

The Human Developmental Biology Resource (HDBR) is a fetal biobanking partnership between the Biosciences Institute, Newcastle University and GOS Institute of Child Health, UCL. Human embryonic/fetal tissues (4-22 post-conception weeks) are collected, stored and distributed to projects investigating human development and the origins of congenital disease. The use of human fetal tissue in research is expanding, especially in the application of contemporary analytical techniques for gene expression (e.g. single cell RNAseq, spatial transcriptomics) and cell lineage (e.g. barcoding methods in slice cultures), and to enable validation of findings on cell/organ differentiation from human pluripotent stem cell lines and organoid systems. Over the next 5 years, HDBR aims to continue providing high-quality biobanking of human embryonic/fetal tissues and evolve its services to meet changing research needs. A recent survey of HDBR users (72 respondents) yielded valuable feedback on future plans for fetal tissue usage. Building on this, the specific aims of the funding proposal are to:

1. Establish 'research clinics' to future-proof HDBR's collection of early-stage embryonic tissues against health service changes: e.g. recent trend towards at-home pregnancy terminations;
2. Extend biobanking into late fetal and early childhood periods, to provide research material in this hard-to-access period of human development;
3. Provide more specialist dissections of embryonic/fetal samples to optimise use of the samples;
4. Expand collection of prenatally-diagnosed abnormal (TOPFA) samples to enable research into the origins and implications of congenital defects;
5. Establish Spatial Transcriptomics as a fully cost-recovered HDBR service;
6. Enhance the HDBR Atlas of publicly available human gene expression patterns, annotated histological and 3D images as a research resource and educational aid.