Human Developmental Biology Resource (HDBR): an embryonic and fetal tissue bank for functional genetics and cell-based research

Lead Research Organisation: Newcastle University
Department Name: Biosciences Institute

Abstract

Birth defects occur in 3% of pregnancies and are responsible for 20% of infant deaths. They include conditions like spina bifida, hole-in-the-heart, and cleft lip and palate which pose often 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.

In addition, many rare diseases of both children and adults first arise owing to a problem during development of the fetus 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 in 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 vital research by providing scientists with access to material from human embryos and fetuses. 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 the pregnancy. The samples are examined for stage of development and their chromosomes are tested to determine if they are normal. The tissues are then either sent to researchers for immediate preparation of cell cultures or 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 in the data. HDBR staff also carry out research work on the human material, on behalf of scientists, where this is required.

To date, over 400 different research projects have received material from the HDBR, and this has led to over 200 scientific papers being published. Discoveries have included genes that interact to cause Hirschsprung's disease (absent nerves in the bowel), an improved understanding of genes contributing to schizophrenia and the identification of genes for 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.

In the present proposal, the HDBR seeks further funding to pursue and extend its service to the international scientific community. New developments will include: (i) a focus on extending the collection to later fetal stages, as required for studies of human brain development; (ii) a new systematic collection of fetal material from pregnancies being terminated because of prenatally diagnosed birth defects, thereby allowing research into these diseases; (iii) expanding the tissue preparations that HDBR provides to researchers, to include material suitable for studies of the genetics of single cells, which is now becoming technically possible; (iv) the provision of 'hotel' facilities in our laboratories to enable researchers to be trained in best use of HDBR material; (v) a new linkage of data from genetics studies with our existing gene expression database (Human Developmental Studies Network; HuDSeN) which will for the first time allow scientists to observe how individual genes are expressed in the human embryo/fetus in relation to all the active genes and proteins that are present in that tissue or at that stage of development.

Technical Summary

The Human Developmental Biology Resource (HDBR; www.hdbr.org) is a human fetal tissue bank that provides the scientific community with: (i) High-quality materials from embryonic and early fetal stages (4-22 post-conception weeks; PCW), including tissues for cell culture, sub-organ-specific dissected regions for 'omics analysis, and slides for spatial gene expression studies; (ii) An In-House Gene Expression Service that undertakes studies for registered researchers; (iii) A unique web-based database (HuDSeN) for dissemination of human gene expression data spatially mapped to 3D models.

Since 1999, the Inst. Genetic Medicine, Newcastle and the Inst. Child Health, UCL have worked in partnership, developing the HDBR to support national and international research into human development. The 4-22 PCW period covers organogenesis when congenital disorders and many childhood/adult disorders originate. Research (e.g. 100,000 Genomes) is identifying ever-increasing numbers of disease-related genes and, while animal models can provide valuable mechanistic information, there is a growing need to access human fetal tissues for genetic and epigenetic research. Development of 'omics technologies, including at the single-cell level, and increasing use of stem and progenitor cell lines in tissue engineering, are further drivers for extending the HDBR tissue bank service.

To meet these growing demands, the HDBR proposes to augment the value of its tissue supply particularly in the older fetal age range, as increasingly required for brain development studies. Systematic collection will begin of tissues from fetuses with prenatally diagnosed congenital anomalies to support research in these diseases. New dissection/tissue preparation methods will cater for single cell 'omics projects, while 'hotel' facilities will be offered to teams wishing to train in use of HDBR material. 'Omics data locations will be linked to HuDSeN to enhance usefulness of the gene expression database.

Planned Impact

The HDBR will have impact in the following ways:

Researchers in Academia: will benefit from HDBR's provision of hard-to-access human embryonic and fetal material, in-house gene expression service and support for interpretation of gene expression patterns and developmental anatomy. These enable researchers to answer questions on in vivo human development that would be impossible without access to these tissues. Researchers also benefit from HDBR's HuDSeN database, as a route to make their data publicly available and more widely accessible. The new "hotel facilities" and upgrades to the HDBR website will enable researchers to learn specialized techniques and dissections and gain knowledge of "tried-and-tested" reagents known to work well with HDBR material.

Translational and Clinical Researchers: will benefit from the range of services outlined above. Investigation of stem-cell based therapies for congenital or other disorders with a developmental origin 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. Furthermore, there can be differences in tissue and organ development and/or prenatal function between human and animal models such as mouse. It is critical for research leading to other types of therapeutic agent (e.g. drugs) that the precise mechanisms used in human are characterized. Even subtle differences may reduce the efficacy or increase the harm of a potential treatment. 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 laboratories will benefit from research training and specialized knowledge about human development. Undergraduate students who are generating learning materials will gain both knowledge of the anatomy and developmental processes for the specific organ they work on, as well as methods for evaluating self-directed learning. 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. By the end of the grant, it is expected that 3D- print-ready instructions and/or 3D printed models of individual organs will be available for use in teaching.

HDBR staff will themselves benefit from the research knowledge and skills of the HDBR registered users who take up the new "hotel facilities". 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.

Publications

10 25 50
 
Description Human Developmental Biology Initiative
Amount £6,148,973 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 10/2024
 
Description Human Developmental Biology Resource: support for Human Cell Atlas
Amount £743,000 (GBP)
Funding ID MR/S036334/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2018 
End 03/2021
 
Title human embryos and embryonic tissues 
Description human embryos between Carnegie stage 8 and 20 post conceptional weeks supplied in a variety of forms including whole embryos, dissected organs/tissues, isolated cells, tissue on sections and nucleic acids (RNA/DNA) In the past 12 months we have registered 70 new projects with the HDBR. Newcastle have sent 2219 tissue samples (4515 across both sites) from material collected in that period, and 524 tissues (761 across both sites) from 'archived' material. In addition, we have sent 1587 microscope slides (1992 across both sites). 
Type Of Material Biological samples 
Year Produced 2018 
Provided To Others? Yes  
Impact this is used widely by the research community for a number or purposes - see publications for outputs 
 
Title human embryos and tissues 
Description In the last 12 months we have registered 72 new projects from 13 different countries. We released 2864 tissue samples to research projects (L-1717, N-1147), 1580 slides (L-284, N-1296), 10 RNA samples (Newcastle only) and 10 cDNA samples (Newcastle only). 
Type Of Material Biological samples 
Year Produced 2019 
Provided To Others? Yes  
Impact see publications list froths award 
URL http://www.hdbr.org
 
Title HDBR Atlas 
Description The HuDSeN Atlas site has now been renamed the HDBR Atlas. The web-pages have undergone a reorganisation and new content has been added to the "Organ Systems" section. This includes new sections on 3D models of brain and cardiovascular development. The latter contains 3D models of heart development, annotated images of heart histology sections and images of dissected fetal hearts. The section on abnormal embryos has been expanded to include movies of embryos with Down's and Turner's syndrome, Triploidy and Neural Tube Defects. Four new 3D fetal models (8, 9, 10 and 11PCW) have been generated from Micro-CT scans. The high resolution eHistology Viewer now contains images from 7 embryonic stages from CS14 to CS23. Gene Expression Database: 619 gene expression images have been archived to the Image Data Resource (https://idr.openmicroscopy.org/). These correspond to 18 genes across 18 stages of development from CS13 to 17PCW. Intellectual Property: HDBR has generated a series of unique 3D models throughout early human development. These models can be shared with other researchers but the copyright will be protected by a material transfer agreement. Education: The HDBR Atlas 3D visualisations of the developing gastro-intestinal tract have been used by colleagues in the School of Medical Education as part of the embryology curriculum for medical students. 
Type Of Material Database/Collection of data 
Year Produced 2009 
Provided To Others? Yes  
Impact Atlas: There have been 5341 site visits - approximately double the number of hits from 2018. Gene Expression Database: There have been 4449 visits to the database site (http://www.biomedatlas.org/hudsenwebapp/pages/hudsen_home.jsf) 
URL http://www.hdbratlas.org/
 
Title HDBR Atlas Website 
Description The HDBR Atlas site has been completely redesigned and rebuilt to make it easier to navigate and link to individual pages. The high resolution eHistology Viewer now contains 11 sets of images from CS12 to CS23. The cardiovascular system has been expanded to include 3 new sets of annotated H&E images at CS14, CS18 and CS22. A new section on the visual system has been added with data submitted by Prof. Linda Lako at Newcastle University. The Central Nervous System section has been extended to include gene expression images in the developing spinal cord, submitted by Prof James Briscoe at the Francis Crick institute, London. Three new 3D models (CS22, CS23 and 13pcw) have been generated from Micro-CT scans. Ten High Resolution Episcopic Microscopy datasets have been reconstructed into 3D models (stages CS12 to CS18) All the HDBR embryonic and fetal 3D models (approximately 300) have been converted to the Amira format. Education: The Atlas and IDR websites were demonstrated as part of an undergraduate online workshop on Genetics of Development and its Disorders. The Atlas continues to be used by colleagues in the School of Medical Education as part of the embryology curriculum for Newcastle medical students with the resources being embedded into online tutorials during the pandemic. We have also been contacted by academics in Dublin and in Pakistan who are using the HDBR Atlas resources for teaching. 
Type Of Material Database/Collection of data 
Year Produced 2009 
Provided To Others? Yes  
Impact There have been over 4000 visits to the HDBR atlas site since March 2020. 
URL http://hdbratlas.org
 
Title HDBR Atlas: Gene Expression in Early Human Development 
Description Gene expression studies in early human development from 3 to 17 post conceptional weeks (PCW). 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact The Image Data Resource gene expression data has now been published and contains over 4500 gene expression images covering stages CS12 to 17 post conceptional weeks. https://doi.org/10.17867/10000137 
URL https://idr.openmicroscopy.org/webclient/?show=project-1104
 
Title HuDSeN 
Description The Human Developmental Studies Network (HuDSeN) aims to provide a forum for researchers in human developmental biology and related fields to meet and establish links. 90 new entries have been made to the HuDSeN human gene expression spatial database in the past year. These correspond to 24 genes (4 of which - DONSON, GFAP, NR2F2 and ZNF804 are novel) across 17 stages of development from CS12 to 17pcw. 3 sets of high resolution H&E images have been added to the HuDSeN atlas of the developing human. In addition, a new eHistology viewer has been added to the Atlas site which now contains CS16, CS17, CS18 and CS19 datasets 
Type Of Material Database/Collection of data 
Year Produced 2009 
Provided To Others? Yes  
Impact There have been 5572 page views on the database site There have been 2371 visits to the Atlas site 
URL http://www.hudsen.eu
 
Description HDBI 
Organisation Wellcome Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution HDBR is the major tissue provider to the HDBI
Collaborator Contribution the other partners will use the tissue we provide in their research
Impact none to date
Start Year 2019
 
Description HDBR UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution HDBR is jointly held between Newcastle and Institute of Child Health, UCL
Collaborator Contribution Newcastle and UCL make an equal contribution to the functions of the HDBR
Impact all outputs are joint with UCL
 
Description MRC- HCA 
Organisation Human Cell Atlas
Sector Charity/Non Profit 
PI Contribution HDBR is the major tissue provider to the MRC-funded Human Developmental Cell Atlas - a component of the HCA
Collaborator Contribution The other partners generate and analyse the transcriptomic data generated
Impact this is still in the early stages so outputs are not apparent yet
Start Year 2018
 
Description SPARTAN 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution SPARTAN (Spatially resolved Transcriptomics @ Newcastle) has been set up as a partnership between the HDBR, and the Genomics, BioImaging and BioInformatics facilities of the Faculty of Medical Sciences at Newcastle University, to provide an end to end service for spatial transcriptomics. The HDBR carries out the tissue end of the process, where thin sections of human embryos are placed on slides and then processed so that the transcriptome of the cells in the embryo can be analysed in situ.
Collaborator Contribution The BioImaging facility images the slides, which is an essential process to allow the mapping back of transcriptomic data to the embryonic region, the Genomics facility sequences the transcriptome, and the BioInformatics Support Unit does the data analysis.
Impact SPARTAN has become a Certified Service Provider for the Visium platform for 10X Genomics - one of only 2 globally and the first in Europe
Start Year 2019
 
Title HDBR/Amira Package 
Description We have liaised with Thermo Fisher Scientific to develop a new software package for Amira. This package is unique to HDBR and allows us to define arbitrary planes in the 3D models and gives us the ability to map 2D gene expression patterns into the 3D models. We have moved away from the obsolete Linux-based software we were using, and the new software package will guarantee that we can view and manipulate the 3D models on Windows PC into the future. 
Type Of Technology Software 
Year Produced 2020 
Impact Without the software we were in danger of losing the ability to map gene expression patterns into the 3D HDBR models. This ability to map to the models is what makes the HDBR Atlas unique. The software package will have a huge impact both within the HDBR group and more widely with students and collaborators, guaranteeing the future-proofing of the collection of the 300+ 3D embryonic and fetal models. 
 
Description Atlas User Feedback Questionnaire 
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 A questionnaire has been sent to all contact in the HDBR mailing list to advertise the updated Atlas site and to get feedback from the wider community about which aspects are most useful, and what additional content would be helpful in an online resource.
Year(s) Of Engagement Activity 2020
 
Description Genetics Matters 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We demonstrated models of human embryos (on screen and 3D printed) and websites to members of the public as part of the Newcastle Genetics Matters Day in February. There were approximately 85 people attending and the images and models seemed to be well received and provoked a lot of questions.
Year(s) Of Engagement Activity 2019
 
Description Genetics Matters 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We demonstrated models of human embryos (on-screen and 3D printed) and websites to members of the public as part of the Newcastle Genetics Matters Day in February. There were approximately 70 people attending and the images and models seemed to be well received and provoked a lot of questions.
Year(s) Of Engagement Activity 2019
 
Description Newcastle Biobank Network 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The Biobank Network was developed and created by the HDBR, designed to bring together researchers who are involved at the operational level of Biobanking. The aim of the forum is to provide a platform, enabling staff to work together, enhance best lab practice, create a gold standard, and share individual expertise. Moreover, the Biobank Network acts as an efficient way for PI's and Persons Designated (PD's) to circulate important information and key HTA changes to the wider target audience. The Biobank Network will be a permanent feature in the HTA newsletter at Newcastle University and is continuing to grow in membership numbers.
Year(s) Of Engagement Activity 2019