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Notes for DGEmap scientific advisory board meeting – October 2, 2008

Richard Baldock overview

Convergence of HDBR Tom Strachan and Susan Lindsay and the Edinburgh mouse atlas to NIH-funded Electronic Atlas Developing Human Brain project.

Design study is being paid to develop a later project – necessity to produce only prototypes as “results”.

DS five elements: 1 = management, 2 = feasibility as to nature and scope of the research infrastructure, 3 = ethics, 4=lab-based technology, 5=information system technology.

DS2 – eg the folder we just received. Flexible to add in bits about other resources eg. Necker. Explore feasibility of funding including non-EU participation. Simon wants to know why was human studies in human even a question? Model organisms very powerful then people think that is sufficient – make assumptions about how a given gene works in human. Ease of obtaining materials.

DS3 – ethics compare literature; report on relevant research centers, survey and interview of researchers already involved in human embryonic research. Desired a set of procedures and protocols but it has not been done. Michel raises issues not yet addressed around cell line derivation from embryonic/foetal tissues. Parallels between processes of obtaining tissues and regulatory frameworks with embryonic stem cells. Comparison between these different ways of getting cells. New ethical problems around cell/tissue use – what do you tell the donor about how they will be used? UK Polkinghome guidelines require a very vague umbrella “informed” consent whereas stem cell research should give very precise information about the use of the donation. Possibility of developing commercial products also need to be evoked? Seeking consent for cell line derivation after voluntary terminations would be welcome.

Vague not precise use is also encouraged for obtaining consent for human tissue research in Russia.

Simon’s point is when you do know precisely what the tissues are used for, you are under a moral obligation to inform the donors, especially when there are grounds for particular objections. Question of trust. Eg use of human-animal hybrids – donation needs a prospective, explicit consent. When women realized that tissues donated were used for stem cell line creation they realized that they had an objection. Avoid by not telling people very much? Example - using “surplus” tissues – after operations. First consideration is why can’t you obtain the specific informed consent? Hans: Legislation is indeed different in different countries. Wanted to set an international guidelines standard but too ambitious within the design study. However, good practice should be possible.

Michel: scarcity is not in numbers but in the logistics to get the quality necessary for research. People do not see real impact of research – eg. monitoring congenital malformations to give public health service. Potential donors do not necessarily see the value of the work, can this be part of the consent as well?

DS4: looked at Ventana, VisionBiosystems, TECAN, InTavis as automated gene expression systems. Tables for cost and cost-to-run. TECAN seemed to do well for most things, but each system could provide equally good results. Apparently it’s possible to get more reliable/consistent results with the automation if you want to optimize an infrastructure and the use of people. Some depend on company-specific wet supplies, but pictures are the output. Also surveys for marker genes to test these systems. Basis of selection of markers – developmental or disease-related genes, and “expected patterns” cf. mouse – discrete subregions of tissue to assess boundaries being respected, useful for QC. Immunohistochemistry patterns as well. Database of spatially restricted expression.

DS5. Embryo collection and processing the materials, workflows for scientific data management, image processing and visualization, a little bit of gene expression mining – once have a lot of data, Jano and Richard want to actually do research with it (computer scientists might find things that biologists wouldn’t in essence).

Databases with standard portal interface. “Gridsphere” with tabs for different kinds of processing.

These are use-cases, brings up Peter Brezany, but could elicit input with an open architecture so that it might evolve.

Much work on image analysis. Most gene expression data is sparse – only a few precise sections to be parsimonious. What can one extrapolate about what is happening in between? Probabilistic approach. (Needed for 3D reconstruction and definition of limited set of expression pattern structures to make gene pathway member hypotheses.)

“Systems biology” conversion of gene expression networks into cell processes. These need to walk hand-in-hand with hard data otherwise the all-possible-combinations imagine not real organisms or circumstances. Take account in quality and mapping of the hard data of this potential use (eg. Precise delimitation of boundaries to define co- or exclusive expression).

Impact of a design study. “Capacity building” (beurk) what are we trying to do and who is expert to do it? Formalization and standardization of protocols, databases. Prototype protocol and management structure. Journal papers. Raised awareness in FP7. Community building – SAC, HuDSEN, LoS.

Mike Hartley – CELS (centre for excellence for life sciences) Business Services (commercial consultant funded by the region Northeast). Using profits from commercial work to underwrite the non-profit activity. Involved in DS2 – need a single center, building, diffuse network of people? Needs of users, where are they, screening of existing services (us) and offerings possible to Europe? How can this be self-sustaining and paid for? Marie-Laure covered medical research councils, European funding bodies, charities, but there are other private possibilities.

BBSRC – Engineering and Biological Systems, or Gene and Developmental Biology 25% success; add an industrial partner and apply for an Industrial Partnership Award (contributions in kind or resources), ups the changes to 40%. Grants to 500K pounds. Larger, longer grants for 2 million, need a track record first and long-term aims. Aspire to this in 2-5 years or more.

EPSRC – Life science interface programme geared to bioinformatics aspect, products and areas of activity could appeal to this – a workpackage could be detached to get this level of funding. Most do novel biology and novel computer science at the same time. Usually one takes second place to the other but reviewed by both sides. Bundle/package up parts of the project to fit different programmes.

RCUK Large Facilities Roadmap also an aspiration to work towards. He thinks we can use commercial approaches to move “products” forwards and “brand” what we do.

Comparable organizations to see how they are tackling problem. • Leeds Tissue Bank, funded by MRC, Wellcome, Genentech, Covance and other diverse sources. But bring results together even if each package got its own money. • Hunt BioBank in Norway. Made up its own commercial entity, Hunt Biosciences. Would like to offer analytical services/expertise only, not the materials. All publicly funded and supports academic work. • onCoreUK – bank of cancer biopsies. Funded by charity and MRC and department of health. Sale of tissue to researchers to become self-financing. But tissue shortage problem, of course. Marketing strategy with advertising, coming with stands to events. • North East Proteome Analysis Facility. Publicly funded proteomics services for both academia and industry, aims for self-financing.

Combine with other tissue banks for certain services in order to get more visibility.

Examples of Abcam and Clinisciences (Biochain). If we don’t provide in a manner with which we are comfortable others will? MRC funding (what about loi de bioethique?) makes explicit that it is not allowable to sell the human prenatal materials directly. The in situ service can be.

Irina Bystron – SFN executive director will publish in the Journal of Neuroscience of a kind of white paper reflection on points to consider in prenatal tissue use. As many institutions and users as possible. Consensus statement on values. Mike says a good opportunity for branding and subsequent applications. Simon wants to call them “The HuDSEN Principles”. Want bullet points.

Interest in developing cell lines that can be used for pharma development eg. Highly proliferative lines for drug discovery – each client would have specific needs. Validation issues apparently.

Companies possible outsource to Tissue Solutions? They supply human tissues to clients and we could supply them with cells/tissues. Or just e-knowledge: expertise in data interpretation or be a subcontractor for them.

Separate out the banking from the use – run the bank, then material is being drawn from it.

Susan Lindsay – HuDSEN and forward.

Organisation – recognition of scarcity of material and focus on gene expression too narrow. Widening increases problem of material.

Move up from individual descriptions (“stamp-collecting”) to more systems-level, functional questions. Also major driver to collect, store and redistribute data transparently.

Comments – properly take account of doing experiments – address newer technological possibilities eg. do a SAGE study of part of every embryo or whole genome sequencing for each embryo – personal data and ethics?

Make explicit and formalized how to integrate new partners in consortium interested in participating for Germany, Italy, Ireland, Poland…?

Different European resources that exist as of today

On each site for HBDR – Director, obstetrician, manager, laboratory staff (2.6 ETP) and a “research nurse”. Steve Robson in Newcastle = research obstetrician ). 0.6 person to map all the data this only works because of the NIH grant that funds another two people. Nurse is the one who talks to mothers and takes consent for materials for collection. They are licensed by the HTA as a tissue bank. Can provide material without separate ethical approval from users.

Monthly management meetings and 6 teleconference/year between two sites. Every 6 months “joint steering committee” with independent chair, scientist representatives from funding bodies, “lay” member, and representative of Human Tissue Authority. Independent chairperson.

Activities: collect material 3.5-14 weeks, register projects for distribution of tissue/slides and gene expression in house service (charges); distribution and care for MRC fetal tissue bank (8-19 wg), and public dissemination of results – archiving, 3D models, web-based public database.

Peak of embryos around C17-21. 80-100 samples per trimester. 2x C12, 3x C13, 13x C23.

Lots of abnormalities detected mostly chromosomal (62/1641). These tissues are not distributed for projects.

Supply info to JSC: how many projects are ongoing (85), pending (11), completed (75). Decisions on projects once a month, then pilot project with three probes from different parts of the gene, and if everything works that takes 4-6 weeks, depending on if have sections from needed stages. Discussion period – what do now? Then full project can be between 3 months to 2 years. What does the person want to know? Now that costing, being more restrictive and rigourous about an expn pattern eg weak or ubiquitous, may not improve. Too bad. Specific about what is really wanted so as to fulfil the contract.

(my presentation, see here on Slideshare.) Won't embed.

Ogur Gonul - Ondokuz Mayis (19 mai – Turkish independence day) University. Clinical Genetics department – service and education and diagnostics, prenatal and leukemia translocations (also cytogenetics).

120-150 subcultures p2-3 from fibroblast lines from the skin - from DPN? 400-600 bone marrow but then 1000+ amniocyte cultures per year. Sometimes tissues go to the pathology department and then they may keep the paraffin blocks. Otherwise no tissue banking. 10 wk voluntary or 24 wk for medical terminations of pregnancy.

DNA for diagnostic or hopes of diagnosis, as well as “interesting” undiagnosed cases. 25% consangionous! Fryns, Fraser (3 cases one year), Joubert cases… Tri 18 with holoprosencephaly. Most of these have only DNA and some have skin biopsy and cell cultures. Also do MRI imaging of fetuses for brain malformations it’s good.

Started a MSC study.

Teresa Wierzba-Bobrowicz: Collection of fetal human brains 12-22 gestation weeks in Poland

PAF and paraffin – 19-30GW (how does that jive with the 12-22 GW above?)

30 cases with no neuropathological findings. From social abortion but only four years’worth than no more a year ago.

200 cases with abnormalities. Down’s, Dandy-Walker, etc.

Also brains from 5-12 years old 60 cases with tumors or meningoencephalitis. In Epon/resin, 6 Downs cases.

Studies: 2008-12 synapthogenesis and neurogenesis in fetal brains with Down’s syndrome Paper in 2008 on CHILD syndrome; 2007 on autism and striatal circuits. Brain malfos in aniridia in a Russian morphology journal.

Started keeping brains in bank since 2007. 1 adult brain. Some frozen, some fetuses whole in formol. Some dissected into blocks.

Richard Baldock – try to get presentation

Have 2 junior and 1 senior editor the latter of whom checks the work and mapping of the first two. There is another group in Spain (Eurexpress) who does the text annotation of the structures.

Mapping whole mount ISH onto ideal standard embryo. Stack patterns. Point at a region without naming and get similar patterns to another. Can analyze in an automated way. Association between different parts of the embryo expression.

5000 submissions as well as a 30K “repository” – source of things that could be mapped. Most enter through the browse button. There is also programmatic access for computer scientists.

Comparisons of patterns – eg. Pax6 and Sox9 have a lot of similarity as do Dlx5. Spatial cluster interfaces – clusters of genes with a similar pattern. Also “cluster to space” for given precursors.

Damien Bonnet - Outside clinicians could provide malformed fetuses? Also thinking that human embryology could increase how information gets back for teaching esp in medical context, human malformations. European Society for Pediatric Cardiology. Communicate in working groups.

Hans van Bokhoven: possible users include consortia involved in particular diseases (patient groups), geneticists (me: also developmental biologists).

Susan – lots of interest and activity that you can not satisfy – target particular groups might better husband resources. Create demand.

Wants to found a HuDSEN website now, as if we already exist. Will fund in part off of DGEmap extra money.

Robert – have a full-time trainer who goes around conducting workshops, get a + feedback cycle.

We want to put together the “how-to manual”, not least in the light of some outside groups obtaining one-shot fetal materials on their own for various gene expression projects.

  • Heather 12:07, 6 October 2008 (EDT):

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