Wfassignment Table Rock

Highlights

  • • Leading UK geneticists share behind-the-scenes insights from their careers.
  • • Recollections of early computing reveal struggles with technology.
  • • Problems with gene nomenclature are revisited: ‘their gene is like their baby’.

Abbreviations: HGMW, Human Gene Mapping Workshops; MPI, mannose phosphate isomerase

1. Introduction

In June 2015 the transcript of a ‘Witness Seminar’ on the history of the Human Gene Mapping Workshops c.1973–c.1991 was published by the History of Modern Biomedicine Research Group (www.histmodbiomed.org/witsem/vol54). The publication came from a meeting held in March 2014 to which key, mostly UK-based scientists contributed, two of whom had participated in the first Human Gene Mapping Workshop in 1973, and many of whom had been involved in subsequent HGMW (Table 1).

Table 1

Locations and dates of the Human Gene Mapping Workshops.

Witness Seminars are meetings to which a group of people who have been involved in particular discoveries, debates or events are invited to share their reminiscences and memories of ‘what really happened, the stories behind the published literature’ to quote Professor Tilli Tansey who heads the Group, and who developed this approach (Jones & Tansey, 2015).

Through the use of oral history in a group format, the Witness Seminar publications make a unique contribution to the international corpus of primary historical resources on twentieth century human/medical/clinical genetics, with a focus on the life stories of UK-based geneticists. The group format enables participants in the seminars to challenge, corroborate, and/or expand on the reminiscences of their peers. Although these Witness Seminar events and publications differ in style and content from the more traditional one-to-one approach to oral history, they also relate to the body of interviews conducted with scientists and clinicians by other individuals and institutions, such as: the Genetics and Medicine Historical Network of Cardiff University led by Professor Peter Harper (Genetics and Medicine Historical Network's, 2016); ‘Conversations in Genetics’ by the Genetics Society of America with USA-based scientists (Conversations in Genetics, 2016), and the National Human Genome Research Institute's staff interviews in Bethesda (NHGRI, 2016).

Similar to other high-quality oral history resources, the Witness Seminar publications are intended to interact with many other primary source materials which researchers and interested publics may engage with; for example, the ‘Codebreakers: Makers of Modern Genetics’ archival collections of geneticists and related organisations digitised by the Wellcome Library, London, in collaboration with other institutions (Codebreakers, 2016). The Witness Seminar publications also stand alone as significant historical narratives of biomedicine in their own right.

Each Witness Seminar meeting is facilitated by a chairman, the entire proceedings are recorded and transcribed, and then edited, with the addition of references, bibliographies and biographies, and published both in hard copy and as a freely available pdf. Several meetings have already been held and published on genetics-related or genetics-focused topics, including on haemophilia (Tansey & Christie, 1999); rhesus factor (Zallen et al., 2004); genetic testing (Christie & Tansey, 2003); clinical genetics (Harper et al., 2010); clinical cancer genetics (polyposis and familial colorectal cancer) (Jones & Tansey, 2013); and clinical molecular genetics (Jones & Tansey, 2014). All publications can be downloaded from the Group's website at: www.histmodbiomed.org/article/wellcome-witnesses-volumes.

2. Meeting report

Held over half a day, the Witness Seminar on the HGMW included a range of scientists and clinicians, as listed below, with Professor Peter Harper acting as a Chairman/facilitator (Fig. 1):

Fig. 1

Participants at the Witness Seminar on Human Gene Mapping Workshops. Photograph copyright: 'Wellcome Library, London'.

Professor Bert Bakker

(Technician in molecular genetics, 1977–1989/Head of the Laboratory for Diagnostic Genome Analysis, 1990–2015, Leiden University).

Professor Tim Bishop

(Assistant/Associate/Adjunct Professor at Department of Medical Informatics, University of Utah, 1979–1997; Director of the Leeds Institute of Cancer and Pathology, 2011–).

Professor Sir Walter Bodmer

(Professor of Genetics, University of Oxford, 1970–1979; Director of Research/Director General, Imperial Cancer Research Fund, 1979–1996; Head of the Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, 1996–2005).

Professor Ian Craig

(Demonstrator/Lecturer, Genetics Unit, 1970–1996/Professor in Genetics (titular), 1996–1998, Department of Biochemistry, University of Oxford; Head of Molecular Genetics 1998–2001/Professor of Molecular Psychiatric Genetics, King's College, London, 2001 — retired as Emeritus Professor 2015).

Professor Malcolm Ferguson-Smith

(Burton Professor of Medical Genetics, Glasgow University, 1973–1987; Professor/Head of Pathology, Cambridge University, then Professor of Pathology at Cambridge's Department of Veterinary Medicine, 1987–1998).

Professor Peter Harper

(Professor of Medical Genetics; University of Wales College of Medicine, 1971–2004; convenor of the Genetics and Medicine Historical Network, Cardiff University).

Professor Veronica van Heyningen

(Postdoctoral scientist, Medical Research Council's Human Genetics Unit, 1977–1992, then Head of the Cell and Molecular Genetics Section, 1992–2012).

Professor Maj Hultén

(Head of the Regional Genetics Service at East Birmingham/Heartlands Hospital, 1975–1997; Professor Emerita, Karolinska Institutet, Stockholm, 2012–).

Professor Sue Malcolm

(Died 2015. Emerita Professor of Molecular Genetics, University College London, Institute of Child Health).

Professor Michael Morgan

(Director of Research Partnerships and Ventures at the Wellcome Trust (WT)/Chief Executive of the Wellcome Trust Campus in Cambridge, retired from the WT in 2002).

Professor Sue Povey

(Chair of the HUGO Human Gene Nomenclature Committee, 1996–2007; Haldane Professor of Human Genetics, University College London, 2000–2007).

Professor Chris Rawlings

(Project Manager of bioinformatics for HGM10.5/11, Imperial Cancer Research Fund; Head of Department of Computational Systems Biology, Rothamsted Research, 2004–).

Professor Ellen Solomon

(Senior/Principal Scientist, Imperial Cancer Research Fund, 1976–1995; Head of the Department of Molecular Genetics, 1995–2009, Prince Philip Professor of Human Genetics, 2004–).

Dr. Susan Wallace

(Director, Americas Office of the Human Genome Organisation; Lecturer, Population and Public Health Sciences, University of Leicester).

Professor Sue Povey (Fig. 2) of the Galton Laboratory gave a historical introduction to the seminar, reviewing that Laboratory's contributions to human gene mapping research from its 1930s work on haemophilia and colour blindness, comparing it with research conducted elsewhere on Drosophila mapping. Later in the seminar she further framed the historical context for the breakthroughs brought by gene mapping thus: ‘In the 1970s, people, I anyway, didn't think we'd ever find a gene by where it was. I think that you (Walter Bodmer) introduced that in 1980, the reality of it’ (Jones & Tansey, 2015). Professor Sir Walter Bodmer (Fig. 3) outlined his own intellectual role in the field, while acknowledging the input of many others, and pointed to the role of somatic cell genetics research in paving the path to human gene mapping, with personal reference to his experience of working in Guido Pontecorvo's lab. On this trajectory, he also cited a particularly influential paper of the late 1960s: ‘…I think the initial, the first real, experiment that showed linkage mapping in hybrids was Weiss and Green, who used the hybrid technique but not with lymphocytes, and they investigated the chromosomal localization of the thymidine kinase marker that was ultimately shown to be on chromosome 17. That was really the first case that you could associate a marker with something you'd selected for …’ (Jones & Tansey, 2015).

Fig. 2

Professor Sue Povey. Photograph copyright: 'Wellcome Library, London'.

Fig. 3

Professor Sir Walter Bodmer. Photograph copyright: 'Wellcome Library, London'.

Sir Walter's comments are illustrative of how he and other participants in the Witness Seminar filled in the historical ‘jigsaw’ of gene mapping research by linking their direct contributions to those of other geneticists.

On the first Human Gene Mapping Workshop, Professor Ian Craig discussed his experience of representing Bodmer's laboratory at HGM1 in Yale, 1973: ‘I have a strong recollection of arriving very nervously late at night at Yale and being introduced to a cocktail party … this very impressive, tall character, Frank Ruddle, came and said, “You have to talk first thing tomorrow morning”, which was not the best news’ (Jones & Tansey, 2015). Craig evidently survived his nerves, and recalled how the distinctive format for the Workshops emerged at that first event, and also some low-tech methods that were employed: ‘You could see John Edwards and Bette Robson going around and calculating lod scores on the backs of envelopes…’ (Jones & Tansey, 2015).

Originally from Sir Walter's laboratory, Professor Veronica van Heyningen (Fig. 4) attended HGM2 in Rotterdam as a post-doc, and also remembered being unnerved by the imposing Frank Ruddle – founder of Yale's Human Genetics Department and the convenor of HGM1 – when she disproved his assignment of mannose phosphate isomerase (MPI) to chromosome 7: ‘… we had assigned very firmly the mitochondrial malate dehydrogenase to chromosome 7 and it didn't co-segregate with MPI (Craig et al., 1974). Then, later on, we put MPI on a different chromosome, on 15.’ (van Heyningen et al., 1975) (Jones & Tansey, 2015).

Fig. 4

Professor Veronica van Heyningen. Photograph copyright: 'Wellcome Library, London'.

The predominantly UK-based perspectives were broadened by Professor Bert Bakker from Leiden University (Fig. 5), who spoke of his own contributions and especially the importance of new techniques emerging in the 1970s for analysing chromosomes, such as heterochromatin staining, and the breakthrough of Y W Kan and A M Dozy's research on restriction fragment length polymorphisms by the end of that decade (Kan & Dozy, 1978). Despite improving techniques, Professor Malcolm Ferguson-Smith conveyed the painstaking work that his lab undertook on locating globin genes at the end of that decade: ‘… we knew which chromosomes the globin genes were on from the solution mapping …. However, their location on the chromosome was not known. But you (Professor Sue Malcolm) were able to show, doing those wretched silver grain counts, that beta globin mapped to the short arm of chromosome 11 and alpha globin to the short arm of chromosome 16’ (Jones & Tansey, 2015).

Fig. 5

Professor Bert Bakker. Photograph copyright: 'Wellcome Library, London'.

The seminar's participants discussed the wealth of data that had begun to proliferate by the late 1970s in terms of gene linkage analysis, and the subsequent influence of computing in the next decade of the Workshops' proceedings and documentation. In particular, Professor Chris Rawlings relived his role in coordinating the ambitious computational infrastructure for HGM10.5 at St John's College in Oxford in 1990, where the first version of the programme Genome Database was used: ‘…I often describe it a bit like running a rock concert, as you had to bring a team of roadies in to get all this stuff in place … there was a fair amount of blood, sweat and tears involved in this operation …’ (Jones & Tansey, 2015). Another novel insight into the gene mapping community concerned the sensitivities of nomenclature, when Professor Sue Povey recalled her time as Chair of the HUGO Human Gene Nomenclature Committee: ‘… criticism is so characteristic of nomenclature, it's always so controversial and people get so het up about it. Their gene is like their baby and everyone always agrees that one gene should only have one name but they are sure it should be theirs’ (Jones & Tansey, 2015). Also on politics, Professor Michael Morgan shared his experience of the rocky road towards funding the Human Genome Project (HGP) within the Wellcome Trust, and its decision ‘… that as soon as two kilobases of human DNA sequence was accumulated it would be released immediately on the internet, the “no intellectual property” position would be taken … That's had as much of an impact outside of genomics as probably the human genome has had within genomics’ (Jones & Tansey, 2015). Such candid behind-the-scenes revelations about the twists and turns of research into human genetics during the late twentieth century are precisely the stuff that our Witness Seminars are made of.

3. Conclusions

The Witness Seminar on Human Gene Mapping Workshops has created a significant addition to our outputs on the recent history of clinical and medical genetics. The resultant publication provides a unique resource for academics and other researchers/readers who are interested in progress towards the Human Genome Project, and current advances in genomics. We launched our volume at the European Society of Human Genetics satellite meeting, the 6th International Workshop on the History of Human Genetics, Glasgow, in June 2015, where we presented a poster on the seminar, and at which Professor Tansey gave the plenary lecture on ‘recording the voices of modern genetics’ (You're all history now, 2015). Since then, the homepage for the Human Gene Mapping Workshops c.1973–c.1991 publication has had over 250 unique page views on our Group's website, and we look forward to attracting future readers and researchers to this little-documented facet of the history of human genetics.

Acknowledgements

Grateful thanks to Professor Tilli Tansey for her assistance with preparing this paper, and also to the participants in the Witness Seminar and the Chair, Professor Sir Peter Harper. This work is funded by a Strategic Award (097271) to Professor Tilli Tansey from the Wellcome Trust.

References

Christie D.A., Tansey E.M., editors. Vol. 17. Wellcome Trust Centre for the History of Medicine at UCL; London: 2003. http://histmodbiomed.org/witsem/vol17 (Wellcome Witnesses to Twentieth Century Medicine). [PubMed]

Codebreakers . 2016. Makers of Modern Genetics', digitised archives.http://wellcomelibrary.org/collections/digital-collections/makers-of-modern-genetics/digitised-archives/ (accessed 26 January)

Conversations in Genetics 2016. http://www.genestory.org (accessed 26 January)

Craig I.W., van Heyningen V., Finnegan D. Analysis of the mitochondrial enzymes citrate synthase (EC 4.1.3.7) and malate dehydrogenase (EC 1.1.1.37) in human–mouse somatic cell hybrids. Cytogenet. Cell Genet. 1974;13:76–78.[PubMed]

Genetics and Medicine Historical Network's . 2016. Interviews With Founders of Human And Medical Genetics.https://genmedhist.eshg.org/8.0.html (accessed 26 January)

Harper P.A., Reynolds L.A., editors. Vol. 39. The Wellcome Trust Centre for the History of Medicine at UCL; London: 2010. http://histmodbiomed.org/witsem/vol39 (Wellcome Witnesses to Twentieth Century Medicine). [PubMed]

Jones E.M., Tansey E.M., editors. Clinical cancer genetics: polyposis and familial colorectal cancer c.1975–c.2010. Vol. 46. Queen Mary University of London; London: 2013. http://histmodbiomed.org/witsem/vol46 (Wellcome Witnesses to Contemporary Medicine).

Jones E.M., Tansey E.M., editors. Clinical molecular genetics in the UK c.1975–c.2000. Vol. 48. Queen Mary, University of London; London: 2014. http://histmodbiomed.org/witsem/vol48 (Wellcome Witnesses to Contemporary Medicine).

Jones E.M., Tansey E.M., editors. Vol. 54. Queen Mary University of London; London: 2015. http://histmodbiomed.org/witsem/vol54 (Wellcome Witnesses to Contemporary Medicine). 3, 46, 13, 17, 24, 20-1, 44, 59, 66-7, 84.

Kan Y.W., Dozy A.M. Polymorphism of DNA sequence adjacent to human β-globin structural gene: relationship to sickle mutation. Proc. Natl. Acad. Sci. 1978;75:5631–5635.[PubMed]

NHGRI . 2016. History of Genomics Program, Oral History Collection.http://www.genome.gov/27557501 (accessed 26 January)

Tansey E.M., Christie D.A., editors. The Wellcome Trust; London: 1999. http://histmodbiomed.org/witsem/vol4 (Wellcome Witnesses to Twentieth Century Medicine). [PubMed]

van Heyningen V., Bobrow M., Bodmer W.F. Assignment of the genes for human mitochondrial malate dehydrogenase to chromosome 7, for mannose phosphate isomerase and pyruvate kinase to chromosome 15, and, probably, for human esterase-D to chromosome 13 using man–mouse hybrids. Cytogenet. Cell Genet. 1975;14:353–357.[PubMed]

‘You're all history now: recording the voices of modern genetics’; talk by Professor Tilli Tansey, Queen Mary University of London, video available at http://histmodbiomed.org/blog/you%E2%80%99re-all-history-now-recording-voices-modern-genetics (accessed 10 September) 2015.

Zallen D.T., Christie D.A., editors. The Rhesus factor and disease prevention. The Wellcome Trust Centre for the History of Medicine at UCL; London: 2004. http://histmodbiomed.org/witsem/vol22 (Wellcome Witnesses to Twentieth Century Medicine).

It is strongly recommended to the student of this book that he obtain specimens of rock, not labelled, and study their features with a view to naming them. The Table for Identification of Rocks will help in naming them.

It may here be mentioned that the identification of rocks presents peculiar difficulties. Rocks are not definite substances; in some cases, they are mixtures of minerals, while in other cases, they are mixtures of pieces of older rocks. The rock is often so fine grained that it is impossible to distinguish the minerals or the fragments without the aid of the microscope and other laboratory appliances. But, in many cases, the nature of the rock is plainly visible. The student need not feel discouraged if he is not able to “spot” every rock at sight; the most experienced geologist is unable to do this. The following illustrative examples will explain the method of using the Table.

  1. Consult the Table and note that this specimen comes under Division C. Distinctly and Evenly Crystalline. Try its hardness with the knife; it comes under (6), Hard to Scratch. Note, further, that there are three minerals in this rock; the reddish one is identified as feldspar by its good cleavage and hardness; the grayish-white one as quartz, by its glassy look, hardness, and lack of cleavage; the black mineral as mica, by its shiny appearance, softness and cleavage into thin, elastic sheets, or as hornblende, by its hardness and good cleavage. The rock is granite.
  2. Study its appearance, and note that it also comes under Division C. Identify the black, or dark, or green mineral as hornblende or pyroxene, by good cleavage and hardness. Note light-colored crystals, hard and with good cleavage, as feldspar. The specimen is diorite, gabbro, or diabase, hard to distinguish from one another. Actually, this specimen is gabbro. Read the description of these three rocks.
  3. Note its fine-grained appearance; it comes under division B. As it is not scratched with a knife, it is rhyolite, flint, chert, or basalt. Its color is light, and thin flakes are white; therefore, it is rhyolite, flint, or chert. It is rhyolite. See if you can find the glassy round spots of quartz called bird’s eyes. Read description and compare the specimen with it.
  4. Study the specimen carefully as a whole, and note that it comes under E in the Table. Identify the minerals in it as feldspar, quartz, and either mica or hornblende, the same as in granite, specimen No. 1; this specimen is gneiss.
  5. Note from the rounded pebbles and grains of quartz, etc., that the specimen comes under F in the Table. The pieces are mostly of the harder minerals and rocks (try with a knife) and feldspar is not noticeable; the pieces are mostly as large as peas or larger. The rock is conglomerate.

ZOOM

Table for Identification or Rocks

A. Glassy in Texture

  1. Glassy luster; conchoidal fracture. Obsidian 
  2. Resinous or dull, pitchy luster. Pitchstone
  3. Cellular; very light. Pumice

B. Fine-Grained, or Dull and without Grain

(a) SCRATCHED BY FINGER NAIL

  1. Strong, clayey odor when breathed upon; greasy feel after long rubbing; does not fizz with acid  Clay also Shale 
  2. No clayey odor (marl may have clayey odor); no greasy feel; fizzes with acid. Chalk + Marl 
  3. Same as (2), but does not fizz with acid. Tripolite 
  4. Harder; does not fizz with acid; good cleavage. Gypsum 
  5. Soft; greasy feel; often in scales, like mica, but not elastic. Soapstone 

(b) NOT SCRATCHED WITH FINGERNAIL, BUT EASILY WITH KNIFE

  1. Laminated; clayey odor; usually gray; no fizzing, or very little, with acid. Shale also Slate 
  2. No clayey odor, or very feeble; usually gray; powder, white; fizzes with acid. Limestone
  3. Same as 2, but fizzes only when acid is hot. Dolomite 
  4. Usually greenish; powder, white; slightly soapy feel; luster, often waxy; sometimes rather hard to scratch with knife; does not fizz with acid. Serpentine

(c) NOT SCRATCHED WITH KNIFE; SCRATCHES GLASS

  1. Color, light, white in thin flakes; sometimes clayey odor. Rhyolite
  2. Very hard, scratches steel and feldspar; usually light in color; conchoidal fracture. Flint + Chert 
  3. Not so hard as 1 and 2; color dark; heavy; sometimes with roundish holes or amygdules. Basalt 

C. Distinctly and Evenly Crystalline

(a) EASILY SCRATCHED WITH KNIFE

  1. Fizzes with cold acid. Crystalline Limestone 
  2. Fizzes only with hot acid. Dolomite 
  3. Does not fizz with acid; brilliant cleavage surfaces. Gypsum 
  4. Glassy luster; cubic cleavage; salty taste. Rock Salt 

(b) NOT SCRATCHED, OR HARD TO SCRATCH, WITH KNIFE

  1. Usually light-colored; composed of quartz and feldspar, with often mica or hornblende. Granite
  2. Same as 1, but no quartz. Syenite 
  3. Dark gray or black; composed of hornblende and feldspar. Diorite 
  4. Dark gray or black; heavy; composed of pyroxene and feldspar. Gabbro + Diabase
  5. Dark green to black; heavy, composed mostly of hornblende, pyroxene or olivine.  Amphibolite + Pyroxenite + Peridotite 
  6. Composed of grains of quartz, more or less rounded. Sandstone + Quartzite 
  7. Same as 6, but with grains of feldspar, etc. Graywacke 

D. A Fine-Grained Mass with some large Crystals

  1. Crystals of quartz and feldspar in a light-colored mass. Quartz Porphyry + Granite Porphyry 
  2. Crystals of feldspar in a light-colored mass. Feldspar Porphyry + Syenite Porphyry 
  3. Crystals of feldspar, hornblende. black mica, etc., in a dark-colored mass; in dikes Lamprophyre etc. 

E. In Layers or Sheets, more or less Distinct

  1. Same composition as granite. Gneiss 
  2. Mica and quartz. Mica Schist 
  3. Green or black, mostly needle-like or bladed hornblende crystals. Hornblende Schist 
  4. Fine-grained; usually gray; often, clayey odor; splits into smooth, even slabs. Slate
  5. Greasy feel; marks cloth; easily scratched with finger nail. Talc Schist
  6. Composed of sericite, a variety of mica, often with quartz or carbonates between the layers; usually light-colored and glistening. Sericite Schist 
  7. Harder than talc; smooth; green; powder, white or gray; shines like mica. Chlorite Schist 
  8. Limestone, Shale.

F. Composed of Fragments of Rocks or Minerals

  1. Rounded pebbles from the size of a pea to boulders. Conglomerate 
  2. Angular pieces. Breccia
  3. Pieces of volcanic rock. Volcanic Tuff + Volcanic Breccia
  4. More or less rounded grains, mostly of quartz from the size of pea down. Sandstone 
  5. Same as 4, but with feldspar grains. Arkose 
  6. Gray color; fine-grained; quartz, feldspar, and other minerals and rocks. Graywacke 

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