by Kirk, Edwin;
Honestly, though, all of the above is also just detail. None of it really adds much conceptually to the text in chapter 1.
that race was won by Lap-Chee Tsui: This was a fiercely competitive international race. Lap-Chee Tsui was working in Toronto, and the work was done in collaboration with Francis Collins, from the US, among others. Tsui, with Ruslan Dorfman, wrote an article called ‘The Cystic Fibrosis Gene: a molecular genetic perspective’, which describes the discovery of the gene and then goes into considerable detail about its structure — kind of ‘everything you wanted to know about CFTR (the gene) but were afraid to ask’. It’s … a tad technical, but if you’re keen, it’s freely available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC3552342/
Edwards syndrome: Reported in the journal The Lancet. Edwards, J.H. et al. ‘A New Trisomic Syndrome’. Published as The Lancet 1960;1:787–90, but now The Lancet 1960;275:787–90. The Lancet, which was founded in 1823, has a rather confusing history of changes of volume numbering.
2. The DNA Dinner
announcing that the human genome had been sequenced: There are some marvellous documents about the Human Genome Project on the website of the Oak Ridge National Laboratory (www.ornl.gov) — an entire archive of material about the HGP. For example, there is a transcript of the press conference at the White House on 25 June 2000 at: web.ornl.gov/sci/techresources/Human_Genome/project/clinton1.shtml
It’s well worth visiting and having a poke around.
good working draft: International Human Genome Sequencing Consortium. ‘Initial Sequencing and Analysis of the Human Genome’. Nature 2001;409:860–921
Venter, J.C. et al. ‘The Sequence of the Human Genome’. Science 2001;291:1,304–51
still 341 gaps: International Human Genome Sequencing Consortium. ‘Finishing the Euchromatic Sequence of the Human Genome’. Nature 2004;431:931–45
the genome browser run by the University of California, Santa Cruz: This is available at: genome.ucsc.edu
The European version of this is the Ensembl Genome Browser, at www.ensembl.org. While I mainly use the UCSC browser, that’s only a personal preference, and both genome browsers are wonderful. They are freely available to anyone with an interest.
the first scientific report of treatment with insulin: Banting, F.G. et al. ‘Pancreatic Extracts in the Treatment of Diabetes Mellitus’. Canadian Medical Association Journal 1922;12:141–6
3. The boy who wasn’t short
Philadelphia chromosome: This and Rowley’s and Garson’s discoveries are described in various places, but the latter part can be found in the remarkably detailed history of cytogenetics at St Vincent’s Hospital in Melbourne: stvincentsmedicalalumni.org.au/wp/wp-content/uploads/2017/11/2010-Egan-prize-joint-winner_History-of-Cytogenetics-at-SVHM.pdf
as many non-human as human cells in your body: This is controversial, and there are widely varying estimates. I’ve gone with some work published a few years ago: Sender R., Fuchs S., and Milo R. ‘Revised Estimates for the Number of Human and Bacteria Cells in the Body’. PLoS Biology 2016;14(8):e1002533 — freely available at: doi.org/10.1371/journal.pbio.1002533. But they may be wrong.
ten quadrillion cell divisions: This one probably comes under the category of ‘well-informed wild guess’. There’s a source for this at ‘the database of useful biological numbers’, which is hosted by Harvard University (but could still be very wrong on this point): bionumbers.hms.harvard.edu/bionumber.aspx?s=n&v=10&id=100379
40 to 80 changes in your DNA … you didn’t get from the genome of either parent: This at least is based on high-quality data: Gómez-Romero, L. et al. ‘Precise Detection of De Novo Single Nucleotide Variants in Human Genomes’. PNAS 2018;115(21):5,516–21
a recent study suggests that, typically, there is one new mistake per cell division: Milholland, B. et al. ‘Differences Between Germline and Somatic Mutation Rates in Humans and Mice’. Nature Communications 2017;8:15,183
what they actually found was … horrifying: The source of the image and accompanying information is: Martincorena, I. et al. ‘High Burden and Pervasive Positive Selection of Somatic Mutations in Normal Human Skin’. Science 2015;348(6,237):880–6
a group of researchers led by Mary-Claire King … narrowed down the location of BRCA1: Hall, J.M. et al. ‘Linkage of Early-Onset Familial Breast Cancer to Chromosome 17q21’. Science 1990:250(4,988):1,684–9
In May 1994, a group from the University of Utah, in collaboration with a group from Cambridge University in the UK: Albertson, H.M. et al. ‘A Physical Map and Candidate Genes in the BRCA1 Region on Chromosome 17q12–21’. Nature Genetics 1994;7:472–9
publication of the sequence of the gene [BRCA1]: Miki, Y. et al. ‘A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1’. Science 1994;266(5,182):66–71
another British-led group, headed by Michael Stratton, published the sequence of BRCA2: Wooster, R. et al. ‘Identification of the Breast Cancer Susceptibility Gene BRCA2’. Nature 1995;378:789–92
Myriad … had applied for a patent: There is a long but fascinating article about the history of this topic: Gold, E.R. and Carbone, J. ‘Myriad Genetics: in the eye of the policy storm’. Genetics in Medicine 2010;12(4 Suppl.):S39–S70
The article is freely available online via Pubmed Central and is well worth a read: www.ncbi.nlm.nih.gov/pmc/articles/PMC3037261/
4. Uncertainty
a majority of couples request termination: A review of 19 studies that looked at choices made after prenatal diagnosis of a sex chromosome condition found that, for Turner syndrome (45,X), pregnancies were terminated on average 76 per cent of the time; for XXY, it was 61 per cent; and for XXX and XYY, 32 per cent. The studies were from 13 different countries, mostly developed nations. Jeon, K.C., Chen, L-S, and Goodson, P. ‘Decision to Abort After a Prenatal Diagnosis of Sex Chromosome Abnormality’. Genetics in Medicine 2012;14:27–38
5. Needles in stacks of needles
Knome’s US$24,500 exome service: MacArthur, D. ‘Knome Offers Sequencing of All of Your Protein-Coding Genes for $24,500’. Wired 10 May 2009. Available at: www.wired.com/2009/05/knome-offers-sequencing-of-all-of-your-protein-coding-genes-for-24500/
Dan Stoicescu: Harmon, A. ‘Gene Map Becomes a Luxury Item’. The New York Times 4 March 2008. Available at: www.nytimes.com/2008/03/04/health/research/04geno.html
James Watson’s genome: The article describing this is open-access — freely available online — from Nature: Wheeler, D.A. et al. ‘The Complete Genome of an Individual by Massively Parallel DNA Sequencing’. Nature 2008;452:872–6. The senior author on this paper was Jonathan Rothberg. It is available at: www.nature.com/articles/nature06884
studies in fish came to a pretty similar conclusion: Halligan, D.L. and Keightley, P.D. ‘How Many Lethal Alleles?’ Trends Genet 2003;19(2):57–9
a Danish group, led by Morten Olesen: Refsgaard, L. et al. ‘High Prevalence of Genetic Variants Previously Associated with LQT Syndrome in New Exome Data’. European Journal of Human Genetics 2012;20:905–8
Andreasen, C. et al. ‘New Population-Based Exome Data are Questioning the Pathogenicity of Previously Cardiomyopathy-Associated Genetic Variants’. European Journal of Human Genetics 2013;21:918–28
Genome In A Bottle: Information about the GIAB consortium is at: www.nist.gov/programs-projects/genome-bottle
For example, the genes CACNB2 and KCNQ1 are both commonly included in panels of genes for testing people with hypertrophic cardiomyopathy: And they aren’t the only ones. There’s a really useful paper that looks at a long list of genes included in hypertrophic cardiomyopathy panels and concludes that many of them have limited or no evidence for a link to the condition: Ingles, G. et al. ‘Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes’. Circulation: Genomic and Precision Medicine 2019;12:e002460. The paper is freely available online at: www.ahajournals.org/doi/10.1161/CIRCGE
N.119.002460
6. Power!
the story of life on Earth: There’s a nice article about this: Marshall, M. ‘Timeline: the evolution of life’. New Scientist 14 July 2009. Available at: www.newscientist.com/article/dn17453-timeline-the-evolution-of-life/
The earliest person whose name we know: Robert Krulwich of Radiolab fame wrote about this: Krulwich, J. ‘Who’s the First Person in History Whose Name We Know?’ National Geographic 19 August 2015. Available at: www.nationalgeographic.com/science/phenomena/2015/08/19/whos-the-first-person-in-history-whose-name-we-know/
nothing but human beings for two kilometres: This assumes a generation time of 33 years, which is conservative, and emergence of modern humans about 200,000 years ago. You can find various estimates for both of these figures. If you assume a generation time of 25 years and emergence of modern humans 300,000 years ago, it would be nothing but humans for four kilometres.
mitochondria live their own little lives: This is fairly full-on science, but, if you are keen, makes for fascinating reading: Sasaki, T. et al. ‘Live Imaging Reveals the Dynamics and Regulation of Mitochondrial Nucleoids During the Cell Cycle in Fucci2-HeLa Cells’. Scientific Reports 2017;7:11,257
as we age, our mitochondria accumulate damage: see Bua, E. et al. ‘Mitochondrial DNA-Deletion Mutations Accumulate Intracellularly to Detrimental Levels in Aged Human Skeletal Muscle Fibers’. American Journal of Human Genetics 2006;79(3):469–80
mitochondrial bottleneck: Khrapko, K. ‘Two Ways to Make a mtDNA Bottleneck’. Nature Genetics 2008;40(2):134–5 — this article is freely available at Pubmed Central: www.ncbi.nlm.nih.gov/pmc/articles/PMC3717270/
a patient who had been seen at Sydney Children’s Hospital more than 20 years previously: Lim, S.C. et al. ‘Mutations in LYRM4, Encoding Iron-Sulfur Cluster Biogenesis Factor ISD11, Cause Deficiency of Multiple Respiratory Chain Complexes’. Human Molecular Genetics 2013;22(22):4,460–73
Pauline’s story: I’ve seen families who have experienced similar events, but the specific mutation-load numbers in this story are adapted from a family reported by David Thorburn and colleagues: Thorburn, D.R., Wilton L., and Stock-Myer, S. ‘Healthy Baby Girl Born Following Pre-Implantation Genetic Diagnosis for Mitochondrial DNA m.8993T>G Mutation’. Molecular Genetics and Metabolism 2009;98:5–6
7. Dysmorphology Club
Later art contained ever clearer depictions of specific conditions: See, for instance, Bukvic, N. and Elling, J.W. ‘Genetics in Art and Art in Genetics’. Gene 2015;555(1):14–22
immigration delay disease: Burger, B. et al. ‘The Immigration Delay Disease: adermatoglyphia-inherited absence of epidermal ridges’. Journal of the American Academy of Dermatology 2011;64:974–80
CATCH22 … John Burn: Burn, J. ‘Closing Time for CATCH22’. Journal of Medical Genetics 1999;36:737–8
Eva Sedláčková: Vrtička, K. ‘Present-Day Importance of the Velocardiofacial Syndrome’. Folia Phoniatrica et Logopaedica 2007;59:141–6
Jacqueline Noonan: Opitz, J. ‘The Noonan Syndrome’. American Journal of Medical Genetics 1985;21:515–18. This is the same John Opitz after whom numerous syndromes are named.
Bettex and Graf: Bettex, M. et al. ‘Oro-Palatal Dysplasia Bettex-Graf — a New Syndrome’. European Journal of Pediatric Surgery 1998;8(1):4–8
Julius Hallervorden: Shevell, M. ‘Racial Hygiene, Active Euthanasia, and Julius Hallervorden’. Neurology 1992;42:2,214–19
John Langdon Down: Down, J. ‘Observations on an Ethnic Classification of Idiots’. London Hospital Reports 1866;3:259–62
the term ‘mongolism’ for Down syndrome was common at least until the 1960s, and probably later: When I was a medical student in the 1980s, I remember the doctors who taught us paediatrics telling us not to use the term, which suggests it may have remained in use by some even then.
Strickland’s rules: Rookmaaker, L.C. ‘The Early Endeavours by Hugh Edwin Strickland to Establish a Code for Zoological Nomenclature in 1842–1843’. Bulletin of Zoological Nomenclature 2011;68(1):29–40
Cantú and his group were expressing uncertainty about this: Garcia-Cruz, D. et al. ‘Congenital Hypertrichosis, Osteochondrodysplasia, and Cardiomegaly: further delineation of a new genetic syndrome’. American Journal of Medical Genetics 1997;69:138–51
Kathy Grange … made the inspired observation: Grange, D.K. et al. ‘Cantú Syndrome in a Woman and Her Two Daughters: further confirmation of autosomal dominant inheritance and review of the cardiac manifestations’. American Journal of Medical Genetics A 2006:140(5):1,673–80
8. How to make a baby
He Jiankui had used the CRISPR technology … to change the genetic make-up of two babies: BBC News has reported extensively on these events. See, for example, ‘China Jails “Gene-Edited Babies” Scientist for Three Years’, 30 December 2019, available at: www.bbc.com/news/world-asia-china-50944461
There is a fascinating article about these events: Lovell-Badge, R. ‘CRISPR Babies: a view from the centre of the storm’. Development 2019;146:dev175778 — freely available at: dev.biologists.org/content/develop/146/3/dev175778.full.pdf
9. Complexity
childproof lid: See the Canadian Medical Hall of fame: www.cdnmedhall.org/inductees/henribreault
Kelsey was a remarkable woman: Bren, L. ‘Frances Oldham Kelsey: FDA medical reviewer leaves her mark on history’. FDA Consumer March–April 2001. Available at: permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2001/201_kelsey.html
‘Heroine’ of FDA Keeps Bad Drug Off of Market: The Washington Post 15 July 1962
There have been questions raised about how reliably they can assess risks: The work of Karavani, E. et al. (Cell 2019;179(6):P1424–1435.E8) provides a detailed critique of the approach. A version of this paper posted ahead of publication is freely available at bioRxiv at: www.biorxiv.org/content/10.1101/626846v1.full
The published research on which the test apparently rests: Lello, L. et al. ‘Genomic Prediction of 16 Complex Disease Risks Including Heart Attack, Diabetes, Breast and Prostate Cancer’. Scientific Reports 2019;9:15,286
10. A spoonful of mannose-6-phosphate
Jesse Gelsinger: There’s an informative piece about the events that led to Jesse’s death, and the aftermath, on the website of the Science History Institute. Rinde, M. ‘The Death of Jesse Gelsinger, 20 Years Later’. 4 June 2019. Available at: www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later
Was the Human Genome Project a Dud? Torrey, E.F. Dallas Morning News 13 October 2019
enzyme replacement therapy: There’s an interesting article about Roscoe Brady’s work from the Office of NIH History at: history.nih.gov/exhibits/gaucher/docs/page_04.html
11. Please, screen me
tributes written by colleagues after his death are carefully worded: These can be found at: www.robertguthriepku.org/tributes/
resisted the addition of some other conditions to newborn screening: Guthrie, R. ‘The Origin of Newborn Screening’. Screening 1992;1:5–15
first successful treatment of a child with PKU: Bickel, H., Gerrard, J., and Hickmans, E.M. ‘Influence of Phenylalanine Intake on Phenylketonuria’. The Lancet 1953;265(6,790):812–13
In 1968, a 29-year-old woman: Valenti, C., Schutta, E.J., and Kehaty, T. ‘Prenatal Diagnosis of Down’s syndrome’. The Lancet 1968;2:220
Malaria remains a serious killer: These are from the World Health Organization www.who.int/news-room/fact-sheets/detail/malaria and the Global Burden of Disease Study — Roth, G.A. et al. ‘Global, Regional, and National Age-Sex-Specific Mortality for 282 Causes of Death in 195 Countries and Territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017’. The Lancet 2018;392(10,159):1,736–88
Israel is the undisputed world leader: Zlotogora, J. ‘The Israeli National Population Program of Genetic Carrier Screening for Reprodu
ctive Purposes. How Should It Be Continued?’ Israel Journal of Health Policy Research 2019;8:73
George Stamatoyannopoulos: Srivastava, A. et al. ‘A Tribute to George Stamatoyannopoulos’. Human Gene Therapy 2016;27(4):280–6