SOURCES for EIGHT LIVES
Although Eight Lives is not a depiction of any real person, event or organisation, the story sometimes unfolds against a background of historical events, and the characters refer to real scientific concepts, medical conditions and drug development processes. In the novel, I’ve mostly simplified the discussion of these topics for clarity, although in some instances I’ve exaggerated them for dramatic effect.
This document is for readers interested in learning about the research that underpinned Eight Lives and understanding how the facts relate to the fiction. It has two sections. The first is a referenced summary of the tragic 2006 London drug trial that prompted me to write the novel. Although Eight Lives is in no sense a fictionalised account of that trial, the pharmacological effects of the fictional drug, SMB1412, largely correspond to those of the drug tested in the trial: TGN1412, otherwise known as theralizumab.
The second section comprises a chapter-by-chapter summary of the key written sources for the novel, with brief comments on how the source content relates to the novel’s text. The page numbers for the chapters refer to the 2019 edition published by Affirm Press. The internet links were correct at the time this document was prepared (March 2019).
Note also that expert opinion may vary about some of the matters touched on in Eight Lives: for example, the number of people who perished fleeing Vietnam after the war, or the extent to which the serious adverse effect of TGN1412 was foreseeable. Inclusion in Eight Lives of a statistic or a character’s viewpoint relating to such topics does not infer my agreement with a side of any argument.
Finally, this document comes with a ‘spoiler alert’. It should be read after the novel, not concurrently.
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The TeGenero Trial
TGN1412 was a novel monoclonal antibody being developed by TeGenero Immuno
Therapeutics AG. Before the trial, TGN1412 was expected to therapeutically balance the immune system in diseases as diverse as chronic lymphocytic leukaemia and rheumatoid arthritis. It was referred to as a superagonist.
The trial took place in London on 13 March 2006 and was conducted by the contract research organisation Parexel. Six of the eight volunteers were randomly assigned to receive
TGN1412; the other two received placebo doses. A single dose was administered to each participant ten minutes apart. Within 90 minutes, all six men who received TGN1412 suffered a severe systemic inflammatory response. TGN1412 had caused a rapid release of proinflammatory cytokines, an event known as a ‘cytokine storm’. The six men became critically ill with multi-organ failure and were placed on life support in hospital.
The men survived the reaction. Five were discharged from hospital within two months; the sixth had more prolonged multi-organ failure, pneumonia and septicaemia. He lost toes and fingers due to gangrene. There have been suggestions that damage to the men’s immune systems will be lifelong. Within six months of the trial, one of the men was reported to have developed early signs of a lymphoid malignancy and another to have early signs of lymphatic cancer.
TeGenero became insolvent in 2006, and the study participants attempted to sue Parexel. The
United Kingdom Secretary of State for Health established an Expert Scientific Group to investigate the incident. Their recommendations included a longer interval of observation between sequential dosing of subjects and a broader approach to calculating safe starting doses for first-in-human drug trials, that incorporate the ‘minimum anticipated biological effect level’ (MABEL), rather than just the ‘no observable adverse effect level’ (NOAEL).
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Since the trial, some scientists have claimed that the harmful effects of TGN1412 were foreseeable. Researchers have discovered that TGN1412 stimulates massive cytokine release because of a specific characteristic of human memory T-cells. The corresponding T-cells of the animals on which TGN1412 was tested lack this characteristic. In vitro assays have been developed to screen new monoclonal antibodies for any propensity to cause similar adverse effects. One of these assay systems predicted that a lower dose of TGN1412 would not cause a cytokine storm.
TGN1412 has been renamed TAB08 and is being developed by TheraMAB LLC. A trial of
TAB08 was conducted in Yaroslovl, Russia, from 2011 to 2013. Cohorts of three healthy male volunteers received doses between 1000-fold and 14-fold less than the volunteers in the
TGN1412 trial. None experienced a cytokine storm.
In 2017, the BBC produced a documentary about the TeGenero trial: The Drug Trial:
Emergency at the Hospital. Three of the men who volunteered for the trial, including actor
Rob Oldfield, appeared in the documentary.
References
Beyersdorf N, Hanke T, Kerkau T, Hunig T. Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Annals of the Rheumatic Diseases 2005; 64(11): IV91(5). Available from: https://ard.bmj.com/content/64/suppl_4/iv91.long
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti- CD28 monoclonal antibody TGN1412. The New England Journal of Medicine 2006; 355(10): 1018-28. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa063842
Yaqoob T. ‘Elephant man’ drug trial victim has cancer. Daily Mail. 7 August 2006. Available from: http://www.dailymail.co.uk/news/article-399350/Elephant-man-drug-trial- victim-cancer.html
Four drug-trial victims ready to sue for millions. Daily Mail. 9 March 2007. Available from: http://www.dailymail.co.uk/news/article-441318/Four-drug-trial-victims-ready-sue- millions.htm
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Ferguson PR. The TGN1412 drug disaster. The SciTech Lawyer Spring 2009; 5: p 12+. Available from: http://go.galegroup.com/ps/i.do?id=GALE%7CA206395206&v=2.1&u=unimelb&it=r&p=L T&sw=w&asid=8e8310d6e67ff14d694a44b727dffac7
Expert Group on Phase One Clinical Trials: Final report. The Stationery Office 7 December 2006. Available from: http://webarchive.nationalarchives.gov.uk/+/http://www.dh.gov.uk/en/Publicationsandstatisti cs/Publications/PublicationsPolicyAndGuidance/DH_063117
Horvath CJ, Milton MN. The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event? Toxicologic Pathology 2009; 37(3): 372-83. Available from: http://tpx.sagepub.com/content/37/3/372.full.pdf
Horvath C, Andrews L, Baumann A, et al. Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial. Nature Reviews Immunology 2012; 12(10): 740. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+22941443
Eastwood D, Findlay L, Poole S, et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. British Journal of Pharmacology 2010; 161(3): 512-26. Available from: http://dx.doi.org/10.1111/j.1476- 5381.2010.00922.x
Stebbings R, Eastwood D, Poole S, Thorpe R. After TGN1412: recent developments in cytokine release assays. Journal of Immunotoxicology 2013; 10(1): 75-82. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541671/pdf/IMT-10-1.pdf
Tabares P, Berr S, Romer PS, et al. Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB08. European Journal of Immunology 2014; 44(4): 1225-36. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24374661
Hunig T. The rise and fall of the CD28 superagonist TGN1412 and its return as TAB08: a personal account. The FEBS Journal 2016; 283(18): 3325-34. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=hunig+the+rise+and+fall
The Drug Trial: Emergency at the Hospital. BBC Documentary. https://www.bbc.co.uk/mediacentre/proginfo/2017/08/the-drug-trial
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Prologue (The Australian Times)
Two books provided background about the exodus from Vietnam after the fall of Saigon in
1975:
Nghia M Vo. The Vietnamese Boat People, 1954 and 1975-1992. Jefferson, NC: McFarland & Company, 2006. and
Carina Hoang, Editor. Boat People: Personal Stories from the Vietnamese Exodus 1975- 1996. Cloverdale, WA: Carina Hoang Communications, 2010.
Nghia Vo describes the history of the exodus, as well as individual case studies. Carina
Hoang’s moving book is a compilation of stories told by boat people, including herself, with photographs and illustrations. In the introduction, she estimates that 1.5 million people attempted to escape Vietnam by sea after the end of the Vietnam War, mainly headed for
Hong Kong, Malaysia, Thailand, Indonesia or the Philippines. Hong Kong was a more typical destination for escapees from Northern Vietnam than for those, like Mai and Dung, leaving regions near Saigon. Most refugees escaped on large and typically overcrowded boats, but both Vo and Hoang include stories of families leaving on rafts or small wooden fishing vessels. Pirates, who were often fishermen, were prevalent, robbing, raping and murdering the refugees.
By mid 1979, there was a major humanitarian crisis in the region, with 200,000 Vietnamese refugees housed in camps, and aid workers suffering ‘compassion fatigue’. Vo reports that
‘Local governments refused to take any refugee picked up at sea by tankers and ships’ and
‘Shipping companies advised their skippers not to pick up any refugee at sea’. Countries were
‘pushing back’ boats that attempted to land and many people are believed to have perished as a result. Overall, Carina Hoang estimates that nearly half a million died attempting to escape
Vietnam.
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The Malaysian government reportedly made, then retracted, the threat referred to in Eight
Lives. See:
Chapman W. Malaysia, in clarification, says it will not shoot refugees. The Washington Post, 19 June 1979. Available from: https://www.washingtonpost.com/archive/politics/1979/06/19/malaysia-in-clarification-says- it-will-not-shoot-refugees/9a70a65e-1e6f-4fd5-9aef- 509cd5d260c1/?utm_term=.8623146f7245
In July 1979, the United Nations hosted an international conference to address the crisis.
Western countries increased their resettlement pledges, and Vietnam undertook to institute an orderly departure programme. See:
Chapter 4. Flight from Indochina. In: The State of the World’s Refugees: Fifty Years of Humanitarian Action, Geneva: UNHCR, 2000. 79-105. Available from: http://www.unhcr.org/3ebf9bad0.pdf
Rosa, page 22
Although the drug David Tran discovered was not intended to treat melanoma, the statistics quoted are accurate. In Australia, there were almost 13,000 cases of melanoma reported in
2013, and every five hours one person dies from melanoma. See:
Melanoma facts and statistics. Melanoma Institute of Australia website. Accessed October 2018. https://www.melanoma.org.au/understanding-melanoma/melanoma-facts-and-statistics/
Rosa, page 56
Monoclonal antibodies are a hugely successful drug class. They have been used to treat breast cancer and rheumatoid arthritis, as well as numerous other diseases. Although they’ve been described as ‘magic bullets’, mAbs, like all other drugs, have side-effects. Rosa was exaggerating about this and their commercial success, but only a little. A paper by Ecker et al
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published in 2015 found that eighteen of the forty-seven monoclonal antibodies on the market had achieved annual sales of over $1 billion.
Milstein and Köhler did work out how to make mAbs and were awarded the Nobel Prize in
1984. The first mAb used to treat patients was OKT3, otherwise known as muromonab-CD3.
Benedict Cosimi and colleagues reported its use to prevent kidney transplant rejection. See:
Yamada T. Therapeutic monoclonal antibodies. The Keio Journal of Medicine 2011; 60(2): 37-46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21720199
Buss NA, Henderson SJ, McFarlane M, Shenton JM, de Haan L. Monoclonal antibody therapeutics: history and future. Current Opinion in Pharmacology 2012; 12(5): 615-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22920732
Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. mAbs 2015; 7(1): 9-14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25529996
Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 1981; 32(6): 535-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7041358
Miles, page 61
In relation to the different side effect profiles of chemotherapy and monoclonal antibody therapy for cancer (Sally talks about the decreased risk of hair loss). See:
What’s the Difference between Chemotherapy Drugs and Antibody Drugs? Insight from Dana-Farber Cancer Institute website. 9 June 2017. https://blog.dana- farber.org/insight/2017/06/whats-the-difference-between-chemotherapy-drugs-and-antibody- drugs/
People of Chinese origin living in Vietnam were referred to as Hoa. See Vo’s The
Vietnamese Boat People, 1954 and 1975-1992 for a discussion of their situation after the
Vietnam War. Vo says that most Hoa felt they were really Chinese and few had taken
Vietnamese citizenship. In Saigon ‘… the Hoa lived in Chalon … They were traditional merchants and good businessmen who did not see a role for themselves in the new socialist economy.’
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The special ‘good cop’ blood cells that Miles refers to are regulatory T cells. See:
Bluestone JA, Trotta E, Xu D. The therapeutic potential of regulatory T cells for the treatment of autoimmune disease. Expert Opinion on Therapeutic Targets 2015; 19(8): 1091- 103. Available from: https://cloudfront.escholarship.org/dist/prd/content/qt6c73b1zw/qt6c73b1zw.pdf?t=oiin33
Ly, page 74
Born to Kill was the name of a 1980s New York gang of first-generation Vietnamese immigrants, as well as the slogan some US soldiers emblazoned on their helmets during the
Vietnam War. The name ‘Hands’ is a fiction. See:
Kifner J. Asian Gangs in New York – A Special Report; Immigrant Waves from Asia Bring an Underworld Ashore. The New York Times. 6 January 1991. Available from: https://www.nytimes.com/1991/01/06/nyregion/asian-gangs-new-york-special-report- immigrant-waves-asia-bring-underworld-ashore.html?pagewanted=all
Abigail, page 82
In 2001 John Howard, then the Prime Minister of Australia, and two of his cabinet ministers claimed that asylum seekers on a boat near Christmas Island had thrown their children overboard in an attempt to gain sanctuary in Australia. A subsequent Senate enquiry into the events, referred to as ‘a certain maritime incident’, found the claim false. See:
A Certain Maritime Incident. Commonwealth of Australia. 2002. https://www.aph.gov.au/Parliamentary_Business/Committees/Senate/Former_Committees/ma ritimeincident/report/index
Groups like People for the Ethical Treatment of Animals (PETA) make the case against animal experimentation, and organisations like Understanding Animal Research make the case for animal research. See Deborah Blum’s book and the Understanding Animal Research website for the statistics Abigail quotes on polio:
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Blum D. The Monkey Wars. New York: Oxford University Press, 1994. On page 46, Blum claims that at least a million monkeys died during polio vaccine research.
Polio Vaccine. Understanding Animal Research website. Accessed October 2018. http://www.understandinganimalresearch.org.uk/why/human-health/polio-vaccine/ Understanding Animal Research claims that millions of lives have been saved by eradicating polio.
The following paper details a more complex version of the hot plate test than that described by Abigail, and in rats rather than mice:
Espejo EF, Stinus L, Cador M, Mir D. Effects of morphine and naloxone on behaviour in the hot plate test: an ethopharmacological study in the rat. Psychopharmacology 1994; 113(3-4): 500-10. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7862866
Bioprosthetic aortic valve replacements (like Abigail’s father received) are compared with mechanical valves in this review article:
Zhao DF, Seco M, Wu JJ, et al. Mechanical Versus Bioprosthetic Aortic Valve Replacement in Middle-Aged Adults: A Systematic Review and Meta-Analysis. The Annals of Thoracic Surgery 2016; 102(1): 315-27. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=wu+and+seco+and+edelman+mchanical+versu s+bioprosthetic
Rosa, page 91
There was a Journal of Negative Results in Biomedicine which ceased to be published in
2017. Its mission was to publish null results, thereby correcting bias in literature. It had an impact factor of around one, compared with an impact factor of forty for the journal Nature.
The impact factor reflects how frequently an average article in that journal is cited by other researchers in a particular year. See:
Journal of Negative Results in BioMedicine. Biomed Central website. Accessed October 2018. https://jnrbm.biomedcentral.com
Journal Selection Process. Clairvate website. 26 June 2018. https://clarivate.com/essays/journal-selection-process/
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Rosa says she was working on a mAb for Alzheimer’s disease. There are mAbs in development for this condition. See the following, which reports mice studies aiming to clear plaque deposits:
DeMattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron 2012; 76(5): 908-20. Available from: https://www.cell.com/neuron/pdf/S0896-6273(12)00950-6.pdf
Milstein and Kohler did develop methods for isolation of monoclonal antibodies and were awarded the Nobel prize in 1984 for their work. See the review article by Yamada (sources for Chapter 6, above).
Hybridomas do very occasionally stop expressing the desired monoclonal antibody. See:
Coco-Martin JM, Oberink JW, Brunink F, Van der Velden-de Groot TAM, Beuvery EC. Instability of a hybridoma cell line in a homogeneous continuous perfusion culture system. Hybridoma 1992; 11(5): 653-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1459588
Hybridomas can be stored frozen. See the following for a protocol:
Fuller SA, Takahashi M, Hurrell JG. Freezing and recovery of hybridoma cell lines. Current Protocols in Molecular Biology 2001; Chapter 11: Unit 11.9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18265081
Foxy, page 98
Various immunotherapeutic approaches, including monoclonal antibodies, have been tried for influenza, but at the time of writing I am not aware of any approved for use, let alone stockpiled for this purpose. See:
Yasugi M, Kubota-Koketsu R, Yamashita A, et al. Human monoclonal antibodies broadly neutralizing against influenza B virus. PLoS Pathogens 2013; 9(2): e1003150. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567173/pdf/ppat.1003150.pdf
Governments do, however, stockpile antiviral drugs as part of their precautionary planning for another influenza pandemic. See: 10
SOURCES for EIGHT LIVES
Board on Health Sciences Policy, Health and Medicine Division, National Academies of Sciences, Engineering and Medicine. The Nation's Medical Countermeasure Stockpile: Opportunities to Improve the Efficiency, Effectiveness, and Sustainability of the CDC Strategic National Stockpile: Workshop Summary, Washington (DC): National Academies Press (US); 2016 Oct.
As Foxy says, Australians did invent the ‘black box flight recorder, Wi-Fi, and that rather neat little contraption to get honey on tap from beehives’. See:
David Warren – Inventor of the black box flight recorder. Australian Government Department of Defence Science and Technology website. Accessed October 2018. https://www.dst.defence.gov.au/innovation/black-box-flight-recorder/david-warren-inventor- black-box-flight-recorder
Morris L. Did You Know Australia Invented Wi-Fi? National Geographic website. 10 November 2017. https://www.nationalgeographic.com.au/australia/did-you-know-australia- invented-wi-fi.aspx
Flow Hive. Accessed October 2018. https://www.honeyflow.com.au
The data on venture capital investment returns are more complex than Foxy and Joe suggest.
See:
Balls A. How High are VC Returns? The National Bureau of Economic Research website. Accessed October 2018. Available from: http://www.nber.org/digest/may01/w8066.html
Rosa, page 104
Frankie was a ‘proxy bride’. Between 1945 and 1976 approximately 12,000 Italian women were married in Italy, with a proxy standing in for the Italian-Australian bridegroom. The bride then emigrated to Australia to meet her husband, often for the first time. Marriage-by- proxy was authorised by the Catholic Church. See:
Sacraro S. Italian proxy brides in Australia. Centro Altreitalie. 2009; 38-39: 85-108. Available from: www.altreitalie.it/ImagePub.aspx?id=78609
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There was substantial migration by Swiss-Italians and Italians to the Victorian goldfields in the 1850s. By 1860 there were an estimated 6,000 Italians in Victoria. See:
A Nation’s Heritage – Italians. eGold website. Accessed October 2018. http://www.egold.net.au/biogs/EG00106b.htm
The Ligurian bee is a subspecies of the western honey bee. A hive was brought from Italy to
Kangaroo Island in 1884 and under the 1885 South Australian Ligurian Bee Act the island was declared a sanctuary for the species. I’m unsure whether Ligurians were brought to the
Victorian goldfields by the Italian settlors. Pep may have been misleading Frankie about his ownership of a Ligurian queen, as well as his Italian-speaking abilities.
Foxy, page 111
The three phases of clinical trial testing that occur before a drug is marketed are summarised on the Australian Clinical Trials website:
Phases of clinical trials. Australian Government National Health and Medical Research Council, Department of Industry, Innovation and Science website. Accessed October 2018. https://www.australianclinicaltrials.gov.au/what-clinical-trial/phases-clinical-trials
The probabilities of success for clinical trials that Joe’s business development staff cite are taken from:
Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics 2018; 00: 1-14. https://www.ncbi.nlm.nih.gov/pubmed/29394327 See Table 2 for an autoimmune/inflammation drug like EIGHT.
A 2003 article puts the cost of clinical development of a new drug at $467 million (in 2000
US dollars). See:
Costing drug development. Nature Reviews Drug Discovery 2003; 2(4): 247. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12680358
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The two examples in Joe’s ‘white paper’ about disastrous outcomes of phase one trials are real. In 2016, during the phase one trial of BIA 10-2474 in Rennes, France one healthy volunteer died and four others suffered irreversible brain damage. See:
Kaur R, Sidhu P, Singh S. What failed BIA 10–2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials. Journal of Pharmacology & Pharmacotherapeutics 2016; 7(3): 120-6. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020770/
Mr Jesse Gelsinger died in 1999 after suffering an immune response to the viral vector used to deliver a gene therapy being tested on him. The researcher in charge, Dr James Wilson, has written about the trial, see:
Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Molecular Genetics and Metabolism 2009; 96: 151-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19211285 as has Professor Robin Fretwell Wilson, a legal scholar:
Wilson RF. The death of Jesse Gelsinger: new evidence of the influence of money and prestige in human research. American Journal of Law and Medicine; 36 (2-3): 295-325. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20726398
Like Rosa, the Professor was exaggerating about the sales of monoclonal antibodies (see sources for Chapter 6, above).
A monoclonal antibody, ranibizumab, administered by intraocular injection, can be used to treat macular degeneration. See:
Frampton JE. Ranibizumab: a review of its use in the treatment of neovascular age-related macular degeneration. Drugs Aging 2013; 30(5): 331-58. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23539234
‘Safe Medicines’, referred to in Eight Lives is a fictitious organisation. The Therapeutic
Good Administration (TGA) is the Australian drug regulator. The approval processes for clinical trials differ between countries. In Australia, at the time of writing, approval from the
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TGA was not always required to conduct a phase one clinical trial, although a ‘clinical trial notification’ was required. A human research ethics committee (HREC) is responsible for the ethical and scientific review and considers the protocol and investigator brochure. The
Australian Government promotes Australia as a site to conduct clinical trials. See:
Clinical trials. Australian Government Department of Health Theraputic Goods Administration website. 21 June 2018. https://www.tga.gov.au/clinical-trials
Why conduct a clinical trial in Australia. Australian Government National Health and Medical Research Council Department of Industry, Innovation and Science website. Accessed October 2018. https://www.australianclinicaltrials.gov.au/why-conduct-clinical- trial-australia#overlay-context=industry-and-sponsors
In the United States, individuals or organisations conducting a phase one clinical trial are required to submit an Investigational New Drug (IND) application to the Food and Drug
Administration (FDA) and the plans must also be reviewed by an institutional review board
(IRB). See:
Investigational New Drug (IND) Application. US Food & Drug Administration website. Accessed October 2018. https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved /approvalapplications/investigationalnewdrugindapplication/default.htm
In the United Kingdom, approval from the Medicines and Healthcare Products Regulatory
Agency (MHRA) is required for a phase one clinical trial. See:
United Kingdom. ClinRegs website. Accessed October 2018. https://clinregs.niaid.nih.gov/country/united-kingdom#_top
Rosa, page 119
The rat experiment that Rosa describes Dave doing is real. Adjuvant arthritis is induced in rats by the administration of heat-killed Mycobacterium butyricum and is a model for human rheumatoid arthritis. The paper by Rodriguez-Palermo et al describes the successful treatment of such adjuvant arthritis with JJ316, a variant of TGN1412, the mAb administered in the
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TeGenero trial. In experiments done by the TeGenero group, superagonist CD28 mAbs like
JJ316 were found to activate regulatory T cells in normal rats; activation of regulatory T cells was found to mediate the therapeutic effect seen in the adjuvant arthritis and other autoimmune rat models. See:
Rodriguez-Palmero M, Franch A, Castell M, et al. Effective treatment of adjuvant arthritis with a stimulatory CD28-specific monoclonal antibody. The Journal of Rheumatology 2006; 33(1): 110-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16395758
Beyersdorf N, Hanke T, Kerkau T, Hunig T. Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Annals of the Rheumatic Diseases 2005; 64(11): iv91-iv95. Available from: https://ard.bmj.com/content/64/suppl_4/iv91.long
Beyersdorf N, Hanke T, Kerkau T, Hunig T. CD28 superagonists put a break on autoimmunity by preferentially activating CD4+CD25+ regulatory T cells. Autoimmunity Reviews 2006; 5(1): 40-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=cd28+superagonists+put+a+break+on
Like Rosa says, regulatory T cells would be assayed on a flow cytometer, with each dot representing a cell. The colour of the dots would depend on choices made by the person doing the assay. See:
How To Differentiate T-Regulatory Cells (Tregs) By Flow Cytometry. ExCyte. Accessed October 2018. https://expertcytometry.com/how-to-differentiate-tregs-t-regulatory-cells-by- flow-cytometry/
ClinHelp is a fictional contract research organisation (CRO). It is common for CROs to administer clinical trials. The following articles provide some background:
Roberts DA, Kantarjian HM, Steensma DP. Contract research organizations in oncology clinical research: challenges and opportunities. Cancer 2016; 122(10): 1476-82. Available from: https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.29994
Gobbini E, Pilotto S, Pasello G, et al. Effect of Contract Research Organization Bureaucracy in Clinical Trial Management: A Model From Lung Cancer. Clinical lung cancer 2018; 19(2): 191-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29153968
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Regarding the regulatory and ethics approvals for phase one trials, see comments and sources under Chapter 13, above.
Payment for people who volunteer for clinical trials would normally be approved by the relevant ethics committee. See the Quorum Review for an indication of the levels of reimbursement. See the New Yorker article by Carl Elliott for a further discussion of some of the ethical and human rights issues involved. The reimbursement for participants in the
TeGenero trial was to be 2000 pounds sterling each.
The Ethics of Compensation for Healthy Trial Participants. Quorum. 10 September 2015. https://www.quorumreview.com/ethics-compensation-healthy-trial-participants/
Elliott C. Guinea-Pigging. Healthy human subjects for drug-safety trials are in demand. But is it a living? The New Yorker. 7 January 2008. Available from: https://www.newyorker.com/magazine/2008/01/07/guinea-pigging
Ferguson PR. The TGN1412 drug disaster. The SciTech Lawyer 2009 Spring; p 12+. Available from: http://go.galegroup.com/ps/i.do?id=GALE%7CA206395206&v=2.1&u=unimelb&it=r&p=L T&sw=w&asid=8e8310d6e67ff14d694a44b727dffac7
Guinea Pig Zero, the ‘occupational jobzine for people who are used as medical or pharmaceutical research subjects’ has an article describing a strike. It was written by one of the strike participants. See:
https://www.guineapigzero.com/human-guinea-pigs-organize-and-win.html
Miles, page 130
Seroquel (generic name, quetiapine) is an antipsychotic that is often prescribed ‘off-label’ for conditions including insomnia. See:
Carton L, Cottencin O, Lapeyre-Mestre M, et al. Off-Label Prescribing of Antipsychotics in Adults, Children and Elderly Individuals: A Systematic Review of Recent Prescription Trends. Current Pharmaceutical Design 2015; 21(23): 3280-97. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26088115
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Flecainide is an anti-arrhythmic drug. See:
Brieger D, Amerena J, Attia JR, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the diagnosis and management of atrial fibrillation 2018. The Medical Journal of Australia 2018. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30067936
The technology that Rupert Stone describes to Miles exists. For example, the Adobe tool
VoCo edits audio. See:
Gault M. After 20 Minutes of Listening, New Adobe Tool Can Make You Say Anything. Motherboard website. 6 November 2016. https://motherboard.vice.com/en_us/article/jpgkxp/after-20-minutes-of-listening-new-adobe- tool-can-make-you-say-anything
And videos of a person talking can be manipulated so that the person appears to be saying different words. See:
The Future of Fake News website. Accessed October 2018. http://futureoffakenews.com
Share your science: Real-time facial reenactment of YouTube videos. NVIDIA Developer website. 6 April 2016. https://news.developer.nvidia.com/share-your-science-real-time-facial- reenactment-of-youtube-videos/
Rosa, page 138
It is standard operating procedure to carry out ‘quality control’ assays on monoclonal antibodies harvested from a hybridoma. The subject is complex, but see:
Coco-Martin JM, Oberink JW, van der Velden-de Groot TAM, Coen Beuvery E. Methods for studying the stability of antibody expression by hybridoma cells in homogeneous continuous culture systems. Analytica Chimica Acta 1991; 249(1): 257-62. Available from: http://www.sciencedirect.com/science/article/pii/0003267091870312
For discussions of the inclusion of homeless, and other disenfranchised, people in drug trials see the New Yorker article by Carl Elliott (sources for Chapter 14 above) and:
Bartlett DL and Steele JB. Deadly Medicine. Vanity Fair. 2 December 2010. Available from: https://www.vanityfair.com/news/2011/01/deadly-medicine-201101
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In the TeGenero trial, the men who volunteered received their infusion of the study drug (or placebo) 10 minutes apart. See Suntharalingam et al. (The TeGenero Trial, above).
Part 2
Miles, page 151
An injection of adrenaline could be used for an anaphylactic reaction or for cardiac arrest.
See:
Ring J, Klimek L, Worm M. Adrenaline in the acute treatment of anaphylaxis. Deutsches Ärzteblatt International 2018; 115(31-32): 528-34. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30149833
Advanced Life Support for Adults Guideline. Australian Resuscitation Council. January 2016. https://resus.org.au/guidelines/flowcharts-3/#
The participants in the TeGenero trial experienced headache, restlessness, nausea, vomiting, bowel urgency, diarrhoea and rigours in the two hours after receiving their infusion of the monoclonal antibody TGN1412. See Suntharalingam et al. (The TeGenero trial, above).
Miles, page 169
Suxamethonium chloride (also known as succinylcholine) is a short-acting muscle relaxant used to facilitate endotracheal intubation. See:
Suxamethonium Chloride 50mg/ml Solution for Injection. eMC. Accessed October 2018. https://www.medicines.org.uk/emc/product/5189/smpc
The intraosseous route can be used to administer drugs in emergencies, when intravenous access is unavailable. For background see:
Sunde GA, Heradstveit BE, Vikenes BH, Heltne JK. Emergency intraosseous access in a helicopter emergency medical service: a retrospective study. Scandinavian Journal of
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Trauma, Resuscitation and Emergency Medicine 2010; 18: 52. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+20929544
Abigail, page 174
Participants in the TeGenero trial experienced extreme swelling, and one was dubbed the
‘Elephant Man’ because of his disfigured head. See the BBC documentary. See The
TeGenero trial, above, and:
Allen F. ‘LIKE A HORROR FILM’ What was the ‘Elephant Man’ drug testing trial, what is TGN1412 and what happened to the men involved? The Sun. 21 February 2017. https://www.thesun.co.uk/news/2917810/elephant-man-drug-testing-trial-tgn1412/
In the BBC documentary, Dr Suntharalingam describes the dilemma his team faced regarding the administration of steroids. All the patients received methylprednisolone.
Rosa, page 190
Rosa refers to the ‘Bali Nine’, a group of nine Australians convicted of smuggling heroin out of Indonesia. See:
Bali Nine. Wikipedia. Accessed October 2018. https://en.wikipedia.org/wiki/Bali_Nine
Foxy, page 201
Patients in the TeGenero trial were treated with the monoclonal antibody, daclizumab, which is an antagonist to the cytokine interleukin-2. See Suntharalingam et al (The TeGenero trial, above).
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Abigail, page 211
Abigail refers to the Rwandan genocide. See:
Rwandan genocide. Wikipedia. Accessed October 2018. https://en.wikipedia.org/wiki/Rwandan_genocide
Like Abigail says, in 2006, Prime Minister John Howard did apologise in Parliament to
Vietnamese veterans. See:
Vietnam Veterans Day and the 40th anniversary of the battle of Long Tan. Parliament of Australia website. Accessed October 2018. http://parlinfo.aph.gov.au/parlInfo/search/display/display.w3p;query=Id%3A%22chamber%2 Fhansardr%2F2006-08-17%2F0039%22
Suntharalingam et al (The TeGenero Trial, above) describe the inflammatory responses and clinical course of a cytokine storm. One of the trial participants suffered gangrene to fingers and toes, which then had to be amputated. See the two Daily Mail articles referenced under
The TeGenero Trial, above.
Miles, page 218
Extracorporeal membrane oxygenation (ECMO) is a real therapy. See:
Lindstrom SJ, Pellegrino VA, Butt WW. Extracorporeal membrane oxygenation. The Medical Journal of Australia 2009; 191(3): 178-82. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+19645652
What Miles says about Professor Barry Marshall is correct. Read his Nobel lecture here:
Marshall B. Nobel Lecture on Helicobacter Connections. Nobel Prize website. 8 December 2005. Available from: https://www.nobelprize.org/prizes/medicine/2005/marshall/lecture/
Tisoncik and colleagues give a good summary of cytokine storm:
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Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiology and Molecular Biology Reviews 2012; 76(1): 16-32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/pdf/zmr16.pdf
Miles is again essentially correct when he describes the role of cytokine storm in the symptomatology of influenza. See:
Kuiken T, Taubenberger JK. Pathology of human influenza revisited. Vaccine 2008; 26 Suppl 4: D59. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+19230162
Oldstone MB, Rosen H. Cytokine storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine-1- phosphate agonist molecule. Current Topics in Microbiology and Immunology 2014; 378: 129-47. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24728596
In relation to the 1918 influenza pandemic, cytokine storm is thought to have played a particularly important role in the many, often sudden, deaths of young healthy people. Many other people died from bacterial pneumonia. See John Barry’s excellent book on the pandemic:
Barry JM. The Great Influenza: The Epic Story of the Deadliest Plague in History. New York : Viking; 2004.
Miles is not correct when he says there is a monoclonal antibody treatment for influenza (see
Chapter 11 sources) although such treatments have been tested.
Miles is pessimistic about his friend’s prognosis when he hears Davey’s lactate level is 10
(mmol/L). This prognostic indicator was suggested to me by an ICU doctor. See:
Shetty AL, Thompson K, Byth K, et al. Serum lactate cut-offs as a risk stratification tool for in-hospital adverse outcomes in emergency department patients screened for suspected sepsis. BMJ Open 2018; 8(1): e015492. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780682/
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Rosa, page 226
The monoclonal antibody OKT3 can cause cytokine storm, particularly after the first dose, and some scientists believe that the similarity between OKT3 and TGN1412 made the cytokine storm observed in the TeGenero trial foreseeable. See Horvath et al references (The
TeGenero trial, above).
Rosa claims that Dave and Prof didn’t observe cytokine release with SMB1412 in their rat studies because they didn’t test for it early enough. I do not suggest that this was the case with the corresponding TGN1412 studies—critiquing the design of the TeGenero animal studies is beyond the scope of this document—but Horvath and Milton (see The TeGenero
Trial references, above) claim that the design of the TeGenero monkey studies in relation to the timing of T cell counts ‘do not allow us to conclude that TGN1412 had no effect on monkey T cells’.
Note also that for Rosa’s claim to be valid, the mAb being tested would need to have been made against rat cells. In the TeGenero preclinical studies, for example, three different mAbs were used: JJ316, a mouse anti-rat CD28; 5.11A1, a mouse anti-human CD28; and
TGN1412, a fully humanised anti-CD28 antibody generated by genetic engineering.
Ly, page 231
The ideas that Ly expresses about death, the next life, and not touching a deceased person’s body for a period after their passing, came from a discussion with Venerable Thich Phuoc
Tan, the Abbot at the Quang Minh Buddhist temple in Braybrook, Victoria, Australia.
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Rosa, page 242
In relation to Rosa’s contention that the absence of evidence is not evidence of absence, in the corresponding experiment for TGN1412 Horvath and Milton claim that there was no evidence of CD28 superagonist properties (i.e. stimulation of regulatory T cells) in the monkey studies.
Abigail, page 246
Genetic differences between humans and chimpanzees. What David says is correct. The difference in DNA between humans and chimpanzees is about 1.2%. See:
What does it mean to be human – DNA. Smithsonian National Museum of Natural History website. Accessed October 2018. http://humanorigins.si.edu/evidence/genetics
The ‘forcing’ experiments with monkeys happened at a research facility in Silver Spring,
Maryland in the late 1970s/early 1980s and have been widely reported. The researcher,
Edward Taub, was tried and convicted of animal cruelty. See:
Fraser C. The Raid at Silver Spring. The New Yorker. 19 April 1993. Available from: https://www.newyorker.com/magazine/1993/04/19/the-raid-at-silverspring
Blum D. The Monkey Wars. New York: Oxford University Press; 1994.
Over the period 2010 to 2015 the use of chimpanzees in scientific experiments was phased out. See the PETA website for a summary:
Chimpanzees in Laboratories. PETA. Accessed October 2018. https://www.peta.org/issues/animals-used-for-experimentation/chimpanzees-laboratories/
Foxy, page 251
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Like the Professor tells Foxy and Joe, self-experimentation by scientists and physicians was once a noble tradition. The history of the practice is comprehensively described in Lawrence
Altman’s fascinating book on the subject. The Washington University Medical School in St
Louis was known as the Kamikaze School of Medicine, and one of Dr William Harrington’s experiments there was nearly fatal. Medicinalco was the Danish pharmaceutical company.
The discovery of disulfiram’s efficacy for the treatment of alcoholism stems from their pharmacologists’ self-experiments. See:
Altman LK. Who Goes First? The Story of Self-Experimentation in Medicine. New York: Random House; 1987.
Sadly, the Professor’s anecdote about the death of a lab technician at Johns Hopkins is true.
See:
Kolata G. Johns Hopkins admits fault in fatal experiment. The New York Times. 17 July 2001. Available from: https://www.nytimes.com/2001/07/17/us/johns-hopkins-admits-fault-in-fatal- experiment.html
Miles, page 265
Miles is basically correct: Roger Federer did beat Marcos Baghdatis in the men’s singles final of the 2006 Australian Tennis Open, although he did not quite trounce him. The score was 5-
7, 7-5, 6-0, 6-2.
Rosa, page 273
Chimpanzees have been taught to communicate with human sign language. See Deborah
Blum’s The Monkey Wars, listed under Chapter 30’s sources.
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Rosa, page 286
Rosa would have needed approval from an ethics committee to experiment on primates because animal experiments conducted at an institution that receives National Health and
Medical Research Council funding must be reviewed and approved by an Animal Ethics
Committee. See:
Animal ethics. Australian Government National Health and Medical Research Council website. Accessed March 2019. https://www.nhmrc.gov.au/research-policy/ethics/animal- ethics
Rosa gives a very simplified description of one of the in vitro methods developed since the
TeGenero incident to predict immunotoxicity of monoclonal antibodies. These methods are reviewed in Stebbings et al (see The TeGenero Trial, above). One method does involve warm air-drying using a hair-dryer. See:
Findlay L, Eastwood D, Stebbings R, et al. Improved in vitro methods to predict the in vivo toxicity in man of therapeutic monoclonal antibodies including TGN1412. The Journal of Immunological Methods 2010; 352(1-2): 1-12. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19895813
Miles, page 293
In relation to the Hoa in Vietnam, before and after the fall of Saigon, see two of the sources cited for the Prologue—Nghia Vo’s The Vietnamese Boat People, 1954 and 1975-1992 and
Chapter 4 of the UNHCR book. Also see the following two books:
The Hoa in Vietnam Dossier. Documents of Vietnam Courier. Hanoi: Foreign Languages Publishing House, 1979.
Tran K. The Ethnic Chinese and Economic Development in Vietnam. Singapore: Indochina Unit, Institute of Southeast Asian Studies, 1993.
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Khanh Tran (page 79) discusses the campaign by the Provisional Revolutionary Government against the ‘compradore bourgeoisie’, a communist term for local tycoons who were believed to be working with foreign agents. Launched on 11 September 1975, and known as X1, the campaign involved confiscation of property, a new currency and arrests. About 70 per cent of those arrested and confirmed as compradore bourgeoisie were ethnic Chinese. Nghia Vo
(page 89) and the UNHCR chapter discuss the increasing Vietnamese hostility to the ethnic
Chinese (Hoa) after the fall of Saigon. Many Hoa people crossed the border by land to China, where they were granted settlement. The border was closed in 1978. The UNHCR chapter estimates that as of 1978, 70 per cent of Vietnamese asylum seekers were Hoa.
Ly, page 307
As for Chapter 27, the information about praying for 49 days after a loved one’s death came from a discussion with Venerable Thich Phuoc Tan, the Abbot at the Quang Minh Buddhist temple in Braybrook, Victoria, Australia.
Miles, page 310
Flecainide is an antiarrhythmic agent for which fatal toxicity has been reported. See:
Brazil E, Bodiwala GG, Bouch DC. Fatal flecainide intoxication. Journal of Accident and Emergency Medicine 1998; 15(6): 423-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9825278
Part 3
The Hoa in Vietnam Dossier (see sources for Chapter 37) discusses the ‘Glutamate King’
(Dao Mau), ‘Rice King’ (Ly Long Than), ‘Gasoline King’ (Ly Hoa) and other ‘magnates’ of
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Chinese origin. The book alleges they were ‘shrewd war profiteers’ who colluded with the
US puppets by ‘dishonest methods’ (pages 22 and 81). Chen says all these ‘Kings’ were arrested as part of the anti-compradore bourgeoisie campaign in 1975, and Khanh Tran
(sources for Chapter 37) says ‘Several committed suicide’. See:
Chen KC. China's War with Vietnam, 1979: issues, decisions, and implications. Stanford, California: Hoover Institution Press, Stanford University, 1987.
Abigail, page 331
The Hotel des Mille Collines and the Kigali Memorial Centre are located in Kigali. The hotel was a shelter for people during the genocide (See: the hotel’s website, https://www.millecollines.rw/about/). The Buranda project is fictional.
Jane Goodall did observe violence in chimpanzee communities, and a multi-centre study was established to investigate whether the presence of humans was likely to be the cause. The results suggest that lethal aggression is a means of eliminating rivals, rather than a response to humans. See:
Wilson ML, Boesch C, Fruth B, et al. Lethal aggression in Pan is better explained by adaptive strategies than human impacts. Nature 2014; 513(7518): 414-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25230664
Abigail’s experience with the chimpanzees Quintana and Tike, the photographer Lucien and the Friends of the Chimpanzees are fictional, but animal rights groups have petitioned on several occasions to have specific animals deemed ‘persons’ rather than things. Their first success was in 2016 in Argentina, where a judge decreed that a chimpanzee named Cecilia was a nonhuman legal person. Cecilia was subsequently transferred from a zoo to a sanctuary. In 2015, PETA sued the photographer David Slater for copyright infringement on behalf of a Sulawesi monkey who had purportedly taken a selfie, possibly at Slater’s behest.
See:
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Jabr F. The Person in the Ape: A history of humans trying and failing to understand the minds of apes. Lapham’s Quarterly Winter 2018; 11(1): 183-90. Available from: https://www.laphamsquarterly.org/states-mind/person-ape
Jeong S. Appeals court blasts PETA for using selfie monkey as ‘an unwitting pawn’. The Verge website. https://www.theverge.com/2018/4/24/17271410/monkey-selfie-naruto-slater- copyright-peta
Rosa, page 348
Vietnamese Australian man Van Tuong Nguyen was executed by hanging in Singapore in
December 2005 after being convicted of trafficking heroin under the Misuse of Drugs Act.
See:
Van Tuong Nguyen. Wikipedia. Accessed October 2018. https://en.wikipedia.org/wiki/Van_Tuong_Nguyen
Bio-Plex assay kits can be used to test samples for cytokines on Bio-Plex readers using Bio-
Plex software. See:
Bio-Plex Readers and Tools. Bio-Rad Laboratories website. Accessed October 2018. http://www.bio-rad.com/en-au/category/bio-plex-reader-tools?ID=317582a5-ac11-4e2c-8ee6- 4cf0799352fd
Ly, page 354
Ly’s explanation of prion diseases, also known as transmissible spongiform encephalopathies, is correct, although simplified. Prion disease can occur either spontaneously (for no apparent reason), or be acquired through contact with, or ingestion of, infected material, or be transmitted genetically. Humans can acquire prion disease through invasive medical procedures, such as corneal transplants from cadavers infected with prion disease, or ingestion of contaminated beef or infected human tissue, particularly brain.
The type of disease acquired through consumption of meat from cows affected by bovine spongiform encephalopathy is called variant Creutzfeldt-Jakob disease (vCJD). Prion disease 28
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acquired through cannibalism is referred to as Kuru. Although Kuru and vCJD have slightly different pathologies, and although there has been no example of the transmission of vCJD by cannibalism, given that vCJD can be transmitted by blood transfusion, there is no reason not to believe that it could be transmitted by ingestion of brain from an infected person.
Severe brain ischaemia, which Dung experienced after his cardiac arrest, is likely to camouflage existing prion-associated brain pathology, and thus his prion disease would not be evident on MRI after his collapse.
For further information about prion disease see:
The National CJD Research and Surveillance Unit website. Accessed October 2018. http://www.cjd.ed.ac.uk
BMJ Best Practice website (subscription required). Accessed October 2018. https://bestpractice.bmj.com/info/
Tragically, the extreme privation many refugees experienced during the sea exodus from
Vietnam led some to resort to cannibalism. Carina Hoang, in her introduction to Boat People.
Personal stories from the Vietnamese exodus 1975-1996 refers to such cases. In his chapter in
Carina Hoang’s book, Talbot Bashall, the Controller of the Refugee Control Centre in Hong
Kong, describes the case of Dao Van Cu, a refugee who arrived in Hong Kong tethered to the mast of a small boat. Dao Van Cu claimed that his companions had eaten a boy who died at sea, and that he was due to be eaten next. The story was subsequently reported in the New
York Times. See:
Kamm H. A Vietnamese orphan tells of killings and cannibalism in 52-day sea escape. The New York Times, 1981. https://www.nytimes.com/1981/08/13/world/a-vietnamese-orphan- tells-of-killings-and-cannibalism-in-52-day-sea-escare.html
The Washington Post also published an account of cannibalism reported by survivors of a 37- day voyage from Vietnam to the Philippines, and Kim Chi, a survivor on a boat that reached
Taipei, gave an interview to Radio Free Asia in 2009 describing her experience of eating human flesh during the voyage. See: 29
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Richburg KB. Vietnamese refugees report cannibalism on voyage. The Washington Post. 10 August 1988. Available from: https://www.washingtonpost.com/archive/politics/1988/08/10/vietnamese-refugees-report- cannibalism-on-voyage/a914a8c6-b50a-434c-adda-ac93dff1eef2/?utm_term=.543ad9c12d83
Boat people ‘Ate Their Relatives’: Radio Free Asia, 11 May 2009. Available from: https://www.rfa.org/english/women/food-05112009123100.html
Epilogue, page 361
Like Rosa, scientists have developed in vitro assays that can assess whether a monoclonal antibody causes a cytokine release at specific dose levels. As I state in the Tegenero Trial section, above, some years after the London trial, TGN1412 was tested in a Russian clinical trial using a much lower dose than in the London trial. See Tabares et al.
30