Inleiding Filosofie en Ethiek6e bijeenkomst

Genomics 1Vrijdag 3 Juni 2005

Van Genetica tot Genomics• 1900: Mendel

• 1953: Watson & Crick

• 2000: Human Genome

Gregor Mendel (1822 – 1884)

Watson & Crick (1953)

Watson & Crick

Molecular structure of Nucleic AcidsWATSON, J. D. & CRICK, F. H. C.Medical Research Council Unit for the Study of Molecular Structure of Biological Systems, Cavendish Laboratory, Cambridge.A Structure for Deoxyribose Nucleic Acid

We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.A structure for nucleic acid has already been proposed by Pauling and Corey1. They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons: (1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other. (2) Some of the van der Waals distances appear to be too small.Another three-chain structure has also been suggested by Fraser (in the press). In his model the phosphates are on the outside and the bases on the inside, linked together by hydrogen bonds. This structure as described is rather ill-defined, and for this reason we shall not comment on it.

1962

Watson & Crick

Director Human Genome Project

The Human Genome Project 1990-2003

The Genome War: How Craig Venter Tried to Capture the Code of Life and Save the WorldPublished in Hardcover by Knopf (06 January, 2004)Author: James Shreeve

Francis Collins

Craig Venter

Craig Venter

Craig Venter

Craig Venter

Craig VenterCraig Venter

Craig Venter

"The sequence of the human genome,“By J. Craig Venter and 284 othersScience, 291(5507):1304-51, 16 February 2001.

The Sequence of the Human GenomeJ. Craig Venter,1* Mark D. Adams,1 Eugene W. Myers,1 Peter W. Li,1 Richard J. Mural,1 Granger G. Sutton,1 Hamilton O. Smith,1 Mark Yandell,1 Cheryl A. Evans,1 Robert A. Holt,1 Jeannine D. Gocayne,1 Peter Amanatides,1 Richard M. Ballew,1 Daniel H. Huson,1 Jennifer Russo Wortman,1 Qing Zhang,1 Chinnappa D. Kodira,1 Xiangqun H. Zheng,1 Lin Chen,1 Marian Skupski,1 Gangadharan Subramanian,1 Paul D. Thomas,1 Jinghui Zhang,1 George L. Gabor Miklos,2 Catherine Nelson,3 Samuel Broder,1 Andrew G. Clark,4 Joe Nadeau,5 Victor A. McKusick,6 Norton Zinder,7 Arnold J. Levine,7 Richard J. Roberts,8 Mel Simon,9 Carolyn Slayman,10 Michael Hunkapiller,11 Randall Bolanos,1 Arthur Delcher,1 Ian Dew,1 Daniel Fasulo,1 Michael Flanigan,1 Liliana Florea,1 Aaron Halpern,1 Sridhar Hannenhalli,1 Saul Kravitz,1 Samuel Levy,1 Clark Mobarry,1 Knut Reinert,1 Karin Remington,1 Jane Abu-Threideh,1 Ellen Beasley,1 Kendra Biddick,1 Vivien Bonazzi,1 Rhonda Brandon,1 Michele Cargill,1 Ishwar Chandramouliswaran,1 Rosane Charlab,1 Kabir Chaturvedi,1 Zuoming Deng,1 Valentina Di Francesco,1 Patrick Dunn,1 Karen Eilbeck,1 Carlos Evangelista,1 Andrei E. Gabrielian,1 Weiniu Gan,1 Wangmao Ge,1 Fangcheng Gong,1 Zhiping Gu,1 Ping Guan,1 Thomas J. Heiman,1 Maureen E. Higgins,1 Rui-Ru Ji,1 Zhaoxi Ke,1 Karen A. Ketchum,1 Zhongwu Lai,1 Yiding Lei,1 Zhenya Li,1 Jiayin Li,1 Yong Liang,1 Xiaoying Lin,1 Fu Lu,1 Gennady V. Merkulov,1 Natalia Milshina,1 Helen M. Moore,1 Ashwinikumar K Naik,1 Vaibhav A. Narayan,1 Beena Neelam,1 Deborah Nusskern,1 Douglas B. Rusch,1 Steven Salzberg,12 WeiShao,1 Bixiong Shue,1 Jingtao Sun,1 Zhen Yuan Wang,1 Aihui Wang,1 Xin Wang,1 Jian Wang,1 Ming-Hui Wei,1 Ron Wides,13 ChunlinXiao,1 Chunhua Yan,1 Alison Yao,1 Jane Ye,1 Ming Zhan,1 Weiqing Zhang,1 Hongyu Zhang,1 Qi Zhao,1 Liansheng Zheng,1 Fei Zhong,1 Wenyan Zhong,1 Shiaoping C. Zhu,1 Shaying Zhao,12 Dennis Gilbert,1 Suzanna Baumhueter,1 Gene Spier,1 Christine Carter,1 AnibalCravchik,1 Trevor Woodage,1 Feroze Ali,1 Huijin An,1 Aderonke Awe,1 Danita Baldwin,1 Holly Baden,1 Mary Barnstead,1 Ian Barrow,1 Karen Beeson,1 Dana Busam,1 Amy Carver,1 Angela Center,1 Ming Lai Cheng,1 Liz Curry,1 Steve Danaher,1 Lionel Davenport,1 RaymondDesilets,1 Susanne Dietz,1 Kristina Dodson,1 Lisa Doup,1 Steven Ferriera,1 Neha Garg,1 Andres Gluecksmann,1 Brit Hart,1 Jason Haynes,1 Charles Haynes,1 Cheryl Heiner,1 Suzanne Hladun,1 Damon Hostin,1 Jarrett Houck,1 Timothy Howland,1 Chinyere Ibegwam,1 Jeffery Johnson,1 Francis Kalush,1 Lesley Kline,1 Shashi Koduru,1 Amy Love,1 Felecia Mann,1 David May,1 Steven McCawley,1 Tina McIntosh,1 Ivy McMullen,1 Mee Moy,1 Linda Moy,1 Brian Murphy,1 Keith Nelson,1 Cynthia Pfannkoch,1 Eric Pratts,1 Vinita Puri,1 HinaQureshi,1 Matthew Reardon,1 Robert Rodriguez,1 Yu-Hui Rogers,1 Deanna Romblad,1 Bob Ruhfel,1 Richard Scott,1 Cynthia Sitter,1 Michelle Smallwood,1 Erin Stewart,1 Renee Strong,1 Ellen Suh,1 Reginald Thomas,1 Ni Ni Tint,1 Sukyee Tse,1 Claire Vech,1 Gary Wang,1 Jeremy Wetter,1 Sherita Williams,1 Monica Williams,1 Sandra Windsor,1 Emily Winn-Deen,1 Keriellen Wolfe,1 Jayshree Zaveri,1 KarenaZaveri,1 Josep F. Abril,14 Roderic Guigó,14 Michael J. Campbell,1 Kimmen V. Sjolander,1 Brian Karlak,1 Anish Kejariwal,1 Huaiyu Mi,1 Betty Lazareva,1 Thomas Hatton,1 Apurva Narechania,1 Karen Diemer,1 Anushya Muruganujan,1 Nan Guo,1 Shinji Sato,1 Vineet Bafna,1 Sorin Istrail,1 Ross Lippert,1 Russell Schwartz,1 Brian Walenz,1 Shibu Yooseph,1 David Allen,1 Anand Basu,1 James Baxendale,1 Louis Blick,1 Marcelo Caminha,1 John Carnes-Stine,1 Parris Caulk,1 Yen-Hui Chiang,1 My Coyne,1 Carl Dahlke,1 Anne Deslattes Mays,1 Maria Dombroski,1 Michael Donnelly,1 Dale Ely,1 Shiva Esparham,1 Carl Fosler,1 Harold Gire,1 Stephen Glanowski,1 Kenneth Glasser,1 Anna Glodek,1 Mark Gorokhov,1 Ken Graham,1 Barry Gropman,1 Michael Harris,1 Jeremy Heil,1 Scott Henderson,1 Jeffrey Hoover,1 Donald Jennings,1 Catherine Jordan,1 James Jordan,1 John Kasha,1 Leonid Kagan,1 Cheryl Kraft,1 Alexander Levitsky,1 Mark Lewis,1 XiangjunLiu,1 John Lopez,1 Daniel Ma,1 William Majoros,1 Joe McDaniel,1 Sean Murphy,1 Matthew Newman,1 Trung Nguyen,1 Ngoc Nguyen,1 Marc Nodell,1 Sue Pan,1 Jim Peck,1 Marshall Peterson,1 William Rowe,1 Robert Sanders,1 John Scott,1 Michael Simpson,1 Thomas Smith,1 Arlan Sprague,1 Timothy Stockwell,1 Russell Turner,1 Eli Venter,1 Mei Wang,1 Meiyuan Wen,1 David Wu,1 Mitchell Wu,1 Ashley Xia,1 Ali Zandieh,1 Xiaohong Zhu1

Wat is genomics?Genomics is a trans-disciplinary field that studies genes and their function. It sets out to map all genetic information of humans, animals, plants and micro-organisms. It unravels their blueprint, by means of DNA sequencing (structural genomics), but its basic objective is to understand the function of genes (functional genomics), the manner in which hereditary characteristics are translated functionally, on the cell level and, ultimately, on the level of the organism, in interaction with the environment. Genomics is a combination of molecular biology, genetics, and Informatics.

Wat is genomics?

• Converging technology• Enabling technology• Synthesis of Molecular Biology,

Genetics and Bioinformatics

Wat is genomics?

• Term “genomics” introduced in 1987• “Structural genomics” (mapping the

genome of model species)• “Functional genomics” (understanding

complexity)

Wat is genomics?

• Traditional genetics• Biotechnology• Genomics

A Quantum-Leap in the life sciences?

• Genomics is not about the function of single genes, but rather about the interaction between large numbers of genes and other (notably environmental) factors

• Understanding Complexity• Post-reductionism• Unlike biotechnology, genomics does not focus on

genetic modification of organisms (knock-out or gene transfer experiments) or on detecting, transferring or deleting single genes. Rather its basic objective is to make visible complex interactions

“Definition politics”(The sceptic view)

• Continuity between genetics, biotechnology & genomics

• Genomics: a buzzword introduced for strategic reasons (ensuring funding, foregoing unfavorable associations in the public realm)

• Genomics “News”• Genomics will eventually reinforce genetic

determinism

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The Human Genome Project1990 - 2003

1953 - 2003• BETHESDA, Md., April 14, 2003 – The International Human Genome

Sequencing Consortium, led in the United States by the National Human Genome Research Institute (NHGRI) and the Department of Energy (DOE), today announced the successful completion of the Human Genome Project more than two years ahead of schedule.

• Also today, NHGRI unveiled its bold new vision for the future of genome research, officially ushering in the era of the genome. The vision will be published in the April 24 issue of the journal Nature, coinciding with the 50th anniversary of Nature’s publication of the landmark paper by Nobel laureates James Watson and Francis Crick that described DNA’s double helix. Dr. Watson also was the first leader of the Human Genome Project.

• The international effort to sequence the 3 billion DNA letters in the human genome is considered by many to be one of the most ambitious scientific undertakings of all time, even compared to splitting the atom or going to the moon.

Nature 431, 931 - 945 (21 October 2004)

Finishing the euchromatic sequence of the human genomeINTERNATIONAL HUMAN GENOME SEQUENCING CONSORTIUM

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers 99% of the euchromatic genome and is accurate to an error rate of 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000–25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.

September 1988NIH establishes the Office of Human Genome Research.

Watson declares that 5% of the genome budget should be devoted tostudies of social and ethical issues.

June 26, 2000Bill Clinton, Craig Venter, Francis Collins announce

completion of the human genome

February 2001The HGP consortium publishes

its working draft in Nature (15 February),and Celera publishes its draft in Science (16 February).

21 October 2004Finishing the sequencing of the human genome

20,000 – 25,000 genes

The Human Genome Project

“The Human Genome Project is the culmination of the reductionist approach characteristic of molecular biology”(Vicedo 1992).

The Human Genome

• 1989: 140.000 genes• 1990: 100.000 genes• 2000: 40.000 genes• 2002: 36.000 genes• 2005: 22.500 genes

Genomes

Model Organism Genes• Drosophila 14.000• C Elegans 19.000• Arabidopsis Thaliana 25.000

Question?How can the genome of an organism that is able to create a highly complex, artificial environment, a technological world, a “technotope”, contain such a small number of genes? While we are exploring and unravelling the structure of the universe, and while we are reshaping our environment at an unprecedented scale and pace, the genetic basis for our unique talents remains unclear.

Freud (1917): “Narcistische krenking”

• Copernicus • Darwin• HGP

Stephen Jay Gould (1941 – 2002)

Humbled by the Genome’s Mysteries

New York Times, February 19, 2001Two groups of researchers released the formal report of data forthe human genome last Monday — on the birthday of Charles Darwin, who jump-started our biological understanding of life's nature and evolution when he published "The Origin of Species" in 1859. On Tuesday, and for only the second time in 35 years ofteaching, I dropped my intended schedule — to discuss the importance of this work with my undergraduate course on the history of life. (The only other case, in a distant age of the late 60's, fell a half-hour after radical students had seized University Hall and physically ejected the deans; this time at least, I told my students, the reason for the change lay squarely within the subject matter of the course!)….

Gould 2001Human complexity cannot be generated by 30,000genes under the old view of life embodied in what geneticists literally called (admittedly with a sense of whimsy) their "central dogma": DNA makes RNA makes protein — in other words, one direction of causal flow from code to message to assembly of substance, with one item of code (a gene) ultimately making one item of substance (a protein), and the congeries of proteins making a body…

Gould 2001Gould 2001

The deepest ramifications will be scientific or philosophical in the largest sense. From its late 17th century inception in modern form, science has strongly privileged the reductionist mode of thought that breaks overt complexity into constituent parts and then tries toexplain the totality by the properties of these parts and simpleinteractions fully predictable from the parts. The reductionist methodworks triumphantly for simple systems — predicting eclipses or the motion of planets (but not the histories of their complex surfaces), for example. But once again — and when will we ever learn? — we fell victim to hubris, as we imagined that, in discovering how to unlock some systems, we had found the key for the conquest of all natural phenomena.

Gould 2001Gould 2001The collapse of the doctrine of one gene for one protein, and one direction of causal flow from basic codes to elaborate totality, marks the failure of reductionism for the complex system that we call biology

Genomics: Profiel

• Epistemologisch: “understanding complexity”

• Ontologisch: Natuurbeeld• Ethisch

§ 1. Epistemological Profile

• Post-reductionism• The genome is not a “blue print”• We now have the tools to study complexity

inside the laboratory

Genetic Determinism †

“Biomedical research over the past decade has been dominated by a genetic determinist understanding of disease and the discredited doctrine of ‘one gene, one protein’. One thing the human gene map does tell us is that there are ten time as many proteins as genes. Genetic determinism is dead.”

The Gene Hunters

• Intelligence Gene IGF2R on Chromosome 6

• Aggression Gene Pet-1 • Etc.

§ 2. Ontological profile

• New attitude towards nature (from modification of “raw material” to understanding complexity)

Jacques Loeb (1859-1924)

Nature = raw material for the biological engineer

The objective of biology = improving nature

Genomics Ontology

• Appreciating the complexity of nature and interacting with nature in a more intelligent and sensitive, less destructive way

Peter Sloterdijk (1947- )

• Allotechnik (“against nature”)• Homöotechnik (“attuned to nature”)

§ 3. Ethisch Profiel

• ELSA• Co-evolution between science and society• Transdisciplinariteit (genomics, sociale

wetenschap, filosofie, bioethiek)• “Elsification”

Ethical Profile 1: Health• Medical genetics → medical genomics• Monogenetic disease → multifactorial Health problems• Individuals at risk → community genetics• Genomics information relevant for virtually everybody• Prevention (gearing life-style to genetic profile)

Ethical Profile 2: FoodShift from issues involved in food production (genetic modification, GM food) to issues involved in food consumption (life style, personal responsibility, gearing consumption patterns to genetic risks)

Ethical Profile 3: Industrial development

• Manipulating raw materials → Understanding complexity (using nature’s bio-resources in a more intelligent manner; ‘greening’ or ‘biologisation’ of industrial production; Solving rather than causing environmental problems

Een juridisch document

Een multidisciplinair team van experts doet onderzoek naar nieuwe materialen voor vullingen en werkt samen met een bedrijf dat hetbetreffende preparaat aanlevert. Bij de zending bevindt zich behalve een sample ook een juridisch document waarin de volgende zinsnede is opgenomen:

Prior to publication of any work relating to the material, investigatorshall furnish X with copies of any such proposed presentation orpublication at least thirty days in advance of the submission of same in order to allow X to comment on same. Further, investigator agrees tomake reasonable changes to such proposed publication if requested byX. In al oral presentations or written publications related to the materialprovided herein, investigator shall acknowledge X's contribution of saidmaterial, unless specifically instructed to the contrary by X.

Het document licht toe wat de juridische gevolgen zijn voor de onderzoeksters zelf, hun afdeling en de universiteit als zij zich hier niet aan houden.

Pre-employment Screening

Een team van onderzoekers ontdekt dat vatbaarheid voor SARS genetisch bepaald is en publiceert hierover een artikel in Nature. Er wordt een contract gesloten met het bedrijf TGS (“Tools for Genetic Screening”) om een test voor vatbaarheid voor SARS te ontwikkelen. Deze test komt korte tijd later beschikbaar en TGS zoekt locaties waar trials kunnen worden uitgevoerd. Tijdens een persconferentie maakt de directeur van het AMC (Amsterdam Medisch Centrum) bekend aan een dergelijke trial medewerking te gaan verlenen. Verpleegkundigen en specialisten die solliciteren bij het AMC zullen voortaan eerst een SST (Susceptibility forSARS Test) moeten ondergaan. Dit leidt tot heftige reacties in de media. De directeur wijst op het feit dat het AMC zich in de nabijheid van een grote internationale luchthaven bevindt. Vatbaarheid voor SARS brengt risico’s met zich mee, voor de betrokkenen en voor derden. Critici vrezen voor een hellend vlak. Er wordt een commissie ingesteld waarin een epidemioloog, een medisch bioloog, een jurist, een filosoof en een oud-politicus zitting nemen. Stel, jij bent een van de leden van deze commissie…….

Pleistocene Park

In de Republiek Jakoetsk (Siberië) wordt in permafrost het lichaam aangetroffen van een mammoet uit het Pleistoceen. Het bevroren lichaam blijkt in goede staat te zijn. Japanse wetenschappers weten uit het oog van de mammoet DNA te isoleren. In de buikholte worden zaden van planten uit het Pleistoceen aangetroffen. Via kloneren en IVF worden enkele mammoet-embryo’s vervaardigd die in de baarmoeder van Afrikaanse olifanten worden ingebracht. Een ander onderzoeksteam weet via DNA uit gevonden zaden Pleistoceneplanten tot leven te wekken. Door een groot Siberisch diamantwinningsbedrijfwordt in het Noorden van Jakoetsk een Mammoet-park ingericht met de bedoeling Westerse toeristen naar dit arme en desolate gebied te lokken.