ESF & TAU Joint Workshop:
Personalized Medicine Europe: Health, Genes & Society
19-21 June 2005
Tel-Aviv, Israel

Organisers:

Gregory Livshits, Tel-Aviv University, Israel
David Gurwitz, Tel-Aviv University, Israel

Report

Summary

The concept of "Personalized Medicine" marks the expected revolution in medicine that would hopefully arrive at the clinic in coming decades, harnessing genomics and proteomics technologies for tailoring the most suitable pharmacotherapy for the each patient, based on individual profiling. Media reports have led to high expectations for better pharmacotherapy, allowing drastic reductions in the current alarmingly high rates of adverse drug reactions, accounting to almost 7% of new hospital admissions. Personalized medicine is also projected to allow improved treatment efficacies for many diseases. Following the recent success of drug tailoring in oncology with the aid of genomic tools, we witness high public expectations for better diagnostic tools to improve treatment outcomes in other fields of medicine. Along with these expectations for improved safety and efficacy in pharmacotherapy, there is a rising anxiety that the arrival of genomic and proteomic technologies to the clinic would jeopardize equity in healthcare, a key principle for national health services of the modern state. Some critics argue that the expectations are too high, given the huge complexity of the human genome and proteome. Moreover, new studies suggest that while genes often contribute to disease phenotypes, they are far from determining them. The old question of Nature or Nurture is not about to be solved soon, and moreover, it becomes clear that genes alone cannot always be blamed for failure of drug treatments.

The current workshop served as a stage for presenting and discussing such new knowledge, at the forefront of science and medicine, along with discussions on societal and ethical implications of such new knowledge. Many questions were raised; some were discussed in our panel discussion, but most remained open, without reaching a consensus. However, we hope that at this workshop, the 'right questions' about personalized medicine were asked, so that we can continue the search for the best answers.

Scientific Content

General Background
The workshop lasted three full days and consisted of 40 invited presentations, 6 oral poster presentations (selected among 14 posters on display), and a concluding panel discussion. As its name implies, our workshop was primarily designed for a multi-disciplinary exchange of views, examining basic biological and clinical, as well as ethical and social aspects of pharmacogenetics. The rapidly evolving field of pharmacogenetics has its routes almost 50 years ago, but is accelerating rapidly since the completion of the Human Genome Project and the realization of the huge scope of human genetic polymorphism, harboring about 11 million single nucleotide polymorphisms (SNPs). Parallel to this, important achievement was made in our understanding that there are genes not only predisposing to a disease development, but also to a disease cure. It has been found that the effect of medicines may depend on genotype, both in terms of threshold and magnitude. This new knowledge offers a unique potential for improving healthcare, by improving both drug safety and efficacy, thereby reducing hospitalizations and morbidity related to adverse drug reactions and to ineffective pharmacotherapy. These hopes are accompanied with justified worries about the capacity of the modern state to maintain equity in healthcare to its citizens - including those whose genes might suggest, according to some not-too-distant future scenarios, that certain medicines would not suit them. Among the problems such scenarios introduce, as discussed during the workshop panel discussion, is "How can society ensure continued equality in healthcare, along with individualization of pharmacotherapy?"
One of the key concerns when organizing this workshop was to ensure diversity of opinions, so that there would be a fruitful exchange of ideas rather than merely reports about new findings. This is quite different from most workshops taking place each year in human clinical genetics, where most presentations typically concern new scientific discoveries rather than policy views. We therefore invited speakers representing different sectors: academia, the bio-pharmaceutical industry, and regulatory and advisory bodies. The latter included the Federal Drug Administration (FDA) from the USA (Felix Frueh), and The Israel Academy for Sciences and Humanities (Michel Revel). As for academic speakers, we tried to have representation from various disciplines, including basic genetics, clinical genetics, community and family medicine, bioinformatics, bioethics, social sciences, political sciences, and law. We also made an effort to maintain, as much as was possible with our workshop budget, a balanced geographic representation for the European Union. Thus, we had speakers coming from the UK, France, Spain, Italy, Netherlands, Germany, Denmark, Greece, Estonia and Lithuania. There was a sizable Israeli representation, as well as few US speakers (see final speakers list). We were also very pleased to have on board speakers from our neighbors, the Palestinian Authority and Jordan. The workshop registrants, who came mostly from Israel, also included a broad geographic scope, including poster presenters coming from as far away as Durham, North Carolina, the USA; Tomsk, Siberia, Russia; and Madurai, Tamil Nadu, India.
In the background information for this workshop, as posted in early 2005 on the workshop website (http://www.functionalgenomics.org.uk/sections/activitites/2005/Livshits/info.htm) we gave some background on personalized medicine as follows:
·Genetic information technologies are forecasted to completely revolutionize medicine by the year 2050. Patients will be diagnosed and treated, to a large extent, according to their genetic profiles and blood proteomics information.
·Are we prepared for the novel challenges?
·Are we fully aware of the societal and ethical dilemmas that will come along with the revolution in medicine?
·This workshop will present the challenges and constraints, and offer insight into potential solutions."
During the workshop, we heard some contrasting views, including frank observations that the above background statement was over-simplified, too optimistic, or just "hype". We heard clear and calculated views explaining why we should not expect too much from genetic information and information technologies (bioinformatics). The views presented at the workshop are summarized in abstracts, printed as a special issue by the recently launched journal, Personalized Medicine (Volume 2, issue 2, 2005).

Day One: "Genes & Medicine: Individual & Community Health"
The 1st day included 16 invited presentations, focusing on "Health, Genes & Society" (morning and early afternoon sessions) continued in the late afternoon with a session on "Medical Genetics and Pharmacogenetics". The workshop was opened by a presentation by Leo ten Kate (VU Medical Center, Amsterdam, The Netherlands), who is among the key advocates for community genetics and is the editor of the journal by the same name. Community genetics is indeed an interdisciplinary field harnessing genomics tools for benefiting society, such as, improving prenatal and workplace genetic screening programs. As presented by our keynote speaker, society must ensure that personalized medicine would follow this path, serving the interests of both the individual and the community.
The first session speakers included Klaus Lindpaintner (Hoffman La-Roche, Switzerland) who presented his views as to how personalized medicine should be promoted. He cautioned the audience not to expect too much from pharmacogenomics, as there are limits to what can be predicted from genes alone. The opening session also included a presentation from Carole Moquin-Pattey from the European Science Foundation (ESF) about the ESF contribution towards building a public-private platform for clinical research in Europe. Among the other notable presentations on the 1st day there was one by Tim Spector from University College London, UK, about the use of twins in genetic research and its implications for personalized medicine. He demonstrated that twin studies have been very constructive in clinical genetics, and have the potential to also provide unique benefits for pharmacogenetics.

Day Two: "Genes & Health: Setting the Clinical Priorities"
The 2nd workshop day featured 12 invited presentations focusing on the medical genetics and personalized medicine themes. Among the speakers of that day were Andre Uitterlinden (Erasmus Medical Center, Rotterdam, The Netherlands) who spoke about analysis of genetic variation in complex endocrine diseases; David Karasik (Harvard University, MA, USA) who presented the complexities of gene environment interactions, using bone mass as an example; Vangelis Manolopoulos (University of Thrace, Greece) who focused on his experience of integrating pharmacogenetics into the clinic at a large hospital in Greece; Uwe Fuhr (University of Cologne, Germany) who spoke about individualization of isoniazid doses based on NAT2 genotype; Julia Kirchheiner (University of Cologne, Germany) who presented her work on using the CYP2C9 polymorphism towards genotype-adjusted drug therapy, and Adrian Llerena (University of Extremadura, Spain) who presented new studies on CYP2D6 genetics in Spanish schizophrenic patients.
The 2nd day concluded with a late afternoon oral poster session, in which students, who received prizes of Euro 300 each, kindly donated by Hoffman La-Roche, presented six of the workshop's 14 posters. The selected posters are marked with an asterisk on the enclosed final workshop programme. The 14 posters were on view for the entire duration of the workshop's second day.

Day Three: "Genes and Society"
On the 3rd day, the workshop was focused on "Genes & Society". The sessions included talks from numerous disciplines and backgrounds. The speakers of the 3rd day morning included Felix Frueh (FDA, USA) who presented the FDA vision of incorporating genomics data to the drug review and approval process; Michel Revel (The Weizmann Institute of Science, Israel) who focused on bioethical aspects of prenatal screening; Jeantine Lunshof (VU Medical Center, Amsterdam, The Netherlands) who spoke about the societal dilemmas surrounding personalized medicine and key cost-effectiveness considerations; Norbert Paul (Johannes-Gutenberg University, Germany) who talked about unique aspects of public health genetics in Germany with a retrospective on past eugenics horrors in Nazi Germany; Claus Moldrup (Royal Danish School of Pharmacy, Denmark) who presented on bioethical aspects of pharmacogenomics from the pharmaceutical sciences perspective, with a focus on the need to educate the public not to fear the new technologies; and Julie Friedman (Bristol Meyers Squibb, USA) who talked about the ethical concerns in applying pharmacogenomics during the drug development process.

The program on the 3rd day afternoon continued with presentations about the theme of "Pharmacogenomics and public policy". These included Vaidutis Kucinskas (Vilnius University, Lithuania) who focused on issues of informed consent in biomedical research; Michael Weingarten (Tel-Aviv University, Israel) who highlighted the view that genomics information should not be treated differently from other medical information; Barbara Prainsack (Vienna University, Austria) who presented her hopes for personalized medicine that should not embrace a conceptual dissonance between individual and common benefit; Inga Peter (Tufts University, USA) who spoke about the novel US aspects of personalized medicine; and Carmel Shalev (Tel-Aviv University, Israel) who talked about the human rights perspective on personalized medicine and the acute need to maintain justice towards poor societies.

The workshop's concluding session featured a talk by David Goldstein from Duke University, NC, USA on prospects for pharmacogenetics and lessons from anti-epileptic drugs.

We concluded the workshop with a Round Table panel discussion. The key questions that were selected for the discussion included:
·Should we oblige industry to do 'something' for people who do not have the right genotype for their drug? What should this 'something' include?
·Equality in access to new health technologies: who pays for genetic diagnostics?
·In how far will individualized medicine change the interrelation of individual and public health, especially with regard to concepts of health responsibility?
·Where do you draw the line about screening fetuses for genetic traits? Schizophrenia, violence, depression?
·How can society ensure better equality in healthcare, along with individualization of pharmacotherapy?
·Will personalized genetic medicine be driven by the pharmaceutical industry in the future?
·What should our priorities be for incorporating personalized medicine into the clinical setting?

No consensus was reached in these discussions. Opposing views were voiced, including within the panel members and from the audience, and there is certainly room for ongoing discussions that would examine alternative solutions. Moreover, it seems that there will not be a clear-cut solution, but rather, solutions that keep evolving hand-in-hand with emerging pharmacogenetics knowledge, development of new technologies, and the availability of new diagnostics tests. Notably, the discussion included the age-old dilemma of "nature or nurture" and the roles of genes and environment in the differing response to drugs among patients. There was agreement among panel participants and the audience, though, that discussion on these key questions must continue, and that being able to formulate these tough questions is an essential key step towards formulating the best answers.

Assessment of the results and impact of the event on the future direction of the field

Public awareness about the scope of adverse drug reactions and the potential of personalized medicine to minimize them has never been more noticeable: recent reports about drug safety issues and the withdrawal of well-known drugs from the marketplace (Vioxx etc.) illustrate how important public awareness and knowledge in this field has become. These recent reports, along with the increased public awareness of drug safety, provide an unprecedented opportunity to dramatically alter the practice of modern medicine, and provide the much needed integration of personalized (individualized) medicine into clinical practice.

Indeed, The Council for International Organizations of Medical Sciences (CIOMS), a division of the World Health Organization (WHO) has recently released a report on pharmacogenetics, pointing out that pharmacogenetic research deserves support from all concerned, and cautioning not to create unrealistic expectations. The FDA also shows increased interest in the potential of pharmacogenetics for improving healthcare, as evident from their web site: http://www.fda.gov/cder/genomics/default.htm

When discussing genes and health, it is vital to recall that genes alone cannot explain the entire large individual variation in drug response. Indeed, several speakers, including Rivka Carmi (Ben-Gurion University, Israel); Hermona Soreq (The Hebrew University, Israel); Gideon Rehavi (Tel-Aviv University, Israel); Ada Rosen (Wolfson Medical Center, Israel), and Michael Weingarten (Tel-Aviv University, Israel) focused on various non-genomic aspects of personalized medicine. These presentations and discussions lead to the conclusion that the practice of personalized medicine must include proteomics tools in addition to the genomics tools. This would allow taking into account non-genomic effects on drug pharmacokinetics and pharmacodynamics, such as the patients' age, gender, diet, exposure to pollutants, stress, life style, presence of other diseases, etc.

Pharmacogenetics, the research field underlying personalized medicine, is almost 50 years old. The more recent term Personalized Medicine, first mentioned in modern scientific literature in 1999, includes a built-in incoherence: medicine is supposed, by definition, to treat the individual patient. Yet, the practice of most drug companies has always been to make "one size fits all" drugs as a means to maximize their profits. Hopefully, original research and commentaries, coming from different disciplines and presented during our workshop, would contribute to the on-going discussions about the need to maintain equity in healthcare along with the incorporation of new genomics and proteomics technologies. In the future, such studies would promote the long-awaited change of making medicine truly custom-made for the individual patient, while serving the needs of communities by improving healthcare for every person. Hopefully, a way would be found to achieve such novel goals while ensuring equity in national healthcare services.

In summary, pharmacogenetics will not replace, but enhance, existing good medical practice. A deliberate approach starts with investing more in studies aimed at clarifying relations between genotypes and drug response phenotypes (both safety and efficacy); educating healthcare professionals by illustrating the benefits of pharmacogenomics; and by educating society about the potential benefits for healthcare from the new genomics and proteomics technologies.

Programme
Day One: Sunday, June 19, 2005
Genes and Medicine: Individual and Community Health
09:00 Registration
9:30 - 10:00 Greetings and opening comments
Dov Lichtenberg, Dean, Faculty of Medicine, Tel-Aviv University
Gregory Livshits, Tel-Aviv University
10:00 - 11:30 Opening lectures: Health, Genes & Society
Chair: Gregory Livshits
Leo ten Kate, VU University Medical Center, Amsterdam, The Netherlands
Is there a link between personalized medicine and community genetics?
Klaus Lindpaintner, Hoffman La-Roche, Basel, Switzerland
Personalized medicine: Health, genes, and society
Carole Moquin-Pattey, European Science Foundation
ESF EMRC contribution to building a public-private platform for clinical research in Europe
11:30 - 11:50 Coffee
11:50 - 12:50 Health, Genes & Society (cont.)
Chair: David Gurwitz
Tim Spector, University College London, UK
The use of twins in genetic research: Implications for personalized medicine
Andres Metspalu, University of Tartu, Estonia
Biobanking and personalized medicine
12:50 - 14:00 Lunch
14:00 - 16:00 Health, Genes & Society (cont.)
Chair: Karen Avraham
Ziad Elnasser, Jordan University of Science and Technology, Irbid, Jordan
Promoting Arab and Israeli cooperation: peace building through health initiatives
Rivka Carmi, Ben-Gurion University, Israel
Cross-cultural genetic counseling
Karen Avraham, Tel-Aviv University, Israel
A Comprehensive Study on the Molecular Genetic Basis of Hereditary Hearing Loss
Moien Kanaan, Bethlehem University, Palestinian Authority
Novel Palestinian mutations in deafness-related genes
Hermona Soreq, Hebrew University, Israel
Neurogenetics of acetylcholinesterase: from stress reactions to Parkinsonism
Sara Cohen, Hadassah Medical Center, Jerusalem, Israel
Polymorphic drug metabolizing genes as modifiers of predisposition and prognosis of adult AML
16:00 - 16:20 Coffee
16:20 - 18:00 Medical Genetics and Pharmacogenetics I
Chair: Gian Franco De Stefano
Gideon Rechavi, Tel-Aviv University, Israel
Abundant A-to-I editing sites in the human transcriptome: relevance to disease
Hanoch Slor, Tel-Aviv University, Israel
Polymorphism in cancer patients' DNA repair capacity as a factor in determining the dosimetry of radiation and chemotherapy
Joab Chapman, Tel-Aviv University, Israel
The role of the APOE genotype in immunomodulation
Lior Sousan-Gutman, Teva, Israel: Cancer Pharmacogenomics
The field that studies the role of an individual's genetics in the response to drugs
Dan Mishmar, Ben-Gurion University, Israel
Mitochondrial Genetics, longevity, adaptation and disease

Day Two: Monday, June 20, 2005
Genes and Health: Setting the Clinical Priorities
09:30 - 11:00 Towards Personalized Medicine
Chair: Tim Spector
Andre Uitterlinden, Erasmus Medical Center, Rotterdam, The Netherlands
Analysis of Genetic Variation in Complex Endocrine Diseases
David Karasik, Harvard University, MA, USA
Gene-environment interactions on bone mass: The Framingham Study
Vangelis Manolopoulos, University of Thrace, Greece
Integration of pharmacogenetics into the therapeutic drug monitoring clinical service of large hospitals
11:00 - 11:20 Coffee
11:20 - 12:50 Towards Personalized Medicine (cont.)
Chair: Gideon Rechavi
Charles Cantor, Sequenom, USA
Automated Mass Spectrometry in Personalized Medicine
Gian Franco De Stefano, University of Rome Tor Vergata, Italy
Possible differences in the immune response to the common environmental disease factor Onchocerca volvulus in two ethnic communities living in the Ecuadorian rain-forest
Uwe Fuhr, University of Cologne, Germany
Individualization of isoniazid doses based on NAT2 genotype. Design features of a randomized clinical trial
12:50 - 14:00 Lunch
14:00 - 16:00 Medical Genetics and Pharmacogenetics II
Chair: Uwe Fuhr
Julia Kirchhneier, University of Cologne, Germany
The CYP2C9 polymorphism: from enzyme kinetics towards genotype-adjusted drug therapy
Sefi Kronenberg, Tel-Aviv University, Israel
Pharmacogenetics of citalopram in pediatric anxiety and depression
Adrian Llerena, University of Extremadura, Spain
CYP2D6 multiplication in Spanish healthy volunteers and schizophrenic patients
Ada Rosen, Wolfson Medical Center, Israel
Genetic breast cancer - a top secret information
Dan Bercowitz, MIGAL, Israel
Pharmacogenetics of fluvastatin in familial hypercholesterolemic patients
Edna Ben-Asher, The Weizmann Institute of Science, Israel
Sequenom MassArray technology and its uses in Israel
16:00 - 16:20 Coffee

16:20 - 18:00 Oral Posters Session
Six of the posters listed below, displayed during Monday, were selected for oral presentations (15 min each). The selected posters are marked with an asterisk:
Amiel A Dror, Ronna Hertzano, Mireille Montcouquiol et al, Tel-Aviv University, Israel
The LIM domain transcription factor LHX3 is a putative target of POU4F3
in the inner ear
M Fellous, Hopital Cochin, France
Genetics analysis of human infertility
*Iris Grossman, Nili Avidan, Clara Singer et al, Technion and Carmel Medical Center, Israel
Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers
*Ronna Hertzano, Mireille Montcouquiol, Sharon Rashi-Elkeles et al, Tel-Aviv University, Israel
Understanding the pathogenesis of human hereditary deafness by expression profiling of inner ears from mutant mice
*EY Levanon, E Eisenberg, Y Kinar et al, Tel-Aviv University, Israel
Identification of A-to-I RNA-editing sites in the human transcriptome
S Lieberman, A Frumkin, M Sagi, Hadassah University Hospital, Israel
Evaluating attitudes towards genetic screening programs among orthodox Jewish students
*Idan Menashe, Yoav Gilad, Orna Man et al, The Weizmann Institute of Science, Israel
Sniffing SNPs - the genetic basis of human olfactory variability
OA Makeeva, LI Minaicheva, VA Stepanov et al, Research Institute of Medical Genetics, Tomsk, Russia
Genetic testing for common diseases in clinical practice
APA Rani, A Aysha Mahmoodha, Lady Doak College, Madurai, Tamil Nadu, India
In silico structural analysis of cytochrome P450-dependent monooxygenase
*Gilad Silberberg, Ruth Navon, Tel-Aviv University, Israel
ErbB4 shows a highly significant association with schizophrenia in Ashkenazi Jews
*Manuela Vecsler, Ronen Loebstein, Shlomo Almog et al, Sheba Medical Center, Israel
Individual sensitivity to warfarin could be predicted from genetic profiles of the components and effectors of vitamin K-dependent gamma-carboxylation system
Shachar Zuckerman, Ephrat Levy-Lahad, Amnon Lahad, Michal Sagi, Shaare Zedek Medical Center, Israel
Genetic screening for Gaucher disease in Israel: genetic screening program for a low penetrant, treatable disease
Frances MK Williams , Lynn F Cherkas , Tim D Spector and Alex J MacGregor, University College London, UK
A common genetic factor underlies hypertension and other cardiovascular disorders

Day Three: Tuesday, June 21, 2005
Genes and Society
09:30 - 11:00 Personalized Medicine: ELSI perspectives
Chair: Leo ten Kate
Felix Frueh, FDA, USA: Personalized Medicine
Ethical and social consequences
Michel Revel, The Weizmann Institute of Science, Israel
Bioethical limits of prenatal genetic testing
Jeantine Lunshof, VU Medical Center, Amsterdam, The Netherlands
Personalized medicine: new perspectives, new dilemmas?
11:00 - 11:20 Coffee
11:20 - 12:50 Personalized Medicine: ELSI perspectives (cont.)
Chair: Jeantine Lunshof
Norbert Paul, Johannes Gutenberg-University Medical School, Germany
Public Health Genetics in Germany: Pandora's Perils or Panakeia's Promise?
Claus Moldrup, Royal Danish School of Pharmacy, Denmark
The prospects and bioethical dimensions of expanding the meaning of pharmacogenomics to encompass individualized pharmacotherapy
Julie Friedman, Bristol Myers Squibb, NJ, USA
Pharmacogenomic Research in Drug Development - The Ethical Concern, Bridging The Gap Between Public Perceptions and Industries Realities
12:50 - 14:00 Lunch
14:00 - 16:00 Pharmacogenetics and public policy
Chair: Norbert Paul
Vaidutis Kucinskas, Vilnius University, Lithuania
The meaning of free and informed consent in biomedical research personalizing medicine
Michael Weingarten, Tel-Aviv University, Israel
The ethics of clinical prediction
Barbara Prainsack, Vienna University, Austria
Personalized Medicine in Times of "Global Genes": Making sense of a "hype"
Inga Peter, Tuffts University, MA, USA
Personalized medicine United States: pros, cons, but no way back
Carmel Shalev, Tel-Aviv University, Israel
A Human Rights Perspective on Personalized Medicine and Justice
16:00 - 16:20 Coffee
16:20 - 18:20 Concluding Session and Round Table Discussion:
Health, Genes & Society: Where do we go from here?
Moderators: Gregory Livshits, David Gurwitz
David Goldstein, Duke University, NC, USA: Prospects for pharmacogenetics: lessons from anti-epileptic drugs
Round Table Discussion Panelists: David Goldstein, Leo ten Kate, Norbert Paul, Michel Revel, Tim Spector