The Human Blueprint

1 The Human Blueprint: Jewish Perspectives on Modern Genetics Fourth Family Fuld Medical Ethics Conference Sam: B’Reshut Roshei Yeshiva, honored speakers, and esteemed guests. Hello and welcome to the Fuld Family Conference, The Human Blueprint: Jewish Perspectives on Modern Genetics. I am Sam Weprin – “and I am Tali Bauman”-, and as co-presidents and conference organizers, we would like to take this opportunity to thank you for your participation and support in the YU Student Medical Ethics Society’s 4th annual conference. We hope that today’s presentations will enrich your understanding of the medical and ethical issues in modern genetics as they relate to Jewish law and Torah values. Before we begin today’s program we would like to take a moment to thank the Fuld family whose generous gift has made today possible. Rabbi Dovid and Mrs. Anita Fuld are founders and supporters of the Shaare Tzedek Zohar PGD laboratory in Israel, which Tali and I had the unique privilege of visiting over Succot. There we were greeted by world class experts in the field of reproductive genetics who assist families in Pre Implantation Genetics Diagnosis. The Fulds’ generosity has enabled over 400 participants here today as well as those joining us in Israel via webcast to partake in this unique event. We are especially honored to have the Fulds joining us through this webcast. We would like to take this opportunity to express our profound hakaras hatov for making today possible. Tali: Yesterday, we read Parshat Bereishit, which discusses the creation of man. In perek aleph pasuk caf zayin, it is written: HEBREW Man was created in the image of G-d. Later, the Torah writes, G-d created man “afer min haadama”, from the dust of the ground. This however is a seemingly simplistic view of the makeup of man. As science has proven, each and every one of us is composed of an intricate pattern of genetic information which makes us unique. One way to understand the significance of man’s holiness as a tzelem elokim is to explore and delve into the intricacies and details of the human body. “Lo Machsevoti Machshetochaicham Ve’Lo darcaichem derachai” While We do not understand G-d’s thoughts and ways, what we do know is that when G-d created man "V’henei Tov Meod”, and he was very good, as opposed to other creations which were merely good. Endeavoring to understand the wholesomeness of man through science and halacha allows us invaluable insight into who we are as people formed in the very image of God. Sam:

2

Today we have been given tremendous tools and opportunities to help in the battle against genetic diseases. As will be presented today, there are many facets of modern genetics: technology, law and science. We have the charge of ‘v’rapo yirapei,’ and “you shall certainly heal” and through the prism of Torah we utilize these technologies to help manage and prevent genetic diseases. This is one of the many goals of the Student Medical Ethics Society. We strive to promote education and awareness of medical ethics issues and halacha not only within YU, but beyond the university walls as well. Tali: It is our obligation to study and continue to understand the development of humanity through the lens of medicine and halacha. Throughout the year, we provide programming that delves into various contemporary issues, whether they be end of life issues, contraception, stem cell research, or many other hot topics in medical ethics. With the support of Yeshiva University and the Center for the Jewish Future, this conference can help individuals and families suffering from genetic diseases and hopefully will impact our participants to become active members of the Jewish community in helping the continuation of the Jewish people. Today’s conference will be recorded and available online at yutorah.org and we know that this vital information will enlighten, enrich and guide Jewish communities for many years to come. Sam: We would like to thank the Center for the Jewish Future, under the leadership of the Dean, Rabbi Kenneth Brander for its constant support and encouragement. Thank you Rabbi Brander for your dedication for and cultivation of MES and your commitment to Jewish medical ethics. A special thank you to Aliza Berenholz who has dedicated countless hours to ensure the success of today’s conference. Thank you, Aliza. We cannot express enough gratitude to and pride in our board and volunteers for their tireless hours of hard work and dedication; Thanks for making us look good. Tali: At this time, we would like to introduce our mentor and conference chairman, Rabbi Dr. Edward Reichman. Dr. Reichman’s support, advice, and words of encouragement have been invaluable in planning today’s event. Sam and I have truly enjoyed cultivating a relationship with you throughout the past 6 months. Thank you for always being available to speak to us and help mold us into the people we are today.

3 Without further adieu, Dr. Reichman… Dr. Edward Reichman: Thank you very much, Sam and Tali. I also want to echo their thanks to the CJF and my dear friend and colleage Kenneth Brander for his extraordinary vision. He is truly the man behind this kind of event. He has facilitated the leadership of so many of the students at Yeshiva University. Want to echo the thanks to the Fuld family without whom this conference would never have been possible in the beauty you see today. Finally want to thank Tali and Sam who I think are genetically engineered – done such a beautiful job. If every day is only Tov, how in the end could it be Tov Meod? Vilna Gaon and many others say the whole is greater than the sum of its parts. Every one of the people here, everyone who was involved are each extraordinary people but the aggregate of all these people today is truly. Had the pleasure of introducing this conference for the past four years. Every conference I’ve introduced with a story about dirt and today the entire contest is about dirt. Story of a scientist who approached God and said we have so many developments in so many medical issues that we don’t need you anymore; we can do just about anything you can do; in fact, we can create man. God said to the scientist: Is that so? How do you do such a thing? Scientist says we take some dirt from the ground, put in some enzymes with a pipette- and God says why don’t you show me. Scientist picks up some dirt and God says no, no, get your own dirt. Put into context all these medical advances into the halakhic world. Our previous conferences have related perhaps to some people but not to all. There is one criterion for today’s conference to make it relevant to you and that is chromosomes. So how many people by a show of hands have chromosomes? Wonderful. Not lost on you the association of Sefer Breishis- first session will be on Peru U’Revu, behavioral genetics, to determine if Chava and Kayin had criminal genes to perform their behaviors. Actually adapted many of the things that we learned from surveys on this conference, so you will have a genetically perfect conference, removed all mutations. To conclude with an idea that God looked into the Torah and created the world. So in essence the Torah was the Divine Blueprint for the creation of the world. I would submit that the converse is also true. Adam mistakla b’alma, bara oraisa. When we delve into the inner workings of the world in a conference like this to see the beauty and extraordinary enhancements in a conference like this, we are bringing Torah to life, showing the glory of God. Would like to begin our conference- Rabbi Brander would you like to add anything? Rabbi Brander: No, let’s just begin.

4 Eddie Reichman: First session will be on reproductive genetics- Dr. Lobel, Dr. Asch and Rabbi Brander- their bios are extraordinary; you will read them in your handouts. Dr. Lobel is our clinican trained at Princeton and Harvard, Dr. Asch who heads the ethics center here, Rabbi Brander who needs no introduction. PLENARY 1: REPRODUCTIVE GENETICS THE NEXT GENERATION Dr. Adrienne Asch, Rabbi Kenneth Brander and Dr. Susan Lobel: Dr. Susan Lobel: Good morning and I would like to start by expressing my appreciation to the organizer of the conference for the opportunity to be here and to reiterate what a wonderful job Sam and Tali have done. First half hour- would like to address basics of reproductive genetics which apparently raises questions which will then be addressed by Dr. Asch and Rabbi Brander. DNA, deoxyribonucleic acid contains genetic instructions used in development and functioning. Four bases (Adenine, Thymine, Guanine, Cytosine) are used to encode information. Gene is the basic unit of heredity within DNA. Human beings contain 46 chromoses. There is 1 set of sex chromosomes and 22 autosomes. Chromosomes composed of DNA, within DNA are structural units called genes. Genetic mutation is formed by abnormality in an individual’s genome (genetic material.) Four basic types: 1. 2. 3. 4.

Single gene Multifactorial Chromosomal Mitochondrial

Single Gene: Mutation in sequence of one gene. When resulting protein product cannot function normally, disorder can occur. More than 6000 gene disorders. Occurs in approximately one in 200 births. Multifactorial: Mutations in multiple genes and environment. Chromosomal (intranuclear DNA): Missing copies, extra copies or translocations. Mitochondrial (least common type.) Mitochondria are organelles found in the cellsmutations in DNA of mitochondria (organelles in cytoplasm of cells.) Most common type is Single Gene Disorder. Most common type is Autosomal Recessive. They must inherit two mutated genes to be affected with the diseases. Inheritance of one mutated gene results in being an unaffected carrier. No risk to individual, has no idea that they are a carrier. Signifiance is when that

5 person goes to reproduce and passes gene on to child- whether or not the child will be affected has to do with status of their spouse. If a carrier marries a non-carrier, none of the children will be affected with the diseases. Each child has a 50/50 chance of being a carrier or an unaffected non-carrier. This is how a mutation can be passed along silently from generation to generation. Even if a carrier marries another carrier, there is only a 25% chance that a child will be affected with the disease. Most of the children will be normal. 50% chance unaffected carrier and 25% chance they will be affected. Important to remember these are theoretical percentages. If carrier marries another carrier and have fewer than 3 or 4 children they may have two children that are not affected. Conversely, they may have 2 children who ARE affected. Autosomal Dominant: Single mutated gene results in the disease so the risk to the children is much higher. If a carrier marries another affected carrier, there is a 75% chance that their child will inherit 1 or 2 mutated genes and a 25% chance that the child will be unaffected. X-linked (least common type of single gene disorder inheritance): While most X-linked disorders are recessive, the mutation occurs on the X chromosome. Because females have two X chromosomes, they are usually not affected. Because males have only one X chromosome, they will be affected. So will be expressed in males. The most well-known example of this is hemophilia. Not only important to consider the mode of inheritance but also what the disease actually is. Genetic diseases can result in early childhood death, impaired quality of life and early adult death. Significance of the diseases is affected by which category the disease falls into. As we learn form the story of Avraham Avinu, one Jew can have a lot of descendants. Intermarriage of descendants when there can be a mutation results in Founder Effect: mutation passed along more frequently and the proportion of descendents with married gene will increase. all ethnic groups hav ea tendency to intermarry so various ethnic groups have various mutations. Until 40 years ago, nothing could be done to identify carriers and prevent the birth of affected children. This changed with Tay-Sachs. Caused by deficiency of the enzyme Beta-Hexamindase A which leads to an accumulation of the fatty substance GM@-ganglioside in the cells of the nervous system. Children appear normal at birth, develop symptoms at six months and die by age five. One in 25 Ashkenazim is a carrier. Before 1970, one in 2500 Ashkenazi newborns had Tay-Sachs disesase. Tay-Sachs carriers are clinically healthy but have lower levels of Hexosamindase A. 1971: First major screening of Ashkenazim to identify carriers organized by Michael Kaback, MD, resident at Johns Hopkins. Widely adopted and if a couple was found to both be carriers, after the woman conceived she could undergo amniocentesis to identify affected fetuses. If it was determined that the fetus had TaySachs then a pregnancy could be terminated. While this was a difficult process to undergo, safer for the mother to undergo second-trimester termination than to undergo full-term delivery when child is going to die.

6 This was accepted within the general Jewish community but not the Haredi community. Rabbi Joseph Eckstein had four of ten children die of Tay-Sachs Disease. His response was: Why did Hashem do this? He felt that Hashem did this so that he could prevent other couples from undergoing the same tragedy. Understanding the Haredi community where marriages for the most part are arranged, he founded Dor Yesharim in the 1980s, a project where teenagers would undergo anonymous screening before a shidduch was made and after the shidduch was made before the couple met it would be checked to see if they were both carriers of Tay-Sachs. If they were, shidduch was called off and if they weren’t, ti was allowed to proceed. This dramatically decreased Tay-Sachs within the Haredi community. By today there are virtually no Jewish children born with Tay-Sachs in the United States and Israel. Most children born with TAy-Sachs today are born to other ethnic groups like French Canadian Cajans. This was a tremendous success for Tay-Sachs but couldn’t be replicated. Most other carriers could not be identified. But then in the 1990s the Human Genome Project was started. Coordinated by US government. Goals was to determine the sequences of the three billion chemical base pairs that make up human DNA. Identify all the approximately 20,000-25,000 genes in human DNA. 1990s identification of actual genetic mutations that are the basis of many diseases. Development of commercial testing to identify carriers of genetic diseases. Genetic basis of over 1000 diseases are now known. The number continues to increase daily. Testing can be done at several levels. We can test adults, usually by simply drawing a tube of blood. Fetuses can be tested by Chorionic Villus Sampling (CVS) or amniocentesis. Most recently, embryos can be tested with preimplantation genetic diagnosis. With CVS, removal of small (5-40 grams) sample of placental tissue for chromosomal, metabolic, or DNA studies. Transabdominal or transvaginal approach. Generally performed between 10 and 12 weeks of gestation. Spontaneous abortion rate comparable to amniocentesis with experienced physician. Possibility of limb reduction defects when performed earlier than 10 weeks. Amniocentesis uslaly done between 16 and 20 weeks of gestation. Fetal cells in amniotic fluid for analysis. Risk of spontaneous abortion less than 0.5% when performed after 15 weeks. Risk of spontaneous abortion 2-5% when performed at 11-13 weeks of gestation (also increased risk of clubfoot and failed cell culture.) Preimplanatation: In vitro fertilization- aspiration of eggs from ovary, combination of eggs and sperm in laboratory, culture of embryos in laboratory for 2-5 days, transfer of embryos into uterus. Dedication of Dr. Yuri Berlinsky who moved to Chicago and I am more dedicated than most because the person who does our PGD was trained by him. Biopsy of embryo can be done, usually on day 3 after fertilization with removal of a single cell. At the early stage, all the cells of an embryo have the same ability to go on and differentiate. They are undifferentiated. This is how identical twins occur- the embryo splits at an early age so even though half the cells were removed, can go on to form a normal individual. Once removed, can be analyzed with Polymerase Chain

7 Reaction (PCR) and Flourescent in Situ Hybridization (FISH) for chromosomal abnormalities. New techniques that will replace FISH but up till now this is what was used. Only nonaffected embryos transferred back into uterus. So avoiding risk of transmitting embryo carrying two mutations for a disease. There are risks of PGD. Main risk is risk of damage to embryo – usually present as lower implanation rate rather than fetal abnormalities. Mosaicism may lead to false positive/ false negative. Test itself may result in false positive/ false negative. However, overall, the results are generally accurate and decrease in pregnancy rate is far outweighed by benefit. Currently eleven diseases commonly tested for in Ashkenazim: Bloom Syndrome, Canavan Disease, Cystic Fibrosis, Familial Dysautonomica, Fanconi Anemia, Gaucher Disease, Type 1a Glycogen Storage Disorder, Maple Syrup Urine Disease, Muscolipidosis Type IV, Niemann-Pick Disease, Tay-Sachs Disease. More recently added Spinal Muscular Atrophy, Usher Syndrome Type 1, Type 2 and Dihydrolipoamide dehydrogenase deficiency. Sephardic Panel: Beta-Thalessemia, Familial Mediterannean Fever, Glycogen Storage Disease Type III. Incidence: Gaucher disease- one in 14 Ashkenazim are carriers. Tay-Sachs, Cystic Fibrosis, CAnavan and Familial Dysautonomia- one in 25 to one in 40. Rest: around one in 100. One in five Jews carrier for at least one of these diseases. Genetic basis of over 1000 diseases identified to date. Chance of a couple both being carriers for same disease low but important. Because when it happens to you, it happens 100%. Having a child with a genetic disorder is a devastating outcome for family. Ideally we like to test a couple before conception- tests we do are based on ethnic background, family history for specific disorders. If a couple are both carriers, we can do PGD to prevent the disease in the offspring. If testing is done after conception occurs and either both parents are carriers for recessive disorder or one carries autosomal disorder, aminoscentesis or PGD can be done. Now, major birth defects occur in two to three per cent of the general population. 90% of infants with congenital anomalies are born to women with no risk factors. American College of Obgyn- “all women should be offered aneuploidy screening before 20 weeks of gestation, regardless of maternal age.” ACOG- “all women regardless of age, should have the option of invasive prenatal diagnosis (ie, CVS or amnioscentesis) for fetal aneuploidy. With multiple gestations, screening not as sensitive because have more than one embryo shedding cells. Counseling more complex. Frist Trimester Screening: Biochemical markers (free beta-hCG), Preganncy-Associated Plasma Proteian A, nuchal translucency measurement, first trimester down syndrome

8 detection. Second trimester screening: biochemical markers, quadruple screen, anatomic survey ultrasound, screening for structural abnormalities. 40 years ago testing for carriers of Tay-Sachs disease. Today testing for carriers of over 1000 genetic disorders and avoiding inheritance of disease through PGD> Antenatal testing for chromosomal and other genetic disorders. Stem cell research: Embyronic stem cells are undifferentiated cells derived from inner cell mass of early embryos which are usually obtained from in vitro fertilization. Pluripotent- have the ability to become all cell types found in the body. Current research on treatment for various genetic disorders. Currently unfortunately for political reasons not allowed in US but is in Israel and hopefully we will have new information to present. Dr. Adrienne Asch: Always amazing to see quality of the speakers, enthusiasm of this group for learning about bio-ethical issues and thinking about the connection of bioethical issues with halakhic views. As a representative of YU it is a great pleasure to be here and join with you and I must say that even though I have been working in field of bioethics and genetics for a good long time, I learned things today from Dr. Lobel’s talk and I hope I will learn from participating here. My task is to try to place some of the reproductive genetics issues we are talking about in an ethical context as bioethics in general talks about them- that is American bioethics (mainstream.) I will leave it to Rabbi Brander to talk about religious perspectives. I as a perhaps mainstream bioethicist want to talk about how these issues are discussed in society both religious or non-religious. And I’m also going to speak a bit not only about reproductive genetic issues but how those issues of reproduction connect to other genetics issues that we face. People have mentioned behavioral genetics and same other things and I’ll say something about those. I just mentioned that although I didn’t provide slides or text of the talk in the materials you have, I did provide a bibliography of readings you can do to learn a great deal more to learn about ethical issues in genetics. I hope that you will be so inspired by this conference that you will want to do that. Dr. Lobel talked about the four kinds of disorders that we are dealing with here. And this conference was introduced as – the title conference is ‘Genetic Blueprint’ – I want to point out two things we should keep in mind. We are more than our genes and we all carry genes for some serious condition. Some characteristic that we label as a disease, disorder, problem- those two facts should give us a certain kind of pause and perhaps a certain kind of humility as we think about the meaning of genetics for our lives. I don’t think any of us wants to be reduced to the genes we carry. And it is very important to recognize that blueprints are important but they are not the whole story. They are not the whole story of the buildings we have – of ourselves. We are affected by our genes; we are also- there are multigenic disorders, characteristics, affected not only by one single gene but interaction of one gene with another, or interaction of genes with our environmentbiological, familial, cultural, psychological. We are the product of many experiences. What that should mean I think is that we need to build a society- let me go back to the implications- let me point out that if we all are carriers of some characteristic labeled a

9 disorder, some characteristic that affects our health, affects physical suffering, lifespan, physical function, cognitive ability, sensory function- if we all carry genes for some of these characteristics, we have to recognize that we are all affected. Every part of our community, every one in our family is affected by these genetic conditions. How we think about ourselves and the communities we create and the society we create must be humbled by that fact. Do we want to create – and it is true that the ultimate main of must genetic research and testing is to improve human health and prevent disease and these are worthy goals- how do we want to think about society knowing that we carry all of tehse conditions and many conditions- we know people living with these conditions. They are our siblings, children, parents, neighbors. Not only very signifanct and very disabling and rare genetic conditions, but many more common characteristics- we need to create societies and communities that welcome and think about how to incorporate people with all of these conditions. We may be able to prevent through genetics/ testing these condtionsa dn there is merit in deciding to do that. But there is also merit in thinking about how the condition impairs the quality of life and how we as a society can do less impairing and more improving. Part of the message is no matter how much of the diseases we are ever able to prevent by testing, we will never prevent all disease and all disability. Most disease and disability is affected by aging, injury, accident, typical aging process and we are working as a society and world to be more inclusive of people with these conditions. IF we are going to do that, we have to think about the process we seem to be engaging in of working to include and working to prevent. Fine to work to prevent as long as we also work to include and recognize that while some diseases- and TaySachs is often and sadly the archetype of the disease where there is an impaired, drastically short and tragic quality of life no matter what medical care does. Some of the other conditions that Dr. Lobel mentioned that are tested for now are diseases that will not be very much affected, at least in the short term and maybe ever by what medicine does in terms of therapy/ cure. Will not be affected by society re: anti-discrimination laws, architectural and environmental access. Not true for some other conditions: Usher’s Syndrome, Gaucher, Spino-muscular atrophy. Spino-musuclar atrophy usually considered an immediately fatal disease but just met physician yesterday who treated a 30-year-old woman with this and she is happy mother of two. Even genetic conditions that we are typically thinking about as very serious – cystic fibrosis that has a typically shortened life span and needed hospitalizations and medications, we also know in our communities people with cystic fibrosis living lives yes, much shorter than lives of typical North American or Israeli but nonetheless able to live lives that don’t only include medication, hospitalization but family, relationships, work, education, recreation. One of the things we have to think about is how genetic disease can be inherently devastating and impairing of the quality of life but how it’s also true that genetic conditions are affected by societal attitudes toward them and the people who have them. And as we strive for betterment in human life, we need to be striving for betterment in the social world we offer to people with all tehse genetic conditions. This is something that especially we as Jews should be especially sensitive to. We know what it has meant to live in a world of persecution, hostility. We face that in certain ways today. Anti-Semitism exists, Israel’s survival is threatened so as we work for a world of improved human health, we need to recognize that notions of quality of life and well-

10 being are affected by more than physical health or sensory or cognitive function. Affected by receipt of people in….If we are all created in the image of God, then we are all created as good and as having something to offer to other people. If life is of benefit, then life is of benefit to people regardless of many of the traits they carry and we as a society/ world need to make that life as good as possible by our attitudes of inclusion, welcome. That is another message that I think is extremely important to have that can go right along with thinking about prevention. I don’t want people to hear this message as don’t prevent but I do want people to hear this message as a message of – we will not prevent everything and how do we deal with including people with these characteristics? How can we make a society and world that is inclusive, respectful and dignified of people with these characteristics and let them contribute as much as possible to family and community? This is a struggle that religious communities, society, medicine, bioethics are dealing with as we figure out how to increasingly prevent and respect people with all kind sof characteristics. That struggle is going to get only greater as the number of conditions and variety of characteristics for which we can test increases. Let me point out that although we now test for only some characteristics we’re going to talk about behavioral genetics, possibilities for genetic enhancement, we have to face the possibility that at some time we will discover that behavioral characteristics- intelligence, impulsivity, perhaps empathy and aptitudes – musicality, athleticism, mathematical ability, you name whatever trait you are interested in- these may be found to have genetic as well as environmental and cultural components. Undoubtedly will never be linked exclusively to genetics. If we can test for them in our embryos, are we going to exclude embryos that don’t have a particular form of athleticism, musicality or intelligence? I leave that as an example of the question that we have to face- what sort of world will we create if we increasingly exclude people with characteristics that we think don’t make life go well? Do we know all the characteristics that make life go well? Can we decide so easily what characteristics automatically make life go badly? Life is, after all, made up of not only the characteristics we are dealt physically or familially but how we learn to adapt to all of the factors in our lives. Similarly, for those conditions not behavioral but physical that are predispositioned that are affected by genetics but not entirely – BRCA1. Not everyone who has the BRCA1 gene will develop breast cancer- are we going to test all our fetuses for breast cancer or are we going to test ourselves and our mates, etc? Those are decisions we will hav eto face in the future and as we face them we have to think about what kind of society we want to create and what kind of society we want to develop. How much we want to give to ideas of certainty, adaptability, resilience, characteristics we will need in all of life. Some other ethical issues that are raised by genetics that I won’t go into very much nowI’m focusing on impact not only of our current reproductive genetics but future of reproductive genetics is what we do with information about ourselves/ children. How much of it is or should be private? How much communicated to other family members who might be affected? How much should insurers now? Exclusions in health insurance plans for preexisting conditions- we are all likely- lose healthcare if people have information of genetic predisposition. Trying to protect against that with legislation in the United States and situation in Israel is different with much better and more inclusive

11 healthcare arrangement, we need to face that as we think about healthcare reform. That, I think is one of the biggest ethical questions as we learn about our genetic characteristics. If we think of a notion of people being created equal- Declaration of Independence, common sense- if we think about trying to create a society that recognizes human difference but preserves moral equality, how do we do that sa we get more and more information about our genetic lottery? Will that create a sense of greater inequality? Will we create workplaces that are safe for only some but not all potential workers when we know some components of workplaces are dangerous for only some people? Taxes that don’t affect everyone but only some- would we then exclude them? Or should we design a workplace that is save for everyone? That is not a reproductive genetic question although it could be- if we start testing people for potential susceptibility to toxins 40 years down the road- question of what kind of society we want to create. Central, perhaps most enduring ethical issue that I would like to leave you with. If we can test for more and more conditions before conceptions- if we test ourselves and our existing children, what sort of society will we create for people who have different characteristics? This is the message I would like to have us think about- how can we improve human health at the same time that we promote a society that is respetufl and inclusive of people with all characteristics? Rabbi Kenneth Brander: Good morning, everybody. I hope everyone is doing well. My name is Kenny Brander- I have a degree from Yeshiva University in computer science and that’s the last time I used a computer. [laughter] So while they are getting this set up, if you don’t mind, I’m going to start my presentation and start with the recognition of Sam and Tali for putting this together and literally I think there’s another 50 students who are involved in this process so I want to thank them all. Want to recognize Dr. Lobel for taking a complex topic and putting it in bite-sized topics for people like myself and to thank Dr. Asch for unbelievable clarity of vision that she brings and to recognize some of my colleagues- Dr. Burns, Dr. Bacon- who both represent the idea of true synthesis of Torah U-Mada as real yirei shamayim. Mori V’Rebbe Rabbi Tendler- always a little complicated to deal with halakhic issues- thank the Fulds for sponsoring a conference. Their commitment is to excxellence in medical education and providing clarity in that field as well as clarity in Halakha and I hope we are up to the challenge this morning and this afternoon. Now, I don’t really want to start with this slide and don’t know how to make this thing go blind (it said fertilization plan.) Open to the sources for Rabbi Brander in the booklet, and for those listening in Israel, Shuki will give you handouts iy’h tomorrow after first seder. There is this whole idea found in various midrashim of a couple wishing ot have a male child. As someone who is blessed with five children and one beautiful girl in the cream and oreo cookie, I always find this a little bit challenging since the girl is so much easier to deal with than the guys. Gemara deals with this- ‘if you make havdala Saturday night on wine, you will have male children.’ Bava Batra 10a Gemara as well- one is the way one treats one’s spouse, one who distributes charity appropriately. We live in a world where we can deal with some of these issues of sex selection in a little more of an aggressive way than is stated in these ideas and I wanted to bring this up to snuff in a lay

12 perspective to understand a little about PGD, talk about genetic disorders and then a little about genetic testing and then when genetic disorders are found is it ever permitted from a halakhic perspective to be involved in an abortion? Major conversation between two great gedolim- R’ Moshe Feinstein and his feelings regarding teshuva of Tzitz Eliezer where he uses language which is inconsistent with language he normally uses when discussing other great Torah personalities. Fertilization process, which normally takes place in the Fallopian tubes, sometimes can take place- male and female sperm and egg coming together to create a fertilized egg- can sometimes happen when there are certain challenges bout the normal way of conceptionmany ways to deal with fertility challenges (not the conversation today) but there is also IVF. In vitro fertilization where fertilization does not take place in Fallopian tube but within a laboraty. Ixi IVF- more aggressive form- when the sperm is weak or there are other challenges, create Ixi IVF – form of IVF where you aggressively insert one sperm into an egg to create fertilization of an egg and hopefully this process works. 15-20,000 dollars in America to fertilize the eggs (not just one, usually many eggs) and returned to womb and the rest of fertilized eggs will often be frozen. In Israel, IVF process is much cheaper. Eventually Ministry of Tourism will run commercials: Come to Israel, See the Land, Have a Child- It’s Half the Price. Have to throw in some jokes. Sperm to egg creating hopefully fertilized egg- cells reproduce and eventually at a certain stage there are eight cells or so, pluripotent which means the cells can/ has the capacity to help develop various organs within the human body and contains entire encyclopedia of information for every organ of the body. One of the cells withdrawing from this mass and through that cell various diseases can be tested for. Various genetic disorders diagnosable by PGD- when I teach this in the Semikha program, go through this in more depth but I want to get to Halakha, especially when discussing this in front of doctors who can do this much better than myself. How does Halakha deal with PGD? Challenges, risks, risks are limited but clearly obviates certain types of issues. For example, both husband and wife are carriers of TaySachs, you can often discern with fertilized eggs carry the dieases of Tay-Sachs and which do not and can often tell various other challenges. How does Halakha deal with PGD, what happens when fertilized egg- you see genetic? Let’s say husband and wife want to have a child, husband has no sperm, use non-Jewish sperm as per R’ Moshe Feinstein’s (also R’ Shlomo Zalman Auerbach in Noam)- house doesn’t get firebombed re: Noam but yes re: Igros Moshe. Non-Jewish sperm because “doesn’t want him to marry his sister”- let’s say this man wants to have a female child because Kohen blood, doesn’t want to have social/ psychological children so can they have only female children as opposed to male children? Very important Gemara that R’ Soloveitchik used to discuss and Dr. Twersky also discussed and that is the famous conversation between Turnus Rufus and R’ Akiva. Turnus Rufus says to R’ Akiva the reason the Jewish people are condemned to hell is because they help the poor. Suppose King incarcerated a person and says no one should give them food or drink. And you sneak food and drink into the prison. Wouldn’t the king

13 be upset? If God willed people should be poor, (and for us, if God decided these people should be infertile) what right do you have to change this ruling? R’ Akiva- suppose a king had incarcerated his son and said no one should give him food or drink, wouldn’t the king be happy if someone snuck in food? And we are the c hildren of God. R’ Soloveitchik said this is a deep philosophical argument. Turnus Rufus said we should wear the eyeglasses of God- world was created in a certain way; we don’t have a right to interfere. R’ Akiva says no- we are God’s junior partners but we are nevertheless partners- we are involved in tikkun olam. We don’t wear the glasses of God. When a tragedy/ challenge happens, we don’t ask: why? We ask when t hose things, what can we do to effectuate change? If we have the capacity through the heavenly gift known as science to change the world, we do what we can. Meiri in 13th century has an unbelievable comment: Anything done through natural sciences is not considered magic (which is considered halakhically unacceptable), even when there will come a time when we will be able to create human beings (with the dirt of God of course) not with the normal sexual relationship- that is not considered off limits but rather permitted. AS it is known in works of Kabbala that this is not an impossibility- it’s permitted for us to do this because anytime it is guided by science with the wisdom of scientists who understand the balance- ano b’klal kishuf- it’s not considered magic- anything that comes through the conduit of medicine is not considered a prohibition of Darkei Emori. Not within the time I have to dsicuss Darkei Emori; we can do that a different time- but this is an unbelievable Meiri. What about that genetic material tested outside the womb? 40 days, blastosis- certainly fertilized egg may have certain genetic challenges and want to disgard it? Gemara in Yevamos as well as highlighted in Shulchan Aruch reminds us that a less-than-40-daysold egg is ‘maya d’alma’- a sac of water- not yet considered to be a fetus. While the notion of aborting a fetus would not be considered a formal act of murder- even the Rambam who considerst he fetus a quasi-human-being in some of his language- anything below 40 days especially in a laboraty does not yet have halakhic status of fetus and thus it is permitted for us to discard fetal material when necessary. That is why it is permitted for us to use said fetal material for stem cell research. Under headline of ‘v’rapo y’rapei’pursuing the value of medicine and healing those who need to be healed. This idea highlighted in Masechet Yevamot 69b and Shulchan Aruch Yoreh Deah, Siman Shin-Hey (305) Seif 23. Woman has miscarriage and next child does not have pidyon haben. But if she has a miscarriage when not yet 40 days then next child born would have a pidyon haben. This idea that genetic material less than 40 days old can be used and discarded when necessary, I don’t want to treat it with disrespect, just want to show that Halakha does not see it this way. R’ Chaim David HaLevi, former Chief Rabbi of Tel-Aviv, discusses this idea and states does not have halakhic status of a fetus. We are told that a woman who is pregnant we are mechalel Shabbos for fetus even if less than 40 days old- but we would not transgress for

14 all the fertilized eggs in a laboraty (bio-preserved) went down because there was a hurricane- a Jewish embryologist cannot violate biblical prohibition of Shabbos to save those eggs. So permitted to test material. Highlighted in article discussed by R’ Zilberstein, married to granddaughter of Aryeh Levine, daughter of R’ Elyashiv- highlighting a case that Dr. Lobel gave in a conversation Rabbi Shlomo Zalman Auerbach had with _____ wash of ____ to alleviate hemophilia, although not always a fan of doing this type of research, however, if it is to obviate genetic diseases like hemophilia he permits one to go through process of a sperm wash to deal with this issues. This conversation regarding PGD and use of PGD to deal with genetics as well as mitzvah of pru-urevu- commandment to procreate. Discussion of what procreation is has to do with trying to have one male and one female children. Let’s say one is blessed to have all male children and wants to make sure last one is female – is it permitted to use PGD in order to be able to fulfill mitzvah of peru u’revu? R’ Menachem Gerstein, head of Mechon Puah, institute I received some training at, asked this question to several different poskim. He said: Can one do sex-selection by one of three methods – diet (which doesn’t work so well), sperm wash and PGD? R’ Nevetzal from the Old City is not so happy with the third approach of using PGD but Rav Amar, Chief Rabbi of Israel is concerned that PGD is under the challenge of Kilayim. His idea is that there are times in which it is – prohibition of Kilayim is based on the fact of mixing different species- we don’t have the right to get involved on a certain level with creation; perhaps PGD is in that category- all of a sudden going to decide male/ female child but in the end says if it is ‘l’tzorech refui’ or ‘l’hashlim peru u’revu’ or ‘mishum shalom bayis’ – his exceptions are like a halakhic Mack truck- then it is permitted. Permitting PGD even for _____. Author of Shemirat Shabbat K’Hilchata- he asks why they are involved with God’s work of making certain genetic decisions of this nature but he reminds everyone to look at R’ Shlomo Zalman Aurbach’s letter. This idea is highlighted on our next page by R’ Ariel who permits it. Brought down article I wrote in Tradition and others wrote that for genetic issues certainly permitted to be involved in PGD. Teshuva that R’ Moshe Feinstein writes- letter that R’ Tendler shlita asked- about idea of doing genetic testing. R’ Moshe Feinstein clearly highlights the responsibility to do genetic testing for young men, young women before they get married, before they get engaged- during the dating process so that they know if there are any genetic challenges, don’t have to Twitter or Facebook it but know for themselves so as to decide. Many genetic challenges that if one marries a spouse who is not a carrier, there will not be those issues. Here at Yeshiva University we do Dor Yesharim and Open Testing- not a convo for us to have in last few minutes but important to know that all the Roshei Yeshiva totally endorse the idea of genetic testing.

15 Also wanted to just mention – in that supplementary handout- that we shouldn’t think that if someone is a carrier for a genetic disorder, does s/he have an obligation to tell siblings/ family, etc that they may also be carriers? Don’t think there is a problem with that at all. Especially if a woman will lose her female gametes at a certain age, why not inform her so that her gametes can be harvested so she can be genetic mother of children. If TaySachs issues, nothing wrong with informing one’s relatives about it if it is appropriate. Just want to point out these are not issurim of Lashon Harah in any way- teshuva of R’ Moshe Feinstein, Sefer Chasidim, lo ta’amod al dam re’echa- times important to communicate effectively, with respect. Pitchei Teshuva reminds us that while lashon hara is an issur gamur, sometimes also a problem to not share information that can also save the person. Local Orthodox Rabbi/ mental health professional before we deal with those issues but it must be mentioned. Two final very important comments: Use of amniocentesis and CVS and recognizing that CVS is a complicated procedure and where one does CVS is important because of expertise certain people have. Amnioscentesis- not my place to contradict but might just be adding- rate of spontaneous miscarriage is a function of age also, as a woman gets older, spontaneous miscarriage grows exponentinally. Important to realize that if there is a lethal disorder like Tay-Sachs or cystic fibrosis, then there is a conversation between R’ Moshe Feinstein and Tzitz Eliezer- with Tzitz Eliezer just focusing on Tay Sachs- but in conversations I have had with poskim in Eretz Yisrael, they _____ - abortion permitted when less than 7 months. R’ Moshe Feinstein is CLEARLY against an abortion in that case. Clearly, no room for wiggle room. But Tzitz Eliezer, posek for Shaare Tzedek Hospital, did permit for TaySachs and many poskim I have spoken to also have extended to cystic fibrosis. In a conference like this we do not pasken shailos. I am just bringing the issue to the front- important to recognize there is this conversation amongst the poskim. Important to recognize when one is involved in doing genetic testing- one needs to ask important questions. If by doing this, couple will be prepared – acclimate life to child with genetic challenges? Very careful about suggesting that abortion is permitted en masse in those cases- not what is permitted. The Gemara in Shabbos tells us a list of questions God will ask us after 120 years. Did we look forward to the coming of the Messiah? Did we engage in our business practices with appropriate self-reflection, integrity? And loosely translated ‘did you fulfill obligation of having children?’ That’s not what the Gemar says. Doesn’t say ‘kiyamta’- it says ‘asakta’ – did you try? There are some times in which we all can’t fulfill all comanndments of Torah and while beauty of science is that it allows couples to actualize dream of having children sometimes certain challenges that will not let us actualize dream. Important that we as mental health professionals and rabbis communicate that Torah is not forcing us to do heroic measures to accomplish those goals. Gifts of science are there for us to take advantage of through prism of appropriate ethics should never become a tool of enslavement to a couple going through a challenging time- use them through appropriate venue.

16 Dr. Reichman: Thank you. Hopefully one day CVS will be done at CVS (laughter.) Open forum for questions. Question: Hi. My name is Meira Katz and I have a niece with ML4. 22 months and just engaged- OBGYN- we found out only offer for 4, or ____ for 9, only 17 can be tested. How do we as community begin to close that gap? Answer: (Lobel) It’s very unfortunate when testing that is available is not done. It’s really incumbent upon physicians and genetic counselors to do the test. We have to balance it because the tests are expensive and there are a thousand tests available. 11 tests done have been pretty standard for a while. Part of the reason for this conference to educate the community so when a couple is engaged they know to get tested and to seek out genetic counselors who are familiar with Jewish. Through education of community to ask for the tests. Question: Hi. I’m Andy. We heard three very elegant presentations that laid out the problem but then veered away from one of the major issues and that is- where does the Halakha put us with respect to issues like slippery slope? Tay-Sachs is simple- fatal disease in which quality of life is very poor etc. BRCA testing though can be done but where do we draw line halakhically of what is something we want to actively prevent vs. something that prevention is probably nto appropriate? Sex-selection testing is a dramatic example but the answers are a little surprising in their breadth because it opens the door for some pretty Draconian… Answer: (Brander) I agree with you immensely. In the article I wrote for Tradition, I am totally against the idea of doing sex-selection but major poskim- what they forgot I’ll never know- permit it. I look at what happens here with very large group of young men and young women; the fact that genetic testing is happening in a robust way here with all the Torah personalities promoting it- I think it sends an issue to Jewish Orthodox and non-Orthodox students around the country. Second piece which cuts to issue is important to recognize can’t deal with all these issues with one fell swoop. Halakha is in an appropriate evolutionary process (not the principles of it) but Halakha writing more and more literature as these technology develops. So for example this year the Rebbetzins Yarchei Kallah that YU runs is focusing on issues of women’s health, in particular genetic testing that perhaps should be done proactively if a woman’s family has been shown to have certain forms of cancer. Converations with 60 or 70 Rebbetzins will translate to conversations with thousands within Orthodox community. Whether pushed by health professionals at Einstein or elsewhere, you will find Halakha and poskim proactively being engaged in this. I think in five years from now, your question will still be there but you’ll define that slope from a different perspective than you would define it right now. Dr. Reichman: Our next session is on cancer genetics- complex issues.

17 Question: Question and clarification- aren’t there couples who find out after they are married that they are Tay-Sachs carriers opting for in vitro so they can have preimplanation genetic testings and would that be halakhically preferred? Answer (Brander): Yes and yes. I get that question many times and tell them not to play Russian Roulette – better to ensure [child is born healthy?] PLENARY 1: CANCER GENETICS Dr. Harry Ostrer, Rochelle Shoretz, Dr. Eddie Burns Good morning, my name is Edward Burns and I’ll be moderating the second session on cancer genetics. My hat’s office or my yarmulke is office to the wonderful organizers of this fantastic symposium. This is the fourth one they have put together and each one has been fantastic. I too wish to extend my wishes to my colleagues- Rabbi Brander, Dr. Asch- Dr. Asch’s words very chilling, etc. First, during lunchtime, for those who want to have the sex-selection process with diet and don’t want to eat lunch, there will be tours of the marvelous Glueck Center next door. I encourage people to take a look at what YU is doing today. I was given all sorts of instruction by Tali- there’s going to be no question because there is no time so I’m going to ask each of the speakers to cut each of their presentations by an hour or two. I was also instructed that each of the speakers has a small allotment of time and I’m supposed to nudge them not to. But why should I do that- they’re my friends and colleagues- let the students do that!  In late 1980s and 1990s, cancer genes were identified. The way these genes worked, the ones discovered in latter part of 20th century, was through something called tumorsuppressor genes. All of us hopefully have tumor-suppresor genes that protect us from getting cancer. But if you have one of the bad genes they inactivate the tumor-suppressor genes. May in fact have an adverse effect on the tumor-suppressor genes. In fact, these tumor-suppressor genes are actually quite rare. In fact, hundreds if not thousands of genes have been identified since this time that have some effect on tumor-suppressor genes. Two most common genes that you’ll hear about from Dr. Ostrer are the BRCA 1 and BRCA 2 gene. Susceptibility to cancer. Problem: Not every gene test translates to a test for disease. While there are tests for breast cancer, increased susceptibility to ovarian cancer/ pancreatic cancer doesn’t help because not particularly good screening for those. Points to ponder- should we test for susceptibility even if not the exact gene? Despite that, important for us to be aware of those tests that are really helpful and thankfully this morning we have a panel of internationally renowned speakers. Great privilege to introduce speakers one by one. Dr. Harry Ostrer- professor of pediatrics in medicine, director of Human Genetics Program at NYU School of Medicine, involved in New York State Bar’s association. Received undergraduate degree from MIT- Columbia, John Hopkins, etc.

18 Dr. Harry Ostrer: Very brief overview of cancer genetics, leave latitude for others. Family history and breast cancer: Breast cancer risk is higher among women whose close relatives have the disease. 20-30% of women with breast cancer have a family history of disease. Male relative/ female relative all important. BRCA 1 and BRCA 2 are major risk factors for development of breast and ovarian cancer. Frontline genes commonly tested for but not the only ones- there are others. PTEN, STK11, etc- therefore we believe genetic counseling is an important part of the process in evaluating someone for risk of ovarian/ breast cancer. BRCA 1/ BRACA 2 gene carriers have markedly increased risk above that of general population. Risk of ovarian cancer following breast cancer diagnosis is a tenfold increase in BRCA carriers as opposed to 2-6% general population. Two important issues- Myriad Genetics lawsuit and possibility of doing genetic screening. ACLU Challenges Patents on Breast Cancer Genes- validity for patents on identification of BRCA genes. US has offered thousands of patents on our genes. Gene patent gets someone exclusive rights to gene sequences. Should anyone use the gene for commercial or non-commercial ____, he can be sued for infringement. Argument for patenting: Needs to be some protection to process new drugs coming out. Myriad = sole source or limited source genetic testing. Patent-holders have virtual monopoly over their patented genes. As the lead counsel for ACLU has noted- I should note I am one of the plaintiffs in the suit so I am not coming to this without a very strong point of view- “The patents on the BRCA genes are particularly broad and offensive. The PTO has granted Myriad Genetics, a private biotechnology company based in Utah, patents on both the BRCA1 and BRCA2 genetic sequences, on mutations along those genes, on any methods for locating mutations on the genes and on correlations between genetic mutations and suspectibility to breast and ovarian cancer. As a result, Myrida’s lab is the only place in the country where full sequencing testing is performed for patients; others are prevented from conducting diagnostic testing or offering alternative tests.” Myriad’s monopoly on the BRCA ½ genetic testing makes it impossible for women to access other tests or get second opinion about their results. There is no price competition for Myriad Genetics’ $3000+ charge. If there were competition, maybe more innovation, etc- alternative results, second opinions. The major arguments of the lawsuits include: 1. Genes are natural products and NOT novella and not obvious discoveries. Patenting a gene is like patenting noses or oxygen. 2. Patented claims on genetic information infringe on free speech. I could develop a new and improved method for genetic risk assessment that involved BRCA ½ genetic testing, but my right to free speech for disseminating this information could be abridged by a cease and desist order.

19

A hearing was held before Judge Robert Sweet of the US district Court for the Southern District of New York on September 30, 2009 about the standing of the plaintiffs. Judge Sweet agreed to rule by the end of October. If favorable, the case wil move on to discovery and trial. Population-based genetic screening for BRCA ½ among Ashkenazi Jews: In the September issue of the journal, Genetics in Medicine, Dr. Wendy Rubinstein and her colleagues from Northwestern University Medical School and North Shore University Health System published an article, “Cost-effectiveness of population-based BRCA ½ testing and ovarian cancer prevention for Ashkenazi Jews: A call for dialogue.” Their premise was that almost half of Ashkenazi Jewish individuals identified with BRCA ½ mutations have a negative family history for cancer and that this confounds efforts toward presymptomatic carrier identification. Their model predicted that a genetic screening program would result in 2811 fewer cases of ovarian cancer, with a life expectancy gain of 1.83 quality- adjusted life years among carriers. At a cost of $560 for founder mutation testing, the cost of the program would be $8300 (discounted) per year of quality-adjusted life gained. Their recommendations were at odds with earlier recommendations of the US Preventive Services Task Force that population-based genetic screening for BRCA ½ should not be offered. Dr. Rubinstein’s recommendation was based in part on an as-yet unpublished study by Dr. Ephrat Levy-Lahad from Shaare Zedek Medical Ecentre in Jerusalem. Dr. LevyLahad’s recruited over 7200 men and identified over 150 families with BRCA1/ BRCA2 mutations. They counseled and tested women in thse families, many of whom were not aware that they are at increased risk, and were not undergoing screening. Their results suggested that cancer risks for carriers are just as high in these famlies and from high-risk families. The website for the Breast Cancer Research Foundation noted, “The researchers are continuing their study, and if more robust risk estimates remain high, they may determine it is justified to offer BRCA1/ BRCA2 screening in the general population.” Similar studies are underway at Women’s College Hospital in Toronto and University College London. Some have called this, “No-brainer testing.” But is this true? Genetic testing without adequate genetic counseling can lead to fear and anxiety. Myriad Genetics conducted such a television marketing campaign in 2002. On the Genome.gov website, under “Direct to Consumer Marketing of Genetic Tests,” it was noted, “In Denver, one of the cities in which the ads ran, cancer genetics centers noted a 30% increase in calls from women interested in BRACAnalysis, but a 30% decrease in referral of high risk women during the campaign. Tehse data signal a potential failure of the ads to reach the target population of women most likely to benefit from the information gained from BRACAnalysis. Further research showed that the advertisements did not accurately portray the test’s ability to predict cancer or encourage consumers to contact their health care provider.” The availability of such a program can create an elite status for Ashkenazi Jews, but not for other Jewish or non-Jewish groups, where comparable tests are not available. AS Dr. Rubinstein suggested, thi si the time for a dialogue.

20

Question: Do you have a patent number? Answer: (Ostrer) Nope. But you can google the ACLU website; it is very extensive. Question: What can you do if you have BRCA genes? Answer: A lot. Screening, take drugs (estrogen, etc) or have risk-reducing surgery. (He elaborated on this.) Ostrer: Another thing I didn’t mention- likelihood that Ashkenazi Jewish person will be a carrier for one of these mutation is high. Burns: I have a hardball question for you. Is there a danger that if someone gets a negative result they may put themselves in excess risk because they’ll feel overly assured and won’t get a mammography? Ostrer: Excellent question, not a hardball, though. We do see people who come from high-risk families. If we don’t identify a BRCA mutation, we don’t currently have a means for reducing their risk. Burns: Unfortunately, testing is not perfect and many women are affected with breast cancer. Rochelle Shoretz is a two-time breast cancer survivor and founded Sharsheret, an organization to fight breast and ovarian cancer. Diagnosed with breast cancer at age 28. In November 2001 while undergoing chemotherapy herself, founded Sharsheret. Since organization’s founding, Sharsheret has responded to over 19,000 calls/ emails. Privilege to welcome Rochelle Shoretz. Rochelle: Thank you, Ed. I’m technologically deficient at this- I’ve done so much yet can’t seem to work at a computer. I’m honored truly to have been invited to participate in this. A two-time cancer survivor, I am the proud founder and executive director of Sharsheret. I’d like to take you back 8 years in time. Just days before my 29th birthday I was diagnosed with breast cancer for the first time with no noteworthy history of cancer. I had heard of BRCA 1 and BRCA 2 genes and knew there was some connection between mutations in those genes and breast cancer. Wasn’t until my stepmother pulled me aside and questioned if I had considered genetic counseling that I began to consider whether my surgery and treatments would help me. Decided to wait to see whether I was a candidate for a lumpectomy or bilateral mastectomy. Now we have lots of education re: breast cancer. Hadassah, Amit, shower self-examination in mikvaot- but when it comes to grappling with the issues women face once they are diagnosed, the Jewish community fell off the cliff before Sharsheret. I was surprised to learn that there were no national organizations dedicated to helping women fighting breast cancer and ovarian cancer in a community like ours that supports so many worthy causes. What was the message we were sending?

21

I founded Sharsheret to pair young Jewish women with volunteers who could share their own personal experiences. From Alaska to Tennessee women are calling to discuss all sorts of issues- Hasidic, Conservative, Reform, etc- questioning spirituality after a diagnosis, going to mikvah with an altered breast, wearing a wig as a single woman. Won’t spend much time on science behind BRCA1 and BRCA2 but to review quickly, scientists have developed two genes. 1 in 345 is mutation in BRCA1 and BRCA2 normally- but 1 in 40 in Ashkenazic Jewish women. Women who carry a mutated gene may have an 82% lifetime risk. Jewish women, those who have been diagnosed and many who have not want to talk about genetics. They want to discuss the test you can take, their fear of the results, what it will mean to their children. They want to talk about the consequences of not taking the test or taking the test but not sharing the results with their loved ones. They want to discuss fear they have that genetic diseases in their family will affect their ability to marry. Also difficulty in tracing family history, much of which may have been obliterated in the Holocaust. Sharsheret pairs women with one another to discuss these issues. Also, Sharsheret callers can speak with a certified genetics counselor. Email I received from one of our callers- a man writes to us: My wife is a 55-year-old breast cancer survivor. My daughter is 26 years old. My wife is undergoing genetic testing at this time but we are in disagreement about what to share with our daughter. My wife’s mother is a two-time breast cancer survivor. My wife has been extremely vigilant and has prepared my daughter for this. Is there any literature on ethics regarding this topic? [Paraphrase- he worried she would feel ‘condemned’ if she heard she had the BRCA mutation in her bloodline. Nothing more she could do beyond what she is doing. In the end, wife tested negative. They were relieved they did not have to figure out what to tell her.] Sometimes it helps to speak to others who understand what you’re going through because they have gone through it themselves. Can address for example questions about implications of testing on health insurance, impacts on other family members. Very often we think of genetic testing and forget there is a process of genetic counseling first. Sharsheret’s Genetics for Life program can help facilitate that counseling first. Sharsheret is a great example of a Jewish communal response to issue. Taking a subject that was once taboo, welcoming new era of education and information. Alter legacy of secrecy that has long enshrouded health issues in our community. For some genetic counseling and testing will lead to testing- prophylactic surgery, increased surveillance. For others who are already vigilant about their medical care, may mean information that seems more frightening than useful. Regardless of how prepared we feel to pursue genetic testing, know your family history. Let’s pass information on to our children when and if we are blessed to have them so that they are educated about their risks and can

22 choose for themselves whether genetic counseling/ testing is meaningful or helpful. In understanding our risk, we can continue to protect our future. Question: You mentioned email from a man- incidence of male breast cancer and the denial among the general population that it exists- how much of the male population has been informed that this is also very viable- not just a female problem? Rochelle: It is worthy of note two emails we received is from men. The incidence of breast cancer in men is much smaller than that in women. At Sharsheret we are committed to publicizing that this is a problem in Jewish *families*- not just women. Mutations in BRCA 1 or 2 gene can also flow down the men’s side. Particularly in a forum like this, when I say get to know your family history I mean your father’s as well. Piecing together genealogy. Ostrar: Men do have these increased risks especially if they are BRCA carriers for breast cancer, pancreatic cancer and melanoma so it is important for men to understand the risk, test, act on information if positive. Question: I hope this is not a question that would entail a whole new panel but I have two brief questions- how did it come to be that gene patterns can be privately patented? Is that halakhically permissible whatever the law may be in the United States? Ostrar: Short answer to number one is yes, the US Trade Office decided it was permissible to patent genes. It is a big issue. AJHS – we don’t think that patenting genes and enforcing that for genetic testing is a good idea. And created a firestorm of criticism from biotech company. But I truly believe patenting genes limits innovation and access to care. Good patents and bad patents, and I think this is a bad patent. Burns: I think we’ll have to hold off on the answer to the second question. I see somber expressions on young women’s faces- that is appropriate but let it be upbeat because what this conference has to offer is knowledge. We’re at YU and YU is not just Mada but Torah U-Mada and while science and ethics are applicable to entire Jewish population, we at Yeshiva place ourselves under yoke of Halakha and Torah. And to the credit of Torah which is always growing and expanding, the Torah always has something to say. Privilege to introduce R’ Mordechai Willig of RIETS. Rabbi Mordechai Willig: There are three issues which halakhists consider as very sensitive and difficult topic. The first: Should all women in the Ashkenazic and Jewish community be tested for the BRCA gene? Is it an obligation, a prohibition or does it lie somewhere in between? We have heard that 1 in 40 Jewish Ashkenazic women are afflicted with this particular problem. It seems to me that from a strict halakhic perspective, it is difficult to consider this to be an absolute obligation- to check for a 1 in 40 chance in this kind of a situation. Nonetheless I believe it is certainly permissiblewould not view this as somehow wounding for an insufficient purpose- taking a little blog is permissible for an individual who feels s/he should be tested fro the BRCA gene. This is for the general Ashkenazi population.

23

In the case of a relative who has BRCA gene or breast cancer. If first-degree relative has mutation in BRCA gene, 50% chance that another first-degree relative will have it. In this case, I think we can request an bligation to test if something can be done to save lives/ action will be taken. If a first-degree relative has cancer then it is difficult to have specific scientific data but it depends on age of onset of cancer and if there is more than one. We heard before from the doctor the statistics go much higher if there are two relatives who have it. It seems to me it is appropriate for such testing to take place. Nonetheless, we have a halakhic principle called ‘shomer pesaim hashem’ which is found in the Gemara in many different contexts. Hashem watches over those who are simple- simple individuals. The question is when do we apply this principle and why do we not? For those who have some halakhic grounding, I’ll suggest one source to look at- footnote in encyclopedic work of Dr. Avraham Steinberg who has been at this medical ethics conference before. He refers to this in his article about smoking- footnote refers back to article on miniat herayon (contraception) – when we do or don’t apply ‘shomer pesaim hashem’- seems to me this principle only applies if the danger to life is a minority. If the danger to life is a majority, more than 50% chance that life will be shortened then this adage would not apply. Thus the conclusion that smoking is prohibited by Torah law since recent evidence has it that someone who smokes has 50% chance of shortening lifespan which was not known to former (gedolim? poskim?) Based on 50% rule you’ll discover when it is mandatory to do this testing or when it’s simply a good idea. My opinion is that it certainly should be done for people who have close relatives who have the BRCA mutation or breast cancer. An expert doctor even told me they can test from the dead, which is not known to the general population. You were tested, you’re positive- what do you do then? What does Halakha say about it? Seems like there can be a number of things that can be done. In my view, testing in these kind of circumstances is critical. Testing for BRCA-carrying individual is different than general community. In general community, mammograms should take place- spoken about it from the pulpit in normal situations. Someone with BRCA mutation, I’m told an MRI, which is not done for general community, would help. So for that reason alone, for screening process, testing should be done. In addition, there’s an unfortunate link as you heard before between BRCA gene and ovarian cancer. I spoke to a number of doctors who told me that generally the idea of removing the ovaries – ovariectomy- is something which can save many, many lives – in most cases, does not need to take place that early in life. I was told that one could wait till past the age of 40- generally- to undergo this and it seems to me that although normally we are strongly against these types of operations which prevent further childbearing, given the high risk of a life-threatening disease which is otherwise almost impossible to detect, in my view this operation is halakhically indicated. Hard for me to use the word absolutely mandatory because depends on percentage. If someone is tested, yes, they can have their children but after they are done having children, they can take this step- even though normally it is a distinct prohibition to engage in these type of surgeries that make

24 one unable to have children, male or female- it could save lives. Practice of pikuach nefesh, overriding to save lives. Mastectomy- my doctors have told me that although this is certainly a medical option, in many cases the MRIs if done frequently enough can be relied upon to provide sufficient protection. But then again every woman is different! Halakhically permissible- no violation of chavalah- wound for no purpose – because there is a purpose in the mind of the patient. Halakha does give significance to attitude of mind of patient in those circumstances. Screening which should be done in a more vigilant and significant way for carriers and ovariectomy at somewhat later age, these in and of themselves, halakhic reasons for action to be taken for those who have the gene, screening, especially for those who have a higher risk based on relatives having cancer. Genetics as we know is associated with childbirth, marriage, but the question is: does the Halakha demand that an individual reveal to a prospective marriage partner genetic history? Excellent question. How far do we go with this? So once again we go back to our “shomer pe’saim hashem” principle which we suggested would not apply in a case of 50% chance of something. My view is that generally speaking if there is a possibility of a test which is not invasive, which presents no statistical threat to life, it certainly should be done even in absence of 50% rule. I do not think we should rely on “shomer pe’saim hashem” in all circumstances. Let’s talk about colonoscopies- I think that’s something that should be done in the way the medical community suggests it- a person shouldn’t close their eyes and look it up on the Internet and say I have less than 50% chance, not going to have it- not wise. Dr. Sheldon Pupkada? wrote an article in Journal of Contemporary Halakha and Society about this- unfortunate part was he was unable to gather a consensus. Even some who say not, which frankly I can’t fathom. My opinion accords with R’ Herschel Schachter’s shlita that it should be done. In Talmudic instances, ‘shomer pesaim hashem’ principle is applied when you’re doing something; how much more so when you’re not, people would argue. Famous teshuva about Tay-Sachs by R’ Moshe Feinstein very squarely teaches us it’s not true – I’m going to close my eyes, have bitachon hashem, etc- look at the teshuva by HaGaon R’ Moshe in Even HaEzer, Chelek Daled, two teshuvas- I think siman yud- you’ll see he says this testing should be done. If you haven’t done it yet, you should do it. Well, as we’ve heard earlier references to comparisons between BRCA and other Ashkenazic Jewish diseases and therefore here too certainly a reason to do it. From R’ Moshe’s teshuva you do see that testing is appropriate. We have no right to make an automatic assumption that in general just say do nothing and close our eyes. Now, what must be revealed to a potential marriage- partner? Very significant topic that goes beyond particulars of BRCA. Great rabbinic decisors have given advice both orally and in print to their questioners about this matter. Dispute over how obligatory it is to reveal- remarkable response by the Steipler who is not known for his response- in Masechet Yevamos has to do with a case of someone who had a non-Jewish father and

25 had a difficultly finding a shidduch even though he is a Jew. He was told to go to a faraway place and nobody should know who his father is. Isn’t this disingenuous? When selling a house or a car, have to reveal every flaw, etc. So he says that when it comes to a car or house, you can buy anybody’s car or house. But with shidduchim no two people are alike! So don’t have to reveal flaws. Any flaw? No, there is a requirement to reveal only if afterwards when the wife finds out she would walk out and ask for a divorce. That is a high standard. [Paraphrase: Rav vs. R’ Moshe on Marfin’s Syndrome. Rav said the woman did not have to reveal it but also the woman was healthy; she wasn’t sick at the time. By R’ Moshe, the sickness had presented. So perhaps Rav and R’ Moshe were not really disagreeing. R’ Moshe: Woman who by age 20 did not have period- didn’t have to reveal it as long as she accepts on herself that if she cannot have children after 3 years, will accept get voluntarily.] Man who has the BRCA gene has the exact same chance of passing it on to a daughter as a mother. There are those who have taken it upon themselves not to check themselves so they shouldn’t have the knowledge and shouldn’t have to reveal it. Interesting way of thinking. On the one hand, knowledge is dangerous. On the other hand, if indeed there are close family members who have breast cancer and the decision is taken not to test for shidduchim, it can backfire. There are people who will assume, if they know the relative has breast cancer, that the girl has the BRCA mutation and may stay away. When do you reveal this? I don’t believe it should be said at the very beginning. Then it’s very hard to get a date. Many men who would like to go out with this girl despite this genetic shortcoming. Till when do you wait? In my position, this matter is you wait till the midpoint. What is the midpoint? It’s like a half-life. Depends which part of the Orthodox Jewish world you come from. Is it two days? Two weeks? Two months? Wait till that point in time. My time is up so I thank you very much for your kind attention. Behavioral Genetics and Free Will- On a Collision Course? Rabbi Moshe D. Tendler, PH.D. Thank you, Professor Burns, Dean Burns. The conference began with a email that made the rounds for the last two years concerning scientists who completed the Human Genome Project, went to HKB”H and challenged him he could make man. Another email that hasn’t gone around yet- the same scientist, after realizing he couldn’t make man without using God’s earth, decided to thank God and asked Him to send down a notarized statement that they are not responsible for their actions. It’s all in the genes. The Geneing of the World. This caption: “Free will, now you have it, now you don’t,” challenges the notion of do you ever have free will. Other coercive forces on man’s decision-making process. Social forces, influence of family in a specific way, whether that inhibits a person from making a free-will decision. This article from some years ago pointed out how difficult it is to

26 separate one’s decision from what others have told him to do and ends up thinking it’s his decision. Yesterday in the Torah we read HKB”H was perturbed that man would exercise his free will for evil as already Adam had done and then gain immortality somehow by eating of the Tree of Life. God feared, now that man knows tov v’ra, can differentiate between good and bad, now we’re in trouble. This cartoon that I had found some years ago in my files- an angel talking to God: “You gave them free will? Now they’re bound to get into trouble!” Or this other one from Pepper…and Salt: “Let’s have some fun- let’s make them responsible for their own actions.” Yet free will is the basis of our religion. It’s the basis of our legal system. We exempt people if they were coerced. To what extent does a person’s genetic makeup serve as a coercive force? I remember some years ago there was an outburst of anger during the services and the response of most of the people was, “You should have heard his father.” A genetic statement. He comes by it honestly- he inherited it. Yet the basis of our religion is free will. “I gave you a choice- choose life or death- u’bacharta b’chayim- I advise you to choose life but it’s your choice.” I can’t compel you, God says. The Rambam/ Maimonides incorporates this as an axiom/ foundation of our faith. Reshus chol adam nesunah- I just hope you don’t publish before I do because someone convinced me to give you everything I had on file. It’s his choice. He can be good; he can be bad. And it’s linked to reward and punishment. If we do well, he’ll be rewarded. If not, he’ll be punished. I scribbled down in my handwriting in the bottom on Maseches Niddah which we are studying in yeshiva this year that there is pre-determination. Before someone is born, it says God is asked to proclaim: What will be with this one? Will he be a strong man, a weak man? Wise or foolish? Rich or poor? But whether he’ll be righteous or not- that’s left for man. God doesn’t comment. Here you have, for those who would like to see it in English, Maimonides translated by Dr. Isadore Twersky. Much has come out of the genome project. 25,000 genes that have been identified as belonging to us- now some of those genes are being associated with behavioral characteristics. Most likely you would think such complex activities as behavior would be controlled by multiple genes. But literature is now reporting propensities/ specific genes that are involved in behavioral traits. And if that is so and if it’s a genetic makeup that a person does not have free will in that activity, that was the question as posed in this caption here on US News. Title page of a popular monthly: “Is a person born bad?”

27 It’s such a frightening question that several years now a conference on criminality in America with Rachel Overtoes has been canceled over and over again for fear of the results. But our Torah also recognizes – in a few weeks you’ll read the story of the birth of Yaakov and Esav. The first child who came out reddened and Rashi comments- seems he has the genes to be a murderer. So it it Esav’s fault? God made him that way. Second- in the Torah, not later commentaries- a comment someone did some kind of genetic cross-breeding and managed to produce some particularly dangerous mule/ crossbreed. So the Talmud comments: “Oh, of course. That’s a fellow born out of an incestuous relationship between a son and his mother. So he had that tendency.” Gemara in Pesachim. And then we have a whole page in the Talmud that associates day of birth with personality traits. If you’re born on Sunday, you’re in good shape. But if you’re born on other days, real problems come in. This was those who follow the Daf Yomi/ learned Bava Basra – realize the significance of what you studied. Job presented an argument that would exonerate every sinner. His argument was: Sin and good deeds are not rewarded, are not punished. Man merely floats in a kind of a vacuum. It so happens that the vacuum opens up and he’s sucked into one area and he becomes a sinner. Sucked into another area and he becomes a tzadik. Calvinism believe in it, etc. But Iyov presented that. What he said was: Man is not responsible for his actions. Iyov could have exempted the whole world from every sense of judgment! Justice presumes free will. In American law if you commit an act because someone put a gun to your head, you’re not responsible for your actions. What difference does it make if there’s a gun to your head or a gene to your cell that compels you to behave a certain away? The Malbim’s comment sums up: That was the whole battle between Job and his three friends who came to visit him. Is there justice in the world? Is man a free agent to choose to live the way he does? Then we have some intriguing developments. “Brain Injury Said to Affect Moral Choices” by Benedict Carey- specific areas of the brain affect how people evaluate a situation. Damage to ventromedial prefrontal cortex makes people less sensitive in certain ways. Let’s say you’re abandoned in a lifeboat and in order to survive you have to throw some people out of the lifeboat and the people wouldn’t survive anyway because they were injured in crash- and the answer changes. What does that say about free will? My brain made me do it. Two comics: 1. “Your son has betrayed his country and joined the Taliban.” Parents’ reply: “He has a learning disorder.” 2. “Like it’s my fault I get D’s- I’m doing the best your genes will let me.” Famous Phineas Gage case. Blow down mountains and this poor fellow was tamping it down, exploded and drove the crowbar through his eye as the picture you see. And his personality changed. Science for the first time found a picture of Phineas Gage this July.

28 It seems also that he ran around with a circus earning a living. Despite this terrible injury, he survived. But his personality was changed – basically losing some of his moral judgment. So you have an organic reason for sin! This was backed up by a number of solid cities- mutation in the A gene. I’m only reporting from peer-reviewed journals, not Amsterdam News. Dealing with impulsive aggression, arson, attempted rape and exhibitionism connected to mutation in this gene. Second study showed up especially if those who had that mutated gene were exposed to mistreatment/ abuse. Made them into abusive personality. When do you express your genes. On Kleptomania: Showing that treating a kleptomaniac with a drug abolishes the urge to take things that don’t belong to him. Now it could be analyzed that this drug overpowers his free will. Or it could mean there is a fault in his metabolism/ physiology and naltrexone repairs that. Can he be held responsible? “Seeds of a Sociopath” from Josh Fischman- damage specific areas of brain leads to this sociopathic activity. Where does free will come in? If you don’t choose, God says, it’s not your fault. If you can’t choose, it’s not your fault! “A man who borrowed cars”- L. Cohen, L. Angladette, N. Benoit, C. Pierrot-Deseilignyfound small lesion in his brain via MRI, associating that with his tendency to steal cars. We are removing man from a sense of responsibility from his actions. “Genes Behind the Campus Drinking Scene” from Science 29 August 03, v. 301- not their fault anymore. They get kicked out of college because they get drunk too often, they have a right to claim it’s not their fault – it’s their genes. This drive has kept up because they want to find genes that exempt you from your actions. Addiction gene- and there was a paper that was not published because someone else published it first. Good paper but because someone published it first they withdrew the paper because there was stolen data from this psychiatrist Laura Beirut. Paper about addiction gene in women of European origin. It is the Not-Me generation that is coming up. Summary from Science of all the genes that are being identified as behavioral genes- with good, experimental work done- how would we respond to it from our Torah point of view which has the absolute axiom you’re not responsible unless you do so voluntarily? Unless you exercise free will? “Experiencing Physical Warmth Promotes Interpersonal Warmth”- if you drink hot tea you have a better feeling for people than if you drink an ice coke. But in shidduchim all the people meet in hotel lobbies and drink iced coke!

29 How far would you go? How about pre-implantation diagnosis? Should we now start screening to make sure the children should not have it? The belief in behavioral genes. Two more comics. 1. Doctor to parents: “The good news is that you will have a healthy baby girl. The bad news is that she is a congenital liar.” Man to employee: “Very nice resume. Leave a sample of your DNA with my secretary.” What is the Torah attitude to behavioral genetics? “Im lavan garti”- b’taryag mitzvos shamarti. One of the Midrashim adds to it- “u’para aduma” – and I bought a red heifer. This is the classic example of a law for which we don’t know the reason. What Yaakov was telling Esav is I have already relinquished my free will! I debated with Lavan so you think you may be better than Lavan. But I want you to see there is no value- I have done something which is the goal of an individual who understands that God’s laws are correct. At some point in life, I’m not going to choose anymore. When I walked into this room, if I were a thinking individual, “This one I want to kill.” If someone thinks that way, he is a psychopath! Why? If you have free will, you can kill people! Answer is that at some point in your development you made a decision I will not be a murderer. This means you gave up your free will in this area. What Yaakov told Esav is that I made a decision I won’t be a murderer- gave up free will. Said to God- if you protect me, I’ll give you 10%. What kind of gift is this? What do you give a God who has everything? “V’haya Hashem li L’elohim”- Hashem refers to the God to whom you can say no. Hashem is the God who watched you eat from the Tree of Knowledge. Hashem is the personal God for whom over the past few weeks we’ve been asking him to give us another chance. Elohim is God of natural law. You can’t jump off the Empire State Building and do teshuva on the way down. They’ll still pick you up with a sponge. You can’t brook natural law. Yaakov said- if Hashem will be with me, I will give up my will and he will become an absolute Elohim. What did Cain mean by saying, “Am I my brother’s keeper?” He was talking to God- he knew who he was talking to. If you look at one of the commentaries- says it very nicely. “Am I my brother’s keeper? You’re my brother’s keeper! You made me a murderer. If you didn’t want there to be murderers in the world, you should have made me incapable of murder.” But what did God answer? God said to Cain before he became a murderer- “I know who you are- I made you- I know you have a tendency to evil. You can overpower it.” God made people with free will – he also made people with different personalities. No one was given a crowbar through the eye to alter the organic brain. People are shorttempered, some are more placid, but everyone has his struggle. A poor man claims, “I stole because I was poor” and a rich man claims, “I stole because I was rich.” Obviously poverty is not the cause of stealing money when rich people steal more money more often than the poor. God determines whether you will be rich or poor but does not determine whether you will or won’t do something that is evil.

30 Call your attention to a legend, not true- had someone translate it into English- legend about Moshe Rabbenu –king sent a painter to paint Moshe – picture of an evil man. Went out himself and saw Moshe, saw picture was accurate. Moshe said every tendency in that picture is one I have but I overpowered them all. It’d be nice to know I have a gene for a bad temper. I would wake up in the morning and say: Okay! So now I need to be more careful. Almost like having a BRCA 1 and BRCA 2 gene where you then have to utilize screening. ~ R’ Herschel Schachter- Rabbinic Session: So this was fascinating- Chana got to have her day as a boy- but if I put it up at all, it will be a separate document and has to be edited much more first. ~ Plenary III: Frontiers in Modern Technology Dr. Gil Atzmon, Dr. Harry Ostrer, Dr. Wayne Rosenkrans, Rabbi Herschel Schachter Moderator: Rabbi Dr. Richard Weiss Rabbi Dr. Richard Weiss: This session will explore how medical ethics and technology can be used to help prevent and manage genetic diseases. Dr. Gil Atzmon – research is on aging and longevity gene. Dr. Harry Ostrer will speak about Jewish population genetics. Dr. Wayne Rosenkrans ____. R’ Herschel Schacter- want to thank him for all of the time he extends to rabbanim worldwide. Dr. Gil Atzmon: Would like to thank the organizers for inviting me to speak here. I’m going to talk today on mutation as a good thing and association with longevity. We started to say- we are designed to live for 120 years. The question is how. I wanted to connect between yesterday’s parsha to next week’s parsha which showed the rainbow as the future, desire. I think that what we do is to give a sense of what’s going to be in the future and what we want to get. Continue with my talk about Ashkenazi Centenarians as a model for healthy aging. List of acknowledgement for everyone who has supported this work. The first three slides: Want to show what happens when it comes to last year of life. Health was $8000 compared to seventeen years ago when it was $24,000. The question is: Is the amount of money spent less because they are healthier or because their doctor gave up on them? With this I’d like to tell you two stories. One from my personal life and one from ____. Family of three siblings, all of them 100 years old. The one from the left is 107 years old. The bottom picture was taken 80 years before the top one. This lady who I just spoke about smoked for more than 88 years. Which shows that if you smoke for 88 years, you probably live long. The other thing was: When she was 102, we couldn’t find her for more than three days. When we eventually found her she told us she was too busy

31 holding 100th birthday party. The one holding the rifle in this picture is still working even though she is 99 years old. My grandmother was a pioneer in Israel. She established a village in Israel. Never visited a hospital. At the age of 90 she came to the doctor and said she had a problem with her hip. So the doctor said she needs to replace her hip- she’s 90 years old. Why treat her? So they treat her with a ___ hip and she walked after that and lived till 100. This is just the background. So what do we have for this longevity study? Longevity Study at Einstein. -Over 495 centeranian (probands) -Genetically homogenous population of Ashkenazi Jews -Over 600 children of Centeranian (offspring) -Over 600 controls (often spouses of offspring) Collected DNA and serum Family history of longevity in the parents of probands -Longitudinal and functional assessments -Excellent model to assess genetic contribution to longevity Is there a genetic component that promotes longevity? Initial: Seems like there is something there but we don’t know exactly what. So initial strategy to identify the gene was to look under the light to prove longevity genes. When we started to discover differences between centeranian’s offspring and regular people. Something beneficial in this gene that allows these people to live longer. So there is longevity gene- people are starting to die because they do not have the longevity gene. Then we switched gear to genomics to allow large scale screening. Let’s scan the entire genome and try to find it. So four years ago we used DNA pools. What are DNA pools? You take 50 subjects, take DNA from them, test them and see which ones – Eventually we came up with candidate genes and instead of doing the whole spectrum of the gene, you focus on just one gene and do it individually. When we did this analysis, we found one gene that was highly prevalent among our long-lived people as compared to the control group. The name of the gene is (Plmna?) Now, in genetics, you have to validate what you find in independent population. In order to be assured that what you have is right, you have to validate in a different population- and as you can see, all of them show the same prevalence of higher in centenarians vs. control. Took 600 people, 250 control, etc- 2 million genetic points on the gene. You don’t do them one by one. This is genomics so in one shot you analyze 2 million elements and see if there are differences between older people and younger. There were indeed genes that had these differences – higher prevalence in long-lived people vs. regular.

32 Then got into epigenomics. Like monozygotic twins. So how come one becomes centarian and one dies early? Maybe epigenomic difference that causes this effect. We took ____ which is close to stem cells and used it to demonstrate difference between the two. Differences in the way line goes to the control vs. _____. And indeed, what we found is that there are changes. Rule of thumb: You need to verify in a different system called secronome. Three examples of epigenomic changes between control and ____ which validate our previous results. When we look farther and say, okay, we know that there are epigenomic changes. Changed expression of gene that we looked for. Question we asked ourselves: We see there are changes epigenomically when you grow older. Genomic expression level? We want to see if there are global changes of expression in communities along with control groups and centenarians. Clear difference between control and centenarian. So there is a different genome expression between centenarian and control. Groups are clearly different/ separate from each other. Finally, the ultimate goal is to do the whole genome sequence. This is a result of the human genome project and there is machinery to clearly know – in its entire genome. By the way, the lady whose picture I showed you in the beginning- her sequence is now running. So I want to conclude: If you ask people about how they got exceptional good life? France, fish. Italy, pasta. Greece, it’s olive oil. Caucasia, all about the yogurt or simply change date of birth. United States, it’s the exercise. In Cuba, it’s the cigar. But in our population, Kiddush every week, wedding, common denominator- be happy. Dr. Henry Ostrer: The Jewish HapMap Project: How does population genetics affect how Jews think about themselves? The issue of who were the Jews has been a source of curiosity to Jews for quite some time. 100 years ago the field of great science was in full flourish and Jews were very active participants in this field. I refer you to Jonathan’s book for more information about that. But one of the illustrious Jewish scientists was Joseph Jacobs who was an Australian polymath trained in ___ University. Great friend of George Eliot’s, wrote a favorable review of Daniel Deronda and became Eliot’s friend. Came to New York at turn of last century to become editor of the Jewish Encyclopedia which at that time was supposed to be the source for all things Jewish. Not surprisingly he wrote the source on anthropology and said remarkable ____ seems to imply a common descent. He knew about rediscovery of Mendel’s laws in 1900. Jacobs suggested that Jewishness might in fact be a dominant genetic trait- one gene makes you Jewish. Can’t make the same claim for longevity, I have to say. There have been many different ways in which the issue of Jewish origins has been explored. These types of approaches have really existed from the early days of population genetics and they’ve involved looking at whole genomes, mitochondria, etc. For those

33 who sat in on Matt Kaplan’s session, the work for this was done in Matt’s laboratory in 2000 and it was an analysis of Y-Chromsome p____. Jewishness is not a patrilineal trait – you don’t have to have a Jewish father to be Jewish. ___ transmitted from fathers to sons and don’t ___. Jews for the most part are a Middle Eastern group who formed a pretty tight cluster between Europeans and North African. Jews- Ashkenazi, Iranian, Iraqui, Kurdan, etc formed this cluster. Superimposed on them are others. Contemporary tools that we have= ways of dissecting this in far greater detail. Along with our partners at Einstein, we at NYU launched the Jewish HapMap Project which was undertaken to develop Jewish HapMaps. They’re called HapMaps because our genomes are found in boxes called haplotypes. Distinctive boxes in which our genes are inherited- hence the term HapMaps. So we have undertaken an analysis of many different Jewish populations- even some that are not indicated here [on the slide.] Some of the populations we are studying include Eastern European, Sephardi (Italian, Greek, Turkish), Syrian and Middle East (Iranian, Iraqui, Yemenite), North African (Moroccan, Tunisian, Djerban, Algerian and Libyan, Ethiopian), Georgian and Indian Jews. Interestingly our genes differ – going to be informative about our ancestry. We want to analyze for lineage-informative haplotypes. And we want to look for evidence of ___ selection. In the throes of completing our first analysis and we would really like to get it in press before we start discussing it in the public. Quite frankly we’re hoping that you might invite us back next year so we can talk about this in far greater detail. Phase 1: We studied several different Jewish populations- run DNA samples on all of these populations- we have done data analysis. Principal Component Analysis- compare Jewish populations to worldwide populations. Jewish populations indicated in yellow form a pretty type cluster- we think there is a cluster called ‘Jewishness’ and fall between European populations and what we call Israeli non-Jewish populations- these are Druze, Beduin and Palestinian volunteers from Israel. We’ve limited ourselves to analysis of Jewish populations- the Jewish groups studied to date each form a demonstrable Jewish genetic cluster. Within that cluster, specific Diaspora groups form sub-clusters. Positioning of these groups is pretty close to European groups- quite close to Northern Italian populations, favoring idea that some of Ashkenazi population comes from people in Southern Europe or in the Italian peninsula. So the themes we have learned from The Jewish HapMap Project: 1. Overall, the Jewish groups studied to date form a demonstrable Jewish genetic cluster. Within that cluster specific Diaspora groups form sub-clusters. 2. Jewish groups are closely related to Middle Eastern and southern Europeans populations with whom they share genetic origins. 3. All Jewish groups show some degree of admixture with Europeans and possibly other groups. Demonstrably different from non-Jewish lineage.

34 Many people seek genetic testing now, especially of their Y chromosomal and mitochondrial DNA types, to determine whether it is “typically Jewish,” in origin, whether it is derived from an illustrious lineage, such as that of Aharon the Priest, or whether they are related to someone else with whom they share a surname. Some direct to consumer genetic testing companies offer ancestry-informative testing as part of their package. One DTC company is starting to report so-called haploblock testing to demonstrate shared genetic segments among Ashkenazi Jews. At this juncture, it is worth exploring how genetic information affects how Jews thinks about themselves. Will genetic information infringe on Halacha on defining who is a Jew? Could a genetic one-drop rule come into common usage? Because genetic information indicates not only peoples’ origins, but also their propensity to certain traits, could certain groups be stigmatized because they have evidence for a higher frequency of specific adverse traits? Only through thoughtful discourse can the misadventures of the 20th century’s eugenics movement be avoided. Dr. Wayne Rosenkrans, Jr: Thank you. Personalized Medicine- I have been seduced to the dark side of public policy so now bear the dual title of scientist and public policy maker. I’m going to talk about something almost nobody has any opinion about, healthcare reform. [Laughter] First of all, what’s the problem? Why is everybody worried about the healthcare system? The head of the Mayo Clinic made a statement to an audience, “I am here to tell you there is nothing wrong with the healthcare system.” Silence throughout the room. “You have to have a system before something can be broken about it!” he continued. We have a sick care system not a healthcare system. Healthcare system affects everybody- everybody is affected by the current cost of healthcare. The other piece you don’t hear much about is the quality of care being delivered today. It is actually sub-optimal. Who can guess where USA ranks in terms of healthcare delivered? 36, depends on who you read. And you say- we have Mayo Clinic, Cleveland _____, etc- and the answer is that if you go to the Mayo Clinic then you do get the best care. But most medicine is practiced by two-docs-in-a-box in Kentucky where people practice the art of medicine the way they always have. Problem is that if you drew a curve around the quality of care in the country and cost of care in the country, cost is going up and quality is going down and those two curves will intersect at some point and the whole system will collapse. Question is when that event will occur and what will happen. You can ask a dozen learned people about that and get many different answers to that and all different. But probably going to happen within the next five years. If we don’t do something now, we are going to be in big trouble later on. The current situation is not sustainable. Big new fact of life –we can’t do it alone. In the past, hospitals, physicians, government all worked on their own, nobody talked to each other and we ended up in a huge issue. At the moment, we have minimal resources to fund change in medical presence. AHRQ and

35 Critical Path are changing quality of healthcare today. Growing amount of influence over medicine in America. Look at this bar NIH vs. FDA and AHRQ. “Starkly put, for every dollar Congress puts to develop breakthrough treatments […] it allocates one penny to ensure Americans actually receive the benefits.” There’s something wrong with that. And I’m all for basic researchnot a matter of cutting the NIH budget but we have got to rebalance this equation a bit. This kind of thinking elicits a reevaluation of the basic value proposition. Problem is we are not getting value from healthcare. But how do you define healthcare? Value in healthcare is often expressed as increment in critical benefit achieved (health and/or quality of life improvement,) for those receiving a particular service or set of services, in conjunction with the investment required. So quality over cost. All we hear nowadays is about cost. But it’s the quality side we need. New refrain that you can’t help but hear: “Pay for what works!” Seems obvious but in fact we pay a lot for what doesn’t work in healthcare today. System is incredibly inefficient. Question: What works best? What works best FOR WHOM? What works best for whom UNDER WHAT CIRCUMSTANCES? What works at Mayo Clinic may be a complete bust somewhere else in the country. Our current system doesn’t recognize that. It also really doesn’t make a differentiation about what works best for whom. People respond differently to diff. modalities. You can interpret these questions- medical community says that what works best is comparative clinical effectiveness. For whom? Personalized healthcare. Under what circumstance? Real world effectiveness. Not sterile world of randomized clinical trial. For Healthcare Sectors including product developers- these statements require new thinking. In the past, if you were going to put a product on the market you had to demonstrate three things for the FDA: 1. That it worked/ efficacious 2. Was it safe/ people won’t turn blue 3. Production assurance Drug industry spends 1.2 to 1.8 billion per drug to meet these requirements. Now those, are no longer sufficient. You now have three new hurdles: 1. Effective – and as effective or more effective than current standard of therapy 2. Why it should be covered 3. Reimbursement

36 That means looking beyond market approval toward greater embedment in clinical practice. Innovation itself is no longer sufficient- the value of innovation must be provenin a clinic with real patients and real providers in a cost effective way to demonstrate what works best, for whom, under what circumstances. We need something different. A possibility is a Learning Healthcare System. It is a system in which evidence emerges as a natural byproduct of the care delivered. Right now, evidence emerges because it will sell a product. Ability to deliver right care to right person at the right time at right place= value. Two needs for evidence: Confirming real-world comparative clinical effectiveness must constitute a core elment of clinical development plans- products for the future should be developed not only with FDA but with CMS (Center for Medical Services). Or with AHRQ. AHRQ has a budget of 330 million dollars which is NOTHING. They have created a truly effective agency. AHRQ was charged with hiding comparative effectiveness recommendations for all products going on the medical formulary. Medical formulary affects 60% of population. And this little tiny agency is charged with putting the good seal on everything. New player on the block which I believe will happen 18-24 months- comparative effectiveness with budget of 3 to 4 billion dollars. So product-development companies are thinking o’my god. Also, what is best for whom? Generating meaningful segmentation of patient populations by whatever technology is appropriate (genomic, imaging, informatic) in order to increase the benefit of therapy. So the creation of a therapy designed for you the individual- slightly broader concept than just genetics but answered question of what works best for whom. Generation of this new evidence offers a unique opportunity for product development sector of healthcare and product usage sector to determine what works best for whom thus increasing quality, hopefully at lesser cost. But, the healthcare cliff looms- you don’t want to go over the cliff. And there’s always someone watching you go over. Some of the solutions: 1. Targeted clinical trials- estimated that drug companies could save up to 100s millions of dollars per drug by incorporating pharmacagenomics data into trials 2. Trials terminated early due to success in a genetically defined subset of breast cancer patients The problem- everybody responds to therapy differently. FDA might say might only be restricted to a particular group- the group you tested. There’s a great drug that works for

37 20% of the population. So they tried a trial that was for everyone in the population and drug didn’t work. But theoretically you could create a diagnostic test to determine who the 20% of the population would be and for them, this drug would be perfect. Now they are close to having a diagnostic that will pick up who will respond to what. Everyone responds to therapy differently. What most people don’t know is that most drugs work in only 20-40% of population. Who suffers when therapies don’t work? Patients, physicians, payers. Let’s say diabetes- there are about eight different therapeutic modalities. Doctor doesn’t know which one you will respond to. So they pick usually the lowest cost one and start you on that. Takes 3-6 months to see if that is working for you. In meantime, you are receiving no benefit, you are paying for it and you might be receiving toxic results from that therapy. What if when you come in with diabetic syndrome you could do a test of some kind that would say this therapy will work for you? That actually is a possibility now- project we did at Cleveland Clinic. Who would respond to which therapy for diabetics- we now have a treatment algorithm. System compares your individual characteristics to model in system and comes back with which therapy will hopefully work for you. Access to the right therapy! Part of the issue that has been around this whole thing is that we are cutting down on who we can treat if we do targeted clinical trials. Well- treat something before it becomes horribly expensive. Quicker uptake of value- two breastcancer therapies, for instance. Graph- one is traditional, the other is the drug linked to a test. Much quicker uptake in therapeutical value. Drug companies would love to see thisif only they could get over the idea that they won’t sell it to everyone. Another story about Coumadin- actually rat poison- nasty stuff. But only blood thinners we have. Management is incredibly important- typical patient will be part of a coumadin clinic while they set the dose. Overdose a person and they cannot clot anymore. We now have a new test that can predict with a high degree of certainty what the opening dose of coumadin should be. We can actually cut the time spent in a Coumadin clinic from 17 days to 2-3 days. The test does not need a doctor. Why? Because hospitals make money from Coumadin Clinics. They don’t want patients not staying there for 17 days. The way we develop products today- Phase I, Phase II, Phase III development, spent 1.2 billion dollars, send it to FDA praying, and if you get approved you go to market it. Incredibly inefficient. Cost of developing a new drug – 802 million, 1.4 billion, and now 1.7 billion per drug. No company can do this. Something has got to change. Necessity of personalized healthcare – need a new way of developing things, not the way we’ve done it for the past 50 or 60 years. We need new ways of thinking, developing a drug with payer and patient in mind. Real world effectiveness, personalized healthcare, comparative effectiveness should be new refrain in healthcare.

38

Hence, a learning healthcare system. Creating the brave new world of future partnerspatient in the center with biotech companies, payers, technology providers, government agencies, providers and diagnostics. Big Health/ New Digs- government agencies that never used to talk to groups are starting to do that. Personalized healthcare is a critical element for healthcare system. We need to start now to develop substantially enhanced capacity for development of evidence and guidance for clinical decision making, stronger incentives and tools for application of proven science and technology, effective communication for and between patients, R’ Herschel SchachterChasam Sofer writes in one of his teshuvos where he reads and re-reads definition of death and says the scientific information in the Talmud is not Halakha l’moshe mi’sinai. Medical knowledge should only be treated as a safek. Students of Chasam Sofer disagreed with him. They said we sometimes treat medical information as a vadai. Some people have the mistaken notion that Halakha is something like magic- whatever you say in the Gemara is the din and you can’t make up your own din. Some Halakha is magicpara aduma, you have to do it. But most of the Halakha is based on common sense. R’ Chaim Soloveitchik- 14th way of 13 hermenutical principles- is sevara, common sense. Cutting edge of science- look in Talmud and Talmud has information that to us seems ridiculous. Medicine keeps on changing. So just like in the days of the Talmud they followed whatever was the latest in science and medicine, we have to follow the latest today. ____ (story of) Man got divorced from wife and didn’t want to support the child and claimed his wife had had an affair. Blood type and takka the child was not his child. So one of the Rabbis said at the time, “You can’t pasken based on blood type.” Now that’s ridiculous! R’ Herzog wrote a letter at that time private where he said like this. People who are advertising- at that time government had kosher conditions where if a butcher shop claimed it was selling kosher food and it wasn’t he would be penalized for lying. So butcher claimed his meat was salted. Chemical test to see if there was salt. So R’ Shlomo did the test and the meat wasn’t salted and gave him a penalty. Butcher came to court and said “I follow R’ Soloveitchik and he says not!” R’ Soloveitchik? I was rolling on the floor. Of course you can use the chemical test to prove there is or isn’t salt. Can you rely on DNA to determine someone was dead? (found DNA by Twin Towersagunot, mamzer, paternity, shiva, etc) Aguna status- to permit woman to remarry if you don’t have the dead body- there is no Halakha that says you need to have the dead body. There is no such law in the Talmud. Just need to ascertain and identify that this is her husband. Talmud speaks about three different types of simanim- muvhak, beinoni and gerua. She says her husband was short. And you find a male dead body that is short.

39 She says short and thin and wore glasses. Still doesn’t add up to anything. Siman Muvhak means her husband had three eyes, two noses, six fingers on right hand and four fingers on left hand- so that is a siman muvhak. So Shulchan Aruch description they give is we know the husband was going on this highway, 1000 people or less, only 1 out of 1000 who have such a situation. Twin Towers= DNA is a siman muvhak. Of course we would accept that to certify the person is dead. If you have evidence that the man is dead then he is dead unless you realize the evidence can be tampered with. There was a piece in the newspaper a couple o fmonths ago a team in Eretz Israel says you can’t put someone in jail because evidence/ DNA can be tampered with. But we’re talking when it’s not tampered with! We have a rule in the Talmud- you cannot have someone awarded money based on their looks. This is also a joke! R’ Akiva Eiger says this only applies if you have a reasonable mi’ut – if you have it so even R’ Meir would say ___ then no question. To establish paternity, of course you establish paternity. Why not? Of course you follow that. To establish mamzerus- let’s say a woman is married, she has a child and based on DNA we see this child cannot possibly be the child of her husband. If the woman was raped by a non-Jew, the child will not be a mamzer. So just because you have proven that the father is not the father of the child doesn’t mean the child is necessarily a mamzer. So he’s a safek mamzer. The rabbis were machmir. Can’t marry a mamzeres, can’t marry an isha keshera. What if father wants his wife to be checked with specific other man and you check and it matches up, then certainty in such a situation. The whole raising of the issue in the first place is a mistake. They have the mistaken notion that Halakha is based on magic. Of course the Torah recognizes scientific evidence. Where did the Talmud get its science from? From the non-Jews and doctors of that era. Yes, we have some chukim like parah adumah. ____ says if you follow the doctors of the Talmud and get sick, “it’s on your head.” You follow the doctors of your generation! And maybe the doctors of another generation will discover that everything is just a mistake. The Halakha is not based on magic- it is based on sevara and common sense and certainly DNA could be used. The question is: if there is a safek on mamzerus of a person, would Halakha require that we should check? Yoreh Deah, Siman TzadikChes- whenever you have a safek that can easily be ascertained, that doesn’t count as a safek. So since easily determined means the test is easy and not too expensive. If it is going to cost half a million dollars it’s not easily ascertained. So you have to determine how expensive it would be- but once you ascertain, it’s not a safek. I think the whole raising of the question is simply an error, a misunderstanding of what the Halakha is about. Question: Rabbi Schachter, I understand the proof in case of aguna, proof DNA came from that person but would you need sufficient proof that person died? You find DNA by Twin Towers, but do you need to put together he is actually dead?

40 RHS: If you find a limb/ part of the body that was obviously scattered about all over the place, obviously the person is dead. Question: For Dr. Rosencrantz- comments- there’s a saying in Pirkei Avos- that if you get too close to the government things will not be good for you longterm. That was true 1800 years ago and I don’t think things have changed much since then. Five-year-plans Russians were famous for didn’t work out very well for them and I don’t think five-yearplans with Obama will work out any better. [Applause from audience. The MES team cracks up, trying to contain their laughter.] Will the benevolent government do it in a way that will benefit the population or are there ulterior motives? Every time a person passes away before their time the government saves money on medicare, etc- and to make decisions to help people re: patients serious conflict of interest. No way of getting around that. You follow the money. Dr. Rosencrantz: Oh boy. Well, just to set record straight I am not in favor of the government option- I think that is a bad way to go. I think getting too close to the government is dangerous and letting the government work in a vacuum is dangerous. Finding the balance is the rub. Good housekeeping seal- fought very long and hard to be set aside – happened in England with organization called NICE, Australia, Canada have similar ones- everyone except USA, really. I gotta tell you- I don’t know where we’re gonna end up- I was at a conference last week in Cleveland Clinic and I am deathly afraid we are going to end up with some kind of a government option. Cost of care and quality of care are both important and so far most of government debate focused on cost of care. Question: The change at the FDA- the FDA as you know has failed consistently to adopt a cost/ benefit analysis. They have kept off the market drugs that could have saved hundreds of lives in name of documentation wasn’t sufficient. You want to do something to convince FDA to adopt cost/effectiveness approach. Second point- vested interest in hospitals- example you gave regarding Coumadin. That derived entirely from economics by government- forced hospitals to try to make money off private pay. Solve this problem? Cost/ benefit. Secondly, the focus on how the government itself has a ____. Dr. Rosencrantz: Character-building exercise- represent pharmaceudical firm and medicare here. Comment on FDA here- it is statutorily confined in what it can do. Its legal basis isn’t brokered for that. I had a talk with new commissioner next week- who by the way I think is fantastic. She looks like she is about 25 but aside from that…there’s a very interesting relationship between FDA, CMS and little bitty agency called AHRQ and this new thing that’s going to be created. When we were putting away proposal for new etentity what we stayed away from was not make decision based on cost/benefit analysis. I don’t think that will last very long. I think it will be pushed to do cost effectiveness. Because Medicare is 60% of market right now, private markets will get a cold very quick. But CMS is one of those strange government organizations that is almost impenetrable- hard to figure out what they do, etc. [long list of places] are working on this. Question: I’m not satisfied with that answer.

41

Dr. Ricky Weiss: I think we’re going to stop now and if you’d like to come up, the panelists will not escape. [Laughter]