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Gene Editing Research: Halakhic Parameters.

THE RAPID RISE OF SYNTHETIC BIOLOGY

Biotechnology is developing so rapidly now that cloning and stem cells are no longer the leading edge of cell research. They are being replaced by the development of gene editing and other research, referred to as "synthetic biology." The goal of synthetic biology is to combine chemicals to make a complete set of DNA, put it into a cell envelope, and thus create a new living organism.

THE SEVEN BRANCHES OF HUMAN KNOWLEDGE
[phrase omitted]

Who is wise? One who learns from every person.
                                          (Mishnah Avot 4:1)


To understand and advise on complex bioethical issues, knowledge from many fields is required. There is a wide gap in the interface between Jewish belief and halakhah (law), on the one hand, and current scientific and medical knowledge on the other. Today there are not many rabbinic authorities qualified to adjudicate on questions relating to the interface of recondite biotechnology and halakhah. This difficulty is illustrated by a midrash on Beha'alotkha. Midrash Rabbah Numbers says that when G-d instructed Moses to make the menorah, the seven-branched lamp for the Tabernacle, Moses asked Him how to do it. G-d replied, "Mikshah taaseh ha'menorah." Make the menorah from one solid piece of gold, not out of pieces welded together. Moses "went down" and then "forgot" what G-d had said. Again and again Moses goes back to G-d to ask Him how to make the menorah. Each time G-d makes the same response, but Moses is still perturbed about its construction. Finally G-d tells Moses to ask Betsalel to make the menorah. Betsalel has no problem understanding G-d's instructions and performing the work. He fashioned the menorah as mikshah, hammered from one ingot of gold.

What does this midrash teach us? "Mikshah taaseh ha'menorah" reveals G-d's intent that the menorah represent all of human knowledge as one unit. The central branch represents the Torah, and the six branches represent all of secular knowledge. Because Moses grew up in Pharaoh's palace he knew the amoral society of Egypt. It was unthinkable for him to represent the secular branches of knowledge intimately, in one unit, with the Torah. Betsalel, however, was only thirteen years old then. He was one of the Jewish children who grew up in the wilderness "under the apple tree... there thy mother brought thee forth" (Song of Songs 8:5), where his mother gave birth to him in hiding so that Pharaoh would not have him thrown into the river. Betsalel had not been exposed to the decadence that the young Moses had seen.

The Gaon of Vilna taught that if you don't know the six secular wisdoms, you will not know the seventh, the Torah, because our composite understanding of the Torah requires our knowing details of scientific fields such as agriculture, physiology, psychology, veterinary medicine, and astronomy. We need this knowledge in order to understand how Torah mitsvot (commandments) function in our lives. But if we don't know the seventh, the Torah, it isn't worth learning the other six branches of knowledge.

The Talmud Sages made great efforts to master the six branches of secular knowledge available to them then in order to better understand the Torah. Mar Shmuel, for example, was an expert in science and medicine. The Talmud states in Hulin 63b that the Sages consulted hunters and trappers for expert help in identifying kosher birds. We know from Sanhedrin 5b that Rav lived with a shepherd for eighteen months to learn which blemishes are permanent and which are temporary, in order to understand which injury is considered a mum (permanent defect) that negates the kedushah (holiness) of the bekhor (firstborn). Rav Zera refused to rule on the status of a menstrual blood specimen because he said that if he did not understand the relevant laws of nature, how could he understand the laws of nidah blood? (Nidah 20b)

The laws of nature, like the Torah commandments, are immutable laws. The common expression used by our Sages, Nishtanah ha'teva, is often mistranslated as "Nature has changed." What our Sages meant is that our "knowledge" of nature changes, permitting us to better understand and observe the Torah laws.

Today there is a new focus on the science of human reproduction. Only relatively recently we have discovered that there is a bidirectional exchange of cells between a gestating mother and the fetus. In a normal pregnancy, fetal cells cross the placental barrier and implant into maternal tissues, while maternal stem cells cross the placental barrier and implant into the fetus, aiding its development. Thus, a woman who serves as a surrogate to bring a baby to term is not only an "incubator" but also contributes from her DNA to the baby. The gestating mother does not change the DNA of the baby, but some of her cells contribute to the development of the fetus. That puts an entirely new view on the so-called incubator mother who brings a baby to term for another woman. If one woman contributes the egg, the baby probably will look like that contributor. The baby will receive the DNA of the one who is the DNA mother (also called the biological genetic mother). The surrogate mother, however, is more than just an incubator. This makes it harder to determine who is the "halakhic mother."

Up until now, it was assumed in the field of science that the mother of a surrogate baby gestated by another woman is the one who contributes the genes. Thus, if a young co-ed (the usual source for eggs used in assisted reproduction technology), is not Jewish, the assumption is that the baby will not be Jewish. For twenty-one years the major rabbinic authorities in Israel ruled that the gestational mother is the halakhic mother. And then, less than five years ago, there has been a shift to considering the DNA mother as the halakhic mother of the baby. In my extensive involvement with assisted reproductive technology, whenever a baby is born from a donated egg we are always careful to put the baby through a conversion process to Judaism--a gerut l'humra. This is a correct safety feature while the halakhic issue is unresolved.

Having learned that the gestational mother contributes cells to the embryo, we now know that a surrogate baby is the product of two women. How many cells the gestational mother contributes is not important. In my opinion, maternal designation should be given to the gestational mother. Those of us who were fortunate enough to build a house first went to an architect for a blueprint. It took five minutes to transfer the blueprint to the home owner. Then came the plumbers, the carpenters, and the electricians. What did they contribute to the house? A young woman contributed the blueprint, the DNA. But the gestational mother contributed the development of the heart, the lungs, the kidneys, and so on. It's hard to call this an inconsequential contribution. It is even harder to find rabbinic authorities with whom to discuss this problem. It requires an accumulation of biological knowledge in order to properly rule on such a question.

When the great posek Rabbi Moshe Feinstein, my father-in-law of blessed memory, was asked to rule on a question of brain death, it took him two years before he was comfortable to rule on the case. During these two years I brought him every head of a department of the Einstein School of Medicine engaged in this life-and-death issue. The head of nephrology slept over in my father-in-law's house twice in order to continue their discussion in the morning. It took two years until he felt that he understood the neurology and the physiology involved well enough to make a halakhic decision.

THE BIOTECHNOLOGICAL PRECEDENT OF ELIMINATING MITOCHONDRIAL DISEASE IN THE NEXT GENERATIONS

In volume 25 of B'Or Ha'Torah, Dr. John Loike and I discussed the commencement of mitochondrial replacement therapy (LOIKE 2016; TENDLER 2016). Since the publication of this article, there have been many more cases of eliminating mitochondrial disease in infants born in the UK.

About 6,500 women in the UK and over 12,000 women in the USA express mitochondrial mutations. The potential for these women to have healthy children, free from mitochondrial-caused diseases, has become a reality in England and the United States. The way that mitochondrial replacement therapy works is that if an aspiring mother is found to have defective mitochondria, an egg is extracted from her and its nucleus is removed and saved. Then an egg is harvested from a woman who has healthy mitochondria, and its nucleus is removed. The affected mother's nucleus is then transplanted into the donor enucleated egg. Using IVF, the reconstituted egg is fertilized by the father's sperm, and reimplanted into the aspiring mother. As a result, her children and their descendants should be free of mitochondrial disease.

Although this procedure is called three-way parenthood, over 99 percent of the child's DNA comes from her genetic parents and less than one percent of the DNA comes from the mitochondrial donor. While more clinical testing needs to be done to ensure the safety of this procedure, it has the potential to provide an effective method for women with mitochondrial mutations to have healthy children.

Mitochondria provide the energy controlling the genetics of the cell. They're not the central genetic pool controlling what the baby will look like, but they are far from inconsequential. Without healthy mitochondrial genes a baby cannot utilize food in order to gain energy. It is irrelevant whether the mitochondria are located in the nucleus or not. What is relevant is that without healthy mitochondria, the baby can't live.

Mitochondrial replacement therapy has set a biotechnological precedent. There was a "red line" that we should not intervene with the basic nuclear material of the cell. This red line has now been crossed. Although mitochondria are not basic nuclear material, anyone who understands cellular biology knows that a cell cannot function without mitochondria. The barrier to moving ahead with gene editing has been removed.

WHAT IS GENE EDITING?

Figure 1 shows the familiar picture of DNA, the molecule of life. For the first time we have the ability to edit and change this molecule as we wish. Gene editing sounds simple. We clip out a gene and put another one in its place, in four steps:

1. Target the site on the DNA

2. Remove the targeted base pairs

3. Replace the base pairs

4. Repair the site

From the therapeutic point of view, gene editing has the potential to correct virtually any genetic mutation in any cell or organ by changing the base pairs (letters) of the DNA cell. If you don't understand the mechanisms, gene editing might sound easy, but there is need for much caution. We still don't know how the new gene will adapt to the other genes. The other genes have never been in contact with the new gene before. How will they connect?

In some of the early animal experiments in gene editing, the animals were born with major defects. There are two haploids, two parts, to our genes. Both parts have to be replaced. As after any surgery, the operated area has to be cleaned and sewn up. You have to seal the damage.

As a good Jew first thing in the morning says Modeh ani lifanekha ("I give thanks to You"), a secular bioethicist recalls these four principles:

1. beneficence (Am I doing good?)

2. non-maleficence (Am I causing harm?)

3. justice (Am I treating everyone equally?)

4. autonomy (Is the patient in acquiescence?)

These principles operate on the assumption that science and technology are morally neutral. There is a principle missing here that we must add from the Torah, and that is the sanctity of life. Life is more than a biological event.

Researchers have been working on gene editing for several years now, and only recently have reports been published (KAEBNICK, GUSMANO, and MURRAY 2014). Because there is much monetary gain in this field, researchers hold back on publishing until they can prove patent rights on their work. The first steps in developing gene editing were completed with great difficulty, and then a new enzyme was discovered that facilitates the work (LEDFORD APR. 2015 and JUN. 2015).

From both the halakhic and the secular points of view, a major bioethics problem that can arise from gene editing is the possibility of designer babies. Replacing a damaged energy mechanism by performing mitochondria replacement therapy is one thing, but intervening in the genome not to save lives is another.

Soon it will be possible for wealthy aspiring mothers to tell the obstetrician, "I don't want to have a baby the usual way. I want you to first fertilize the egg to examine the genes and remove those that I don't like and replace them with those that I want. I want a child who will be a gifted athlete."

There are secular bioethicists who are alarmed that gene editing would be "playing G-d" by altering nature. It would cause a permanent change in human DNA (LANPHIER, URNOV, HAECKER, et al. 2015). Altering the genetics of a potential baby without first obtaining informed consent from that child (possible only when he or she reaches legal age) violates the principle of autonomy. This possibility of infringing autonomy is being widely discussed in secular bioethics publications. From the Torah vantage point, we don't see such a problem. The Mishnah says that a newborn baby is an open book. The first chapters of the book are written by the parents. As the child matures we hope that he or she will continue the storyline in the way we like. But in the child's early years Jewish parents have the right to decide what is best for their child. Autonomy is superseded by our responsibility to perform the mitsvah of hinukh, to educate our children and care for their physical development.

Parents can now demand babies who will be seven feet tall or who will have perfect pitch. Can gene-editing designer babies lead to eugenics?

On the other hand, the potential medical advantages to correcting the genome are overwhelming. Mice are currently being cured of diseases by undergoing gene editing. A single base pair mutation that causes cataracts in mice was replaced with the normal base pair, and as a result about 33 percent of the mutant zygotes that were injected with CRISPR/Cas9 grew up to be cataract-free mice. There is a great potential to delete pathogenic viruses from the genome. Researchers believe that gene editing could disrupt the HIV-1 genome to provide a means to vaccinate against pathogenic viruses, and thus excise the HIV genome in infected people. The Chinese have jumped ahead and published on the changes they made to the human genome, correcting a genetic liver damage (LIANG, XU, ZHANG, et al. 2015). Using the newly discovered enzyme Cas9 with CRISPR makes gene replacement much easier (RAN, CONG, YAN, et al. 2015).

CHANGING THE ENVIRONMENT BY GENE EDITING

Teams at the Irvine and San Diego campuses of the University of California have developed genetic modifications in the Anopheles stephensi mosquito that would make the spread of malaria impossible in certain areas (GANTZ, JASINSKIENE, TATARENKOVA, et al. 2015).

Preventing mosquitoes from spreading malaria is benign, but environmentalists are worried about the possible ecological effects of editing the genomes of other animals. An ethicist in a genome-engineering lab published her concern about gene editing in wild animals. If you make one species more dominant than another, you don't know what the result will be (LUNSHOF 2015). She's worried about what is going to happen, and it's already happening, both in the wild and in domestic agriculture.

When cattle are penned in "feeding lots" rather than free range for final fattening, there is the danger of the animals killing one another with their horns. The conventional solution to this problem is to hire a veterinarian to remove the horns. This is painful for the cattle and expensive for their breeders. An alternative solution is already in practice of editing the horns out of the DNA of heifers. After the gene editing has been performed once, every succeeding generation will be born without horns (HARMON 2015).

MIRACLES VERSUS THE ADVANCE OF SCIENCE AND TECHNOLOGY

While debates rage about keeping mice experiments going, gene editing is being performed on humans. Infant Layla Richards was dying after having been treated with every known cure for leukemia. In a desperate attempt, new genes were engineered to attack her leukemia and injected into her T-cells at the Great Ormond Street Hospital in London. Several months after the gene editing, Layla was cancer free (NBC NEWS 2015). Is this a miracle? No, it is not a miracle. It is an exercise of G-d's laws of nature being revealed by human study.

The Holy One not only created the world, but He directs it from day to day.

When I was the civilian ethicist for the US Navy, teaching bioethics to officers in training, the local Navy newspaper published an article about an area in Korea where the waters recede four times a year. Twenty-two feet of water recede a distance of more than half a mile for seven to eight hours. People rush in to collect their favorite shellfish and sea cucumbers, and then the water returns (MOONEY 1986). Does this diminish the miracle of the splitting of Yam Suf (the Sea of Reeds)? The answer is that neither is a miracle. This is how the world was created. Our Sages tell us that the recession and the return of the sea were programmed by the Creator when He created water and the seas. The Torah says:
[phrase omitted]

Just before morning the sea returned to its normal conditions.
                                          (EXODUS 14:27)


Midrash Rabbah says on this verse that when Moses asked G-d how could He possibly split the sea, G-d replied:
[phrase omitted]

The Holy One Be Blessed said, "Didn't you read the beginning of the
Torah [Genesis 1:9]? And G-d said, 'The waters... shall be gathered
together;' I am the one who instructed [the sea] from the beginning
that I shall divide it [at the time of the splitting of the Sea of
Reeds]. It is written 'Just before morning the sea returned to its
normal conditions,' to the conditions that I originally set."


THE MITSVAH OF VOLUNTEERING FOR EXPERIMENTAL TRIALS

No progress can be made in the field of experimental medicine without people volunteering to join a research effort. A research effort requires three phase studies. There's always an uncertainty, a possible danger, in ingesting a new drug. Phase One studies are safety trials to determine if the new drug is not too toxic for human studies. The participants need not be people who suffer from the medical problem being studied. Phase Two is designed to determine proper dosages on a relatively small number of patients. Phase Three is conducted on a large number of patients to confirm or refute claims of efficacy.

In order to join a trial, a participant must undergo batteries of biochemical and medical tests. Because of the possibility of untoward side effects of any experimental trial, most people hesitate to volunteer.

I believe that we have a moral obligation to participate in medical research. Although it is halakhically forbidden to expose oneself to danger, halakhah permits risking a modicum of danger for personal benefit. Halakhah permits a worker to endanger himself by climbing up trees to pick dates (TALMUD BAVA METSIAA 112a). People engage in risky activities in order to earn money. It is halakhically permissible to undertake a certain degree of risk in order to earn a living. It is therefore also permissible to take a modicum of risk to perform a mitsvah that benefits society.

In doing so, volunteers follow the example set by our forefathers Abraham and Jacob, as recorded in the Talmud Shabbat 33a. Abraham stopped at the same inn on his return from Egypt as he had when he went down to Egypt (GENESIS 13:3). Why? Because a motel that serves the needs of a traveler benefits society. The motel owner must have repeat guests in order to provide this social service.

When our forefather Jacob settled in Shkhem (GENESIS 33:18-20), in addition to teaching monotheism and the rejection of idolatry, he made three contributions to society:

1. He taught the local population how to organize wholesale markets.

2. He taught them how to set up a coinage system.

3. He taught them how to build bath houses.

These are examples of derekh erets:
[phrase omitted]

Appropriate societal behavior preceded the Torah.
                                          (MIDRASH RABBAH LEVITICUS 9:3)


"Derekh erets" is often mistranslated as "good manners," but the proper meaning of the above midrashic excerpt is that G-d was concerned with societal needs centuries before He instructed the Jewish nation at Mount Sinai. Isaiah makes an even more fundamental statement:
[phrase omitted]

He did not create a wasteland, He formed it to be inhabited.
                                          (ISAIAH 45:18)


G-d didn't make the world to be empty, He made it to be populated. It's the duty of a human being to foster G-d's will that human society function successfully.

Jews have an additional reason to want to earn the approval of society because of the reality that Gentiles hate us. We have to be careful not to antagonize them. According to strict interpretation of the halakhah, Jewish doctors would not be allowed to treat non-Jews on Shabbat. In previous times Gentiles understood that Jews have to abide by our religious laws and restrictions, and they by theirs. But social mores have changed, new "gentlemen's agreements" are in effect, and sages like the Hatam Sofer and Rabbi Moshe Feinstein have decreed that because of the hatred against us, it is pikuah nefesh (a life-saving measure) for Jews to treat non-Jews on Shabbat, lest they seek to harm us if we refuse to treat them on our Sabbath.

PRAYING FOR THE SICK

We discussed above advances in science that are enabling cures of previously incurable diseases. In light of the advances in medicine, what is the role of prayer? Recently there was a case of a little girl who was dying of leukemia but recovered. Is this because someone's prayer worked? Can prayer really do such things? Talmud Nedarim 40a records that one of the students of Rabbi Akiva was critically ill but was neglected and not visited by his colleagues. Rabbi Akiva visited him and helped him recover. He then lectured his students, "He who does not visit the sick is as if he shed blood. Even if you knew he can't recover," chastised Rabbi Akiva, "it would be to his advantage that you should pray that he should die and end his suffering."

What does Rabbi Akiva mean by saying that you should pray that someone should die? He said this because we should not pray for miracles. In Igrot Moshe, Orah Hayim, part 2, siman 111, my father-in-law cited the halakhah that it is forbidden to pray for a miracle. The reason is, as I have said earlier, the laws of nature are G-d's laws of nature. It is an article of our faith that G-d does not change our Torah or the laws of nature. If a person cannot survive according to the laws of nature, then it is improper to ask G-d to cure him.

There is a report of five people who had bladder cancer, and one of them survived. Is it a miracle that he did not die? No, it's not a miracle. That individual had a special genome. That's another step for us to understand in the laws of nature, why one survived and the other four died (NBC NEWS 2015).

In another case, people dying of brain cancer were given tetanus vaccinations. Three of them are still alive today. According to their diagnoses, these patients should have died months ago. What happened? Was there a miracle?

There are two blessings in the daily prayers that concern health. The first one clearly is:
[phrase omitted]

Refaeinu Ha'Shem v'nerafeh. Heal us, O L-rd, and we will be healed.


This is praying to G-d to heal the individual. There are limits to this. The Talmud says that a husband must not pray that his pregnant wife should give birth to a boy. He cannot ask G-d to change the laws of nature. Such a prayer can be offered only before she becomes pregnant.

There is a second blessing that concerns health (my personal interpretation). If the physicians conclude that someone has no chance to live, it's not proper to plead when praying refaeinu that he "miraculously" recover. However, aware of the rapid advances in biomedicine, it is rational to add a personal component after:
[phrase omitted]

Atah honen l'adam daat. You graciously bestow knowledge to humankind.


G-d, I can't ask you to cure this individual, but--aware of the limitations of current medical therapy--I can ask You to give wisdom to some medical researcher studying this disease entity in the hope of finding a cure. The prayer is asking G-d to facilitate a response from within the laws of nature.

May G-d, the source of all knowledge and wisdom, help us to more fully master these laws for the benefit of humankind.

REFERENCES

GANTZ, VALENTINO M., NIJOLE JASINSKIENE, OLGA TATARENKOVA, et al. 2015. "Highly Efficient Cas9-Mediated Gene Drive for Population Modification of the Malaria Vector Mosquito Anopheles stephensi." Proceedings of the National Academy of Sciences, vol. 112: 49. E6736-E6743. doi:10.1073/pnas.1521077112

HARMON, AMY. 2015. "Open Season Is Seen in Gene Editing of Animals." New York Times, 27 Nov., p. A1.

KAEBNICK, G.E., M.K. GUSMANO, and I.H. MURRAY. (Eds.) 2014. "Synthetic Future: Can We Create What We Want out of Synthetic Biology?" Hastings Center Special Report, Dec.

LANPHIER, E., F. URNOV, S.E. HAECKER, et al. 2015. "Don't Edit the Human Genome." Nature, vol. 519, no. 7544. 12 Mar., pp. 410-411.

LEDFORD, HEIDI. 2015. "Mini Enzyme Moves Gene Editing Closer to the Clinic." Nature, vol. 520, no. 7545.

LEDFORD, HEIDI. 2015. "CRISPR, the Disruptor." Nature, vol. 522, no. 7554. 3 Jun." Liang, P., Y. Xu, X. Zhang, et al. 2015. "CRISPR/Cas9-Mediated Gene Editing in Human Tripronuclar Zygotes." Protein & Cell, vol. 6, no. 5. May, pp. 363-372.

lUNSHOF, jEANTINE. 2015. "Regulate Gene Editing in Wild Animals." Nature, vol. 521, no. 7551, 12 May.

MOONEY, MIKE. 1986. "Festival Marks Parting of the Deep." Pacific Stars and Stripes, 11 May.

NBC NEWS. 2015. "Saved by an Experimental Cancer Treatment." The Week, 17 Nov. NBCnews.com

RAN, F. ANN, LE CONG, WINSTON X. YAN, et al. 2015. "In Vivo Genome Editing Using Staphylococcus aureus Cas9." Nature, vol. 520, no. 7546, 9 Apr.

RABBI PROFESSOR MOSHE DOVID TENDLER

Based on a presentation at the Eleventh Miami International Conference on Torah and Science at The Shul of Bal Harbour, Surfside, Florida, December 12, 2015

ABOUT THE AUTHOR

RABBI PROFESSOR MOSHE DOVID TENDLER, noted authority on medical ethics and the relationship of medicine and science to Jewish law, is rosh yeshivah at the Yeshiva University affiliated Rabbi Isaac Elchanan Theological Seminary (RIETS) and professor of biology at Yeshiva College, and he holds the Rabbi Isaac and Bella Tendler Chair in Jewish Medical Ethics at Yeshiva University. Rabbi Tendler was ordained at RIETS in 1949 and received Yadin Yadin in 1953 from Rabbi Moshe Feinstein, of righteous memory. He earned a PhD in biology from Columbia University in 1957. He has served on the Medical Ethics Task Force of the Federation of Jewish Philanthropies, for which he edited the Compendium of Medical Ethics. For nine years he served as its chairman. For decades he chaired the Bioethical Commission of the Rabbinical Council of America. A former president of the Association of Orthodox Jewish Scientists and current member of its board, Rabbi Tendler is the author of Pardes Rimonim (a text on Jewish family life); coauthor with Professor Fred Rosner, MD, of Practical Medical Halachah, a primer for physicians; and author of Care of the Critically Ill--Responsa of Rav Moshe Feinstein, as well as many articles on science and religion in leading publications. He is frequently consulted by the media and public officials on ethical issues.

Tendler@YU.edu

Note: Since this lecture was given, gene editing has progressed at a pace never before known to cellular genetics research and is raising hopes for major contributions to medical science. Dr. John Loike of Columbia University will discuss further developments in gene therapy at the Twelfth Miami International Conference on Torah and Science at The Shul of Bal Harbour, December 21-24, 2017.

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