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Home , Clone (cell biology), Cloning

: Past, Present, and the Exciting Future by Marie A. Di Berardino, Ph.D.

The not-too-distant cessfully cloned from an adult , the cell’s nucleus and they carry the one taken from a ewe’s mammary DNA, which is the genetic blueprint future gland. for an individual. Jimmy walks into the neighborhood The process that produced pharmacy to fill his prescription for a differs from ordinary in protein he was born without. He two major ways. First, body (or lacks the for blood clotting Dolly was not created in the ordinary somatic) cells from an adult ewe’s factor IX and relies on the local way. Typically, a lamb is the product udder (this is the donor) were placed drugstore for his medicine. Jimmy of natural reproduction—two germ in a culture dish and allowed to grow. pulls open the bag that contains his cells, a from an adult male and The nutrients were then removed 90-day supply of patches, removes an (oocyte) from an adult female, from the culture, which stopped the the old patch from his chest, and fuse at fertilization. Each of these cells’ growth. One of these non- attaches a new one. He adjusts his germ cells (the sperm and the growing cells was then fused (by jersey and heads out to meet his oocyte) contributes half the chromo- electric jolts) with another ewe’s buddies for a game of touch football. somes needed to create a new indi- oocyte from which the nucleus had Even though he is hemophiliac, Jimmy vidual. are found in been previously removed (i.e., isn’t worried about the bruises and scrapes he is sure to get.

Similarly, Ø Christine is scheduled to have her own genetically reprogrammed skin cells transplanted to replace her severely damaged heart cells. Ø Margo, who has Parkinson’s disease, receives special nerve cells. She is not concerned about tissue incompatibility and rejection, because these cells are her own genetically reprogrammed skin cells. Ø Patients routinely buy anti-cancer or anti-viral drugs in large quanti- ties to treat their conditions.

This is the future. It is what Dolly so wondrously has wrought. Born July 1996, she is the first mammal suc-

1 Federation of American Societies for Experimental Biology Office of Public Affairs enucleated, so it had no chromo- somes). This procedure is known as ‘ nuclear transfer’. Within a day the fused cells began to divide in the culture dish. After several divisions, the early was transferred to the uterus of a surrogate mother and allowed to develop. Second, unlike the sperm and the egg, each of which contributes half the number of chromosomes at fertilization, each body cell contains twice the number of chromosomes in each germ cell. So fusion of a sperm and an egg forms an individual whose full genetic composition is unique to that individual. On the other hand, the embryo cloned from somatic cell nuclear transfer begins development with the diploid (double) number of chromosomes, all derived from one somatic cell (adult udder) of a single individual. This embryo has the same nuclear genetic composition as the donor of the somatic cell. In the end, three contributed to the production of a single lamb : a Finn Dorset sheep donated her udder cells for culture; a Scottish Blackface sheep donated the enucle- ated oocyte (with its nucleus re- moved, thus losing its own genetic identity in the process); and a Scottish Blackface sheep became the surrogate

Timeline This illustrated timeline shows essential milestones in basic research that led to the cloning of Dolly and beyond, and some benefits derived from that research. Some of the initial hypotheses have been refuted by later studies.

18 8 0s 1888 19 01 Wilhelm Roux and August Weismann Wilhelm Roux performs the first test of the splits a 2-cell newt embryo independently propose the germ plasm germ plasm theory: Destruction of one cell of into two parts, successfully producing two theory: The egg and sperm contribute the 2-cell frog embryo with a hot needle results larvae. chromosomes equally to the zygote in development of a half-embryo, supporting (fertilized egg). The chromosomes are carriers mistakenly the Roux-Weismann theory. of the hereditary potentials, and the germ cells (gametes) of the embryo are the only 1894 ones to carry the complete set of hereditary Hans Dreisch isolates blastomeres of 2- and potentials (nuclear determinants), whereas 4-cell of sea urchins and observes each somatic (body) cell type contains only development of blastomeres into small but part of these potentials required for the complete larvae. These and other experi- specific cell type. ments disprove the Weismann-Roux theory.

2 Breakthroughs in Bioscience http://www.faseb.org/opar mother, carrying the embryo to . ing ‘transgenic cells’, or cells contain- the sheep milk. Obviously, researchers The clone (Dolly) was easily identified ing a transferred gene. still need to conduct controlled clinical because she had the physical traits of These transgenic cells were then studies before this protein is available the Finn Dorset sheep that donated the separated from those without human for hemophiliacs like Jimmy, but they udder cells and differed from the traits DNA and used to create Polly, the have already made an astonishing of the Scottish Blackface sheep used transgenic sheep that today produces breakthrough. as the surrogate mother and the the human clotting factor IX in her oocyte donor. milk. Purposely, scientists genetically Transgenic clones And now Dolly herself is a designed the transgenic sheep clones mother—the old-fashioned way—by so that the human gene would The importance of the transgenic mating with David, a Welsh mountain function only in the . clones is that is now ram, and giving birth to Bonnie. In It will soon be possible for the being extended to produce different fact, Bonnie now has other siblings. human clotting factor IX protein to be human proteins like insulin (diabetes), routinely harvested and purified from interferon (viral infections), clotting Can Dolly help Jimmy, Christine, and Margo? Imagine herds of female sheep, , and goats producing large quantities of human proteins in their milk, an ideal place for those proteins to be harvested and used to treat patients like Jimmy, the hemophiliac, whose blood cannot clot. We can realize this dream today—one step at a time, because the process that produced Dolly also can be used to produce the transgenic (one carrying another species’ ) clones. Scottish scientists first removed cells from a fetal lamb and grew them in a culture dish. Multiple copies of fragments of DNA (deoxyribonucleic acid, which holds genetic information) containing the human gene for blood clotting factor IX were added to the dish and coaxed into the cells. Some cells incorporated the human DNA into their chromosomes, thus becom-

1914 Spermann conducts early nuclear transfer. By using a strand of baby hair, he partially constricts a newly fertilized (zygote), forcing the nucleus to one side and only to the other. As the nucleus side of the cell divides successively to the16-cell stage, a nucleus slips over to the cytoplasm on the other side. Cell division starts on this side also, and the hair knot is tightened, preventing further nuclear transfer. larvae develop, one slightly older (the side with the initial nucleus) than the other (the side with the initial cytoplasm). This proved that the nucleus from a 16-cell stage could direct the growth of another larva.

3 Federation of American Societies for Experimental Biology Office of Public Affairs factor VIII (hemophilia), and tissue This cloning process simply acceler- tural industry has intentionally propa- plasminogen activator (dissolving ates the older, slower, and less gated—by cloning—bananas, grapes, blood clots). In other words, female predictable methods of crossbreeding apples, sugar cane, pineapples, clones of such animals as cattle, and hybridization. potatoes, asparagus, and many other sheep, and goats are being genetically Strictly speaking, clones obtained plants. Identical and triplets designed to be dairy/pharmaceutical from nuclear transfer are not exact that occur among many multicellular producers, a virtual living bio- copies of the donor. A clone like animal species including humans, are pharmaceutical industry. Transgenic Dolly produced by oocyte-somatic derived by a cloning process. A cell, clones of mammals are a major cell fusion is a mosaic—a mixture of isolated from other cells growing in a advance in biotechnology because the oocyte and body cell. In addition culture dish, gives rise after cell they can synthesize, in large quanti- to the nucleus, the donor cell contrib- division to a clone. All these examples ties, complex critically utes a tiny amount of cytoplasm and include the exact duplication of the whole body cell, including the nucleus, cytoplasm, and cell mem- We are only beginning to understand the molecular brane. changes involved in nuclear , yet this line of basic research may result in some of the most beneficial Why is this such a big applications to humans. It might permit us to de-differenti- deal? ate mature cells and re-differentiate them into specific cell Dolly has debunked a long-held, types required for tissue repair. generally accepted biological concept: Adult cells have their fate sealed; put another way, once an udder cell, required for patient care. The current cell membrane to the oocyte, but the always an udder cell. This means that recombinant DNA technology in egg cell contributes an enormous the genetic status of the adult donor bacteria is capable of synthesizing amount of cytoplasm and cell mem- nucleus had to be reprogrammed, and only simple proteins, but not the brane to the fused product. In fact, that the oocyte cytoplasm seems to complex molecules that sheep can virtually all mitochondria (the or- contain the appropriate molecules to produce in large quantities in their ganelles in the cytoplasm that are the trigger this reprogramming. The milk. Indeed, Jimmy will be able to major source of cell energy and value of cloning from an adult cell is wear his patch very soon. contain DNA of their own) are that we can predict that the clone will While these advances are on the derived from the oocyte cytoplasm. be very much like the donor animal, horizon for us, beneficial applications So cloning of multicellular whereas we cannot do so when the to agriculture are already being is not equal to true cellular cloning clone is derived from an embryonic or implemented. Transgenic cloning can that results from asexual reproduc- fetal cell. Even when the parents of be used for the genetic improvement tion, when a one-celled like embryos and are known, we of livestock related to milk produc- the amoeba divides and clones itself. cannot yet foretell exactly the physical tion, quality of , growth rate, Similarly, plants clone themselves traits of their offspring; they are a reproduction, , behavioral when they reproduce by budding or combination of traits from both traits, and/or resistance to diseases. sprouting new shoots. The agricul- parents. Additional variations occur

1940s – 1950s 1961-62 1962-65 Various species of mammalian embryos are John B. Gurdon and Robert G. McKinnell, Robert G. McKinnell, Thomas J. King, and cloned by embryo splitting, but success is by using the nuclear transfer method on Marie A. Di Berardino obtain swimming limited to splitting of embryos at stages prior to different species of frog (Xenopus and Rana, larvae from enucleated oocytes injected with implantation to the uterus. respectively), obtain adult frogs that adult frog kidney carcinoma cell nuclei. This 1952 produced normal progeny. This demon- demonstrates that some cancer cells can be strates totipotency of embryonic nuclei. controlled by the differentiation process, and Robert Briggs and Thomas J. King transplant a that inducing cancer cells to differentiate may nucleus from a frog embryo somatic cell into an stop the cancer process. unfertilized, enucleated oocyte. These injected developed into tadpoles and many metamor- phosed into juvenile frogs. This technique, nuclear transplantation (nuclear transfer) becomes the prototype experiment for cloning multicellular organisms. 4 Breakthroughs in Bioscience http://www.faseb.org/opar because, during the maturation of the organs of an adult. These studies transplanted, the more likely it is that parents’ sperm and egg before showed that frogs, salamanders, the injected oocyte will develop fertilization, the genes are randomly insects, fish, and mammals (mice, abnormally. In fact, only a few distributed to sperm and egg cells. rats, rabbits, pigs, goats, cattle, and tadpole nuclei from frogs have been Thus, offspring cloned from adult sheep) could be produced by this shown to be totipotent, and those may cells are more similar to their donor process. Furthermore, many of these have come from immature cells. than are offspring that result from species were fertile. (The only When fully differentiated cell types , i.e., a combina- to have been cloned by (pigment, skin, red and white blood tion of sperm and egg. There is, nuclear transfer thus far are two cells) from adult frogs were used as however, no guarantee that an exact Rhesus monkeys produced from the donors, their nuclei gave rise to copy will evolve, because variations in nuclei of an eight-cell stage embryo.) tadpoles but not to fertile frogs. In the physical traits of the donor may mammals, very few fetal cell nuclei result from environmental influences (approximately 0.3-2%) from sheep during pre- and postnatal development and cattle led to the normal develop- and, in some cases, from the mito- ment of living newborn animals. chondrial DNA of the oocyte. Dolly, produced from an adult cell, represents only a 0.2% cloning Totipotency success. The inability to clone most nuclei from advanced stages probably Animal cloning began more than a results from protein changes that century ago when scientists wondered occurr in the chromosomes during how an initially formless mass of cell differentiation, changes that will cells, the , develops into a have to be identified and controlled in structured organism composed of the future. separate skin cells, blood cells, muscle cells, brain cells, stomach cells, and so on. They specifically wanted to Genetic reprogramming know whether these many different Scientists found that cloning actually cell types were irreversible or whether reprograms nuclear function and these differentiated cells could reverse returns some nuclei to an undifferenti- and express again the totipotency of ated state. This discovery followed a the early embryo. line of basic research that may result Early Embryonic Cells Are Totipo- in some of the most beneficial applica- tent—By using an early version of the tions to humans. nuclear transfer technique in their Soon after a nucleus is transferred initial studies, scientists established to an egg, there occurs a two-way that nuclei from early embryonic cells Few Nuclei Remain Totipotent transfer of specific proteins between were indeed totipotent; that is, they throughout Development—Scientists the nucleus and cytoplasm. This could develop into complete fertile now know that the older the donor transfer causes modifications in organisms, with all the cell types and cell from which the nucleus is chromosomal proteins, resulting in

1964 1970s 19 83 F.C. Steward grows a complete carrot plant By using nuclear transfer, researchers obtain James McGrath and Davor Solter develop from fully differentiated carrot root cell. pre-feeding larvae from nuclei of differenti- nuclear transfer technology for mammalian This and the previous experi- ated frog skin (J.B. Gurdon, R.A. Laskey, embryos. Fertile mice were obtained when a ments led some scientists to believe that O.R. Reeves) and lymphocytes (M.R.Wabl, nucleus surrounded by minute amount of cloning from differentiated animal cells was R.B. Brun, and L. Du Pasquier). cytoplasm from a 1-stage fertilized egg was possible. fused with another enucleated fertilized egg. 1966 John B. Gurdon and V. Uehlinger succeed in growing adult frogs from injection of tadpole intestinal cell nuclei into enucleated oocytes.

5 Federation of American Societies for Experimental Biology Office of Public Affairs nuclear DNA synthesis, and later in In Hawaii, 17 months after the muscle rigidity and tremors in the expression of a new set of genes. announcement of Dolly’s birth, 32 parkinsonian rats were improved These and other changes reflect mice were cloned from cumulus cells by transplanting cloned transgenic reprogramming of nuclear function by (i.e., cells that surround the develop- bovine neurons into their brains. chemicals in the oocyte cytoplasm. ing oocytes in the ovaries), confirm- This research, called When investigators identify the role of ing successful cloning from adult xenotransplantation, is one of the these proteins, we will understand cells. Ten of these clones have many avenues being pursued in an how to convert a nucleus from a themselves produced normal progeny, attempt to alleviate the desperate differentiated adult cell type into one and some of the 31 clones themselves shortage of human tissues for that is relatively immature. This might came from clones, demonstrating the transplantation. permit us to actually reprogram feasibility of augmenting the number Ø Domestic animals can be geneti- mature cells and turn them into of clones. In December 1998, eight cally designed to express a certain specific cell types required for tissue calves were cloned from a single adult human disease and therefore serve repair. By doing this, we could cow’s cumulus and oviductal cells as models for the study and potentially replace damaged heart or (cells lining the tubes of the oviduct treatment of human illnesses. brain cells by reprogramming the that transport oocytes to the uterus). Although many mouse models of patients’ own skin cells into heart These studies showed that not only human diseases are available today, muscle cells and nerve cells (for adult cells could be reprogrammed, such models in large domestic people like Christine and Margo). but also that some differentiated cells animals physiologically more (such as cumulus and oviductal cells) similar to humans are sparse and Dolly is only the first! had the same capability. Keep in mind critically needed. that not all adult cells are differenti- Ø Dolly is no longer unique, although ated; for example, undifferentiated Somatic cell nuclear transfer might she always will be the first animal cells are found in bone marrow, the help preserve cloned from an adult cell. Being the intestinal lining, etc., of adults. such as pandas that have low result of a nuclear transfer between an reproductive rates. adult ewe udder cell and an enucleated Direct advantages oocyte, she showed that an adult Indirect advantages mammalian cell could be repro- Transgenic clones can be directly grammed genetically to be totipotent beneficial to humans, other animals, Two other significant gains from and give rise to an entire individual and agriculture in additional ways. clones are worth mentioning. that grew to maturity and gave birth Ø They may be developed for tissue First, inducing cancer cells to to offspring of her own. Soon after and transplantation. Al- differentiate is a useful type of Dolly was born, a set of triplet though not yet a reality, there is therapy. We know that many types of transgenic calves bearing a foreign promise that large animals can be cancer cells are less specialized than gene was cloned from fetal cells, all genetically designed and cloned so their normal counterparts. For this sharing the same nuclear genes. This that their tissues and organs will reason investigators suspected that the indicates the feasibility of producing not trigger immunological re- precursors of cancer cells could be herds of sheep and cattle capable of sponses in the recipient and cause immature cells or stem cells that fail producing the same protein. them to be rejected. Recently, to complete differentiation. If this is

1983-86 19 8 6 Marie A. Di Berardino, Nancy H. Orr, and Robert McKinnell obtain pre-feeding and feeding Steen Willadsen clones lambs by fusing a tadpoles from transplanting nuclei of adult frog erythrocytes (unlike humans, frog mature red nucleus of an 8-cell embryo to enucleated blood cells contain nuclei). oocyte. An electrical impulse usually was used for the oocyte fusion and activation process. Other researchers subsequently succeeded in producing full-term cattle, sheep, pigs, goats, and rats by using a similar approach, as long as the blastomere nuclei were obtained from embryos prior to implantation.

6 Breakthroughs in Bioscience http://www.faseb.org/opar so, then by using information gained active ones. If we could isolate these chromosomes and others with from nuclear transfer technology, we substances, we might be able to abnormal ones. So far, the pros- may be able to induce the cells to alleviate—or reverse—. pects for identifying an abnormal mature and stop making tumors. embryo prior to transfer to the Previous studies have demonstrated Perils uterus are poor. that we can control at least some And there are other scientific con- Although Dolly, mice, and calves have cancer cells by using the differentia- cerns: been the first animals cloned from tion process. Ø adult cells, the low efficiency in the span of the clone is un- Second, aged cell nuclei can be known, as is rejuvenated. People and other organ- producing them negates attempts to Ø isms change as they age. Environ- clone humans. The Dolly experiment the compatibility between the mental insults and diseases cause these began with 434 attempts to fuse a genetic products in the cytoplasm mammary gland cell to an oocyte, and of the oocyte and the donor cell, If we could isolate these ended with only a 0.2% success rate; and the remaining attempts resulted in Ø during the normal process of substances, we might be death either during fusion or in sexual reproduction, there is a various developmental stages. More- able to alleviate—or re- of the fittest germ over, the 1-2% success rate with verse—senescence. cells in fertilization. Although this mouse and 1-5% with calf cloning process is not perfect (i.e., it fails from adult cells are equally low. And to eliminate some harmful muta- high frequency of fetal (approximately changes; others are intrinsic to the tions), it does not exist in cloning. organism. Studies using 60%) and neonatal (approximately So we can see that it is unlikely that have shown that body cells grow and 50%) deaths are common. In a real cloning of a human being from any divide normally in culture for awhile, sense, cloning is a roulette game. donor age will happen any time soon. but eventually stop dividing, become Even if cloning from adult cells did Indeed, the scientific community was senescent, and die. An exception was become efficient, there still would be so strongly opposed to the production seen in aged frog red blood cell nuclei serious hazards. of a human being by cloning tech- (human red blood cells lack nuclei): Ø Donor cells could suffer mutations niques that the Federation of Ameri- After their transfer into enucleated from radiation, chemicals, aging, can Societies for Experimental Biology oocytes, frog red blood cell nuclei and/or errors in DNA replication and other professional organizations were rejuvenated. They carried out the during the lifetime of the donor, representing more than 67,000 formation of tadpoles that survived which would be transferred to the scientists have issued a voluntary almost a third of the way to metamor- clone. moratorium against such an act. The phosis. The oocyte cytoplasm Ø Mutations could arise in donor cells groups endorsing this position in- contains an abundance of chemicals during cell culture, not an unusual cluded those scientists most capable that promote DNA synthesis and cell event, and there is no way of of performing this type of work. division after normal fertilization. We distinguishing a normal donor cell Although these scientists believe believe that these substances also from a mutant one. that cloning a human being is unethi- rejuvenate aged cell nuclei and turn cal and reprehensible, they are still non-cycling frog red blood cells into Ø The embryo may be a mosaic of cells, some with apparently normal concerned that some of the anti-

19 93 19 97 19 9 8 M. Sims and N.L. First report for the first Dolly, the first mammal cloned from an adult The Honolulu group, led by Teruhiko time production of calves by transfer of cell, is produced in Scotland. and Wakayama, reported the production of a nuclei from cultured embryonic cells. colleagues report the birth of a lamb derived large number of live mice from injecting from the transfer of a nucleus obtained from nuclei taken from adult ovarian cells into an adult ewe udder cell into an enucleated enucleated oocytes. These investigators also oocyte that was then implanted into a report success in recloning efficiently the surrogate mother. first clones. cloning: Two Rhesus monkeys The Japanese group, led by Yoko Kato, are the first and only primates thus far produced eight calves from cumulus and cloned by nuclear transfer from the 8-cell oviductal cells derived from one adult donor. stage—Don ’s laboratory at Oregon Regional Primate Research Center.

7 Federation of American Societies for Experimental Biology Office of Public Affairs cloning legislation designed to prevent concerns. Cloning is only one of For original articles on cloning cancer the cloning of a human being contains many discoveries in which society cell nuclei, see T. J. King and M. language that also will prohibit vital will have to choose which applications A. Di Berardino (1965) Transplan- biomedical research that can lead to are ethical and which ones are not. tation of nuclei from the frog renal the repair of diseased and damaged adenocarcinoma. I. Development human tissues and organs, and to Suggested Readings of tumor nuclear-transplant possible treatments and cures for embryos. Ann.N.Y.Acad.Sci. diabetes, cancer, Parkinson’s disease, For the original report on Dolly, see I. 126:115-126 and R.G. McKinnell, and other neurodegenerative diseases. Wilmut et al. (1997) Viable Off- B.A. Deggins and D.D. Labat Other nations have found a suc- spring Derived from Fetal and (1969). Transplantation of cessful balance between these two Adult Mam-malian Cells. , pluripotential nuclei from triploid concerns. Many European countries 385:810-813. frog tumors. 163:394-396 have outlawed attempts to clone For a general treatment of cloning, see For an article on cloning red blood cell humans, while preserving the freedom I. Wilmut (1998) Cloning for nuclei, see M.A. Di Berardino and of scientists pursuing cloning studies Medicine. Scientific American, N. Hoffner Orr (1992) Genomic in non-human organisms because of December 58-63. potential of erythroid and leuko- the potential benefits. In the United cytic cells of Rana pipiens ana- States, the National Advi- For the original report on transgenic lyzed by nuclear transfer into sory Committee recommended an lamb clones, see A. E. Schnieke et diplotene and maturing oocytes. “imposed period of time in which no al. (1997) Human Factor IX Differentiation 50:1-13. attempt is made to create a child using Transgenic Sheep Produced by somatic cell nuclear transfer.” In their Transfer of Nuclei from Trans- For a thorough coverage of the 1997 statement, the committee fected Fetal Fibroblasts. Science, science and history of animal cautioned, “Any regulatory or legisla- 278:2130-2133. cloning, see Marie A. Di Berardino tive actions undertaken to effect the For the original report on transgenic (1997) Genomic Potential of foregoing prohibition on creating a calf clones, see J. B. Cibelli et al. Differentiated Cells, Columbia child by somatic cell nuclear transfer (1998) Cloned Transgenic Calves University Press, N.Y. should be carefully written so as not Produced from Nonquiescent Fetal to interfere with other important areas Fibroblasts. Science, 280:1256- of scientific research.” 1258. For the original report on cloning mice Knowledge: threat or from adult cells, see T. Wakayama, promise? A.C.F. Perry, M. Zuccotti, K.R. Marie A. Di Berardino, Ph.D., is Johnson and R. Yanagimachi Professor Emerita of Biochemis- (1998). Full-term development of try, The Medical College of When scientists first discovered mice from enucleated oocytes Pennsylvania-Hahnemann School anesthesia, atomic energy, and injected with cumulus cell nuclei. of Medicine, MCP Hahnemann recombinant DNA, we did not know Nature, 394:369-374. University, 2900 Queen Lane, if these breakthroughs might lead to Philadelphia, PA 19129. She has deleterious applications. The choices For the original report on cloning conducted research on the we make for the application of from adult cow cells, see Kato, Y., developmental potential of knowledge reside in ethical decisions Tani, T., Sotomaru, Y., Kurokawa, differentiated frog cells and by humans. Animal cloning, like other K., Kato, J., Doguchi, H., Yasue, cancer, and has lectured and research, was initiated to seek funda- H., and Tsunoda, Y. (1998) Eight published widely on this subject. mental knowledge for the benefit of calves cloned from somatic cells of Science editor for this article humankind. In addition to expanding a single adult. Science, 282:2095- was Ida Chow, Ph.D., a natural the knowledge base in cellular, 2098. clone herself (her identical twin developmental, and , For the original article on treating sister is a physicist living in as well as in cancer and aging, cloning parkinsonian rats, see W. M. Brazil). She is the Executive has now been applied to enhance Zawada et al. (1998) Somatic cell Officer of the Society for Devel- medicine and agriculture. Presently, cloned transgenic bovine neurons opmental Biology. Her research is hospital committees in the United for transplantation in parkinsonian on cell-cell interaction during States bar attempts to clone humans rats. Nature Medicine, 4:569-574. vertebrate development. because of clinical, safety, and ethical

8 Breakthroughs in Bioscience http://www.faseb.org/opar