Many will remember the famous cover photo of Nature reporting the chimeric geep (goat-sheep). However in the following decade there has been less publicity. A paper looking at the use of these chimeras in study of immunological rejection of fetuses is R.A. Gustafson et al., "Failure of sheep-goat hybrid conceptuses to develop to term in sheep-goat chimeras", J. Reproduction & Fertility 99 (1993), 267-72.

A review of genetic modification of Drosophila, to make no-winged flies is Nature 366 (1993), 305-6. A nematode C. elegans mutant that lives twice as long as the normal one is reported in Nature 366 (1993), 461-4. The mechanism of the increased lifespan is of broad interest!

The expression of hemoglobin in pigs has been previously reported, the methods are published in A. Sharma et al., "An isologous porcine promoter permits high level expression of human hemoglobin in transgenic swine", Biotechnology 12 (1994), 55-9. A general method for chicken genetic engineering is in J. Love et al. "Transgenic birds by DNA microinjection", Biotechnology 12 (1994), 60-3. The use of ultrasound to examine meat quality (reported also 1-2 years earlier in Australia, in EEIN, is being used in beef bull breeder's in some US states; Science 263 (1994), 327.

A paper from fruit fly genetic engineering that supports a free radical theory of aging is W.C. Orr & R.S. Sohal, "Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster", Science 263 (1994), 1128-30.

Researchers in Cornell have engineered beta-lactoglobulin, a milk protein found in whey, so that yoghurt that is made from this should form less liquid; GEN (15 March 1994), 32. When yoghurt is stored, it generally forms liquid.

The mapping of the genetic locus for fat deposition in pigs is reported in L. Anderson et al., "Genetic mapping of quantitative trait loci for growth and fatness in pigs", Science 263 (1994), 1771-4. New methods for genetic engineering of animals are discussed in GEN (1 March 1994),32-3. One is the use of chicken genetic engineering, which has potential for the use of eggs to produce proteins, with the added argument that not being a mammal there is less chance of passing human disease, compared to sheep or goats, etc. The other advance was to use somatic cell transfer vectors to genetically transform the mammary gland of goats, which may give quicker results than germ-line genetic engineering - if a reliable cheap vector is found.

A special issue of Reproduction, Fertility & Development 5 (6), (1993), 585-712 is from a symposium on sperm encapsulation and preservation. A paper looking at geep studies is L.A. MacLaren et al., "Reproductive cycles and pregnancy in interspecific sheep-Goat chimaeras", Reproduction, Fertility & Development 5 (6), (1993), 261-70.

A genetically engineered vaccine against cattle ticks is being mass produced in Australia, that should help control tick infestation; Science 264 (1994), 1398. The tick is an external parasite, but ingests blood, and the vaccine is a modified version of a tick protein from the gut cells, which produces immune response in the cattle which in turn prevents reproduction of the tick.

A 166 acre farm in western Massachusetts is to be the home of a herd of goats of Genzyme Transgenics, which will make the anticoagulant antithrombin III, Science 264 (1994), 902. This will be the first transgenic farm in the USA, Europe has two already. The Dutch bull, Herman, who carries the human lactoferrin gene recently gave rise to at least eight calves who inherited the gene.

A gene, reaper, that appears to turn on the program for cell death in fruit fly, Drosophila is reported in K. White et al., "Genetic control of programmed cell death in Drosophila", Science 264 (1994), 677-83; and a review of studies in other organisms is pp.668-9. The gene encodes a special peptide whose mRNA is found in cells about to undergo cell death. A monkey model of memory loss is reported in P. Alvarez et al., "The animal model of human amnesia: Long-term memory impaired and short-term memory intact", PNAS 91 (1994),, 5637-41.

A Finnish paper reporting dairy cow production is J.-M. Hyttinen et al., "Generation of transgenic dairy cattle from transgene-analyzed and sexed embryos produced in vitro", Biotechnology 12 (1994), 606-8. The secretion of human growth hormone in milk of goats after direct gene transfer is reported in PNAS 91 (1994),, 6840-4. The induction of human tissue plasminogen activator in goats is reported in Biotechnology 12 (1994), 699-702. A short review suitable for teaching materials on pharmaceutical protein production in farm animals is in J. Biol. Education 28: 90-6. A book review of A. Puhler, Genetic Engineering of Animals, is in TIBTECH 12 (1994), 335.

The USDA has approved a recombinant vaccine for chickens, against Newcastle disease and fowlpox; Science 265 (1994), 1358-9; Biotechnology 12 (1994), 962-3. Controlled release methods in animal health are discussed in GEN (1 Sept 1994), 1, 30-1. A review of Journal of Marine Biotechnology is in Nature 371 (1994), 456.

A series of papers describing genetic dissection of memory in Drosophila (fruit fly) are in Cell 79 (1994), 35-68. One cAMP responsive element-binding protein was specifically found to inhibit long-term memory. Electrode insertion in rats found a link between memory and sleep, Scientific American (Oct 1995), 32-3. Experiments in rats (not-genetic but of a model) are Kordower, J.H. et al. "Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease", PNAS 91 (1994),, 9077-80.

Neuromuscular changes in Xenopus are reported by changes in expression of cholinergic proteins, PNAS 91 (1994),, 9072-6. The eyeless gene of Drosophila has been found to be related to human genes despite a large difference in structure, Quiring, R. et al. "Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans", Science 265 (1994), 785-9. A paper on the genetics of a pheromonal difference in Drosophila is Science 265 (1994), 1461-4.

GenePharming Europe has reported the production of human collagen in the milk of transgenic mice, EBN 189 (1994), 5. Collagen is used in tissue repair, and is a triple helix structure, which is quite complex. GenePharming Europe has recently joined FinnGene Oy of Finland to consolidate activities in producing proteins in milk, EBN 191 (1994), 3-4. A general review of the wait for products from bioreactors is GEN (1 Nov 1994), 8, 30. A study of mice with BST genes is J. Animal Science 72: 2812-9. The production of transgenic toads from nuclei transplants is a shortcut to producing transgenic animals, Kroll, K.L. & Gerhart, J.C. "Transgenic Xenopus laevis embryos from eggs transplanted with nuclei of transfected cultured cells", Science 266 (1994), 650-3.

In the UK at Cambridge, human genes have been transferred into pig organs in what is hoped will increase the number of organs available (see also the Organ Transplant section below). Among the piglets made, 38 were transgenic for the correct gene; CMAJ 151 (1994), 72. A paper describing chimeric pigs is Biology of Reproduction 51: 1069-75.

A salmon that reportedly grows 400-600% faster than ordinary salmon has been developed by A/F Protein Inc., W. Newton, MA. It is called Biogrow Salmon; Biotechnology Notes (Feb), 2. Aquaculture in India is discussed in Biotechnology and Development Monitor 21 (Dec 94), 16-7.

In Lincoln University, New Zealand, a gene marker for resistance to footrot in sheep has been identified. It will be used to identify sheep flocks with resistance, Christchurch Press (16 March 1995), 26. A mouse study has found that the casein kinase II gene that is overexpressed in cattle infected with the protozoan parasite Theileria parva, is an oncogene, Science 267 (1995), 894-7. A book review of Mad Cow Disease is in New Scientist (18 Feb, 1995), 42.

A review of when we can expect to see transgenic fish, following the development of female fish which have a male sex genotype, and can produce gynogenetic offspring, is GEN (15 May 1995), 1, 28. A recent book is Maclean, N., ed., Animals with Novel Genes (Cambridge University Press 1994, ISBN 0-521-43256-1). A paper looking at the fertility genes of Drosophila and discussing selfish genes is TIG 11 (1995), 195-200; and on homeotic genes and wing number, Nature 375 (1995),58-61. A review of mechanisms for sex adjustment in mammals and birds is Biol. Rev. 70 (1995), 225-41.

A review of US guidelines on protein production in transgenic milk is in GEN (July 1995),16-8. The FDA is about to release its new Points to Consider on transgenic proteins. GenZyme Transgenics have announced the production of a monoclonal antibody in the milk of a goat (at levels up to 4 grams per litre), GEN (1 June 1995), 26. On organs from genetically engineered pigs and animals, see Organ Transplants section. The use of goats as models for biomedical research and teaching is reviewed in ILAR News 36 (1995), 21-9.

Research to develop a recombinant vaccine against feline immunodeficiency virus is described in GEN (July 1995),10. The use of mimicry to make a foot and mouth disease vaccine is reported in Biotechnology 13 (1995), 801-4. Research to control cockroachs by birth control is reviewed in GEN (July 1995), 23. The transfer of fatal familial insomnia by a tissue transfer to mice, suggesting a virus, is reported in Tateishi, J. et al. "First experimental transmission of fatal familial insomnia", Nature 376 (1995), 434-5. The targeting of non-Immunoglobulin sequences to replace the variable region in Ig is reported in Nature 376 (1995), 225-9. This could have future use also in human gene therapy.

The European Commission discussions on use of substances to make animals grow faster is reported in Nature 377 (1995), 381. A conference report on canine models of genetic disease is JMG 32 (1995), 751-4. A homeobox gene is found to be essential for zebrafish notochord development, Nature 378 (1995), 150-7. Expression of a foreign gene in silk worm is reported in Biotechnology 13 (1995), 1005-7; and on modeling Lou Gehrig's disease in Drosophila, PNAS 92 (1995), 8533-4; and on cell death models, Science 269 (1995), 753.

A rhesus monkey cell line has been made which may make them the next animal model for genetics, Tomson, J.A. et al. "Isolation of a primate embryonic stem cell line", PNAS 92 (1995), 7844-8. An embryonic stem (ES) cell line with a genetic marker, WW6 cells, are described in PNAS 92 (1995), 7357-61. It is possible to generate hematopoietic stem cells from ES cells, PNAS 92 (1995), 7530-4. A new vector polyethylenimine is reported to be good for gene transfer, PNAS 92 (1995), 7297-301. A male marker, human H-Y is described which may be useful for screening, Science 270 (1995), 1588-90.

The production of transgenic animals to produce proteins in milk is expanding, and a list of a dozen proteins under consideration including alpha1 anti-protease inhibitor, alpha1 anti-trypsin, collagen, Factor IX, Factor VIII, fibrinogen, human fertility hormones, human hemoglobin, human serum albumin, lactoferrin, TPA, monoclonal antibodies, protein C and TPA, GEN (15 Oct 1995), 8-9. A Scottish company Otter Ferry Salmon, Ltd., plans to hatch genetically modified salmon which grow ten times faster than normal, and export them to Chile, GenEthics News 9 (Nov/Dec 1995), 12. The fish will be grown on land in tanks. It can also be given as a hormone, Garber M.J. et al. "Dose-Response Effects of Recombinant Bovine Somatotropin (PosilacTM) on Growth Performance and Body Composition of Two-Year-Old Rainbow Trout (Oncorhynchus mykiss)",J. Animal Science 73 (1995), 3216-22.

A review of genetic mapping in livestock is TIG 11 (1995), 488-92, and in mice, TIG 11 (1995), 471-7. Efforts are being made to genetically engineering the gut microorganisms of ruminant livestock to reduce the toxicity of plants they may eat, TIBTECH 13 (1995), 418-21. Methods to improve digestion efficiency are discussed in Search 26 (1995), 245-7. Chromosome engineering in mice in ES cells of mice is reported in Nature 378 (1995), 720-8. The expression of a human beta-amyloid peptide (involved in Alzheimer disease) in the nematode Caenorhabditis elegans is reported in PNAS 92 (1995), 9368-72. The use of amphibian skin to produce antimicrobial peptides is being researched, TIBTECH 13 (1995),205-9. On gene transfer into the Medfly with a Drosophila transposable element, Science 270 (1995), 2002-2005.

Sex selection through sperm separation has been used for cattle in Colorado University, USA, GEN (15 Jan 1996), 1, 11. They used a flow cytometer cell sorter, and predicted 15 of the 17 calves, as well as reducing the number of sperm required to induce pregnancy to 200,000, to reduce the expense of separating the sperm. A report on the success of a double vaccine against rinderpest and capripox in cattle in Kenya is NS (17 Feb 1996), 20. Several sheep have been successfully cloned from a cell line totipotent for nuclear transfer (TNT4), raising the possibility for a new and simpler method of genetic manipulation, Campbell, KHS. et al. "Sheep cloned by nuclear transfer from a cultured cell line", Nature 380 (1996), 64-66; 24-5, 383; BMJ 312 (1996), 658. Although only about 15% of embryos develop into blastocysts, harvesting of oocytes from slaughtered sheep means numbers should be no problem. A method to determine sex and chimerism in sheep is reported in Animal Reproduction Science 41 (1996), 131-9. Improved wool production in sheep has been obtained by overexpressing insulin-like growth factor 1, Biotechnology 14 (1996), 185-8.

Human lactoferrin has been produced from transgenic cow milk by the Dutch company, Pharming BV, EBN 218 (1996), 2-3. The proteins are identical to natural proteins it is claimed. The people who may use lactoferrin include those with lower immune defenses, including cancer patients on chemotherapy and AIDS patients, and premature infants.

On transformation of malaria parasites, Trends in Microbiology 4 (1996), 43-5. A reset button for fruit fly circadian rhythms has been found, Science 271 (1996), 1671-2. On RFLP mapping of expressed sequence tags in chicken, J. Heredity 87 (1996), 6-9.

A report from PPL Therapeutics in Edinburgh on the production of alpha-1-anti-trypsin from transgenic sheep is GEN (1 May 1996), 1, 22. The pilot plant is expected to make 10kg of the protein a year, enough for clinical trials before it obtains approval. Another company, Genzyme Transgenics in the USA is also close to clinical trials with antithrombin III from blood of goats, GEN (1 May 1996), 37. Exceptions to simple Mendelian genetic expression seem to be involved in some sheep genes controlling body size, Science 272 (1996), 1099-100.

Rat spermatogenesis has been achieved in mice, Nature 381 (1996), 418-21. A method for genetic transformation of surfclams and shellfish has been reported using a retrovirus, PNAS 93 (1996), 3482-6. On genetic mapping in cows, sheep and goats, PNAS 93 (1996), 3450-4. Increasing the expression of recombination repair protein, Rrp1, results in less somatic mutation and increased recombination frequency in Drosophila, PNAS 93 (1996), 1607-12.

Genetic engineering to stop vectors carrying a virus is reported in Olson, KE et al. "Genetically engineered resistance to dengue-2 virus transmission in mosquitoes", Science 272 (1996), 884-6; NS (11 May 1996), 16.

On the ethical issues, Mepham TB, Transgenesis in farm animals: Ethical implications for public policy. Politics and Life Sciences 13 (1994), 195-203. Germ-line genetic engineering at the zygote stage is now reported in Lakso, M. et al. "Efficient in vivo manipulation of mouse genomic sequences at the zygote stage", PNAS 93 (1996), 5860-5. Site specific DNA recombination is discussed in PNAS 93 (1996), 6191-6; and on modified gene vectors, NS (24 August 1996), 23. A review of how to build a better oyster is BioScience 46 (1996), 240-4.

New approaches to animal transgenesis are discussed in Nature Biotechnology 14 (1996), 942-3; Tsukui, T. et al. "Transgenesis by adenovirus-mediated gene transfer into mouse zona-free eggs", Nature Biotechnology 14 (1996), 982-5. Current approaches to generating transgenic animals fall into two broad categories: first, direct manipulation of the zygote or early embryo; and second, manipulation of pluripotent cells in vitro, and new methods are being sought. A study of social barriers to gene flow in fire ants is Nature 383 (1996), 613-6.

Two clinical trials of antithrombin III products from animals are entering clinical trials, GEN (1 Nov 1996), 5, 20. Drosophila melanogaster sex drive has been traced to a single gene, called fru Science 274 (1996), 1836. We should note that the genes influencing sexual differentiation in flies and mammals are unrelated. On insect protection against viruses, Nature 383 (1996), 767.

Canadian scientists are using Tilipia fish into producers of cells that make insulin, the Islets of Langerhans of the pancreas, NS (16 Nov 1996), 20. The use of insertional mutagenesis and cloning of genes in zebrafish is described in Nature Genetics 14 (1996), 258-63; Nature 383 (1996), 829+. A review of genetic methods in transgenic frogs, Xenopus laevis, is Nature 383 (1996), 765-6; Development 122 (1996), 3173-83; TIG 12 (1996), 439-40.

The news of the month has been the cloning of sheep in Scotland; Wilmut, I. et al. "Viable offspring derived from fetal and adult mammalian cells", Nature 385 (1997), 810-3, 769, 771. The abstract of the paper reads "Fertilization of mammalian eggs is followed by successive cell divisions and progressive differentiation, first into the early embryo and subsequently into all of the cell types that make up the adult animal. Transfer of a single nucleus at a specific stage of development, to an enucleated unfertilized egg, provided an opportunity to investigate whether cellular differentiation to that stage involved irreversible genetic modification. The first offspring to develop from a differentiated cell were born after nuclear transfer from an embryo-derived cell line that had been induced to become quiescent. Using the same procedure, the authors now report the birth of live lambs from three new cell populations established from adult mammary gland, fetus and embryo. The fact that a lamb was derived from an adult cell confirms that differentiation of that cell did not involve the irreversible modification of genetic material required for development to term. The birth of lambs from differentiated fetal and adult cells also reinforces previous speculation, that by inducing donor cells to become quiescent it will be possible to obtain normal development from a wide variety of differentiated cells."

The possibilities for human cloning have filled Internet discussion groups, and the popular press, Newsweek (10 March, 1997), 2, 42-50; Nature 385 (1997), 753, 757. American researchers also announced they had used nuclear transfer in rhesus monkeys to make two clones. The US has made a ban on federal funding of human cloning, see the statement:

Remarks By President Clinton On Cloning (March 4, 1997) were reported:

Good morning. I'm glad to be joined this morning by the Vice President, Secretary Shalala, Dr. Harold Varmus, the head of NIH; Dr. Harold Shapiro, the President of Princeton and the Chairman of our Bioethics Advisory Commission; and Dr. Jack Gibbons, the President's Advisor on Science and Technology, all of whom know a lot about and care a lot about this issue we are discussing today.

The recent breakthrough in animal cloning is one that could yield enormous benefits, enabling us to reproduce the most productive strains of crop and livestock, holding out the promise of revolutionary new medical treatments and cures, helping to unlock the greatest secrets of the genetic code. But like the splitting of the atom, this is a discovery that carries burdens as well as benefits.

Science often moves faster than our ability to understand its implications. That is why we have a responsibility to move with caution and care to harness the powerful forces of science and technology so that we can reap the benefit while minimizing the potential danger.

This new discovery raises the troubling prospect that it might someday be possible to clone human beings from our own genetic material. There is much about cloning that we still do not know. But this much we do know: any discovery that touches upon human creation is not simply a matter of scientific inquiry, it is a matter of morality and spirituality as well.

My own view is that human cloning would have to raise deep concerns, given our most cherished concepts of faith and humanity. Each human life is unique, born of a miracle that reaches beyond laboratory science. I believe we must respect this profound gift and resist the temptation to replicate ourselves.

At the very least, however, we should all agree that we need a better understanding of the scope and implications of this most recent breakthrough. Last week, I asked our National Bioethics Advisory Commission, headed by President Harold Shapiro of Princeton, to conduct a thorough review of the legal and the ethical issues raised by this new cloning discovery, and to recommend possible actions to prevent its abuse, reporting back to me by the end of May.

In the meantime, I am taking further steps to prevent human cloning. The federal government currently restricts the use of federal funds for research involving human embryos. After reviewing these restrictions, our administration believes that there are loopholes that could allow the cloning of human beings if the technology were developed. Therefore, today I am issuing a directive that bans the use of any federal funds for any cloning of human beings.

Effective immediately, no federal agency may support, fund, or undertake such activity. Of course, a great deal of research and activity in this area is supported by private funds. That is why I am urging the entire scientific and medical community, every foundation, every university, every industry that supports work in this area to heed the federal government's example. I'm asking for a voluntary moratorium on the cloning of human beings until our Bioethics Advisory Commission and our entire nation have had a real chance to understand and debate the profound ethical implications of the latest advances.

As we gain a fuller understanding of this technology, we must proceed not just with caution, but also with a conscience, by insisting that not a single taxpayer dollar supports human cloning. And by urging a moratorium on all private research in this area, we can ensure that as we move forward on this issue, we weigh the concerns of faith and family and philosophy and values, not merely of science alone. Thank you very much.

Question: Mr. President, what is the extent of your order today? How much funds -- do you know how much funds were being spent toward this human cloning, if any?

Answer: We attempted previously to have a ban on this, going back to '94, I believe. The nature of the new discovery raised the prospect that the technology was not covered specifically by the nature of the ban. So as far as I know, nothing is going on in government-funded research. I just want to make sure that we keep it that way, because our research dollars are spread all across the country in different institutions.

With regard to the private sector, let me say that our staff here in the White House has been in touch with a number of people in the biotech industry, and they seem to be glad that we called and anxious to participate in a moratorium until we think through the implications of this.

I mean, I imagine a lot of you, not as journalists but in your own private homes have sat around talking about this discovery in the last few days; I know we have in our home. And I just think that we need the best minds that we can bring to bear and the distinguished people on the Bioethics Advisory Committee to think through this, tell us about what we may be missing about if there's anything positive that could come from this, and also think through the other implications.

How can we get the benefits of our deep desire to find any possible cure for any malady that's out there without raising the kind of ethical implications that, in effect, we're in the business where people are trying to play God, or to replicate themselves.

A review of transgenic livestock as drug factories is SA (Jan 1997), 70-4. A team of US researchers has created a genetically engineered mouse capable of generating a fully human antibody response, Xenomouse II, Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice", NatGen 15 (1997), 146-57. The genetic relationships among production traits in pigs is analyzed in J. Animal Science 75 (1997), 51-60. Gene searches in zebrafish are reviewed in Nature 385 (1997), 515-6. On insecticide resistance genes in mosquitoes, J. Heredity 87 (1996), 444-9.

A number of reports on cloning continue; BME 125 (1997), 3-4; GenEthics News 16 (Jan-Mar 1997), 1, 10; BMJ 314 (1997), 623; Lancet 349 (1997), 661. Scientists have been arguing for the benefits of the research which may be banned if broad measures are passed to stop cloning, Nature 386 (1997), 8-9, 431; Nature Biotechnology 15 (1997), 293; NS (8 March 1997), 4-5; Science 275 (1997), 1415. The claimed benefits include generation of somatic cells for example skin cells for grafts or bone marrow for people undergoing chemotherapy for cancer. The cloned animals are being supported as bioreactors for production of pharmaceuticals, GEN (15 March 1997), 1, 10. The homepage of the Roslin Institute includes some basic information and background. Researchers in Ruakara, New Zealand, have also reported cloning by nuclear transfer from embryonic cells, Otago Daily Times (17 March 1997), 27. China has reported cloning of pig, rabbits and a bull using embryonic cells. Research in Denmark and Australia is making cloned cows, EBN 241 (1997), 2. In Australia they plan to have commercial cloning of cows within 3-4 years.

The question of a right size for a mammal is discussed in Nature 386 (1997), 332-3; American Naturalist 149 (1997), 352-80. There is a wide range within mammals, for example mice or elephants. A discussion of genetic modification of mosquitoes to control disease is TIBTECH 14 (1996), 447-8; Nature 386 (1997), 538. Therapy for Huntington's disease may be aided by the results of Emerich, DF. et al. "Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease", Nature 386 (1997), 395-9.

More biotechnology companies are investigating mammalian cloning for commercial production of transgenic animals, GEN (1 May 1997), 1, 14, 31. A study of the 6 thousand year old Coupland enclosure (or henge) in the UK suggests it was for keeping cattle, having a chest-high gate at each end of a 110m diameter enclosure, Nature 387 (1997), 553-4; Waddington, C. Land of Legend (The Country Store, Northumberland, 1997).

Domestic Animal Diversity Information System (DAD-IS) is a global information system from FAO with data on 3800 breeds of farm animals. DAD-IS contributes to document and enhance the worlds animal genetic resources. DAD-IS assists countries to better manage their animal genetic resources through tools, guidelines and contacts (Email: Comments to: DAD-IS@fao.org) <http://www.fao.org/dad-is/>. They have made a CD-ROM with 7000 pages of information, and also have the Internet site. Those wanting to write can write to : Senior Officer, Animal Genetic Resources, FAO, Via Delle Therme di Caracalla, Rome 00100 ITALY.

A study of the rate of evolution in a fish, guppies, found that rates seven orders of magnitude higher could be induced in the laboratory than seen in nature, Science 276 (1997), 1934-7. Males could be selected faster than females. Evolution and the platypus is becoming clearer, Nature 387 (1997), 549-50. Bacteria can increase mutation rates when under stress, Nature 387 (1997), 557-8, 700-2, 703-5.

Following the birth of Dolly, the cloned sheep, at the Roslin Institute in Edinburgh, Scotland, a company in Wisconsin has now announced the first cloned cow. In August, ABS Global, a bovine reproductive services company, and their new commercial venture, Infigen (DeForest, WI), introduced "Gene," a six-month-old bull calf, NatBio 15 (1997), 833. In general on transgenic livestock, NatBio 15 (1997), 416.

Fruit flies that have a gene for wandering have a selective advantage in overcrowded conditions, NS (19 July 1997), 8. On the role of serotonin in sex in psychiatric disease, PNAS 94 (1997), 4823-4.

A report from ABS Global Inc. which introduced a 6 month old cloned cow is in GEN (1 Sept. 1997), 31; the name is Gene, Nature 388 (1997), 611; NS (16 Aug. 1997), 11; Science 277 (1997), 903. Genzyme Transgenics and Advanced Cell Technology Inc. are cloning cows to produce human proteins in their milk, and the first product may be human albumin, Reuters (8 Oct. 1997). On Polly and sisters, 5 lambs that were cloned with addition of extra human genes, Science 277 (1997), 631. The introduction of artificial chromosomes to make humanized pig organs for xenografts is reported in NS (30 Aug. 1997), 6.

A pig model is described in Peters, RM et al. "Genetically engineered large animal model for studying cone photoreceptor survival and degeneration in retinitis pigmentosa", Nature Biotechnology 15 (1997), 965-70, 947. Other pigs are modified in a study, Paleyanda, RK et al. "Transgenic pigs produce functional human factor VIII in milk", Nature Biotechnology 15 (1997), 971-5, 945-6. The secretion of 2.7 micrograms/ml of rFVIII in milk was made, over tenfold higher than in normal plasma. Up to 0.62 U/ml of rFVIII was detected in an assay in which rFVIII restored normal clotting activity to FVIII-deficient human plasma.

The characterization of a hyperactive antifreeze protein from beetles is in Nature 388 (1997), 727-8. A review of aquaculture systems for producing plant and animal food is GEN (1 Sept. 1997), 13, 46. On the evolution of fossil limbs, Nature 388 (1997), 639-48; and genomic imprinting, Nature 388 (1997), 669-71.

On the production of proteins in milk of transgenic animals, GEN 17 (15 Oct 1997), 16, 36-7. Urine may be even better than milk; Kerr, DE. et al. "The bladder as a bioreactor: Urothelium production and secretion of growth hormone into urine", NatBio 16 (1998), 75-9; 21-2. Uroplakin genes are expressed in a bladder-specific and differentiation-dependent fashion. Using a 3.6-kb promoter of mouse uroplakin II gene, transgenic mice that express human growth hormone in their bladder epithelium, which secrete it into the urine at 100-500 ng/ml, for over 8 months were made. On the use of insect larvae to produce proteins, Biotechnology & Bioengineering 56 (1997), 239-47.

Enhanced growth is observed by ectopic expression of growth hormone releasing hormone, NatBio 15 (1997), 1248, 1285-9. Myostatin hormone call also lead to more meat in animals, Science 278 (19971), 922-3. A new transgenic animal production facility has been opened by Nexia Biotech in Quebec, Canada, GEN 17 (15 Oct 1997), 26, 39. On the long history of camel husbandry and animal domestication, Nature 390 (1997), 658-9. A report from the Transgenic Animals in Agriculture Conference, August 1997, Tahoe City, Calif., is NatBio 15 (1997), 1246. Norgetomet implants are used to prevent pregnancy in beef heifers on pasture, J. Animal Science 75 (1997), 3089-93. A series of papers on interspecies hybrids in mammals are in J. Heredity 88 (Sept. 1997).

The use of nuclear transfer can double the success of producing transgenic sheep compared to microinjection, Schnieke, AE. et al. "Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts", Science 278 (1997), 2130-3. In general on cloning, Science 278 (1997), 2038-9. The estimated efficiency by PPL therapeutics of Polly was 1 in 60, much better than the 1 in 300+ for Dolly, Nature 391 (1998), 21. More discussion of cloning is in the Assisted reproduction section below. Cloned cows have also now arrived, Probe VI (No. 6, Jan 1998), 5. Cloned cows, named George and Charlie, have been announced in January 1998, made by Advanced Cell Technology Inc. and Univ. Mass, USA. A book review of Kolata, G. Clone: The Road to Dolly and the Path Ahead (Penguin, 1997, ISBN 0413992212, 16 pds) is NS (29 Nov 1997), 52. The Sunday Times(19 Oct 1997), 1; ran a story titled "Headless frog opens way for human organ factory", see Science 278 (1997), 798, for more discussion.

A review of cloning technology a year after Dolly is GEN 18 (15 Jan 1998), 1, 10, 34. It also discusses the commercial aspects of the research. A letter calling for confirmation of Dolly as adult cloning is Science 279 (1998), 635-8. Polly has been confirmed to contain and express the gene for blood clotting factor IX, GEN 18 (1 Feb. 1998), 28; Science 279 (1998), 646-8. Urine may be better than milk for biopharming, BMJ 316 (1998), 169.

Viral sequences enable efficient and tissue-specific expression of transgenes in Xenopus, NatBio 16 (1998), 253-7. On headless frog embryos, SA (Jan 1998), 41.

Efforts to clone extinct moa birds of New Zealand by nuclear transfer into chickens in Japan were delayed by Maori protests over who owns the moa bones, NZ Herald (16 March, 1998), A15. The use of ART for horse breading has been accomplished, Time (6 April, 1998). There have been claims that Dolly was not a clone, but Ian Wilmut has defended this, BMJ 316 (1998), 573; and a French group has made totipotent cells in cows and several cows have been born, Nature 392 (1998), 113.

Sponges may be good bioreactors, TIBTECH 15 (1997), 130-4; as may be termites, TIBTECH 15 (1997), 16-21. The use of urine instead of milk as a media for drug production is reported in Science News 153 (10 Jan 1998), 21.

On cloning for profit, Science 280 (1998), 1400-1. The New Zealand dairy industry expects to gain NZ$40 million a year when the Ruakura animal research centre at AgResearch allows commercial use of its cloning techniques for cows; Christchurch Press (16 July 1998), 23. Nuclei from freeze-dried mouse spermatozoa can support normal embryonic development even after three month preservation in a dried state, Wakayama, T. et al. "Development of normal mice from oocytes injected with freeze-dried spermatozoa", NatBio 16 (1998), 639-41; 618-9; NS (4 July 1997), 4. Pig embryos can be chilled and stored then successfully implanted, NS (28 March 1997), 17.

A success rate of 3 calves from 28 embryos transferred to 11 cows is reported in Cibelli, JB. et al. "Cloned transgenic calves produced from nonquiescent fetal fibroblasts", Science 280 (1998), 1256-8. Cibelli, JB. et al. "Transgenic bovine chimeric offspring produced from somatic cell-derived stem-like cells", NatBio 16 (1998), 642-6; 620; developed a method using nuclear transplantation to produce transgenic embryonic stem (ES)-like cells from fetal bovine fibroblasts. When reintroduced into preimplantation embryos, six out of seven (86%) calves born were found to be chimeric for at least one tissue. Cloning may be useful for treating neural disease, Zawada, WM. et al. "Somatic cell cloning-produced bovine neurons for transplantation in Parkinsonian rats", NatMed 4 (1998), 569-74, 557-8. French researchers have also announced a calf, Marguerite, a clone from muscle cells from a calf fetus, NS (21 March 1997), 24.

Dolly the cloned sheep had a lamb, and a photo of Bonnie the lamb is in Science News 153 (2 May 1998), 278. A review of the research into chicken transgenics is GenEng News 18 (July 1998), 17, 39; and of the Trimera mouse, TIBTECH 16 (1998), 242-6. Germ cells can be kept in culture for up to four months. Castrated racehorses can still sire offspring using IVF, NS (11 April 1997), 23. A review of efforts to increase muscle mass in livestock by genetic engineering is GenEng News 18 (15 May 1998), 28, 33. Production of biologically active salmon calcitonin in the milk of transgenic rabbits is described in NatBio 16 (1998), 647-51. One eyed animals have been made which suggest cholesterol is involved in development, Science 280 (1998), 1528-9.

A study of frogs suggests that females do actually pick mates with better genes by the choice of flamboyant males, Science 280 (1998), 1837-8. A review on environmental aspects of aquaculture is Boyd, CE. & Clay, JW. "Shrimp aquaculture and the environment", SA (June 1998), 58-65. A colorimetric gene marker has been developed for manipulated mosquitoes, Science News 153 (1998), 213. A review of use of fruit fly to research genetics of alcoholism is Cell 93 (1998), 909-12.

As reported in the last issue mice have been cloned, Wakayama, T. et al. "Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei", Nature 394 (1998), 369-73; as well as calves, NS (18 July 1998), 4-5; BMJ 317 (1998), 298; Science 281 (1998), 495-6; Nature 394 (1998), 303, 315-6; GEN (August 1998), 1, 3, 36. It has been shown by DNA studies that Dolly really is a cloned adult, 329-30. However in the Netherlands there are major restrictions on production of cows through cloning, Chemistry & Industry (18 May 1998), 380-1.

A technique using epidermal growth factor to make sheep lose their wool, is being marketed in Australia from October, 1998, to save the work of shearing sheep, Science 281 (1998), 511. The reason why arctic fish do not freeze is not in amino acids but in antifreeze molecules that stick to ice crystals and prevent ice crystallization, NS (18 July 1998), 7. Baculovirus infected insect cells can secrete active lipase enzymes, Biotech. Letters 20 (1998), 697-702. Dual models of aging are reported in fruit fly females, Science 281 (1998), 996-9. A paper on development of porcine embryos in vitro is Biology of Reproduction 59 (1998), 451-5.

In general on the future of transgenic animal research, GEN (15 Oct. 1998), 20, 44. A series of papers on sustainable animal production systems in India is Indian J. Animal Sciences 68 (August 1998), 701-850+. Feeding cattle hay just before they are killed may reduce the presence of harmful bacteria in their digestive systems reducing risks to humans, NS (19 Sept. 1998), 13. Widespread use of new assays based on transgenic animals could significantly cut the time and cost of testing new pharmaceuticals for carcinogens, NatBio16 (1998), 902.

A letter from Ian Wilmut on quiescence in nuclear transfer is in Science 281 (1998), 1611. Cloning improvements are suggested, NatBio16 (1998), 809. Researchers at Texas A&M have been promised an anonymous donation of US$2.3 million to clone Missy, the donor's dog! Nature 395 (1998), 8. For news of the dog cloning project <www.missyplicity.com>. The Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF; Tokyo) has started investigating the seemingly high death rate of calves cloned from somatic cells of adult cows. Since the birth of twin calves cloned by researchers from Kinki University (Osaka, Japan) and Ishikawa Prefectural Livestock Research Centre (Ishikawa Prefecture, Japan) (NatBio 16 (1998), 703), 15 cloned calves have been born, one of which was dead at birth and seven of which died from respiratory complications within three days of birth. With another cows currently pregnant with adult somatic cell clones, MAFF is becoming involved because of the high public interest in cloning, NatBio16 (1998), 992.

Stable clones of neural stem cells (NSCs) have been isolated from the human fetal telencephalon, Flax, JD. et al. "Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes", NatBio16 (1998), 1033-1039, 1007-8. Chimeric brains have been generated by intraventricular transplantation of fetal human brain cells into embryonic rats NatBio16 (1998), 1040-1044. Functional gene transfer from intracellular bacteria to mammalian cells is reported in NatBio16 (1998), 862-6. Gene transfer into mouse muscle by electroporation in vivo is reported in NatBio16 (1998), 867-70, 818.

A paper using bovine cumulus and oviductal epithelial cells as nuclear donors is Kato, Y. et al. "Eight calves cloned from somatic cells of a single adult", Science 282 (1998), 2095-8, 1975-6. Transgenic cattle have been produced by reverse-transcribed gene transfer in oocytes, PNAS 95 (1998), 14028-33; Science 282 (1998), 1619-20. There are concerns still about why many cloned animals die young, NS (2 Jan. 1999), 4, 28-9. A book on genetics of the pig is Rothschild, MF. & Ruvinsky, A. The Genetics of the Pig (CAB International 1998). Many animals that are bred for domestic use have lost the ability to survive in nature, NS (2 Jan. 1999), 40-1. Convictions for smuggling unapproved animal drugs into the USA have been upheld, FDA Consumer (Nov 1998), 32-3. There is evidence of dairy farming 2300 years ago in Britain, NS (28 Nov. 1998), 25. A paper on the production of pharmaceuticals in animals is Biotechnology & Development Monitor 36 (Sept/Dec 1998), 19-22. Japan is developing guidelines to look at the safety of such drugs, NatMed 4 (1998), 1213.

Zebrafish models include: hepatoerythropoietic porphyria, NatGen 20 (1998), 239-43; congenital sideroblastic anaemia, NatGen 20 (1998), 244-50. Transgenic rabbits overexpressing growth hormone develop acromegaly and diabetes mellitus, FASEB J. 12 (1998), 1455-60. A primate model of Parkinson disease is studied in NatMed 4 (1998), 1308-12. A rabbit model of human hemolytic disease can be induced in the rabbit neonate, AJO&G 179 (1998), 1353-8.

The Roslin Institute is developing nuclear transfer technology with a company Roslin Bio-Med, GEN (15 Feb. 1999), 1, 17, 28. A review is Wilmut, I. "Cloning for medicine", SA (Dec. 1998), 58-63. Australia is likely to establish a non-human primate center for medical research including support for cloning research, which otherwise will only be within guidelines on human embryo research, NatMed 5 (1999), 133. The use of embryonic stem cells to produce medicines and other substances is reviewed in Science 283 (1999), 1468-70. The high mortality of cloned animals is discussed in Down to Earth (18 Feb. 1999), 15. A letter on confirming clones are really from adult donor nuclei is Nature 396 (1998), 19; also see Science 283 (1999), 487-8. Goats have been cloned, Baguisi, A. et al. "Production of goats by somatic cell nuclear transfer", NatBio 17 (1999), 456-461; 405.

A letter on animal domestication is Science 283 (1999), 329-30. Genetics can be used to modify insects so that they are not disease vectors or aid agriculture, SA (Dec. 1998), 90-5. A further paper on bioreactors is John, DCA. et al. "Expression of an engineered form of recombinant procollagen in mouse milk" , NatBio 17 (1999), 385 - 389; Jost, B. et al. "Production of low-lactose milk by ectopic expression of intestinal lactase in the mouse mammary gland" , NatBio 17 (1999), 160-164, 135-6.

Male mice have been cloned from adult tail tip cells, NatGen 22 (1999), 127-8. The possible affects of short telomerases in cloned sheep is discussed in GEN 19 (15 June 1999), 6. A hybrid cloned panda embryo has been made by inserting the nucleus into rabbit eggs, Nature 400 (1999), 10. They are trying to implant the embryo into a foster mother of a black bear to see if cloned pandas can come. California has created a research centre for transgenics on large animals, Nature 400 (1999), 806.

The 1997 annual report of the Committee for Animal Biotechnology in the Netherlands is available (Contact: Prof. E. Schroten, Commissie Biotechnologie bij Dieren, Heidelberglaan 2, Postbus 8359, 3503 RJ Utrecht, Netherlands, 15pp. +16pp. Translation of the law). A report in Dutch is Visser, T. & Verhoog, H., De Aard van het Beestje. Onderzoek naar de morele relevantie van "natuurlijkheid" in discussies over biotechnologie bij dieren (NOW Ethiek & Beleid, 1999, 123pp, ISBN 90-70608-58-8). A study on how mice interact with the environment is Crabbe, JC. Et al. "Genetics of mouse behavior: Interactions with laboratory environment", Science 284 (1999), 1670-2, 1599-600. Variation in environment may alter results of bahavioural tests that were thought to be genetically determined.

Pig growth can be enhanced by growth hormone gene transfer at the somatic level, NS (18 Dec. 1999), 22. The maternal contribution to fertility in cattle is reported from field trials in New Zealand in Animal Reproduction Science 57 (1999), 127-40. Ectopic gene expression in anthropods using Sindhis viral vectors is reported in Current Biology 9 (1999), 1279-87. A universal marker for transgenic insects is reported in Nature 402 (1999), 370. Neurodegeneration in Drosophila can be suppressed by HSP70, Nature Genetics 23 (1999), 425-8. Gene transfer is discussed in Toshiki, T. et a. "Germline transformation of the silkworm Bombyx mori L. using a piggyBac transposon-derived vector", Nature Biotechnology 18 (2000), 81-4. MRI scanners for small animals have been made, Science 286 (1999), 2261-2.

On 24 January, 2000 Japanese scientists at Kagoshima Prefectural Cattle Breeding Development Institute announced the birth of a recloned cow, that resulted from nuclear transfer from the ear cell of a 3 month old cloned cow (CNN 25 Jan. 2000). Cloned calves have been produced from adult fibroblast cells after long-term culture, PNAS 97 (2000), 990-5; BMJ 320 (2000), 136. Nuclear cloning from ES cells in mice is reported in NatGen 24 (2000), 109-10. A review on the future of cloning is Nature 402 (1999), 743-6. A book review of Wilmut, I. et al. The Second Creation: The Age of Biological Control by the Scientists that Cloned Dolly (Headline 2000, 362pp.) is Nature 403 (2000), 479-80. A Workshop on Natural, Scientific, Legal, Ethical, Economic and Social Aspects of Animal Cloning was conducted at the European Academy for Environment and Economy, University of Lüneburg, Germany, 28-30 January, 2000. Contact Prof. Dr. Jürgen Simon for details. The proceedings will be available later.

Genetic engineering of Xenopus and germ-line transmission is reported in NatGen 24 (2000), 11. A review of Drosophila in cancer research is TIG 16 (2000), 33-9. A review of insect walking and biorobotics is BioScience 50 (2000), 23-33. Genomic interval engineering of mice has produced a modulator of triglyceride production, PNAS 97 (2000), 1137-42. On gene targeting in animals other than mice, PNAS 97 (2000), 956-7.

PPL Therapeutics has reported success in the cloning of piglets, NatBio 18 (2000), 365; GEN 20 (1 April 2000), 20, 46; Splice 6 (March 2000), 16; Time (27 March 2000), 43. Direct cloning of mice from ES cells is reported, NatBio 18 (2000), 135; PNAS 96 (1999), 14984-9. Deciding animal breeding goals for sustainable production is discussed in J. Animal Science 78 (2000), 570-82. A review is Bulfield, G. "Farm animal biotechnology", TIBTECH 18 (2000), 10-13. Genetic imprinting and breeding is discussed in NS (15 April 2000), 8. Book reviews of Wilmut, I. Et al. The Second Creation: Dolly and the Age of Biological Cloning (Farrar Straus & Giroux 2000, ISBN 0374141231) are in NS (18 March 2000), 50; Science 287 (2000), 1404-5; Nature Genetics 24 (2000), 347; Lancet 355 (2000), 661. The cloning of pets is still available to the rich and sentimental (if successful), NS (15 April 2000), 33; NatBio 18 (2000), 366.

Genetically modified anopheline mosquitoes that carry malaria have been made, which opens possibilities for malaria control, Lancet 355 (2000), 2225. Gene targeting in Drosophila is discussed in Nature 405 (2000), 896-7. Drosophila p53 is a structural and functional homolog of human tumor suppressor p53, Cell 101 (2000), 91-101.

Long life flies are reported by a gene that may mimic caloric restriction in Rogina, B. et al. “Extended life-span conferred by cotransporter gene mutations in Drosophila”, Science 290 (2000), 2137-40, 2048. Research on Drosophila may aid efforts to enhance human memory, JAMA 284 (2000), 2857-8. Aquaculture is expected to overtake cattle as the largest animal protein source, with an annual growth rate in the 1990s of 11%, Animal Pharm< 456 (3 Nov. 2000), 14. On average 2kg of grain give 1 kg of fish meat, compared to 7kg of grain for cattle. A critique of aquaculture in developing countries is Nature 408 (2000), 514.

The paper reporting GM monkeys is Chan, AWS. Et al. "Transgenic monkeys produced by retroviral gene transfer into mature oocytes", Science 291 (2001), 226, 309-12; NatBio 19 (2001), 99; NS (20 Jan. 2001), 3, 6. Technology has developed a sorting procedure for embryos, Furlong, EEM. Et al. "Automated sorting of live transgenic embryos", NatBio 19 (2001), 153-6. A growth hormone transgene has been found that boosts the size of wild fish but not domesticated trout, Nature 409 (2001), 781-2.

The future for genetically modified pets looks likely to expand, NS (14 July 2001), 10-1. The world's first cloned dairy herd of 18 cows is now producing milk at the farms of Infigen Inc., AgraFood Biotech. 59 (10 July 2001), 2-3. Animal cloning experiments are banned in Italy, NatMed. 7 (2001), 753. The USDA considered whether to regulate cloned animals, but probably will not require regulations, although the question of FDA regulation for food is not yet decided, AgBiotech Reporter (July 2001), 6. The nuclear transfer protocol affects messenger RNA expression patterns in cloned bovine blastocysts, Biology of Reproduction 65 (2001), 309-17. Epigenetic instability has been noted in ES cells and cloned mice, Science 293 (2001), 95-7. An evaluation of the gestational deficiencies in cloned sheep fetuses and placentae is in Biology of Reproduction 65 (2001), 23-30. DNA allografts are being used to keep track of cows, NS (21 July 2001), 19. However these may not be useful for distinguishing clones. A call for trout cDNA clones by the USDA has been made, AgBiotech Reporter (July 2001), 11.

Discussion of whether transgenic fish will be of much benefit over their risks is Science 298 (2002), 1715. A New Zealand company, Boviquest has discovered a cow milk production gene, APBN 8 (2002), 867-8.

The euthanasia of Dolly at age 6 years is discussed in AIBA Newslink 6 (April 2003), 5-6; Lancet 361 (2003), 711; NS (22 Feb. 2003), 5; Nature 421 (2003), 776. The stuffed Dolly skin is in the National museum of Scotland, Nature 422 (2003), 654. A rare bovine from Java called a banteng has been cloned, Science 300 (2003), 421. There may be fundamental chromosomal problems in cloning primates, Science 300 (2003), 225-6. Cloned cats can vary in physical and behavioural traits, SA (April 2003), 14; NatBio 20 (2002), 328. On variation in clones, NS (26 April 2003), 5; NatBio 20 (2002), 455-9. Health problems are discussed in NatBio 20 (2002), 13-4, 35. Cloning of zebrafish is reported in NatBio 20 (2002), 785-7, 795-9. On epigenetics and nuclear transfer, Lancet 361 (2003), 1243. A naturally occurring crayfish that can clone itself, reproducing parthenogenetically has appeared in Germany, NS (22 Feb. 2003), 8.

Human therapeutic proteins can be produced in silkworms, NatBio 21 (2003), 34-5, 52-6. Production of stronger silk is possible, NatBio 20 (2002), 989. Producing factor IX in mice is reported in NatBio 20 (2002), 1124-8; and on lactoferrin in transgenic cows, NatBio 20 (2002), 484-7. Cloned cattle carrying an artificial chromosome for human immunoglobulin genes are one way to make antibodies, NatBio 20 (2002), 881-3, 889-94. US regulation of transgenic animals is discussed in NatBio 20 (2002), 959.

There is a ban on cloned horses competing in races but it may not last long, NS (7 June 2003), 5. A report on death of Dolly is NatBio 21 (2003), 349. A cloned mule has been made, Science 300 (2003), 1354. A review of cloning and animal production is FDA Consumer (May 2003), 28-33. A series of papers on electroporation techniques are in Differentiation 70 (2002), 131-80. On animal transgenesis, GEN 23 (1 June 2003), 40-41. Fluorescent GM fish are being sold in Taiwan, Science 300 (2003), 1368. The chicken genome may be completed in draft in March 2004, Science 300 (2003), 1669.

The company that helped to make Dolly, PPL Therapeutics, may collapse following the failure to develop clinical trials of therapeutic AAT protein in their milk, Nature 423 (2003), 907; Science 300 (2003), 2015-6. They have 4000 sheep in New Zealand making On biopharming, NatBio 21 (2003), 480-1. Making drugs in eggs is reviewed in Science 300 (2003), 729-30.

Advances in mammalian cloning are discussed in GEN 23 (1 April 2003), 17-8, 68; Reproduction 126 (2003), 1-11. A mule can now reproduce, thanks to cloning, Woods, GL. Et al. "A mule cloned from fetal cells by nuclear transfer", Science 301 (2003), 1063. A review is Gurdon, JB & Byrne, JA, "The first half-century of nuclear transplantation", PNAS 100 (2003), 8048-52. A cloned horse foal could be born from its cloned surrogate horse, Nature 424 (2003), 635. A new method for introducing transgenes in sperm is discussed in Nature 424 (2003), 604. On the cow genome project, Nature 424 (2003), 606.

The genome sequence of rat has been published making further studies of genetics and disease possible, Science 303 (2004), 455-9; Nature 428 (2004), 464-6, 475-6. On rodent models of hypertension, J. Physiology 554 (2004), 56-63. In general on genetics of complex traits in animals, Nature Reviews Genetics 5 (2004), 202-12. Artificial insemination in beef cattle and fertility is discussed in J. Animal Science 82 (2004), 987-93. Animal models of hypertension are discussed in TIG 20 (2004), 136-45.

Fluorescent enhancement of signaling in mantis shrimp is reported in Science 303 (2004), 51. A description of the Drosophila genome and a stock center for genetic variant flies is in NatGen 36 (2004), 205, 207, 209, 211-2, 283-7, 288-92.

Social risks of animal cloning are discussed in Law and the Human Genome Review 19 (July 2003), 231-8. Use of GM fish as vaccines is discussed in APBN 8 (2004), 374-5. Variation in omega-3 fatty acid metabolism can alter animal fat content, APBN 8 (2004), 376-7.

Isolation of pancreatic precursor cells from mice have been reported, NatBio 22 (2004), 1115+. The expression of a single gene, vasopressin V1a receptor in moles has enhanced partner preference in a promiscuous species, Nature 429 (2004), 754-6; Nature Reviews – Genetics 5 (2004), 560. Serial targeting of cow genes is reported in NatGen 36 (2004), 671-2; and on transgenic livestock, TIBTECH 22 (2004), 157-60. A fatherless mouse has been made, NatMed. 10 (2004), 559. The kangaroo genome will be sequenced, following the opossum genome completed last year, Nature 429 (2004), 692. Domestic donkeys were bred from wild African asses, NS (26 June 2004), 14, Trout born from surrogate salmon fathers have been born, NS (7 Aug. 2004), 11.

Serial bull cloning by somatic cell nuclear transfer is reported in NatBio 22 (2004), 693-4. Fertile rats were cloned by regulating oocyte activation, Science 302 (2003), 1179. The genetic structure of purebred domestic dog is constructed in  Science 304 (2004), 1160-4. Horse cloning research is progressing, NS (15 May 2004), 9. Only a few males have contributed genes to domestic horses, NatGen 36 (2004), 335-8. A review of cloning in different animals is TIBTECH 21 (2003), 471-3. A hyperactive antifreeze protein in fish is described in Nature 428 (2004), 153. Mice with parents of the same sex make us consider whether the same will be applied humans, NS (24 April 2004), 8-9;  Science 304 (2004), 501, 507-8. Testis transplant culture in cows is reported in Biology of Reproduction 70 (2004), 625-31. Cows were born from sperm frozen for 40 years in Kyoto, Japan Times (24 April 2004), 2. Cross species mixes are discussed in Science 302 (2003), 1154-5.

A zebrafish model of aortic coarctation is discussed in NatBio 22 (2004), 595-9. Transgenic zebrafish can be made by retroviral infection of in vitro-cultured sperm, PNAS 101 (2004), 1263-7. Gene-centromere distances in salmon are reported in Genetica 121 (2004), 1-11. Transgene driven expression of the Doppel protein in Purkinje cells causes cell degeneration and motor impairment, PNAS 101 (2004), 3644-9. Comparison of the sec chromosome genes ZFX and ZFY in bovine, porcine and equine cells is reported in Genome 47 (2004), 74-83.

A review of recent transgenic mice that are commercially sold is in GEN (1 Nov 1993), 1, 10-1. It also talks about the international repository at Jackson Laboratory in Bar Habor, Maine, reported earlier in 1993. A review on recent experimental models of human carcinogenesis is in Nature Genetics 5 (1993), 207-8; and it describes how mice with deficiencies in a DNA repair gene have elevated levels of p53 and die very young, J. McWhir et al. "Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning", Nature Genetics 5 (1993), 217-24. Another paper argues that p53 deficient mice may be useful for some in vivo carcinogenesis assays, M. Harvey et al., "Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice", Nature Genetics 5 (1993), 225-9.

A general review of chimeric mice, and in particular their use in studying the development of the intestine is PNAS 90 (1993), 8866-70, 8871-5. Other models include: mice that produce human hybrid immunoglobulin, Science 262 (1993), 1212-3, 1271-4; a model of malignant skin melanoma, PNAS 90 (1993), 8817-21; IL-2 deficient mice that suggest IL-2 is not so important in immune response as suggested by in vitro studies, Science 262 (1993), 1059-61; IL-4 deficient mice are resistant to murine AIDS, Science 262 (1993), 240-2; Mice with altered spatial learning, Science 262 (1993), 760-3; studies looking at genes that can prevent diabetes in non-obese diabetic mouse models are, Nature 366 (1993), 16-7, 69-72 72-3; PNAS 90 (1993), 9566-70; and on mice with altered brown fat deposits and their role in obesity research, Nature 366 (1993), 720-1, 740-2; and a variety of papers are in Cell 75 (2 Oct 1993), 203-282.

A book review of M. Hooper, Embryonal Stem Cells: Introducing Planned Changes into the Animal Germ Line, (Langhorne, Penn: Haywood Academic Publishers, 1993), 147pp., US$58, is in Cell 76 (1994), 5-7. Recently reported genetically engineered mice lines include: A mouse that has central nervous system damage by expression of a HIV protein, Nature 367 (1994), 188-90; an inactivated neural cell adhesion molecule gene results in reduced size of olfactory bulb and deficits in spatial learning, Nature 367 (1994), 455-9; mice expressing gamma interferon in the liver get chronic active hepatitis, PNAS 91 (1994),, 614-8. A commercially available genetically engineered mice that expresses the human plasma enzyme, cholesterol ester transfer protein, which may accelerate heart disease, is reported in GEN (1 Jan 1994), 31.

Studies of transgenic mice for human disease include: deficiencies in the homeobox gene Msx1 cause palate, craniofacial and tooth development abnormalities; Nature Genetics 6 (1994), 348-56; a model for Menkes disease; Nature Genetics 6 (1994), 369-73, 374-8; epilepsy in mice was found to be associated with a defect in the ceruloplasmin gene, Nature Genetics 6 (1994), 426-31; sensory and sympathetic neuropathies due to a disrupted Trk/NGF gene, Nature 368 (1994), 246-8; sensory defects with a lack of neurotrophic factor, Nature 368 (1994), 147-50; various physiological changes result from lose of plasminogen activator gene, Nature 368 (1994), 419-24; altered muscle growth and movements from disrupted neurotrophin 3 receptor gene, Nature 368 (1994), 249-51; altered spleen development from changing the homeobox gene Hox11 suggests that this gene controls the genesis of the whole spleen, one gene one organ?, Nature 368 (1994), 747-9. The loss of endothelin 1 gene expression results in abnormalities the prevent mice breathing, as well as altered embryonic development, Nature 368 (1994), 703-10, 693-4. A general review is J. Breslow, "lipoproteins and heart disease. Transgenic mice models are helping in the search for new therapies", Biotechnology 12 (1994), 365-70.

Transgenic mouse models and genetic engineering experiments include: C.A. Milano et al., "Enhanced myocardial function in transgenic mice overexpressing the §2-adrenegic receptor", Science 264 (1994), 582-6, which is a mouse model for gene therapy to overcome chronic heart failure; T.E. Willnow et al., "Inhibition of hepatic chlyomicron remnant uptake by gene transfer of a receptor antagonist", Science 264 (1994), 1471-4, which suggests both LDL receptor and lipoprotein receptor-related protein are involved in clearance of remnants of chylomicrons, the carriers of dietary cholesterol; and a similar study supporting a role for apoE binding to two proteins including LDL receptor is S. Ishibashi et al., "The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins", PNAS 91 (1994),, 4431-5. Mice lacking type IX collagen develop noninflammatory degenerative joint disease, PNAS 91 (1994),, 5070-4. A mutation in the ryanodine receptor gene that is thought to be a calcium channel for release of calcium from the sarcoplasmic reticulum in muscle that prevents muscle action, and causes early death is described in Nature 369 (1994), 556-8. A study of the role of cyclin in breast cancer is in Nature 369 (1994), 669-71; a role for perforin in the immune system has been shown in D. Kagi et al., "Cytotoxicity mediated by T-cells and natural killer cell is greatly impaired in perforin-deficient mice", Science 369: 31-7; a review is J.C. Crabbe et al., "Genetic animal models of alcohol and drug abuse", Science 264 (1994), 1715-23; J.S. Takahashi et al., "Forward and reverse genetic approaches to behavior in the mouse", Science 264 (1994), 1724-33. The mutagenesis and mapping of a mouse gene, clock, which is essential for circadian behaviour is reported in Science 264 (1994), 719-25; New Scientist (7 May 1994), 15; mice lacking neurotrophin-3 show severe sensory and sympathetic defects, Nature 369 (1994), 658-61; studies on cellular and scrapie prion interaction are in PNAS 91 (1994),, 5690-4; and on spastic mice, Nature Genetics 7 (1994), 136-41.

A mouse model of ALS -amyotophic lateral sclerosis, Lou Gehrig disease, has been reported in M.E. Gurney et al., "Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation", Science 264 (1994), 1772-75; 1663-4.

The use of retinoic acid to induce limb and lower body duplications in mice is described in PNAS 91 (1994),, 5436-40. Specific changes were induced in embryos before gastrulation of the embryo, suggesting that some aspects of pattern formation of limbs and lower body occur before then.

Transgenic mice studies on the interaction between p53 and the retinoblastoma tumour suppressor gene (Rb) are S.D. Morgenbesser et al., "p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens", Nature 371 (1994), 72-7, 21-22. The model produced allows understanding of the effects of both these tumour suppressor genes, which are frequently mutated in human cancer. Cooperative effects between these genes are reported in mice in Nature Genetics 7 (1994), 480-90. A model for radiation studies is suggested in C.J. Kemp et al., "p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis", Nature Genetics 8 (1994), 66-9. Calorie restriction has been found to delay tumorigenesis in p53-knockout transgenic mice, PNAS 91 (1994),, 7036-40. A study on gene dosage with PAX6 genes in mice is Nature Genetics 7 (1994), 463-71.

Other transgenic mice studies include: alpha-lactalbumin-deficient mice show its role in milk production, and may be useful to develop further "bioreactors", PNAS 91 (1994),, 6544-8; beta-casein deficient mice show beta-casein appears to be nonessential, PNAS 91 (1994),, 6138-42; fertility of mice without the c-mos gene is reduced, and parthenogenetic development begins, Nature 370 (1994), 20-1, 65-71; active anaphylaxis (a hypersensitivity reaction) is found in IgE-deficient mice, Nature 370 (1994), 367-70; on apolipoprotein(a) mice, Nature 370 (1994), 460-2; on hox gene mutations, Nature 370 (1994), 304-7; and on superoxide dismutase mutations, Science 264 (1994), 1772-5.

A description of the newest method of making knockout mice is Science 265 (1994), 26-8, 103+. Genetic models of hypertension are discussed in Lancet 344 (1994), 167-8. Maternal rescue of a fetal gene deficiency is reported in J.J. Letterio et al., "Maternal rescue of transforming growth factor-b1 null mice", Science 264 (1994), 1936-8. Homeobox genes in Drosophila are reviewed in Cell 78 (1994), 181-9; Science 265 (1994), 44-5; and on general fly studies, Science 264 (1994), 1702-13; and Hox genes in vertebrates in Cell 78 (1994), 191-201. A short review of studies on the neurology of the nematode, Caenohabditis elegans is Science 264 (1994), 1698-9.

A series of review papers on mouse models are in Science 264 (1994), 1715-33, 1690-3. A mouse model for amyotrophic lateral sclerosis (ALS) is reported in Science 264 (1994), 1663-4. A gene therapy model is J.S. Khillan et al., "Partial rescue of a lethal phenotype of fragile bones in transgenic mice with a chimeric antisense gene directed against a mutated collagen gene", PNAS 91 (1994),, 6298-302. The use of zebrafish as a model is enhanced by the paper, S. Lin et al., "Integration and germ-line transmission of a pseudotyped retroviral vector in Zebrafish", Science 265 (1994), 666-9.

Examples of transgenic mice studies include: Mice without collagen X appear to be normal, with normal long bone growth, Nature Genetics 8 (1994), 129-35. Mice lacking transcription factor GATA-2 have a hemopoietic defect, Nature 371 (1994), 221-6; the Ikaros gene is required for all lymphoid cells, Cell 79 (1994), 143-56; insulin-promoter factor 1 is required for pancreas development, Nature 371 (1994), 606-9; immunodeficient anti-myelin basic protein T cell receptor mice have a high incidence of spontaneous autoimmune encephalomyelitis, Cell 78 (1994), 399-408; Valera, A. et al. "Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus", PNAS 91 (1994),, 9151-4. A review of homeosis research is TIG 10 (1994), 341-43. Treatment of mice models of motor neuron disease with two proteins, ciliary neutropic factor and brain-derived neurotrophic factor, stopped the disease, Mitsumoto, H. et al., "Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF", Science 265 (1994), 1107+.

A mouse model for Alzheimer's disease (in fact 3 types) has been described, Nature Genetics 9 (1995), 21-30; and one for Tay- Sachs disease, Yamanaka, S. et al. "targeted disruption of the Hexa gene results in mice with biochemical and pathological features of Tay-Sachs disease", PNAS 91 (1994),, 9975-9; Science 266 (1994), 968-9. Two mouse studies for development of a therapy for Duchenne muscular dystrophy is in Cox, G.A. et al. "Dp71 can restore the dystrophin-associated glycoprotein complex in muscle but fails to prevent dystrophy", Nature Genetics 8 (1994), 333-9; Greenburg, D.S. et al. "Exogeneous Dp71 restores the elevates of dystrophin associated proteins but does not alleviate muscle damage in mdx mice", Nature Genetics 8 (1994), 340-4, 311-2. Mice made without vimentin, one of the components of intermediate filaments, appear to be quite normal, Cell 79 (1994), 679-74.

Other transgenic mouse models have been reported for: Alpha- 1-antitrypsin related liver disease, Ann. Hum. Genetics 58: 305- 20; amylotrophic lateral sclerosis, NEJM 331 (1994), 1091-2; Science 266: 1586-7; Waardenburg Syndrome type 2, Nature Genetics 8 (1994), 256-63. depressed mice, Cell 79 (1994), 377-88; aggressive mice, Science 266 (1994), 291-4; slow-learning mice, Cell 79 (1994), 365-75; modified dopamine receptors, Cell 79 (1994), 729-42; insulin studies, Nature 372 (1995), 182-6, 186-90, 128-9; mice lacking estrogen receptors, Science 266 (1994), 1524-7; metabotropic glutamate receptor 1 deficient mice have motor deficits, Nature 372 (1995), 237-43; mice that have a receptor for an avian virus, which can be used for genetically engineering, Federspeil, M.J. et al. "A system for tissue-specific gene targeting: Transgenic mice susceptible to subgroup A avian leukosis virus-based retroviral vectors", PNAS 91 (1994),, 11241-5; models of prion disease, PNAS 91 (1994),, 9936-40. An immune deficiency gene of the nude locus of mice has been shown to be a member of the Drosophila winged-helix proteins, which cause homeotic transformations, Nature 372 (1995), 103-5. A review of limb development and genes is Science 266 (1994), 575-6 (and many other papers in that issue are on developmental genetics which has been developed by transgenic animal studies).

A series of mice studies on the sex-determining gene(s) are reported in Nature 372 (1994), 525-30; Cell 79 (1994), 1111-20; Science 266 (1994), 1494-500; Nature Genetics 9 (1995), 1-2, 15-20. Although the SRY (sex-determining region, Y chromosome) 14kb region can make a female mouse a male (except for spermatogenesis), other SOX (SRY-type HMG box) genes can have strong effect, and a double dose of a 160kb region on Xp21 can make a male a female.

A study in which bone marrow from normal mice was transferred into ApoE deficient mice which prevented diet-induced atherosclerosis is Linton, M.F. et al. "Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation", Science 267 (1995), 1034-7. The transfer of a gene for human prion protein PrP can rescue mice that lack it, providing an assay for study of the 18 human prion gene mutations found, Nature Genetics 9 (1995), 197+.

A report on the development of varieties of the green fluorescent protein as a marker gene from jellyfish that could be used as a fluorescent signal of gene expression is New Scientist (4 March, 1995), 23. A bladder-specific promoter from the uroplakin II gene that can help express foreign genes that are transferred is described in Lin, J.-H. et al. "A tissue-specific promoter that can drive a foreign gene to express in the suprabasal urothelial cells of transgenic mice", PNAS 92 (1995), 679-83.

A transgenic mouse model for study of Alzheimer's disease is discussed in GEN (1 March 1995), 1, 3, 31. Behavioural genetic models include: Tecott, L.H. et al. "Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors", Nature 374 (1995), 542-6; Picciotto, M.R. et al. "Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain", Nature 374 (1995), 65-7; altered nerve cell junctions with laminin deficiency, Nature 374 (1995), 258-62. Other mutation studies include, sexually dimorphic sterility phenotypes, Nature 374 (1995), 460-3; altered heart signals through overexpression of b2-adrenoceptor, Nature 374 (1995), 272-6, 214-5; head organisation gene, Lim1, Nature 374 (1995), 425-30; activin deficiency and skeletal and facial abnormalities, Nature 374 (1995), 356-9; follistatin-deficient mice, die within a few hours of birth, Nature 374 (1995), 360-3; limb polarity control, Nature 374 (1995), 350-3; Cell 80 (1995), 671-4. There is growing news from mouse genetics studies and the Mouse Newsletter has changed title to Mouse Genome from this year (Oxford University Press, quarterly, US$75 overseas).

A method to disrupt and restore lactation is possible following Stacey, A. et al. "Lactation is disrupted by alpha-lactalbumen deficiency and can be restored by human alpha-lactalbumen gene replacement in mice", PNAS 92 (1995), 2835-9.

A general review of transgenic mice studies is Cripp, A.J. "Death before birth: clues from gene knockouts and mutations", TIG 11 (1995), 87-93; Nature Medicine 1 (1995), 215-7; and general comments are in Nature 375 (1995), 543. A discussion of the animal model of Alzheimer's disease is NEJM 332 (1995), 1512-3. A model looking at genetic affects on alcohol tolerance is Harris, R.A. et al. "Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioural actions of ethanol and latered function of gamma-aminobutyrate type A receptors", PNAS 92 (1995), 3658-62. Also on brain study, deficits from changing the expression of BDNF or NT4 are reported in Nature 375 (1995), 235-8, 238-41.

Mice lacking p53 tumour suppressor gene are predisposed to cancer, but a subset appears to be useful as models for a type of neural tube defect, exencephaly, Nature Genetics 10 (1995), 175-80. A knockout for BRCA1 is reported in Nature 375 (1995), 541-3. Mice deficient for the G-protein subunit alpha-12 are found to have retarded growth and deficient thymocyte maturation and function, and may be models of ulcerative colitis and adenocarcinoma of the colon, Nature Genetics 10 (1995), 143-50. A mouse model of hemophilia A was made by targetted disruption of the mouse factor VIII gene, Nature Genetics 10 (1995), 119-21.

Other mouse models include: b-amyloid deficient mice, Cell 80 (1995),525-31; nitric oxide synthase alters immune response, Nature 375 (1995),408-11; bcl-2 knockouts, Science 267 (1995), 1506-10; luteinizing hormone knockout leads to infertility, PNAS 92 (1995),1322-6; a dioxin receptor knock out, Science 268 (1995), 638-9; a thalassemia study, Nature 375 (1995),318-22; models for homocysteinemia, PNAS 92 (1995), 1585-9; prostrate cancer, PNAS 92 (1995),3439-43; amylotrophic lateral sclerosis, Nature 375 (1995),61-4; for hepatitis B, PNAS 92 (1995),1470-4; and a model for Helicobacter pylori infection, that is associated with ulcers, Science 267 (1995), 1655-8. Studies on obesity and insulin processing are discussed in Nature 375 (1995), 433-4; see section on genetic disease markers. Imprinting can be disrupted by deletion of the H19 gene region of mice, suggesting some causative factor, Nature 375 (1995), 34-9.

Transgenic mice models include: Generation of a cystic fibrosis deltaF508 mutated mouse model, Nature Genetics 10 (1995), 445-52. Mice with ADA deficiency show quite different symptoms to humans, dying prenatally; Nature Genetics 10 (1995), 279-87. Some fatal genetic omissions include, NF-kB, Nature 376 (1995), 167-70; and the Huntington's disease gene, Cell 81 (1995), 811-23; Science 269 (1995), 407-11; EGF receptor, Science 269 (1995), 230-4, 234-8; Nature 376 (1995), 337-41. Mice lacking hoxa-11 and hoxd-11 lack the radius and ulna, Nature 376 (1995), 791-5. CaMKII mutant mice have impaired spatial but not contextual memory, Cell 81 (1995), 905-15. Age-related learning difficulties come from expression of the human b-amyloid precursor protein (associated with Alzheimer's) in mice, PNAS 92 (1995), 5341-5. A gene linked to aggression is seen in Cases, O. et al. "Aggressive behaviour and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA", Science 268 (1995), 1763-6. Predisposition to cancer arises from inactivation of Msh2 gene, due to hyper-recombination, and DNA repair deficiencies, Cell 81 (1995), 321-30.

The strategy of adding genes as opposed to knockout of genes is being used in transgenic mice studies, Science 269 (1995), 636. An analysis of sperm quality in transgenic mice lines is J. Reproduction & Fertility 104 (1995), 347-54. A review of the effects of the agouti gene, which affects coat colour, is PNAS 92 (1995), 4721-4, 4728-32.

Studies in transgenic mice include: A model for Down's syndrome is reported in Reeves, R.H. et al. "A mouse model for Down syndrome exhibits learning and behaviour deficits", Nature Genetics 11 (1995), 177-84. Mouse models and breast cancer, CMAJ 153 (1995), 1123+; Use of IL-2 to treat cancer in a breast cancer model is reported in PNAS 92 (1995), 8522-6. On a general plasmid-based transgenic mouse model for mutations, Nature 377 (1995), 657-9; the protein peripheral myelin protein PMP22 has been shown to be required for correct development of peripheral nerves, Nature Genetics 11 (1995), 274-80: and mutations in the myelin recognition molecule protein zero (P0) have been reproduced in mice giving rise to models of inherited human neuropathies, Nature Genetics 11 (1995), 281-6; and a model for anxiety is Science 269 (1995), 1432-5; and on a model for the hyper-responsiveness of the airway in asthma, Nature Genetics 11 (1995), 150-4. Absence of DNA excision repair gene XPA increases susceptibility to UV-B and carcinogens, Nature 377 (1995), 162-5, 165-8, 169-73; p53 deletion rescues a lethal mutation of mdm2-deficient mice, suggesting the function of the mdm2 gene is negative regulation of p53, Nature 378 (1995), 203-6, 206-8.

A review of studies on the Weaver mouse is Nature Genetics 11 (1995), 107-9, 126-9. The gene for Huntingtin is found to be indispensable to mice, Nature Genetics 11 (1995), 155-63. A comparison of Tay-Sachs and Sandhoff disease models is Nature Genetics 11 (1995), 170-6. Mutation of GATA3 gene causes severe abnormalities in the nervous system, and liver, Nature Genetics 11 (1995), 40-44; Ras GTPase-activating protein deletion results in vascular system defects, Nature 377 (1995), 695-701; absence of angiotensin II type-2 receptor results in blood pressure and exploratory behaviour changes, Nature 377 (1995), 744-7, 748-50; absence of guanylyl cyclase-A receptor results in salt-resistant hypertension, Nature 378 (1995), 65-8; also on cardiac defects, Nature 377 (1995), 151-5; SCA1 transgenic mice are a model for neurodegeneration caused by CAG trinucleotide repeat expansion, Cell 82 (1995), 937-42; and mice defective in tissue non-specific alkaline phosphatase gene do not have skeletal abnormalities like humans, but have fatal seizures at about 2 weeks of life, Nature Genetics 11 (1995), 45-51; on Parkinson's disease models, Nature 377 (1995), 424+; Science 269 (1995), 856-7; and AIDS, PNAS 92 (1995), 8210-4; Science 270 (1995), 1819, 21. Genetic control of mating behaviour is reported in Nature 378 (1995), 59-62; An extreme form of spina bifida has been made in a double-mutant mouse, Nature Genetics 11 (1995), 60-3.

Human disease models in transgenic mice include: beta thalassaemia, PNAS 92 (1995), 9259-63; prostaglandin synthase 2 gene disruption causes renal pathology, Cell 83 (1995), 473-82; lacking the CNTF receptor causes mice to have motor neuron defects at birth, unlike mice lacking CNTF itself, Cell 83 (1995), 313-22. Inhibition of farnesyltransferase induces regression of carcinoma in ras mice, Nature Medicine 1 (1995), 792-7. A review of heart and lung disease in transgenic mice is Nature Medicine 1 (1995), 749-51; and of AIDS research models, TIBTECH 13 (1995), 142-50; and of tuberculosis for vaccine development, Trends in Microbiology 3 (1995), 418-24. Mice lacking the ErbB4 neuregulin receptor have abnormal neural and cardiac development, Nature 378 (1995), 390-4.

There is reported to be an increase in aggressive behaviour and excess sexual behaviour in mice lacking the NOS enzyme, Nelson, R.J. et al. "Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase", Nature 378 (1995), 383-6. Studies on tumor necrosis factor are in Cell 83 (1995), 793-802.

Transgenic mice studies include: Analysis of the mouse Snell's waltzer deafness gene finds that it encodes an unconventional myosin required for integrity of inner ear hair cells, Nature Genetics 11 (1995), 369-75; superoxide dismutase deletions cause lethality, Nature Genetics 11 (1995), 376-81; on the lessons from xeroderma pigmentosum mice, Lancet 347 (1996), 278-9; and endothelin gene links to disease, BMJ 312 (1996), 195-6; loss of type 1 inositol 1,4,5-triphosphate receptor results in symptoms like epileptic seizures, Nature 379 (1996), 168-71; on neurological disorders, Nature 379 (1996), 262-5; PNAS 92 (1995), 11294-8. Ets2 mutant mice have Down's syndrome-like skeletal abnormalities, Nature 379 (1996), 534-7. Lack of the dopamine transporter makes mice indifferent to cocaine, Nature 379 (1996), 606-12.

A review of transgenic animals is NEJM 334 (1996), 653-5. A discussion of the stock takeover of ABS Global in the IVF cattle company MasterCalf, is EBN 220 (1996), 3-4. ABS Global has 25% of the US market of bull semen, and interests in many other countries. A cynomolgus monkey model of TB is reported in Nature Medicine 2 (1996), 430-6.

A review of mice genetics progress and mice mutants is an editorial in Nature Genetics 12 (1996), 221; and on knockout mice, NEJM 334 (1996), 904-7; and on Internet resources, TIG 12 (1996), 117-8. A mouse model for ocular retardation is reported in Nature Genetics 12 (1996), 376-84; and for tubby mutation, Nature 380 (1996), 534-8. Mice lacking fibroblast growth factor receptor 3 have skeletal overgrowth and deafness, Nature Genetics 12 (1996), 390-7; and disrupting the plasminogen gene impairs wound healing, Nature Medicine 2 (1996), 287-9; and lacking a single vascular endothelial growth factor results in abnormal blood vessel development and lethality in embryos, Nature 380 (1996), 435-442.

Transgenic mice studies include: mice without neuropeptide Y, thought to regulate feeding, actually maintain normal body weight, Nature 381 (1996), 377-8, 415-8; mutated D3 dopamine receptor gene is associated with hyperactivity in mice, PNAS 93 (1996), 1945-9; mice lacking p27 have increased body size and various problems, Cell 85 (1996), 707-20; and male infertility results from HSP-70-2 disruption, PNAS 93 (1996), 3264-8. Overexpression of the human prefoil peptide pS2 results in increased resistance to intestinal damage in mice, PNAS 93 (1996), 2137-42. A mouse model of familial hypertrophic cardiomyopathy has been made, Science 272 (1996), 731-4; a review is Sandhu, JS et al. "The use of SCID mice in biotechnology and as a model for human disease", CRC Reviews in Biotechnology 16 (1996), 95-118; and another, Breslow, JL. "Mouse models of atherosclerosis", Science 272 (1996), 685-8.

A gene that alters the nurturing of mothers has been found, Brown, JR. et al. "A defect in nurturing in mice lacking the immediate early gene fosB", Cell 86 (1996), 297-309.

The mapping of genes that may be related to stroke has been performed in a rat model, Rubattu, S. et al. "Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease", Nature Genetics 13 (1996), 429-34. Lean mice result from disruption of the RII-beta subunit of protein kinase A, Nature 382 (1996), 622-6; a model of diabetes has been made, PNAS 93 (1996), 7283-8; and for ataxia telangiectasia, Cell 86 (1996), 159-71. Mutations in CREB reduce morphine abstinence in mice, Science 273 (1996), 657-9; and protection against atherogenesis can be effected by apolipoprotein A-IV, Science 273 (1996), 966-8.

An Internet database of ES cell knockout mouse mutants is on-line, TBASE, <http://www.gdb.org/Dan/tbase/tbase.html, which eliminates the need for the general mentioning of examples here. As of last year over 250 different mouse gene knockouts were reported, and there are over 1000 examples submitted to TBASE (see also Trends in Genetics updates), Nature Genetics 13 (1996), 251-2, 259-60.

One US company is planning to offer for sale mice with mutations in all human genes, and maybe 500,000 different knockout mice; NS (19 Oct 1996), 22. Transgenic mice are being promoted as a cheaper and faster cancer probe, EST 30 (1996), 383A. A new genetically engineered strain of mice that suffers both brain degeneration and memory deficits, and develops the same brain deposits of a protein called amyloid that are seen in human sufferers, should allow researchers to test the idea that the amyloid deposition actually causes the brain changes that leads to memory loss in Alzheimer's, Science 274 (1996), 177-8; Karen Hsiao, K et al. Correlative Memory Deficits, A Elevation, and Amyloid Plaques in Transgenic Mice", Science 274 (1996), 99-103.

A mechanism for sustained somatic gene inactivation by viral transfer of Cre recombinase is described in Nature Biotechnology 14 (1996), 1562-5, 1537. A correction of a muscular dystrophy mouse model is Tinsley, JM et al. "Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene", Nature 384 (1996), 340-2. The use of adenovirus to transfer genes into neuronal precursors of adult mouse brain has been described in PNAS 93 (1996), 11974-9; and the use of a cationic lipid to enhance plasmid delivery to 1% level in mouse lung is PNAS 93 (1996), 11454-9. The target for morphine action has been found to be the u-opioid-receptor gene, Nature 383 (1996), 819-23. A new target for therapy to prevent atherosclerosis has been found, lecithin: cholesterol acyltransferase, PNAS 93 (1996), 11448-53.

Over 1200 mutations have now been catalogued in mice, with a wide range of phenotypes, reviewed in TIG 12 (1996), 433-5. A review of rodent studies on the genetics of obesity is TIG 12 (1996), 441-3. The mouse homologue to the C. elegans cell death gene ced-3, is CPP32, and CPP32 deficient mice have decreased apoptosis in the brain but premature lethality, Nature 384 (1996), 368-72. On dwarf mice and aging, Nature 384 (1996), 33. Mice that lack coagulation factor V have fetal haemorrhage, Nature 384 (1996), 66-8. A mouse model for pregnancy-induced hypertension has been made in University of Tsukuba, Science 274 (1996), 922, 995+; and on one for arthritis, NS (14 Dec 1996), 16. Genome mutation studies are reviewed in GEN (15 Nov 1996), 1, 16, 19.

On ES cell lines and mice: The mechanism of action of serotonin 5-HT2C receptor in reducing obesity is the subject of much research. There are 14 subtypes of receptor, and they may affect the satisfaction with food, EBN 239 (1997), 3. If normal mice are treated with leptin they have early onset of reproductive function, Science 275 (1997), 88-90. On the agousti locus, Nature 385 (1997), 119-20, 165-8. On obesity Science 275 (1997), 751-3. A mouse model of Down syndrome that has developmental abnormalities and age-related neurodegeneration has been reported, PNAS 93 (1996), 13333-8. Other models include one of familial combined hyperlipidemia, Science 275 (1997), 391-4; on memory models, Science 275 (1997), 32-3; Silva AJ. et al. "A mouse model for the learning and memory deficits associated with neurofibromatosis type I", NatGen 15 (1997), 281-4. A homeobox mutation which alters cell cycle control is in Nature 385 (1997), 454-8. A series of papers on cell life and death models are in Cell 88 (1997), 287-366. Chromosomal deletion complexes in mice can be made by radiation of embryonic stem cells, NatGen 15 (1997), 285-8. Transgenics on the Internet are reviewed in NatBio 15 (1997), 289. A technical review of the microinjection of genes into mouse oocytes is, Molecular Biotechnology 6 (1996), 191-9.

A number of reports on cloning continue; BME 125 (1997), 3-4; GenEthics News 16 (Jan-Mar 1997), 1, 10; BMJ 314 (1997), 623; Lancet 349 (1997), 661. Scientists have been arguing for the benefits of the research which may be banned if broad measures are passed to stop cloning, Nature 386 (1997), 8-9, 431; Nature Biotechnology 15 (1997), 293; NS (8 March 1997), 4-5; Science 275 (1997), 1415. The claimed benefits include generation of somatic cells for example skin cells for grafts or bone marrow for people undergoing chemotherapy for cancer. The cloned animals are being supported as bioreactors for production of pharmaceuticals, GEN (15 March 1997), 1, 10. The homepage of the Roslin Institute includes some basic information and background. Researchers in Ruakara, New Zealand, have also reported cloning by nuclear transfer from embryonic cells, Otago Daily Times (17 March 1997), 27. China has reported cloning of pig, rabbits and a bull using embryonic cells. Research in Denmark and Australia is making cloned cows, EBN 241 (1997), 2. In Australia they plan to have commercial cloning of cows within 3-4 years.

The question of a right size for a mammal is discussed in Nature 386 (1997), 332-3; American Naturalist 149 (1997), 352-80. There is a wide range within mammals, for example mice or elephants. A discussion of genetic modification of mosquitoes to control disease is TIBTECH 14 (1996), 447-8; Nature 386 (1997), 538. Therapy for Huntington's disease may be aided by the results of Emerich, DF. et al. "Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease", Nature 386 (1997), 395-9.

A review of making mice with YACs is TIG 13 (1997), 61-7; and on chromosomal deletion complexes by radiation of ES cells, Nature Genetics 15 (1997), 285-8. The creation of mice with human immune systems for therapeutic use is described in Nature 386 (1997), 25-6; Nature Genetics 15 (1997), 146-56.

Radiation hypersensitivity is mediated by lack of BRCA2 in Rad51 mice, Nature 386 (1997), 804-10. Mice lacking matrix GLA protein have spontaneous calcification of arteries and cartilage, Nature 386 (1997), 78-81; and lacking haemotopoietic transcription factor PU.1 causes osteoporosis, Nature 386 (1997), 81-4. Cdx2 mutant mice develop tumours, Nature 386 (1997), 84-7; however Dcc gene deletions do not lead to tumourigenesis, Nature 386 (1997), 796-804. The X-chromosome inactivation centre has been found by transgenic mice experiments to be Xist, Nature 386 (1997), 272-9. A snail-related zinc finger gene appears to control vertebrate left-right asymmetry, Science 275 (1997), 1301-4. Retinoid X receptor agonists sensitize diabetic and obese mice to insulin, Nature 386 (1997), 407-10; also on obesity in mice, Nature Genetics 15 (1997), 397-401; and lack of the protein ARNT makes mice abnormal in responses to glucose and oxygen, Nature 386 (1997), 403+. On obesity research, Nature Genetics 15 (1997), 223-4.

Germline transmission in transgenic mice of a bacterial artificial chromosome is reported in NatBio 15 (1997), 859-65. A method to selectively produce transgenic mice using green fluorescent protein (GFP) as a marker has been made, Takada, T. et al. "Selective production of transgenic mice using green fluorescent protein as a marker", NatBio 15 (1997), 458-61; Science 276 (1997), 1993.

A review of making mice with YACs is TIG 13 (1997), 61-7; and on chromosomal deletion complexes by radiation of ES cells, Nature Genetics 15 (1997), 285-8. The creation of mice with human immune systems for therapeutic use is described in Nature 386 (1997), 25-6; Nature Genetics 15 (1997), 146-56.

Radiation hypersensitivity is mediated by lack of BRCA2 in Rad51 mice, Nature 386 (1997), 804-10. Mice lacking matrix GLA protein have spontaneous calcification of arteries and cartilage, Nature 386 (1997), 78-81; and lacking haemotopoietic transcription factor PU.1 causes osteoporosis, Nature 386 (1997), 81-4. Cdx2 mutant mice develop tumours, Nature 386 (1997), 84-7; however Dcc gene deletions do not lead to tumourigenesis, Nature 386 (1997), 796-804. The X-chromosome inactivation centre has been found by transgenic mice experiments to be Xist, Nature 386 (1997), 272-9. A snail-related zinc finger gene appears to control vertebrate left-right asymmetry, Science 275 (1997), 1301-4. Retinoid X receptor agonists sensitize diabetic and obese mice to insulin, Nature 386 (1997), 407-10; also on obesity in mice, Nature Genetics 15 (1997), 397-401; and lack of the protein ARNT makes mice abnormal in responses to glucose and oxygen, Nature 386 (1997), 403+. On obesity research, Nature Genetics 15 (1997), 223-4.

One of the mouse substrains, 129, that is used for gene studies has been found to have significant genetic variation, which may need to be considered for experimental effects such as lethal mutations, Simpson, EM. et al. "Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice", NatGen 16 (1997), 19-27. A review is Nomura, T. "Practical development of genetically engineered animals as human disease models", Laboratory Animal Science 47 (1997), 113-8; also pp. 118-131. Despite the often anti-genetics theme of Steven Spielberg's movie, the Lost World, the opening show was to raise money for a research institute using transgenic mice, Science 276 (1997), 667. Merck is giving Lexicon Genetics Inc., Woodlands, Texas, US$8 million to create 150 new "knockout" mice strains, Science 276 (1997), 527.

Tay-Sachs model mice treated with N-butyldeoxynojirimycin do not develop the lysosomal storage disease, Science 276 (1997), 428-31. A study of Nurr1 deficient mice found dopamine neuron agenesis and has implications for Parkinson's disease research, Science 276 (1997), 248-50; and altered processing of amyloid precursor protein results in impaired learning, Nature 387 (1997), 500-5. Overexpression of VEGF-C (Vascular endothelial growth factor) in skin of mice resulted in lymphatic blood vessel enlargement, Science 276 (1997), 1423-5. Other mice studies include, cardiac morphogenesis, Science 276 (1997), 1404-7; deafness and connexin 26 mutations, Nature 387 (1997), 80-3; epilepsy, Science 276 (1997), 1699-702; p57KIP2 is involved in Beckwith-Widemann syndrome, Nature 387 (1997), 151-8; uteroglobin deficiency resulting in fibronectin-deposit renal glomerular disease, Science 276 (1997), 1408-12; a model of psoriasis, NatMed 3 (1997), 475-6; and on alcohol withdrawal genes, Science 276 (1997), 1201; J. Neuroscience (15 May 1997). Letters on raising energy expenditure in ob/ob mice are in Science 276 (1997), 1132-3. A new TGF-beta superfamily has been implicated in regulation of muscle mass, McPherron, AC. et al. "Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member", Nature 387 (1997), 83-90.

A report on the 10,000 mutant mice in the Institute of Mammalian genetics in Munich is NS (14 June 1997), 22. A general review of ES cells is PNAS 94 (1997), 5709-12. Mice over-expressing lecithin-cholesteryl acyltransferase have high plasma HDL concentrations, NatMed 3 (1997), 744-9; and other models of heart disease, PNAS 94 (1997), 6391-6, 8121-6; NatGen 16 (1997), 226-34. The overexpression of bcl-2 prolongs the life of the mouse model of familial Amyotrophic Lateral Sclerosis, Science 277 (1997), 559-62. An animal model for acute Epstein-Barr virus infection has been made, Science 276 (1997), 2030-3; and measles infection of the brain, PNAS 94 (1997), 4659-63. Presenilin-deficient mice have skeletal and CNS defects, Cell 89 (1997), 629-39. Mice lacking dopamine 2 receptors do not have opiate rewarding effects, Nature 388 (1997), 586+.
ES cell and transgenic mice studies of human disease include: basal forebrain neuronal loss in mice lacking neutrophin receptor p75, Science 277 (1997), 837-9; on several genes including one called disabled, Nature 388 (1997), 730-3; mice lacking adenosine receptors have been made as a model for various studies, and they seem to be more aggressive Nature 388 (1997), 624, 674-8; sound induces seizures in serotonin 5-HT2c receptor mutant mice, Nature Genetics 16 (1997), 387-92; Alzheimer's disease models, Science 277 (1997), 839-41; NatMed 3 (1997), 855-9; stroke model rats, Nature Genetics 16 (1997), 364-7; leptin, NatMed 3 (1997), 952-3; Nature 389 (1997), 374-7; obesity, Nature 388 (1997), 610-4; and on photoreception, Nature 389 (1997), 505-9. Mice lacking vitamin D receptor exhibit impaired bone formation, and growth retardation, Nature Genetics 16 (1997), 391-6. On cancer studies, telomerase and the knockout mice, Nature 389 (1997), 551-2. A general review is Hicks, GG. et al. "Functional genetics in mice by tagged sequence mutagenesis", Nature Genetics 16 (1997), 338-44.

Transgenic models for the short-term assessment of chemical and drug safety provide alternative systems to traditional animal toxicology studies, Sacco, MG. et al. "A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds", NatBio 15 (1997), 1392-7; 1349-50. They engineered a mouse lineage with the human growth hormone (hGH) gene under the control of the human hsp70 promoter, in which a plasma-detectable hGH response can be elicited by exposure to heat shock. Transgenic mice injected intraperitoneally with sodium arsenite, cadmium chloride, copper sulphate, or methylmercurium chloride showed significant hGH levels in plasma.

Maternal behaviour changes are noted in Thomas, SA. & Palmiter, RD. "Impaired maternal behavior in mice lacking norepinephrine and epinephrine", Cell 91 (1997), 583-92. The optimization of mice to be used for genetic studies of sequence affects on function is reviewed in TIG 13 (1997), 423-6; and a review of how to make congenic mouse strains is NatGen 17 (1997), 280-4. Loss of p21 increases sensitivity to ionizing radiation in atm-deficient mice, PNAS 94 (1997), 14590-5. A lethal milk mouse model has a mutation in zinc transport gene, NatGen 17 (1997), 292-7; a model of sickle cell disease, Science 278 (1997), 803-4, 873-6, 876-8; and an animal model of disrupted dystrophin-associated glycoprotein complex has been made, PNAS 94 (1997), 13873-8. Disruption of alpha3-connexin gene leads to proteolysis in mice, Cell 91 (1997), 833-43; overexpression of Agrt leads to obesity, NatGen 17 (1997), 273-4; and mice lacking bombesin receptor subtype-3 also develop obesity, Nature 390 (1997), 165-9. On methods to examine development in utero, Science 278 (1997), 1397-9; and expenses of frozen mice, Science 278 (1997), 393.

Models for gene therapy include Murphy, JE. et al. "Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin", PNAS 94 (1997), 13921-6; and tissue specific expression of herpes simplex virus thymidine kinase gene inhibited growth of a human hepatocellular carcinoma, PNAS 94 (1997), 13891-6.

There are several discoveries towards the mechanisms of aging, in transgenic mice, Kuro-o, M. et al. "Mutation of the mouse klotho gene leads to a syndrome resembling ageing", Nature 390 (1997), 45-51; 18-9; on the role of telomerase, NatGen 17 (1997), 257-8; Science 278 (1997), 1013. Chaperones may be involved, Nature 390 (1997), 30; and serine/threonine kinase, Nature 390 (1997), 116-7. Telomerase loss also leads to tumors, Cell 91 (1997), 25-34. In the nematode worm, C. elegans the loss of food leads to deceased level of a protein hormone, daf-16, which doubles the lifespan, Science 278 (1997), 1319-22; NS (22 Nov 1997), 7.

Mutation of dynein affects left-right asymmetry, Nature 389 (1997), 963-6; lack of functional enzyme for Fyn tyrosine kinase makes mice susceptible to alcohol, Science 278 (1997), 573; lacking GLUT4 leads to developing insulin resistance and diabetes, NatMed 3 (1997), 1096-101; Poly (ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia, NatMed 3 (1997), 1089-95; slow-wave epilepsy mutant mice have a sodium/hydrogen exchanger gene defect, Cell 91 (1997), 139-48; on prostaglandin knockouts, NatMed 3 (1997), 1326-7; Hox gene variation, Nature 391 (1998), 225-8.

A review is Darvasi, A. "Experimental strategies for the genetic dissection of complex traits in animal models", NatGen 18 (1998), 19-23. Mice with gene targeted changes to prion protein are reported in NatGen 18 (1998), 118-25. A mouse model of SCID and therapy of hematopoietic stem cells is reported in Bunting, KD. et al. "Restoration of lymphocyte function in Janus kinase 3-defieicnt mice by retroviral-mediated gene transfer", NatMed 4 (1998), 58-64. Accelerated Alzheimer's has been generated in mice, NatMed 4 (1998), 97-100. Transgenic mice have been validated and shown to be cheaper as carcinogen tests, EST 32 (1998), 76-7A.

A paper reporting multiple gene tagging by mutagenesis is Zambrowicz, BP. et al. "Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells", Nature 392 (1998), 608-11. Telomerase has an essential role in highly proliferative organs of mice, Nature 392 (1998), 569-74. On origins of telomerase, Cell 92 (1998), 587-90. On mice models for apoptosis, Nature 392 (1998), 126-30, 442-3. More apoptosis genes have been identified in yeast that do not die, Cell 92 (1998), 425-7. A review is Balmain, A. & Nagase, H., "Cancer resistance genes in mice: models for study of tumour modifiers", TIG 14 81998), 139-44. On a genetic model of hereditary hemochromatosis, PNAS 95 (1998), 2492-7; and Gaucher disease, PNAS 95 (1998), 2503-8. Mice with altered aggression are reported in De Felipe, C. et al. "Altered nociception, analgesia and aggression in mice lacking the receptor for substance P", Nature 392 (1998), 394-7.

A review of genetically engineered mice is Laboratory Animal Science 48 (1998), 121-2; and efforts to make a global mouse house are reported in NatGen 19 (1998), 299-300. A positive mutation is reported in Yamasaki, L. et al. "Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-) mice", NatGen 18 (1998), 360-4. M33 mutant mice have been made that have male to female sex reversal, Nature 393 (1998), 688-92. Several mice models have suggested genetic bases for nonsyndromic hearing loss in humans, NatMed 4 (1998), 560-1; and correction of deafness in shaker-2 mice could be effected by