A humanized mouse is a mouse carrying functioning human genes, cells, tissues, and/or organs. Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics.

A humanized mouse or a humanized mouse model is one that has been xenotransplanted with human cells and/or engineered to express human gene products, so as to be utilized for gaining relevant insights in the in vivo context for understanding of human-specific physiology and pathologies.^[1] A lot of our knowledge about several human biological processes has been obtained from studying animal models like [[rodent]s] and non-human primates. In particular, small animals such as mice are advantageous in such studies owing to their small size, brief reproductive cycle, easy handling and due to the genomic and physiological similarities with humans; moreover, these animals can also be genetically modified easily. Nevertheless, there are several incongruencies of these animal systems with those of the humans, especially with regard to the components of the immune system. To overcome these limitations and to realize the full potential of animal models to enable researchers to get a clear picture of the nature and pathogenesis of immune responses mounted against human-specific pathogens, humanized mouse models have been developed. Such mouse models have also become an integral aspect of preclinical biomedical research.^[2]

History

The discovery of the athymic mouse, commonly known as the nude mouse, and that of the SCID mouse were major events that paved the way for humanized mice models. The first such mouse model was derived by backcrossingC57BL/Ka and BALB/c mice, featuring a loss of function mutation in the PRKDC gene. The PRKDC gene product is necessary for resolving breaks in DNA strands during the development of T cells and B cells. Dysfunctional PRKDCgene leads to impaired development of T and B lymphocytes which gives rise to severe combined immunodeficiency (SCID). In spite of the efforts in developing this mouse model, poor engraftment of human hematopoietic stem cells (HSCs) was a major limitation that called for further advancement in the development humanized mouse models.^[3] The next big step in the development of humanized mice models came with transfer of the scid mutation to a non-obese diabetic mouse. This resulted in the creation of the NOD-scid mice which lacked T cells, B cells, and NK cells. This mouse model permitted for a slightly higher level of human cell reconstitution. Nevertheless, a major breakthrough in this field came with the introduction of the mutant interleukin 2 receptor α (IL2rα) gene in the NOD-scid model. This accounted for the creation of the NOD-scid-γcnull mice (NSG or NOG) models which were portrayed to have defective interleukins IL-2, IL-4, IL-7, IL-9, and IL-15. Researchers evolved this NSG model by knocking out the RAG1 and RAG2 genes (recombination activation genes), resulting into the RAG^null version of the NSG model that was devoid of major cells of the immune system including the natural killer cells, B lymphocytes and T lymphocytes, macrophages and dendritic cells, causing the greatest immunodeficiency in mice models so far. The limitation with this model was that it lacked the human leukocyte antigen. In accordance to this limitation, the human T cells when engrafted in the mice, failed to recognize human antigen-presenting cells, which consequated in defective immunoglobulin class switching and improper organization of the secondary lymphoid tissue.^[4]

To circumvent this limitation, the next development came with the introduction of transgenes encoding for HLA I and HLA II in the NSG RAG^null model that enabled buildout of human T-lymphocyte repertoires as well as the respective immune responses.^[5]

Types

Engrafting an immunodeficient mouse with functional human cells can be achieved by intravenous injections of human cells and tissue into the mouse. This section highlights the various humanized mice models developed using the different methods.

Hu-PBL-scid model

This model is developed by intravenously injecting human PBMCs into immunodeficient mice. The peripheral blood mononuclear cells to be engrafted into the model are obtained from consented adult donors. The advantages associated with this method are that it is comparatively an easy technique, the model takes relatively less time to get established and that the model exhibits functional memory T cells.^[6] It is particularly very effective for modelling graft vs. host disease.^[5] The model lacks engraftment of B lymphocytes and myeloid cells. Other limitations with this model are that it is suitable for use only in short-term experiments (<3 months) and the possibility that the model itself might develop graft vs. host disease.^[5]

Hu-SRC-scid model

Hu-SRC-scid mice are developed by engrafting CD34+ human hematopoietic stem cells into immunodeficient mice. The cells are obtained from human fetal liver, bone marrow or from blood derived from the umbilical cord,^[7] and engrafted via intravenous injection. The advantages of this model are that it offers multilineage development of hematopoietic cells, generation of a naïve immune system, and if engraftment is carried out by intrahepatic injection of newborn mice within 72 hours of birth, it can lead to enhanced human cell reconstitution. Nevertheless, limitations associated with the model are that it takes a minimum of 10 weeks for cell differentiation to occur, it harbors low levels of human RBCs, polymorphonuclear leukocytes, and megakaryocytes.^[5]

BLT (bone marrow/liver/thymus) model

The BLT model is constituted with human HSCs, bone marrow, liver, and thymus. The engraftment is carried out by implantation of liver and thymus under the kidney capsule and by transplantation of HSCs obtained from fetal liver. The BLT model has a complete and totally functional human immune system with HLA-restricted T lymphocytes. The model also comprises a mucosal system that is similar to that of humans. Moreover, among all models the BLT model has the highest level of human cell reconstitution.^[8]

However, since it requires surgical implantation, this model is the most difficult and time-consuming to develop. Other drawbacks associated with the model are that it portrays weak immune responses to xenobiotics, sub-optimal class switching and may develop GvHD.^[5]

Established models for human diseases

Several mechanisms underlying human maladies are not fully understood. Utilization of humanized mice models in this context allows researchers to determine and unravel important factors that bring about the development of several human diseases and disorders falling under the categories of infectious disease, cancer, autoimmunity, and GvHD.

Infectious diseases

Among the human-specific infectious pathogens studied on humanized mice models, the human immunodeficiency virus has been successfully studied.^[5] Besides this, humanized models for studying Ebola virus,^[9] Hepatitis B,^[10]Hepatitis C,^[11] Kaposi's sarcoma-associated herpesvirus,^[12] Leishmania major,^[13] malaria,^[14] and tuberculosis ^[15] have been reported by various studies.

NOD/scid mice models for dengue virus ^[16] and varicella-zoster virus,^[17] and a Rag2^null𝛾c^null model for studying influenza virus ^[18] have also been developed.

Cancers

On the basis of the type of human cells/tissues that have been used for engraftment, humanized mouse models for cancer can be classified as patient-derived xenografts or cell line-derived xenografts.^[19] PDX models are considered to retain the parental malignancy characteristics at a greater extent and hence these are regarded as the more powerful tool for evaluating the effect of anticancer drugs in pre-clinical studies.^[19][20] Humanized mouse models for studying cancers of various organs have been designed. A mouse model for the study of breast cancer has been generated by the intrahepatic engraftment of SK-BR-3 cells in NSG mice.^[21] Similarly, NSG mice intravenously engrafted with patient-derived AML cells,^[22] and those engrafted (via subcutaneous, intravenous or intra-pancreatic injections) with patient-derived pancreatic cancer tumors^[23] have also been developed for the study of leukemia and pancreatic cancer respectively. Several other humanized rodent models for the study of cancer and cancer immunotherapy have also been reported.^[24]

Autoimmune diseases

Problems posed by the differences in the human and rodent immune systems have been overcome using a few strategies, so as to enable researchers to study autoimmune disorders using humanized models. NSG mice engrafted with PBMCs and administered with myelin antigens in Freund's adjuvant, and antigen-pulsed autologous dendritic cells have been used to study multiple sclerosis.^[25] Similarly, NSG mice engrafted with hematopoietic stem cells and administered with pristane have been used for studying lupus erythematosus.^[26] Furthermore, NOG mice engrafted with PBMCs has been used to study mechanisms of allografts rejection in vivo. ^[27]

See also

• Nude mouse

• SCID mouse

• NOG mouse

• NSG mouse

• Mouse model of colorectal and intestinal cancer

• Mouse models of breast cancer metastasis

References

• ^ Stripecke R, Münz C, Schuringa JJ, Bissig KD, Soper B, Meeham T, et al. (July 2020). "Innovations, challenges, and minimal information for standardization of humanized mice". EMBO Molecular Medicine. 12 (7): e8662. doi:10.15252/emmm.201708662. PMC 7338801. PMID 32578942.

• ^ Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD (January 2017). "Humanized Mouse Models of Clinical Disease". Annual Review of Pathology. 12 (1): 187–215. doi:10.1146/annurev-pathol-052016-100332. PMC 5280554. PMID 27959627.

• ^ Ito R, Takahashi T, Katano I, Ito M (May 2012). "Current advances in humanized mouse models". Cellular & Molecular Immunology. 9 (3): 208–14. doi:10.1038/cmi.2012.2. PMC 4012844. PMID 22327211.

• ^ Bosma GC, Custer RP, Bosma MJ (February 1983). "A severe combined immunodeficiency mutation in the mouse". Nature. 301 (5900): 527–30. Bibcode:1983Natur.301..527B. doi:10.1038/301527a0. PMID 6823332. S2CID 4267981.

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• ^{a b c d e f} Yong KS, Her Z, Chen Q (August 2018). "Humanized Mice as Unique Tools for Human-Specific Studies". Archivum Immunologiae et Therapiae Experimentalis. 66 (4): 245–266. doi:10.1007/s00005-018-0506-x. PMC 6061174. PMID 29411049.

• ^ Tary-Lehmann M, Saxon A, Lehmann PV (November 1995). "The human immune system in hu-PBL-SCID mice". Immunology Today. 16(11): 529–33. doi:10.1016/0167-5699(95)80046-8. PMID 7495490.

• ^ Pearson T, Greiner DL, Shultz LD (May 2008). "Creation of "humanized" mice to study human immunity". Current Protocols in Immunology. Chapter 15 (1): Unit 15.21. doi:10.1002/0471142735.im1521s81. PMC 3023233. PMID 18491294.

• ^ Karpel ME, Boutwell CL, Allen TM (August 2015). "BLT humanized mice as a small animal model of HIV infection". Current Opinion in Virology. Animal models for viral diseases / Oncolytic viruses. 13: 75–80. doi:10.1016/j.coviro.2015.05.002. PMC 4550544. PMID 26083316.

• ^ Lüdtke A, Oestereich L, Ruibal P, Wurr S, Pallasch E, Bockholt S, et al. (April 2015). "Ebola virus disease in mice with transplanted human hematopoietic stem cells". Journal of Virology. 89 (8): 4700–4. doi:10.1128/JVI.03546-14. PMC 4442348. PMID 25673711.

• ^ Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, et al. (March 2014). "Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages". PLOS Pathogens. 10 (3): e1004032. doi:10.1371/journal.ppat.1004032. PMC 3961374. PMID 24651854.

• ^ Bility MT, Zhang L, Washburn ML, Curtis TA, Kovalev GI, Su L (September 2012). "Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis". Nature Protocols. 7 (9): 1608–17. doi:10.1038/nprot.2012.083. PMC 3979325. PMID 22899330.

• ^ Wang LX, Kang G, Kumar P, Lu W, Li Y, Zhou Y, et al. (February 2014). "Humanized-BLT mouse model of Kaposi's sarcoma-associated herpesvirus infection". Proceedings of the National Academy of Sciences of the United States of America. 111 (8): 3146–51. Bibcode:2014PNAS..111.3146W. doi:10.1073/pnas.1318175111. PMC 3939909. PMID 24516154.

• ^ Wege AK, Florian C, Ernst W, Zimara N, Schleicher U, Hanses F, et al. (2012-07-24). "Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response". PLOS Neglected Tropical Diseases. 6 (7): e1741. doi:10.1371/journal.pntd.0001741. PMC 3404120. PMID 22848771. S2CID 7657105.

• ^ Amaladoss A, Chen Q, Liu M, Dummler SK, Dao M, Suresh S, et al. (2015-06-22). "De Novo Generated Human Red Blood Cells in Humanized Mice Support Plasmodium falciparum Infection". PLOS ONE. 10 (6): e0129825. Bibcode:2015PLoSO..1029825A. doi:10.1371/journal.pone.0129825. PMC 4476714. PMID 26098918. S2CID 543860.

• ^ Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB, Sutjita P, et al. (2013-05-17). "A humanized mouse model of tuberculosis". PLOS ONE. 8 (5): e63331. Bibcode:2013PLoSO...863331C. doi:10.1371/journal.pone.0063331. PMC 3656943. PMID 23691024. S2CID 17215038.

• ^ Frias-Staheli N, Dorner M, Marukian S, Billerbeck E, Labitt RN, Rice CM, Ploss A (February 2014). "Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing". Journal of Virology. 88 (4): 2205–18. doi:10.1128/JVI.03085-13. PMC 3911540. PMID 24335303.

• ^ Moffat JF, Stein MD, Kaneshima H, Arvin AM (September 1995). "Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice". Journal of Virology. 69 (9): 5236–42. doi:10.1128/jvi.69.9.5236-5242.1995. PMC 189355. PMID 7636965.

• ^ Zheng J, Wu WL, Liu Y, Xiang Z, Liu M, Chan KH, et al. (2015-08-18). "The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice". PLOS ONE. 10 (8): e0135999. Bibcode:2015PLoSO..1035999Z. doi:10.1371/journal.pone.0135999. PMC 4540487. PMID 26285203. S2CID 10461525.

• ^

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• ^{a b} Tian H, Lyu Y, Yang YG, Hu Z (2020). "Humanized Rodent Models for Cancer Research". Frontiers in Oncology. 10. doi:10.3389/fonc.2020.01696. ISSN 2234-943X. S2CID 221589508.

• ^ Hausser HJ, Brenner RE (July 2005). "Phenotypic instability of Saos-2 cells in long-term culture". Biochemical and Biophysical Research Communications. 333 (1): 216–22. doi:10.1016/j.bbrc.2005.05.097. PMID 15939397.

• ^ Wege AK, Schmidt M, Ueberham E, Ponnath M, Ortmann O, Brockhoff G, Lehmann J (2014-05-08). "Co-transplantation of human hematopoietic stem cells and human breast cancer cells in NSG mice: a novel approach to generate tumor cell specific human antibodies". mAbs. 6 (4): 968–77. doi:10.4161/mabs.29111. PMC 4171030. PMID 24870377. S2CID 34234807.

• ^ Her Z, Yong KS, Paramasivam K, Tan WW, Chan XY, Tan SY, et al. (October 2017). "An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia". Journal of Hematology & Oncology. 10 (1): 162. doi:10.1186/s13045-017-0532-x. PMC 5639594. PMID 28985760.

• ^ Her Z, Yong KS, Paramasivam K, Tan WW, Chan XY, Tan SY, et al. (October 2017). "An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia". Journal of Hematology & Oncology. 10 (1): 162. doi:10.1186/s13045-017-0532-x. PMID 28985760. S2CID 25506701.

• ^ Chen Q, Wang J, Liu WN, Zhao Y (July 2019). "Cancer Immunotherapies and Humanized Mouse Drug Testing Platforms". Translational Oncology. 12 (7): 987–995. doi:10.1016/j.tranon.2019.04.020. PMC 6529825. PMID 31121491.

• ^ Zayoud M, El Malki K, Frauenknecht K, Trinschek B, Kloos L, Karram K, et al. (September 2013). "Subclinical CNS inflammation as response to a myelin antigen in humanized mice". Journal of Neuroimmune Pharmacology. 8 (4): 1037–47. doi:10.1007/s11481-013-9466-4. PMID 23640521. S2CID 503830.

• ^ Gunawan M, Her Z, Liu M, Tan SY, Chan XY, Tan WW, et al. (November 2017). "A Novel Human Systemic Lupus Erythematosus Model in Humanised Mice". Scientific Reports. 7 (1): 16642. Bibcode:2017NatSR...716642G. doi:10.1038/s41598-017-16999-7. PMC 5709358. PMID 29192160. S2CID 5604139.

• ^ King, Marie; Pearson, Todd; Shultz, Leonard D.; Leif, Jean; Bottino, Rita; Trucco, Massimo; Atkinson, Mark A.; Wasserfall, Clive; Herold, Kevan C.; Woodland, Robert T.; Schmidt, Madelyn R. (2008-03-01). "A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene". Clinical Immunology. 126 (3): 303–314. doi:10.1016/j.clim.2007.11.001. ISSN 1521-6616.

Further reading[edit]

• Brehm MA, Wiles MV, Greiner DL, Shultz LD (August 2014). "Generation of improved humanized mouse models for human infectious diseases". Journal of Immunological Methods. 410: 3–17. doi:10.1016/j.jim.2014.02.011. PMC 4155027. PMID 24607601.

• Ito R, Takahashi T, Katano I, Ito M (May 2012). "Current advances in humanized mouse models". Cellular & Molecular Immunology. 9 (3): 208–14. doi:10.1038/cmi.2012.2. PMC 4012844. PMID 22327211.

• Scheer N, Snaith M, Wolf CR, Seibler J (December 2013). "Generation and utility of genetically humanized mouse models". Drug Discovery Today. 18(23–24): 1200–11. doi:10.1016/j.drudis.2013.07.007. PMID 23872278.

• Peltz G (May 2013). "Can 'humanized' mice improve drug development in the 21st century?". Trends in Pharmacological Sciences. 34 (5): 255–60. doi:10.1016/j.tips.2013.03.005. PMC 3682766. PMID 23602782.

• Grompe M, Strom S (December 2013). "Mice with human livers". Gastroenterology. 145 (6): 1209–14. doi:10.1053/j.gastro.2013.09.009. PMID 24042096.

• Leung C, Chijioke O, Gujer C, Chatterjee B, Antsiferova O, Landtwing V, et al. (September 2013). "Infectious diseases in humanized mice". European Journal of Immunology. 43 (9): 2246–54. doi:10.1002/eji.201343815. PMID 23913412.

WASHINGTON, April 5 — Scientists at Brookhaven National Laboratory have developed way of producing human blood and blood‐forming cells inside a living mouse.

An announcement today from the laboratory at Upton, L.I., said the research makes it possible, for the first time, to duplicate the living, continuously functioning system of human blood cell reproduction outside the human body.

The method, is said to offer important possibilities for studying the complex process of blood formation in health and disease and for monitoring the effects of drugs. Since bone marrow is the main blood‐forming tissue, the research might ultimately lead to a source of marrow for livesaving transplants. This is now only a theoretical possibility.

The blood cell formation takes place inside a small coinshaped chamber that is implanted inside the animal's abdominal cavity. The sides of the chamber are filters of extremely fine pore. This allows nutrient fluids from the animal to pass in and out, but prevents the cells inside from escaping and prevents the animal's cells from invading the chamber.

In the experiments, Dr. Eugene P. Cronkite, chairman of the laboratory's medical department explained by telephone today, only a small number of human bone marrow cells are put in the chamber. The number ranges between 1,000 and a million.

The chamber is then implanted in the mouse where the cells are allowed to grow for several weeks. At first, the total number of cells dwindles as the mature ones die, he said. Later the total grows to as many as 10 million and they differentiate into all the types found in normal marrow, the scientist said.

This includes not only the several different kinds of white blood cells, including scavenger cells and other immunologically active types, but also some red blood cells. Among the immunologically active cells are a type called plasma cells, which are normally responsible for generating protective antibodies.

Dr. Cronkite said they appear to be producing antibodies in the experiments at Brookhaven, but whether these are directed against something from the mouse or from the cell's original human environment is unknown.

The mouse is prevented from producing antibodies against the contents of the chamber by heavy doses of radiation given before the experiments begin. During the research, so far, mouse cells have been grown in chambers implanted in mice; rabbit cells in rabbits; goat cells in goats and human cells in mice.

Dr. Cronkit said other methods of growing bone marrow cells under artificial conditions were known, and used at many research centers, but that in general, these tended to produce only a few types of white cells and no red cells. Furthermore, unlike the system in use at Brookhaven, he said, the colonies of cells are not so easily studied during the process of growth and differentiation.

Several laboratories have also developed artificial substitutes for red blood cells, but research in this area is entirely distinct from the studies at Brookhaven on natural components of blood and the cells that form it.

Tool for Analysis

One of the advantages cited for the system is that the chamber can be removed at any time for study of its contents. Thus, the blood‐formation process can be analyzed in some detail.

The scientists at Brookhaven have already used the system to grow cells from patients suffering from leukemia, a cancer of the blood‐forming tissues, and hope that it may prove possible to test the effectiveness of drugs against such cells growing in the chambers.

Perhaps more important in the long run, they hope to study in detail the extremely complex process of blood formation itself as well as the derangements of the process that occur in leukemia and other diseases.

The research at Brookhaven is supported by the Atomic Energy Commission. It has been in progress since 1969, the announcement, said today, when Dr. Arne Boyum, a toxicologist from the Norwegian defense research establishment come to Brookhaven as a research collaborator in residence, bringing the basic idea with him.

Although Dr. Boyum returned to Norway more than two years ago, he is still an active participant in the studies, the announcement said. Other current collaborators with Dr. Cronkite in the research are Drs. Arland L. Carsten and Gundabhatktha Chikkapa. Two technical reports were published last year in an issue of Blood, a scientific journal, Dr. Cronkite said. Progress in the research has also been reported at scientific meetings.

A long‐range goal of the studies is a system that would allow hone marrow to be readily produced for transplantation. This cannot be done with the present system.

Calling it a ''singularly historic event,'' the United States today issued to Harvard University the world's first patent for a higher form of life, a mouse specially developed by researchers at the Harvard Medical School through techniques of genetic manipulation.

The United States Patent and Trademark Office issued patent No. 4,736,866 for ''transgenic nonhuman mammals'' developed by Dr. Philip Leder, a 53-year-old geneticist at Harvard Medical School, and Dr. Timothy A. Stewart, 35, a former Harvard researcher who is a senior scientist at Genentech Inc., a leading biotechnology company in South San Francisco.

The two scientists isolated a gene that causes cancer in many mammals, including humans, injected it into fertilized mouse eggs and developed a new breed of genetically altered mice. An Effective Research Model

Because half the females develop cancer, the altered breed serves as a more effective model for studying how genes contribute to cancer, particularly breast cancer, Dr. Leder said.

Other experts said the invention presented scientists with a more efficient biological system for testing new drugs and therapies to treat cancer, and for determining whether chemicals and other toxic substances found in food or the environment are harmful.

The announcement elated researchers and biotechnology industry executives who said it would attract more investments for research and lead to safer and more effective biological inventions in medicine, agriculture, forestry and other industries.

But critics, including several powerful members of Congress, protested the decision, arguing that a handful of officials appointed by the Reagan Administration had in a single act determined a new and important public policy without a public debate and in defiance of a request from Congress to delay the action.

Donald J. Quigg, the Assistant Secretary of Commerce, who is also Commissioner of Patents, said approving the animal patent was a logical and lawful extension of previous decisions by the 198-year-old agency. In 1930 the first patent for a crop plant was approved. In 1980 the Supreme Court ruled that scientists could patent genetically altered microorganisms. A year ago the Patent Office announced that it would allow inventors to patent new forms of animal life created by gene-splicing and other biological technologies.

Mr. Quigg said today that the 13th Amendment prevented the patenting of human beings. Patent attorneys said, however, that portions of the human genetic code, including specific genes, will be patentable. 'Can Anyone Say This Is Wrong?'

Mr. Quigg said the potential of the altered mice to hasten the development of treatments for cancer was an important factor in granting Harvard the first animal patent, which allows the inventor the exclusive right to use a product for 17 years. ''I know I'm not supposed to get on a soapbox,'' he said in an interview today, ''but how can anybody say this kind of development is unethical or wrong?''

But some members of Congress protested, and in a letter to be sent later this week after more signatures are sought they called on the Patent and Trademark Office to refrain from issuing another animal patent. The office said 21 patent applications for genetically engineered animals are pending.

Both the House and Senate are considering legislation that would impose a moratorium on approving patents for genetically altered animals. It would be in force until Congress has more thoroughly considered a range of economic and moral issues raised in the last year by farm groups, religious leaders, animal welfare organizations and environmental groups. Quickening Pace in Field

The Patent Office decision recognizes the quickening pace of developments in biotechnology, particularly in creating and duplicating new forms of animals. Along with genetically engineered pigs, cattle and sheep that have been produced in laboratories across the country, scientists are also beginning to transform aquatic species.

Critics found today's action cause for concern. Jeremy Rifkin, president of the Foundation on Economic Trends in Washington, who is a leader of the coalition that seeks to halt animal patents, said: ''For the first time, the Patent Office has formulated a public policy and taken the authority of Congress in their own hands.''

Other experts saw dangers if Congress interferes in the Patent Office's procedures. Robert P. Merges, a patent specialist at Columbia University School of Law, said, ''Is Congress now going to say, for the first time, that here's a new technology that we're going to delay because we're going to presume it's bad until it's proven good?''

Scientists have transplanted the major elements of the human immune defense system into living mice, a stunning achievement that should provide a powerful new tool for medical research.

Describing the new experiments as ''exciting'' and ''incredible,'' leading researchers predicted that the technique will have many important uses, including the study of AIDS and leukemia and the testing of treatments and vaccines. The altered mice are also expected to give scientists, for the first time, a direct way of studying the development of the human immune system and its functions.

The mice lack natural immune defenses of their own, but circulating in their blood is the full spectrum of human white blood cells, which play key roles in warding off infection and produce human antibodies in response to infectious agents. Work of Separate Teams

These human attributes have been produced in mice by two research teams working independently of each other and using different methods. Although the research is considered highly promising, it is still in an early stage at both institutions involved.

Researchers at the Medical Biology Institute, an independent research center in La Jolla, Calif., reported today in the journal Nature that they had produced mice that had the major functional elements of the human immune defenses. They did this by injecting the animals with purified lymphocytes, immune defense cells, from normal human adults. The cells, injected into the abdominal cavity, reproduced and migrated throughout the blood and lymphatic systems.

Dr. Donald E. Mosier, leader of the research team, said the human immune defenses had persisted in some mice for as long as eight months so far. When such animals were injected with tetanus toxoid, used to produce immunity against tetanus bacteria, the animals developed human antibodies against the bacteria. The experiments also produced evidence of activity by the other fundamental arm of the human immune defenses, cell mediated immunity, which is mainly produced by two classes of cells: T cells and B cells. Surprisingly Simple Technique

The method of transplanting the immune defenses was relatively simple, but the scientists had hardly expected it to succeed. The normal expectation was that the transplanted human tissue would attack the mouse's body in a process, graft-versus-host disease, that is often fatal. Although there was some graft-versus-host disease, it was less destructive than expected.

The other research team, led by Dr. Joseph M. McCune and Dr. Irving Weissman of Stanford University, succeeded in a much more formidible task: transferring the entire human immune defense system into mice by transplanting human fetal tissues that are responsible for the development of the complete human blood-forming and immune system.

The team has developed a colony of more than 200 of the mice that have human immune defenses, according to a report that will be published in the journal Science. The scientists are not yet certain how complete the transplanted defenses are. But mice that would ordinarily die within three to four months because they lacked immune defenses, became healthy and have survived as long as 15 months to date. Among other things, they withstood pneumocystis carini infections, a major cause of death among AIDS patients.

The Stanford researchers will report on their experiments in next week's issue of Science, but the editors of that journal permitted the results of the study to be described in advance so that the two reports could be made public at the same time. Use of Fetal Tissue

The scientists at Stanford injected the mice with small amounts of fetal liver and lymphatic tissue as well as fetal thymus and spleen; all of them tissues vital to formation of blood and immune defenses. The tissues were obtained after abortion with the consent of the women involved. The use was approved by Stanford panels that regulate human and animal research. The work did not violate any Federal rules, Dr. Weissman said.

Only small amounts of tissue were needed and they were obtained before the current moratorium on Federal support for fetal research. The scientists at Stanford received support from the National Institutes of Health for the mouse research.

Crucial to both research teams was a breed of mice called SCID, for severe combined immune deficiency, that are almost totally lacking in immune defenses of their own. Because the animals lacked defenses, they did not reject the foreign human tissues. The breed of mice was discovered five years ago by Melvin J. Bosma and Gayle C. Bosma, a husband and wife research team at the Fox Chase Cancer Center in Philadelphia.

Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, in Bethesda, Md. said the research by both groups was important. Dr. Fauci, an expert on both immunology and AIDS, described the experiments as ''very exciting work'' that ''has major potential for being able to establish a small-animal model of the human immune system.'' Possible Insight on AIDS

For example, he said, the mice may allow direct step-by-step studies of the manner in which the AIDS virus attacks cells of the human immune defense system. Such animals may also prove valuable for testing new drugs and new vaccines for AIDS and other important diseases.

At present there is no animal in which the acquired immune deficiency syndrome produces precisely the same effects that it does in humans. Chimpanzees, the closest animals to humans that can be infected with the HIV virus, are in short supply and do not develop an equivalent disease to AIDS. Whether the mice will do so is not yet known, but the scientists believe they will at least be able to follow the progression of the virus infection on cells of the human immune system in a direct manner that has not previously been possible. Research Termed Remarkable

In a commentary written for Science, Dr. George D. Yancopoulos and Dr. Frederick W. Alt, of Columbia University, described the research at Stanford as ''remarkable.'' They said animals in which the immune defenses have been manipulated in various ways permit many important studies of the way in which the immune system functions.

''The Weissman group now report remarkable experiments that appear to push this system to its incredible but logical extreme,'' they said.

Authors of the report from Stanford with Dr. Weissman and Dr. McCune were Dr. Reiko Namikawa, Dr. Hideto Kaneshima, Dr. Miriam Lieberman of Stanford and Dr. Len Shultz of the Jackson Laboratory in Bar Harbor, Me.

Authors of the Nature article with Dr. Mosier are Dr. Richard J. Gulizia and Dr. Darcy B. Wilson of the Medical Biology Institute and Dr. Stephen M. Baird of the Veterans Administration Medical Center in La Jolla.

In a series of bold experiments, scientists have created laboratory mice with tiny samples of human organs growing in them: lungs, intestines, pancreases, lymph nodes, thymuses, and livers. The purpose is to study the viruses of human diseases in living human tissues.

The mice provide a singular opportunity to gauge the effectiveness of various antiviral drugs. They have been successfully infected with the AIDS virus and with two cancer viruses that cause leukemia.

Researchers plan next to infect the mice with cytomegalovirus, which can damage the brains of unborn children. After that will come infections with the viruses of influenza, chronic infant diarrhea, genital warts and hepatitis. Because these viruses attack only humans, it has been impossible hitherto to study them in animals. Not Carbon Copies

The organ structures are not miniature copies of adult organs but contain complete sets of cells that make them able to function as well as the organs of a newborn baby.Thus, each organ, about the size of a pencil eraser, can carry out its normal function in tandem with the mouse's own organs.

The novel mice were developed by Dr. J. Michael McCune, an immunologist who treats AIDS patients at San Francisco General Hospital.

A second kind of mouse, carrying adult human blood cells, has been developed by Dr. Donald E. Mosier, an immunologist from the Medical Research Institute, a private research laboratory in La Jolla, Calif.

Both scientists announced two years ago that they had implanted human immune system tissues into immune deficient mice and reported the mice formed human white cells. Since then, they have learned how to grow other organs in mice and to infect the animals with human viruses. Many of those experiments are being carried out by companies recently formed by Dr. Mosier and and Dr. McCune. Researchers at Duke University, Stanford University and the University of California at Los Angeles have also replicated the work.

Because human fetal tissues are being implanted into animals and not humans, Dr. McCune and his colleagues are not subject to the Federal ban on the use of such tissues in medical research. The ban, imposed two years ago by the Department of Health and Human Services, was intended to prevent women from having abortions for the sake of donating fetal tissue to people, but the regulations make no mention of mice, said Dr. McCune, whose work has been financed largely by the National Institutes of Health. Important New Tool

The mouse "is potentially quite an important model" for studying AIDS and other viral diseases, said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. The mouse is "phenomenally important," said Dr. David Baltimore, president of the Rockefeller University in New York. "It offers you the opportunity to look at viruses without having to deal with human beings" and to conduct imaginative experiments. Dr. Baltimore helped form Dr. McCune's company, Systemix of Palo Alto, Calif., two years ago.

Dr. McCune said his notion for creating the mouse was born of frustration. In his work with AIDS patients, he developed concepts for therapies that needed to be tested in animals, yet the AIDS virus infects only human cells. His idea was to insert tissues from human fetal organs into mice with deficient immune systems that would not reject the implants. Such mice had been developed at the Fox Chase Cancer Center in Philadelphia.

To create mice with human immune systems, Dr. McCune takes the thymus, liver and lymph nodes from human fetuses less than 22 weeks old and divides them into hundreds of pieces, each about the size of a grain of rice.

Using a microscope, he implants a piece of each organ under the kidneys of young mice. Within days, the mouse's blood vessels move into the human tissue, nourishing it and encouraging it to grow. In a month or two, the human organs are the size of blueberries and are able to engender the cells of the immune system.

Though small, the organs are functionally complete, Dr. McCune said. Human immune T-cells circulate in the mouse's bloodstream, he said, while B-cells and other human immune system components reside in the liver and thymus.

Dr. Mosier's company, Lidak Pharmaceuticals in La Jolla, Calif., makes an immune deficient mouse that supports immune system cells taken from adult humans. Dr. Mosier injects white blood cells from adult donors into a mouse's abdominal cavity. The cells migrate to the mouse's spleen and lymph nodes and create a functioning human immune system. For reasons that are not understood, Dr. Mosier said, the human cells do not attack the mouse's tissues. Trials With AZT

Such mice are being studied under a wide range of experimental conditions, said Dr. McCune. In one experiment, which is to be published shortly, researchers treated mice with the drug AZT at different intervals after infection to test the advantages of early treatment. The answer may help guide the treatment of hospital workers who accidentally stick themselves with AIDS-contaminated needles, Dr. McCune said.

Hundreds of antiviral compounds are being screened in both versions of the mice. Because the AIDS virus mutates rapidly, the researchers plan to test combinations of the most promising drugs.

At Stanford University, Dr. Edwin Mocarsky plans to infect mice with cytomegalovirus, an organism that can cause blindness in AIDS patients. At U.C.L.A., Dr. Irvin Chen is studying two human leukemia viruses to find out how the virus transforms human cells into a cancerous state.

Scientists at Systemix are beginning to implant other human organs in the mice, including lungs, intestines, pancreases, pituitary glands, skin, brain cells and placenta. The work is in very early stages, but so far the tissues have correct structural elements and a healthy blood supply, said Dr. McCune. "The only thing holding us back is having enough hours in the week to do the experiments," he said.

Certain brain cells and pituitary gland cells grow well in the mice, Dr. McCune said, as do beta cells and islet cells of the pancreas. But a major goal of the research, he said, is to isolate the human blood stem cell -- a master cell that gives rise to all the various types of blood and immune cells.

Possible stem cells will be inserted into mice whose human blood-forming system has been destroyed by radiation. Real stem cells should then disclose their identity by regenerating blood and immune cells. "You just can't do this experiment in people," Dr. McCune noted.

Human stem cells will be invaluable for gene therapy, he said, and for isolating blood growth factors for treating cancer and other diseases.

Dr. McCune said the research has not encountered any opposition from anti-abortion or animal rights groups. A Mouse With Tissues Of a Human When a deficient immune system gets implants of fetal thymus, liver and lymph nodes cells, the tissue is not rejected. Instead, the mouse's blood vessels nourish it, and human organs the size of blueberries develop. They function along with the organs of the mouse and make cells of the human immune system, including T-cells that circulate in the mouse's bloodstream and B-cells and other immune cells that reside in the liver and thymus. The mice can be used to study viral activity in human tissue and anti-viral drugs.

For the first time, scientists have created mice with fully functioning human immune systems by replacing the mice's bone marrow with human bone marrow. Researchers expect that the mice will be able to make human antibodies to order and could be testing grounds for vaccines and AIDS drugs.

The mice could be the missing link between test tube experiments, which often fail to reflect what happens in people, and studies in humans, which are expensive, difficult and often risky.

As far as their immune systems go, the mice are "humans with fur," Dr. Andrew Saxon, an immunologist at the University of California at Los Angeles, said in a telephone interview this week. Boon to AIDS Researchers

The mice could be particularly important to AIDS researchers because they produce the human immune system cells the AIDS virus attacks. Thus researchers could use them to speed the testing of vaccines and new drugs in experiments that would be too dangerous for humans. The mice could also be used as factories to make antibodies for transfer to humans to fight diseases.

Previous attempts to establish human immune systems in mice were of limited use because the methods were too complicated and because the immune systems did not function normally. But experts said they had high hopes for the new technique because it is simple and for the first time the mice produced a full array of circulating human immune cells.

The work, by Dr. Yair Reisner and his colleageus at the Weizmann Institute of Science in Rehovot, Israel, was reported today in the journal Science.

"This is really quite exciting," said Dr. Jerome Groopman, an AIDS researcher at the New England Deaconess Hospital in Boston. "It's a whole new field of biology."

Dr. George Santos, who directs the bone marrow transplant unit at Johns Hopkins University in Baltimore, agreed. "I really think it's an advance," he said.

The spongy red bone marrow makes red blood cells, which carry oxygen; platelets, which help blood clot, and the body's entire repertoire of disease-fighting white blood cells, the heart of the immune system.

Dr. Reisner and his colleagues began by destroying mice's own bone marrow cells with high doses of radiation. This erased the mice's immune systems so that the animals had no cells that could attack the foreign marrow, and also created a cavity in the marrow where new cells had room to grow.

Then, the scientists dripped human marrow cells into the slender veins of the mice. The human cells moved into the bones of the mice and took up residence there.

To help the mice survive until the human marrow began producing red blood cells, the mice were given transplants of mouse marrow from a strain whose marrow can make red blood cells and platelets but not white cells.

A past attempt to create mice with human immune systems was to transplant human fetal organs onto the kidneys of mice that are genetically incapable of making their own white blood cells. The fetal organs constituted an entire fetal immune system. But that approach proved tricky. It was hard to keep the mice alive, and even when the method worked, the human white blood cells remained in a puddle near the kidney.

A second method was to inject human white blood cells directly into the abdomens of mice that lack immune systems. But the transplanted cells lived for a just few months before petering out and never generated new cells.

The new method, said Dr. Saxon, has the advantage of being simple and easy for others to reproduce. The mice make circulating white blood cells, make antibodies and make new cells.

Dr. David Golde, an immunologist at the University of California at Los Angeles, said that it could even be possible to maintain immmune system cells in the mice and isolate those cells that are the best disease fighters. The idea, he said, would be to transplant your marrow into a mouse, train the white blood cells, take the cells out of the mice and put them back into yourself.

Dr. Groopman said he would like to see the mice used for two purposes. One, his own special interest, would be to study AIDS. Since the mice make white blood cells of the sort that the AIDS virus infects, it should be possible to study AIDS in the animals and to test AIDS drugs and vaccines in them. The virus that causes acquired immune deficiency syndrome only infects human cells.

A second possible boon would be to use the mice as factories to produce human antibodies to fight disease. Molecular biologists have found ways to isolate mouse cells that will churn out potent antibodies, but the use of these monoclonal antibodies that have one parent cell has been limited because people develop allergies to the mouse proteins

The next step, scientists said, is for others to repeat Dr. Reisner's experiments.

TWO groups of scientists working separately say they have prepared genetically altered mice that can be used to produce human disease-fighting antibodies of unusual purity.

In a technically daunting technique, the mice's own antibody-making genes were knocked out and replaced with the equivalent genes from humans. When such a mouse is injected with a foreign substance like a virus or bacterium, its immune system generates antibodies against the invader in the usual way, except that these are human and not mouse antibodies.

The advantage is that the antibodies, after being mass-produced outside the mouse by another method, called the hybridoma technique, can be injected into humans in hope that it will cause far less of an immune reaction than the mouse's own antibodies, which the human immune system attacks as a foreign protein.

To produce the antibodies in bulk, the mouse cells that produce them are removed from the spleen and fused in the test tube with a special kind of cancerous cell that immortalizes them. Each clone of cells produces a single, pure antibody, known as a monoclonal antibody. The procedure, known as the hybridoma technique, was invented in 1975 but until now has proceded in mice that made conventional mouse antibodies.

If the mouse-made human monoclonal antibodies work as well against diseases in people as laboratory tests indicate, researchers said, the findings could revitalize interest in using these antibodies as "guided missiles" against cancer, arthritis and other maladies.

Two Different Approaches

Scientists at two competing California biotechnology companies report that they have produced mice equipped to make the human antibodies.

In a report in the current issue of the journal Nature, scientists from GenPharm International in Mountain View, Calif., said cell lines from these so-called transgenic mice made antibodies that appeared so human that the human body should ignore them long enough to be medically useful.

"We are now routinely using our transgenic mouse system to generate a range of novel, completely human monoclonal antibodies and expect that many of these will have significant therapeutic potential," said Dr. Robert M. Kay, GenPharm's vice president for research and development.

The GenPharm team, led by Dr. Nils Lonberg, used a form of genetic targeting to remove major mouse immune system genes. The researchers also injected pieces of DNA containing human immune genes into single-cell mouse embryos and produced animals that carried the human genetic information. The report said the researchers mated the two kinds of mice and produced offspring that constituted a new strain with human antibody genes replacing almost all of the mouse antibody genes.

When members of this new strain were injected with a target protein, the report said, most of their antibody-making cells produced human antibodies. These "humanized" cells were then removed and cloned with tumor cells to make a cell line that produced pure human monoclonal antibodies, the researchers said.

Researchers from Cell Genesys Inc. in Foster City, Calif., in an article in the current issue of Nature Genetics, also said they had produced human monoclonal antibodies from mice, using a different approach. The reports from both research groups were submitted for publication within a week of each other last December.

The Cell Genesys researchers, led by Dr. Aya Jakobovits, used a technique called "yeast artificial chromosomes," or YAC, to place human immune system genes into their mice. With this method, the genetic material of yeast is used as a carrier for large human genes. The group used YAC's to fuse the human DNA into mouse embryo cells, and subsequent generations of the animals incorporated the human genetic material. Breeding these animals with others that had had their mouse immune genes removed produced a strain that made human antibodies, and cells from these animals were used to produce test-tube cultures of monoclonal antibodies, the report said.

A major question remaining about both developments is whether these antibody products retain enough mouse characteristics for the human body to see them as foreign, experts said.

While neither company would say specifically what types of monoclonal antibodies it was focusing on as potential therapeutic products, Cell Genesys said that some of its mice made antibodies to a protein involved in a number of acute inflammatory disorders, including tissue injury from trauma, and that other antibodies might be directed against allergic reactions. GenPharm officials said they had formed a partnership with a major drug company to investigate antibodies associated with cancer.

Shares in Protein Design Labs Inc. lost one-third of their value today following the company's announcement late Friday that its lead drug had failed in advanced clinical trials.

Protein Design shares tumbled $6.875, or 33 percent, to $13.875 in Nasdaq trading. The stock had reached a 52-week high of $26.75 earlier this year.

Protein Design, a biotechnology company based in Mountain View, Calif., and Hofmann-La Roche Inc., its corporate partner, announced after the market's close on Friday that their jointly developed monoclonal antibody, Zenapax, had not been effective in the prevention of graft-versus-host disease, a common complication involving the rejection of bone marrow transplants. Hofmann- La Roche, based in Nutley, N.J., is a unit of Roche Holdings Ltd. of Switzerland.

Roche said it planned to continue two Zenapax trials to evaluate the drug's efficacy in preventing acute rejection of kidney transplants.

Concerning the safety of the drug, the two companies said their preliminary analysis indicated that the safety profile for Zenapax associated with graft-versus-host disease was good, with only two reports of serious adverse effects.

Cary L. Queen, Protein Design's vice president for research, said in a telephone interview that it was difficult to extrapolate the prospects of the drug from a trial for one disease to another. "Graft-versus-host disease is a very difficult indication and has a very high mortality rate," he said. "We think kidney transplant is a less challenging indication." he said. Early trial data regarding kidney transplants was encouraging, the company said.

In the graft-versus-host trial, only one patient among 140 treated developed an immune response to the drug, Mr. Queen said. That indicated that Protein Design's technology for "humanizing" antibodies derived from mice was effective. The response to the so-called human anti-mouse antibody has limited the possible uses of traditional monoclonal antibodies.

The failure of Zenapax in graft-versus-host disease was "very surprising from the standpoint that Roche has been very bullish about this molecule in this indication and in kidney transplant," said Edmund Debler, an analyst with Mehta & Isaly. He noted that Roche had gone from a 24-patient study for the treatment of the disease to a 210-patient study for its prevention, an uncharacteristic jump for a large pharmaceutical company. "They went down the classic biotech path to a failed trial," he said.

Protein Design has two other monoclonal antibodies, both derived from humans, for the treatment of hepatitis B and cytomegalovirus, in a collaboration with Corange, the German pharmaceuticals conglomerate. Both of these molecules have been delayed by as much as one year in clinical trials because of difficulties in manufacturing.

Corange owns 15 percent of Protein Design Labs and Hofmann-La Roche 8 percent. Mr. Queen said the company has $110 million in cash.

Occasionally the digitization process introduces transcription errors or other problems; we are continuing to work to improve these archived versions.

A NUMBER of drug companies are pressing to develop an inflammation-blocking drug that will alleviate, without side effects, the symptoms of rheumatoid arthritis, a chronic disease that afflicts two million Americans. Such a drug could be worth hundreds of millions of dollars annually and might be prescribed to treat other autoimmune diseases like multiple sclerosis.

The aim is to suppress the activities of a protein known as tumor necrosis factor, or T.N.F., which normally helps jump-start the immune system but sometimes goes haywire. In the case of rheumatoid arthritis, T.N.F. starts a series of events that can result in irreversible damage to the body's joints.

In 1985 Dr. Bruce A. Beutler, now an investigator at the Howard Hughes Medical Institute and an associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, was one of the first scientists to isolate and clone T.N.F. Dr. Beutler has now received a patent covering what he contends is the most effective way to thwart the wayward protein.

There are several possible ways to block T.N.F. One is to administer monoclonal antibodies, large Y-shaped proteins that originate from the immune cells of mice. These antibodies bind to the T.N.F. and neutralize it. Centocor Inc. is taking this approach, as are other companies.

The problem with this method, Dr. Beutler contends, is that even when these antibodies have been "humanized," the body will recognize them as being foreign in origin and eventually will produce its own antibodies that will nullify any therapeutic effect. "Rheumatoid arthritis is a lifelong illness, so you need a drug that will work for years and years," Dr. Beutler said.

Dr. Beutler's approach is to splice two genes together to produce a new gene that codes for a Y-shaped molecule that is essentially an artificial monoclonal antibody. The two arms of the Y are T.N.F. receptors; the stem of the Y is a fragment of a normal human antibody.

"It's a thousand times more potent in neutralizing T.N.F. than a typical monoclonal antibody would be," Dr. Beutler said. "Another important advantage is that it is made of pieces of two molecules that already exist in the human body, so it is invisible to the immune system. It's very probable that this could be given indefinitely, just as human insulin is given to diabetics.

Hoffmann-LaRoche, a unit of Roche Holding Ltd., and the [Immunex Corporation] are testing a similar concept clinically; patent attorneys at both companies said they were not aware of Dr. Beutler's patent.

"We actually own the molecule -- or at least we think we do," Dr. Beutler said.

Ray Wheatley, director of technology transfer at the Southwestern Medical Center in Dallas, said the university had not spoken yet with any companies about the patent. "We haven't tried to market it yet, but our patent could be seen as being very powerful," he said.

Dr. Beutler, Karsten Peppel and David F. Crawford received patent 5,447,851, which was assigned to the University of Texas.

[...]

ALREADY, when you make a first impression, you are preparing the groove for a memory. And so I will remember Dr. Jan Moor-Jankowski, world expert in the scientific use of chimpanzees, standing in a doorway, in a stiff rather military dress jacket with brass buttons, with a portable telephone in each hand, his tall body at peace somehow with the low ceilings and walls of this early 19th century whaler's cottage in Orient.

I did not know how I would feel about the moral issues involved in his kind of animal testing. He had done some of the ground-breaking work that allowed monkeys and apes to survive and to breed in a medical testing environment. He also was a central figure in a significant libel case, defending the right of letters to the editor to the protection of the First Amendment. And he was also a key person in a dispute with New York University, which gave his laboratory in Sterling Forest, N.Y., to his arch foe in the world of animal experimentation and dismissed him from his post as director.

Before the late 50s, when Jan came onto the scene, most work with monkeys had been behavioral. Monkeys were usually allowed to die once experimentation was done, and many died along the way from diseases.

Jan, who became the director of the World Health Organization's Collaborating Center for Hematology in Primate Animals, designed cages based on the wire-bottomed chicken coops then in use in America, so apes and monkeys could be kept away from their feces.

A medically trained physician, he was committed to creating conditions as humane as possible during the testing situations. He was, from the beginning, opposed to using primates in toxicology studies and for the testing of cosmetics, to any waste of animal life in an area of research he hopes will grow extinct as more and more tissue cultures can be substituted for live animals.

He himself, as a medical doctor in research, had made some important contributions in discovering that not only the red cells but the blood serums and white cells contain antigens that create immune responses in mice, monkeys and men.

Together with Alexander Wiener, the discoverer of the Rh factor, Jan's exploration of blood groupings in primates helped pave the way for the first successful test of a vaccine for Hepatitis B, conducted at his laboratory.

His work would continue to be in the area of blood diseases, where non-human primates, even when they are infected with AIDS or hepatitis, do not develop symptoms or die. So it is mostly the enforced isolation and distortion of their natural life that creates the hard choices for scientists.

But this was not all to Jan Moor-Jankowski. He had been one of those lesser known of the Polish Resistance rescuing Jews. He was given the French Government's Cross of Merit for this, as well as for his scientific discoveries.

As the editor of the Journal of Medical Primatology, he had stood up for his right to publish a letter by an animal rights activist, criticizing a multinational pharmaceutical corporation.

His victory in the seven-year Immuno A.G. Corporation libel suit that was leveled against him is considered a landmark in judicial interpretation of First Amendment rights as they apply to letters to the editor, and the case is often cited in libel defense litigation today.

In the weeks to follow I would talk to Suzanne Roy of the California-based In Defense of Animals, and would find out that many in the animal activist community considered him a kingpin in the battle between animal advocates and an often impenetrable medical research front. But right now I would have something far more complicated and confusing to try to unravel. "You will see that I am in the middle of a critical moment. I will explain," Jan said, as I entered his house, taking one of the two portable telephones momentarily away from his ear.

It would take a little while for Jan's side of the story to come, and still it seems as if there must be much more to it.

"The laboratory that I founded and directed for 30 years was taken away from me last August," Jan said when he got off the phone. It was a laboratory run under the administration of New York University, where Jan had enjoyed 30 years on their research staff.

The trouble began, Jan said, with a telephone call from an animal activist group, the California-based In Defense of Animals, accusing Jan's Sterling Forest Laboratory for Experimental Medicine and Surgery in Primates, known as Lemsip, of the deaths of three monkeys after improper surgery.

When Jan realized that the accusations referred to another New York University laboratory, adjacent to his, he began to investigate.

The experiments in question, conducted at the Institute of Environmental Medicine, involved giving monkeys crack, a practice Jan feels is exploitative and cruel to the animals, and even scientifically cannot yield any meaningful results.

Jan told the Department of Agriculture what he knew when their investigators came to him mistakenly because of the complainants' confusion as to where the experiments were taking place. When the medical school's oversight committee asked that the charges be handled internally, Jan said, he resigned because he felt the committee was trying to cover up the charges.

On Aug. 8, 1995, shortly after Jan was elected to the French Academy of Medicine, to take Linus Pauling's place, the Department of Agriculture faxed the president of New York University to say that a whistle blower investigation had begun. The next day, Jan's employment was terminated without notice or written explanation, he says.

What further complicates the case is that Lemsip -- well-liked even by many animal activists for the pains taken for the chimpanzees' quality of life -- is being given away. It will go to Dr. Frederick Coulston, a toxicologist who works a great deal with cosmetics and industrial chemicals, and who, during the libel suit against Moor-Jankowski, supported Immuno.

According to Dan Perkes of the public relations office of New York University's medical school: "In this changing era of medical care, with the decreases in income impacting all medical centers, they had thought it prudent to unload Lemsip. They couldn't afford to keep it. Moor-Jankowski went along with the facility, when the resposibility for running it was turned over to Coulston."

Officially the changeover will not occur until this August. Why then was Jan dismissed a year earlier?

"The Aaron Diamond AIDS Research Center, already affiliated with New York University, had wanted to take it over, and they would have retained me," Jan said. "I also had already formed a group of scientists who were willing and able to take it over."

Jan tells me that because of his whistle-blowing activity he is now deprived of invaluable laboratory notes that he and Alexander Wiener made together, of his own laboratory protocols, unpublished manuscripts and books, as well as the frozen biological reagents accumulated in the course of 30 years.

Recently the Department of Agriculture dismissed the whistle blowing charges as groundless. For New York University this is proof of the insubstantiality of Jan's case. For Jan it is further evidence of the way that power and money -- the industrial complex allegedly behind Dr. Coulston's kind of research -- obstruct academic freedom and justice.

As I sit in Jan's dining room a foot-fall away from the secret room, with only a few loose boards for an entry -- he suspects it had been used in a boat route by the Underground Railway to transport slaves through Orient to Canada -- I think about the complex issues in university-administered research situations, of who owns what in this sort of "over-seeing," especially when grant money is frequently raised by the scientists themselves.

As we move from his quarrels with New York University into issues of animal ethics, my eye rests on the dried bittersweet in the window, and dried leaves no one else would have thought to make beautiful, aglow in the late afternoon sun.

I am immediately upset when he tells me that although he would not use the heart of a chimpanzee for transplant, he would use the heart of a baboon.

This valuing of life according to its closeness to what is human will continue to trouble me as he tells me over a lunch -- that does include meat -- that ever since he was 5 years old, growing up in the town of Czestochowa in Poland, he had known that he would go into medical research.

Three of his uncles were doctors. But when his aunt was dying of cancer and he asked them why they couldn't help, they told him there were things that doctors didn't yet know.

A sadness comes over him when he talks of a childhood filled with music and art that was ruptured so suddenly when the Nazis took over, as he talks of his mother, who had trained as a concert pianist, bringing small chamber groups into their house. His father, an engineer, was the sort of man who used to ball out drivers for beating their horses, he says.

When the Germans invaded Poland, Jan immediately volunteered to fight in the resistance, and was injured trying to defend Warsaw's main railroad station.

The years that followed were ones of repeated injury and periodic interment, as he worked to create escape routes for Jews from the burned-out Warsaw Ghetto at a time when the Polish Underground was reluctant to allow people to hide in its units in the forest. He went from one set of false identity papers to another, even masquerading for a while as a German officer, helped by the knowledge of the language he had acquired in childhood.

"When the war came and nobody knew whether and how long one would survive," he says, "people cast aside formal religious and social taboos. There was a general feeling that if one should die there would be at least a child who would live on."

He became the father of a son he saw once, when the baby was two weeks old. He wasn't to see him again for 35 years.

I listen to the stories of how he eventually escaped to Switzerland, where he was able to pursue his medical studies. He had managed to get his matura or high school equivalency in the schools run secretly by the Underground, after all the official schools were closed.

It was a time when refugees were not well looked upon in Switzerland, and despite his good school record the only work that he could get was in the high mountains, studying the blood groups of the people "who clung to their fields, which were so steep there was no way to use a tractor, but they loved their freedom."

When he was working in Cambridge he began to experiment on himself. He was injecting himself with the red cells of some monkeys that a friend who had finished a behavioral research project had given to him.

Friends discovered this and told him that if he submitted a request to an appropriate agency in the United States, he would be given a group of prisoners to work with. He spent a sleepless night thinking about what it meant to be subjected to experimentation involuntarily. It was then that he decided to learn all that he could about monkeys and apes, the closest relatives to human beings.

I struggle with my feelings as I watch the Lemsip video Jan has given me.

I watch a chimpanzee with a toothbrush in one hand and a mirror in the other. I watch baby chimpanzees in diapers and humanized clothing being held lovingly and learning to do human things. I ponder Jan's telling me that it was when he saw this behavior he knew that he couldn't take a chimpanzee heart.

Then the video flashes to the separated cages with bars on all sides, so the animals can see one another at all times.

"It's not that I have a right to do this to you," James Mahoney, the veterinarian who is Lemsip's daily director says, large on the video screen. "Only that I need you. Therefore I owe it to you to make it up to you as best I can."

No matter how costly it is to care for chimpanzees in captivity, Jan feels it is his moral responsibility to provide them with as close as possible to a "normal" life within the isolation that being infected demands.

I think of the words of Suzanne Roy of In Defense of Animals who had said, when I called her: "We disagree on the most basic philosophical issues. But once we have agreed to disagree, we are able to work with each other on common ground."

There is a moment, only, when in the course of a seven-hour visit that Jan grows very tired and has to lie down. I too am very tired, I realize, for interwoven with the current legal situation is the case with Immuno -- the seven years of libel trials, the expenditure of $200,000 and much of his own research time.

In 1983, as the editor of the Journal of Medical Primatology, he had published a letter to the editor written by Dr. Shirley McGreal, the chairwoman of the International Primate Protection League, questioning a plan to do research with chimpanzees in Sierra Leone in a study of hepatitis proposed by Immuno A.G.

McGreal's letter had argued that Immuno's plan violated international accords for the protection of endangered species, while keeping the chimpanzees in Africa instead of importing them for study very cleverly circumvented international trade agreements.

She expressed her concern about the way baby chimpanzees are captured by killing their mothers and about whether the infected animals would be returned to the wild, with no proper plans made for them after their use

McGreal's insurance company, having spent more than $100,000, settled "for her, against her will," Jan says, The uninsured publishers also decided to settle. Jan continued to fight.

The case shuttled two times to the United States Supreme Court and back down, as well to courts in Sierra Leone and Vienna. In June of 1991 Justice Judith Kaye of the New York State Court of Appeals issued the final decision that opinion, as it was expressed in letters to the editor, could not be subjected to silencing.

Interestingly, among the 34 groups that backed Jan in court -- CBS, NBC, The New York Times and Time, as well as many major universities, environmental, civil rights, and animal welfare organizations among them -- there was not one big scientific organization or medical society.

On Nov. 9, 1994, Jan was given the William J. Brennan, Jr. Defense of Freedom Award by the Libel Resource Center.

Jan's eyes are steady, as we return to the issues of academic freedom and his disillusionment, as a European, with the way academic freedom is often taken away in America.

Even as I can feel the pressure of a battle with New York University beginning again, and he tells me of the real pain of his war injuries, ever with him -- why, I ask him, does he emanate such a centeredness and calm?

"It comes from the time I spent living under the Nazis, and the fact that I was lucky in that even though I was occasionally captured, I always had the opportunity to fight back," he says steadily, looking at me.

For the first time, geneticists have made mice whose cells contain whole, functional human chromosomes along with their own mouse DNA, allowing the mice to make a range of human proteins potentially useful against cancer, autoimmune diseases and infections.

Scientists said they were shocked that such large chunks of human genetic material could be put into mice with no apparent ill effects to the animals, and equally surprised that the large human chromosomes functioned normally in the mice.

"It's stunning," said Howard Petrie, director of the monoclonal antibody core facility at Memorial Sloan-Kettering Cancer Center. "The sheer impact of transferring a piece of DNA that big is amazing. It opens up a whole array of things that can be done."

Petrie said the work, conducted in Japan, suggests that mice or other animals may someday be engineered to mass-produce various therapeutic products -- such as human antibodies -- that often are not made in sufficiently high quantities to cure diseases in people. In high enough doses, antibodies can shrink tumors and can interfere with the reactions that cause autoimmune diseases such as rheumatoid arthritis. They can also kill bacteria and viruses.

Other scientists said the chromosome transplant technique could help them study in mice the key genes involved in human embryo development. Still others said the method could facilitate research on genes that cause inherited diseases. The transferred chromosomes hold as many as 1,000 genes each -- more than 50 times the amount of genetic material ever before transferred from a human to a mouse.

"Its very elegant work," said John Harrington, a geneticist at Case Western Reserve University and a vice president at Cleveland-based Athersis, a biotechnology company that recently made news for its creation of the first artificial human chromosomes.

"It suggests that human artificial chromosomes could also be transferred to mice and perhaps to other animals as well," Harrington said. For example, artificial chromosomes could be designed to carry specific human genes, such as those that help make virus-fighting proteins. A colony of mice endowed with such chromosomes might make vast quantities of the therapeutic proteins in their blood, which could then be purified and given to people suffering from viral infections.

Scientists have made incremental progress over the years getting larger and larger pieces of human DNA into laboratory animals, especially mice. The standard technique is to transfer the human DNA into mouse embryo cells, which are then implanted into the wombs of female mice. The resulting newborn mice bear the transferred human genes.

But only a limited amount of DNA can be transferred using standard techniques. Mice given some, but not all, of the genes needed to make human antibodies end up making hybrid antibodies that are part human and part mouse. These hybrids have mostly proved disappointing when injected into sick people, because the mouse portions are recognized as foreign by these patients' immune systems and are destroyed.

In the new work, led by Kazuma Tomizuka of the Kirin Brewery Technology Laboratory in Yokohama, researchers moved entire human chromosomes into mouse embryo cells by fusing human skin cells to mouse embryo cells. The researchers kept the embryo cells that captured human chromosomes 14 and 22, which together contain the genes necessary to make human antibodies, and implanted those cells into female mice.

The resulting newborns produced antibodies made of human components when the scientists gave them a shot of a foreign protein, showing that the transplanted genes were working normally, the researchers report in the June issue of Nature Genetics, released yesterday.

Using a different technique, a company called Cell Genesys in Foster City, Calif., recently made completely human antibodies in mice. Their method allows mice to make only a limited variety of human antibodies, however, and does not transfer the extra chromosomal portions that ensure the antibodies get made only in the spleen and thymus, as the Japanese method does. Those are the organs where antibodies are produced in people -- a detail that may be important to their proper function. In the Japanese experiments, several human genes worked only where they should. For example, genes that normally operate only in liver cells became active only in the liver cells of the mice. That indicates that the complex genetic machinery that regulates when and where a gene should work arrived in working order along with the genes themselves on the transferred human chromosomes.

But Stanford University immunologist Ronald Levy said the Japanese did not "knock out" the mouse's own antibody genes, which Cell Genesys did. That means the Japanese mice may be making both mouse and human antibodies, and the human ones may have to be purified from the mixture before being given to patients.

In separate experiments, the Japanese team showed that human chromosome pieces can in some cases be passed on to the offspring of humanized mice, a surprising finding because extra chromosomes typically interfere with reproduction.

Mice normally have 40 chromosomes, but those given human chromosomes had more. In one case, one of the mouse chromosomes mysteriously got lost in the process. That mouse was born with shrunken testicles because the mouse chromosome that got lost was the male-determining Y chromosome.