History Museum of CIEA

History Museum of CIEA

The Central Institute for Experimental Animals (CIEA) is a global leader in the in vivo experimental medical arena. It is a very unique, independent organization that has never been controlled by a government organization, educational institution or a private company. This museum introduces the history of CIEA that extends to almost 70 years, together with various interesting events that have actually taken place over the decades.

1)The Very Beginning

Age Matters
1947 Tatsuji Nomura’s mother Masuko and sister Michiko started to rear mice as laboratory animals in their house.
1951 Kyoji Ando and Yoshio Tajima established the Experimental Animal Research Association.
1952 The Central Laboratory for Experimental Animals (CLEA) was established in Nishitama, Tokyo. Masuko and Michiko Nomura succeeded in establishing the Mongolian Gerbil as a laboratory animal.
1954 Supply of pelleted diet started.
左から安東、田嶋、野村
Tatsuji Nomura (right standing), Dr. Tajima (center) and Dr. Ando (left), at the time when the Central Laboratory for Experimental Animals was originally established

There are certain moments in life that could decide your destiny.
In the case of the current CIEA Chairman Tatsuji Nomura, that very moment came when he was having a conversation with Dr. Koji Ando of the Tokyo University Epidemic Disease Research Institute. Dr. Ando was his well revered boss at his workplace who continued to be his mentor in life for many years to come. One day, Dr. Ando said to Tatsuji, “I admit that there is great meaning in continuing your medical studies and making new discoveries through your research. But you could also go another way and upgrade the level of the laboratory animals you are currently using. By doing so, you can raise the entire level of medical research in Japan as a nation. So, which way will you go?”
That question was raised only five or six years after World War II when the completely battered country of Japan was still trying to rise from the devastating aftermath of the war. Those were the days when people had barely enough to eat. Consequently, laboratory animals were more like wild animals that happened to be bred by farmers as a side job. Thus, quality was beyond question.
Against such a backdrop, Tatsuji Nomura gave up his medical research and became an experimental animal breeder in 1954.

But Tatsuji actually had a good reason to become an animal breeder.

How and when did Tatsuji get acquainted with those animals for the first time?

Let us trace back to the very beginning of where everything started.

The Encounter

大磯にあった旧野村邸
The former Nomura residence in Oiso

In 1945, Tatsuji graduated from the School of Science of Keio University. His career was guaranteed at the Epidemic Disease Research Institute (current Institute of Medical Science) of the University of Tokyo. But due to some health problems, he was forced to take leave and rest at home for a while. While recuperating, he thought of his work as a researcher. As he dreamed on, he suddenly realized just how many laboratory animals he would need in his studies. His dream was unrealistic considering the horrendously expensive price of the animals. Those were the times just after World War II when there was a severe shortage of everything. He also recognized that he was very unlikely to be given a chance of even getting close to those rare laboratory animals. After all, he was merely a young medical student fresh out of school and the most junior at the workplace.

Agonizing over this dilemma, he eventually hit upon the idea of breeding those animals himself while he was still resting at home in the seaside town of Oiso. Hearing his idea, a sympathetic close friend brought him three pairs of mice. Tatsuji's mother, a great animal lover, took over the mice and started breeding them at home.

This was how the Nomura Family started raising laboratory animals.

In fact, the close friend who brought Tatsuji the first three pairs of mice was Ms. Hisako Mitsui, who later became Tatsuji's beloved wife.

Dr. Ando, Dr. Tajima and the Experimental Animal Research Association

安東洪次博士
Dr. Koji Ando

After some years, Tatsuji eventually went back to work for the Epidemic Disease Research Institute at Tokyo University, his original workplace.



田嶋両博士
Dr. Yoshio Tajima

There, he entered Dr. Koji Ando’s laboratory. Before and during World War II, Dr. Ando had worked at an upscale research institute in mainland China. Never having to worry about money, food or his work environment, Dr. Ando was taken aback by the dire poverty of his country upon returning. The inferior breeding conditions of the laboratory animals were especially overwhelming: Rabbits and mice died one after another, sitting in their many layers of excretions and bedding hay. Urged by a sense of need to do something about the situation, Dr. Ando consulted Dr. Yoshio Tajima, an old-time friend from his time in China.. Dr. Tajima happened to be working at the National Institute of Infectious Diseases located in the same building as Dr. Ando’s lab. He had a similar past as Dr. Ando, and had conducted studies in China receiving ample funding and breeding his own high-quality laboratory animals. He thus shared the same feelings and need as Dr. Ando, and the two doctors soon established the Experimental Animal Research Association in 1951.

Central Laboratory for Experimental Animals Established in Mizuho Town, Nishi-Tama County

Led by Dr. Ando and Dr. Tajima, the Experimental Animal Research Association preached the importance of improving the breeding environment of animals. It also stressed the need to provide high-quality laboratory animals to society. Such a stance and philosophy of the Experimental Animal Research Association was put into action by the Central Laboratory for Experimental Animals (CLEA), the private institution established by the Nomura family. Upon construction, Tatsuji's father Shunkichi Nomura provided the funding for the machinery. Meanwhile, Tatsuji's youngest brother Ryozo Matsukata prepared the necessary capital for the actual facility. Built within Ryozo’s farmland in 1952, CLEA took over the work of breeding mice that had so far been done by the Nomura family in Oiso. CLEA also started developing a pelleted diet and breeding containers to carry and deliver the reared animals to the clients.

かつて西多摩郡瑞穂町にあった実験動物中央研究所
CLEA in Mizuho Town

Masuko and Michiko

野村達次の母 故 増子
Tatsuji’s mother Masuko

The existence of Tatsuji's mother Masuko and his elder sister Michiko, should not be forgotten in the history of CIEA. They were the two women who played a vital role in the early years of bringing up CIEA’s laboratory animals.
While Japan was still rising from the ashes, Masuko and Michiko started breeding mice at their home, once an elegant summer home of the Edo era ruler Tokugawa. Warming the breeding room with a briquette stove when any heating means for humans were still lacking, they even turned their huge Western garden into a vegetable patch for growing feed for the mice.


野村達次の姉 美智子
Tatsuji’s elder sister Michiko

Bringing up the animals with utmost care, the ‘Nomura mice’ had become prime-quality laboratory animals by the time they were sent to CLEA’s newly constructed facility in 1952. Masuko’s close observation of animal behavior also became the precious base data for CLEA, upon its production and supply start of a pelleted diet.
After all the mice at the Nomura home in Oiso had been moved to Ryozo’s farm, Masuko and Michiko turned to other animals, assessing the possibility of establishing new laboratory animals. The Mongolian Gerbil, which later became a popular experimental animal in the US and Europe, was one such species they succeeded in establishing after seven years of trial and error.

1973年になって紹介されたスナネズミの歴史(朝日新聞5月11日朝刊)
The history of The Mongolian Gerbil(Introduced in the morning newspaper article of Asahi, May 11th 1973)

2)Institutionalization

Age Matters
1956 Contract commenced with the US Military 406 Medical General Laboratory to supply 60,000 mice and 12,000 kg of diet annually.
1957 The Central Laboratory for Experimental Animals was established as a nonprofit organization under the direct control of the Ministry of Education.

Contract with the US Military discontinued.
Major salmonellosis outbreak occurred.
1958 Rearing facilities constructed in grounds of Tatsuji Nomura’s house for maintenance of mouse breeding stock. Aoyama branch opened.
1959 Meguro Branch opened.
Oizumi Branch (Gunma Prefecture) opened.
All colonies in Nishitama were disposed of as elimination of salmonellosis was impossible. The Nishitama facilities were closed and demolished.
Production of Wistar strain rats was discontinued because of a fire in rearing facilities in the Oizumi Branch.
1960 Grant received from the US National Institute of Health.
1961 First Specific Pathogen-free (SPF) animal facility completed in Meguro.
1962 SPF animal production facilities completed in Nogawa, Kawasaki.
SPF mouse breeding stock imported from the United States. SPF mouse production started in Nogawa.

Tatsuji’s Decision and the Large Order from the US Military Facility

In 1953, the Silver Hamsters that the Nomura family had raised with utmost care all died at CLEA, due to the inexperienced breeding skill of the laboratory staff. This incident becomes the very moment in life for Tatsuji to decide whether he should continue being a medical researcher or choose to become a laboratory animal breeder.
After continuously being preached the importance of raising the level of laboratory animals in Japan by Dr. Ando, the boss of his workplace and leader in life, Tatsuji decided to become the latter in 1954.
The decision was not an easy one, though, and as Tatsuji started knocking on the doors of medical schools, laboratories, pharmaceutical companies and so on, he found himself being looked down upon and ordered to come through from the back door. Even his former colleagues from school or work talked nastily about Tatsuji, saying that “he’s just indulging in his pastime,” or “he’s given up research to make money by rearing those animals.” But then, a helping hand was extended. As Tatsuji continued his visits, he ran into the US Military 406 Medical General Laboratory. The staff there appreciated the premium quality of the Guinea pigs that Tatsuji brought in, and rated them as being “platinum class.” By 1955, the US facility therefore requested CLEA to supply 60,000 mice and 12 tons of diet on an annual basis. This was a massive order reaching a total of 7.2 million yen.

Institutionalization of CLEA and the Closing and Demolition of the Mizuho Town Facility

実中研の寄附行為
Donations of CIEA
実中研設立許可申請書
Establishment license application of CIEA

In response to such a generous order from the US Military facility, construction work progressed at CLEA in Mizuho Town to expand its breeding buildings and improve its facilities. For the first time, the local bank also agreed to lend money without any mortgage. Backed by such tailwind, people around Tatsuji started suggesting that he should turn CLEA into a legally approved institution. Against such a backdrop, the Central Laboratory of Experimental Animals becomes a formal foundation on August 6th, 1957 by appointing Dr. Koji Ando as its Representative Director, and Tatsuji Nomura as its Director. It was a humble foundation however, with most of its paid-in capital of 5.99 million yen being in the form of the already used property and buildings borrowed from Tatsuji's father and brother. Meanwhile, the remaining minor monetary contributions were collected from Tatsuji’s friends.

Last Resort

Just as CLEA was institutionalized, the US Military abruptly terminated its contract. Two months later in October, 1957, salmonellosis germs brought in from elsewhere quickly spread among the CLEA mice. Consequently, the laboratory was forced to put down 6,000 mice in October, 1958. They then had to euthanize another 5,000 in September, 1959. Even so, the breakout could not be stopped. Thus the Mizuho Town facility was soon forced to be closed and demolished.

The saved handful of healthy breeding stock was evacuated to a small rearing hut hastily built on the land where Tatsuji’s residence stood. Tatsuji considered this place as his last resort. Concurrently, CLEA staff began searching for new land suitable for the production of large numbers of laboratory mice.
By July, 1959, a new breeding facility was constructed in Oizumi Town of Gunma Prefecture. In order to prevent rats from being infected with salmonellosis, they were also transferred to the new facility together with the evacuated mice.
But then in December, another disaster struck. This time, the rat breeding building was burnt to ashes by a fire.

Pelleted Diet: The Savior

Going through one disaster after another, CLEA was not in any condition to breed or sell laboratory animals on a regular basis. Worse, the existence of the laboratory itself was being questioned. Luckily, however, CLEA was rescued by the success of its pelleted diet. Ever since being institutionalized in 1957, the production and sales of CLEA’s original animal feed grew steadily, from a monthly supply of five tons in the beginning that came to exceed eight tons by 1960. Sales figures were also favorable for the pelleted diet, and while the sales profit of laboratory animals in 1957 was a mere 2.28 million yen, the profit for the pelleted diet reached 3.47 million yen. The sales for the pelleted diet exceeded that of the experimental animal sales, which was a trend that continued for almost a decade.

飼料製造のために、野村達次が浅草で購入したタイプの石鹸製造機。写真は1912年当時、実際に石鹸を製造している現場の様子。
The soap-making machine originally used for producing the pelleted diet. Someone had found it at a wholesaler in Asakusa. Courtesy: Kao Corporation

Towards the Production of Specific Pathogen free Animals

SPFラット(SD系統)
SPF Mouse and SPF Rat

In 1958, CLEA’s Dr. Ando attended the First International Conference on Experimental Animals in Paris. There, he found out that the US and the UK were already joining hands to start full-fledged production of SPF (Specific Pathogen Free) animals. Determined not to be left behind by such a trend, CLEA also decided to establish and supply SPF animals. But to do so, there was a need to build a proper facility with strict sanitary and hygiene conditions. This required a lot of money, which CLEA did not have.
Stuck in such a predicament, a helping hand was extended again from the US. This time, help came from the NIH (National Institutes of Health). NIH suggested to offer CLEA a total of 42.7 million yen assistance for four years, starting from 1959. This encouraged CLEA to take further action, and in Japan, it negotiated with the Science and Technology Agency to receive a total funding of 30.12 million yen up until 1962. Furthermore, CLEA turned to the Japanese business community and was able to receive a total of 81.8 million yen of contributions by 1964.

The First SPF Facility of CLEA

In June, 1961, the first SPF facility was completed in Meguro. Incorporating an eye-catching innovative cylindrical design, this two-storied concrete building occupied a total floor space of 390 ㎡. The disinfection and sterilization area was located to the right of the second floor, whereas the clean room was to the left. The clean room had a vinyl isolator for breeding germfree mice. In order to maintain a completely aseptic condition, everything sent into the clean room was disinfected or sterilized, including air, people, tools, water and feed.
After being grown for several weeks, baby mice in the clean room were transferred to the SPF vinyl isolator. There, they were colonized with specific microflara and became SPF mice.

目黒に完成した斬新なデザインのSPF施設とその内部の間取り
The eye-catching cylindrical SPF facility constructed in Meguro

The New SPF Facility in Nogawa

川崎市野川のSPF生産施設
The new SPF animal production facility in Nogawa, Kawasaki City

The SPF animal production facility in Nogawa was established in May, 1962. This facility was to produce and breed SPF mice on a greater scale. But things did not go as planned there. Upon birth, the weight of prenatal fetus is only around 1.5 grams. Being so tiny, the staff had great difficulty in taking it out from the mother’s uterus by caesarean section. Without the breeding stock being germfree, no SPF mouse production system could possibly be established. Under such critical circumstances, CLEA issues an urgent order for 40 germfree mice to be imported from the US.
In contrast, no such problems occurred for rats that are around 10 times larger than mice. Hence their artificial nursing went smoothly, and CLEA had established their germfree breeding skill by 1965.

3)The Development

Age Matters
1963 Supply of SPF mice started.
Her Imperial Highness Princess Chichibu visited Nogawa Branch.
Artificial nursing of rats achieved.
1964 Establishment of diet and environmental control and microbiologic testing methods for SPF animals.
Production of 20,000 SPF mice a month achieved.
Supply of SPF rats started.
Managing Director Kyoji Ando receives the Medal of Honor with Purple Ribbon from the Japanese Government.
Monthly production of diet reaches 60 tons.
1965 Production/supply divisions separated to form the business entity, CLEA Japan Inc.
Tatsuji Nomura is awarded the First Saburo Kojima Memorial Culture Prize.
1965~1970 Collaborative research with Armour Co. in the US.
1966 Reproduction and rearing of germfree animals achieved.
Tatsuji Nomura becomes Director of CLEA.
Medical Research Division established.
Collaborative research with National Institute of Health (NIH) and Michigan University.

R&D activities at CLEA started becoming very active from around 1963, when the production and sales of laboratory animals and pelleted diet finally went on track. Establishing the Medical Research Department in 1966, CLEA started to aggressively exploit the pre-clinical research area that contributes to the medical research and treatment of humankind.

Establishment of CLEA Japan Inc.

The start of the full-fledged operation of the SPF animal production facility in Nogawa pushed up the production number of laboratory animals and pelleted diet. In figures, the supply number of mice reached 150,000 in 1963, 120,000 of rats, and 410 tons for pelleted diet. By 1964, the figures rose sharply to 250,000 for mice, 150,000 of rats and 543 tons for pelleted diet.
Consequently, the financial conditions of CLEA greatly improved, and the institution came to mark a 180 million yen profit by 1964. Out of the total, 140 million was churned out by its business-operating divisions, while the non-profit sectors marked a total profit of 36 million yen. In total, the surplus reached almost 7 million yen.
Legally speaking, however, a foundation should be non-profit. Hence, the business operating departments were separated from the activities of CLEA to form CLEA Japan Inc. in February, 1965.

日本クレアのロゴマーク
Logo of CLEA Japan Inc.

Thalidomide

サリドマイド事件

It is ironic that the strong growth of CLEA in the latter half of 1960s is owed greatly to the Thalidomide Scandal. Thalidomide was a sleeping tablet released by a West German pharmaceutical company in 1957. To the shock of the international society, many children with malformed arms were born from mothers who took Thalidomide in their early stages of pregnancy. In Japan, 936 such children were born in the five years from 1958, when Thalidomide was first released in Japan, until 1963, when its production was finally stopped.
This was the first time in medical history that humans found out that drugs did not only harm the actual persons who took the dose but also those beyond, which in this case were the fetuses.
Hence in April, 1964, the Ministry of Health issued a notice of obligation to all pharmaceutical producers, requesting them to attach a document of proof on having conducted appropriate animal tests, whenever they applied for the approval and release of any new drug. In response to this legal decision, all pharmaceutical companies in Japan scrambled to arrange their own experimental animal facilities. This followed with the request of a large volume of high-quality laboratory animals, and CLEA consequently came to receive large orders from them.

Dr. Yanagita‘s active and establishment of Basic Research Division of Medicine

野川に完成した研究棟
Research Building Completed in Nogawa

A movement to consolidate a full-fledged research system arises, together with the progress of CLEA. One move was to change the English name from the Central Laboratory for Experimental Animals (CLEA) to the Central Institute for Experimental Animals (CIEA).
Another significant move was the establishment of the Medical Research Department in 1966 by inviting Dr. Tomoji Yanagita, a post graduate of the University of Michigan who had specialized in the areas of drug dependence and psychopharmacology, and was already world-renowned for developing a machine that could measure an animal’s “quest for drugs.”
Dr. Yanagita actively promoted joint research with American universities, received consignment study requests from overseas pharmaceutical companies, and conducted long-term joint studies with the World Health Organization (WHO). The Medical Research Department became more independent with the construction of the research facility in Nogawa in 1968. Its R&D activities progressed further from 1969 onwards in the five areas of reproductive physiology, pharmacology, psychopharmacology, pathological toxicology and clinical pharmacology.
Despite such expansion in the research area, CIEA always focused its activities in the “preclinical area,” thereby studying the cause and cure of human diseases by using laboratory animals. To date, this basic principle of CIEA remains unchanged.

Long-Term Support of the Ford Foundation and the Research on Monkeys

Approaching the Ford Foundation by selecting the study on monkeys as its main theme, CIEA succeeded to receive a generous ten-year grant in 1967 that totaled to US $100,000. In its second-term contract with the Ford Foundation that started from the autumn of 1972, CIEA planned to turn Japanese Monkeys into laboratory animals by constructing their colony away from humans and other animals. Selected as the proposed location was an unmanned island called Edateku, far off the Amami Oshima coast. This plan had to be cancelled abruptly, however, as the island became subject for tourism development, followed by another plan to build an oil refinery plant there.
Various voluntary research projects on small- to medium-sized monkeys were continued at CIEA even after the contract with the Ford Foundation ended in 1977. But costs of commodities and manpower were high in Japan, and production fees became astronomical. Hence, CIEA’s action to turn monkeys into an experimental animal stagnated until artificial breeding of crab-eating Macaques were commenced in 1988 on an unmanned island in Indonesia.

4)The Challenge

Age Matters
1967 Name changed from CLEA to CIEA (Central Institute for Experimental Animals).
Koji Ando, Director Emeritus, was awarded the Order of the Sacred Treasure, Gold Rays with Neck Ribbon.
Research grant from the US Ford Foundation commenced (US$100,000 over 10 years).
1969 International Council for Laboratory Animal Science (ICLAS) International Laboratory Animals Asian Pacific Meeting Secretariat established.
Gnotobiotes Research Facilities completed in Nogawa, Kawasaki.
1970 Japan EDM Co. Ltd. established.
Collaborative research with Ciba-Geigy in Switzerland.
Collaborative research with Schering Plough in the US.
Collaborative research with the World Health Organization (WHO).
1971 Tatsuji Nomura becomes Japan’s Representative in ICLAS.
1972 Tatsuji Nomura becomes a member of the ICLAS Board of Directors.
Tatsuji Nomura becomes Treasurer of ICLAS.
Yoshio Tajima, Technical Consultant is awarded the Medal of Honor with Purple Ribbon.
Muneo Saito, Technical Researcher is awarded the Mainichi Industrial Technology Prize.
1973 Biosciences Research Division established.
1974 Microbiology Building completed in Nogawa. Successful establishment of the rock rabbit as a laboratory animal.
1975 All divisions are brought together in Nogawa with the completion of research facilities.
Leukocytosis phenomenon observed in nude mice for the first time in the world.
Tatsuji Nomura receives the highest merit award of the Japan Medical Association.
Nude mouse production reaches 10,000.
1976 The 2nd International Workshop on Nude Mice was held in Tokyo with Tatsuji Nomura as President.
1977 His Imperial Majesty Crown Prince Akihito (the current Heisei Emperor) visited the CIEA.
1979 The CIEA was designated as theICLAS Monitoring Center.
1981 The CIEA Support Group system started (34 companies).
1982 Developmental Engineering Research Laboratory established.
1984 Kosaburo Ezaki, Chief Investigator, received the Minister’s Prize of the Science and Technology Agency.
Tatsuji Nomura was awarded the Medal of Honor with Purple Ribbon.
1985 Laboratory Animal Monitoring Building completed.

Based on its accumulated know-how over many years of research, CIEA started producing various kinds of germfree animals from the early 1970s. This, in turn, raised the issue of how the quality level of those animals could be maintained for a long time. That question eventually led to the establishment of the ICLAS (International Council for Laboratory Animal Science) Monitoring Center within the CIEA site in1986. By the end of the 1970s, CIEA started researching and developing physiological model animals with physiological functions and organs very similar to human beings. Furthermore, CIEA also actively studied disease-model animals suffering from similar sicknesses as human beings. Also sensational was the world’s first discovery of the G-CSF (Granulocyte Colony Stimulating Factor) by CIEA researchers in 1975. Inducing the number of white blood cells to soar at enormous speed, CIEA staff happened to come across G-CSF while they were studying the Nude Mouse in relation to human cancer.

Production of Gnotobiotes

1974年に受賞した毎日工業技術奨励賞
Mainichi Industrial Technology Prize Certificate

Gnotobiotes are animals that possess clearly defined microbes. They are very unique for discharging cancer-causing substances from the body in the original form, even when injecting them directly into the intestines. Having several other distinctive characters that contribute to medical research, gnotobiotes started attracting much attention as a new type of experimental animal from the 1960s. But in those days, Charles River, an American company, was the only place that could produce gnotobiotes. Furthermore, there were only a handful of institutions in the world that could supply germfree breeding stock that would be necessary to produce those gnotobiotes. As a consequence, all those animals were very expensive, and transportation costs were extremely high. Hence, it was next to impossible for anybody in Japan to import and use gnotobiotes.
Based on the bitter past experience of failing to prepare germfree breeding stock mice and having to import them from the US, CIEA staff had the strong desire to produce and supply a sizeable amount of those animals. Considering the situation at that time, CIEA chose to commit itself to the full-fledged development of germfree mice, germfree rats and gnotobiotes in 1969. By 1972, it established a monthly production system of 300 germfree mice, 700 gnotobiote mice and 200 gnotobiote rats. At the same time, CIEA also established a consolidated system of gnotobiote inspection methods through to their transport. Such R&D activities were commended highly by the society, and CIEA comes to be awarded the Mainichi Industrial Technology Prize in 1974.

Hybrid Animals

MCHマウス
MCH mouse

Generally speaking, the genetic uniformity of an experimental animal is established by inbreeding a certain species for over 20 generations, or by forming and breeding a closed colony of a specific animal comprised of 20 to 30 individuals. But a problem rose in relation to such approach: While inbreeding raised genetic uniformity, it also heightened the natural occurrence rate of deformities. Moreover, it became relevant that controlled breeding of a closed colony sometimes reversed the distribution pattern of the blood type or raised the infection rate among the animals within the colony. To overcome such defects, CIEA started researching the establishment of hybrid animals in 1976. This was done by crossbreeding a certain group of uniform-quality animals with another group of uniform-quality animals. After much trial and error CIEA succeeded in the volume production of Multi-Cross Hybrid (MCH) mice and MCH rats by 1984, and started marketing them from CLEA Japan in 1985.

ICLAS Monitoring Center

実中研の構内に設立された世界初のICLASモニタリングセンター(上)とその表札
The ICLAS Monitoring Center within CIEA facility site, ICLAS logo

By the late 1970s, the need grew for the long-term quality control of laboratory animals after selling them to the clients. Hence in 1978, CIEA monitored the quality of laboratory animals by receiving funds from the Ministry of Education. This was the first time that such monitoring was ever conducted in Japan. Specifically, CIEA scrutinized the issues of genetic transformation and microbes, together with the possibility of computerizing the monitored data. Around the same time, CIEA also suggested to the US National Institutes of Health (NIH) that the guaranteed quality of the inspected laboratory animals should be defined and shared on an international level. Accordingly, the International Council for Laboratory Animal Science (ICLAS) issued a notice in 1979 stating that a monitoring center conducting global standard checking should be established in each area around the world. In response, CIEA started to raise funds in 1981 to collect a total of 200 million yen for building such a facility in Japan. Meanwhile by 1986, CIEA established the world’s first ICLAS Monitoring Center within its laboratory grounds.

Development of Various Physiological Model Animals

ゲッチンゲン・ミニブタ
Gottingen Miniature Pig

Physiological model animals can be used as human ‘models,’ since they have very similar physiological functions and organs as human beings. Furthermore, preparation of a wide phylogenic variety of such animals would be useful to conduct broad-scale safety tests of pharmaceuticals. According to such way of thinking, CIEA started the research and development of numerous animal species including the Gottingen Miniature Pig, Rock Rabbit, Volcano Rabbit and the Suncus Murinus.

ナキウサギ
Rock Rabbit

Referring to their crossbreed and pathogenic status, as well as their ease of handling, CIEA started trying to turn Gottingen Miniature Pigs into laboratory animals in 1975. Weighing only 20 to 60 kilograms in contrast to ordinary pigs that weigh around 300 kilograms, the project that CIEA started with eight female and two male Gottingens turned into a large-scale joint research with Toray, receiving financial assistance from the Ministry of Education, as well as the Ministry of International Trade and Industry. By 1980, CIEA succeeded in turning the Gottingen Pigs into germfree animals, and formed a closed colony of over 120 Gottingen Pigs with a uniform genetic character by 1982.
In 1984, CIEA led the world again by turning the Rock Rabbit into an experimental animal. Weighing only around 300 grams and being much smaller than a common house rabbit which is around 4.5 kilograms, Rock Rabbits became a popular laboratory animal for being easy to handle, requiring smaller breeding space and amount of feed, and thus being much cheaper and economical than a house rabbit.

メキシコウサギ
Volcano Rabbit

CIEA also succeeded in the artificial breeding of the Volcano Rabbit, an endangered species, in 1985. By giving away a pair to the Jersey Foundation that works to protect and breed animals on the Red List, CIEA contributed to save the Volcano Rabbit that were once common animals found in the highlands of Mexico.

スンクス
Suncus Murinus

Meanwhile, CIEA also turned the Suncus Murinus of the mole family, which is unique for showing symptoms of seasickness, into a laboratory animal. Today, the Suncus Murinus has come to be used for studying the space sickness conditions of astronauts, as well as for scrutinizing the nausea symptoms caused by anticancer medicine.

Development of Disease Model Animals

The concept of using disease model animals to study specific diseases of human beings evolved from around the end of the 1960s. Corresponding to such thinking, CIEA has also developed a variety of such model animals.

Muscular Dystrophy Animals

Muscular dystrophy is caused by the lack of certain genes. When the disease progresses to a critical stage, the patient can die from respiratory failure. In search of the cause and an effective cure, the Ministry of Health established Japan’s first special research unit on muscular dystrophy in 1968. Becoming a member of this unit, Tatsuji Nomura was requested to expanded breeding and produce muscular dystrophy mice that are also found in the natural environment. By 1970, CIEA established a system capable of a monthly steady production of 50 muscular dystrophy mice. This was the first time that CIEA was involved in the production of a disease model animal. By 1972, CIEA started to work on producing SPF muscular dystrophy mice, and succeeded in doing so by 1983. Developing and producing other muscular dystrophy animals over the 20-year study period, the research unit eventually found out that the mechanism of muscular dystrophy caused in human beings is completely different from that of other animals.

Nude Mouse

ヌードマウス
Nude Mouse

AA Nude Mouse is a natural mutant with immune deficiencies. Discovered for the first time in 1962, this mouse is short-lived, undergrown and has a low reproduction capability as it has no thymus gland. But due to the lack of this gland, it cannot eliminate intrusive foreign substances that invade from outside, thus allowing easy transplantation of human cancer.
Taking note of the advantages the Nude Mouse offered in medical research, CIEA started the planned mass production and breeding of Nude Mice from 1973. By 1974, it established an annual production system of 300 such mice. The annual production capacity of Nude Mice reached 15,000 by 1975, and a full production cycle starting from the preparation of the breeding stock was established in 1976.
Concurrently, CIEA developed a highly sophisticated transplanting technology that contributes to human cancer research. This also enhanced the effectiveness of anticancer medicine measurement by using several hundred Nude Mice at once. Such results were obtained by CIEA staff, who systematically transplanted various different types of human cancer on the mice, letting the cancer cells grow and colonize, removing the colonized cancer cells and deep freezing them, and then transplanting the defrosted cancer cells onto other Nude Mice. By repeating this process, CIEA has come to preserve over 400 different kinds of human cancer, a rare and precious existence in the world.

Observing the Wild Increase in the White Blood Cell Count for the First Time in the World

While studying the Nude Mouse in 1975, CIEA researchers come across an abnormal incident where the white blood cell count suddenly increases. This was the first time that any person in the world observed the very moment when the human cancer cell induced the G-CSF to produce white blood cells. Since leucopenia could be effectively treated if this G-CSF could be specified, CIEA collaborated with Chugai Pharmaceutical in 1985 to promote further studies in this area. Finally in 2007, Chugai was able to release a medicine called Neutrogin, an effective treatment drug for leucopenia, based on CIEA’s original discovery in 1975.

1991年発売されたノイトロジン
Chugai Pharmaceutical’s Neutrogin

5)Exploiting the New Horizon

Age Matters
1986 ICLAS Monitoring Center Building commenced operation.
1987 The Imperial Highnesses Prince and Princess Hitachi visited the CIEA.
Reproductive Engineering Experimental Manual published.
1988 Tatsuji Nomura is awarded Muhlbock Memorial Prize at the ICLAS General Assembly Symposium.
Special “Laboratory animal monitoring project” commenced.
Hereditary disease clarification of the Shiverer Mouse successful for the first time in the world.
1989 “Life Programming I” and “Life Programming II” won prizes at the 30th Science and Technology Film Festival. Preclinical Medical Institute established. “Life Programming II” won prizes at the Italian International Film Festival.
1990 “Life Programming I” won the gold prize in the science department at John Muir Medical Film Festival in the United States
1991 Polio mouse created. “It Started with Six Mice,” a book depicting CIEA’s history, published.
1992 Laboratory animal cryopreservation facilities completed.
1993 WHO decided to use the polio mouse in its polio eradication program.
1995 RasH2 mouse was announced at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH. Contributed to the shortening of the period required and the simplification of evaluation of results of carcinogenicity test for new drugs.
2001 US NPO Center for the Advancement of Health and Biosciences (CAHB) established.
2002 Overseas project development started.
NOG mouse produced as “super immunodeficient mouse.”
2005 Patent granted for NOG mouse.
2006 Tatsuji Nomura becomes Director and Chairman of the CIEA Board.
The 1st International Workshop on “Humanized Mice” was held in Tokyo with Tatsuji Nomura as President.
2007 Collaborative research on leukocytosis in nude mice with Chugai Pharmaceutical.
Based on this phenomenon, lenograstim, a granulocyte colony-stimulating factor (brand name: Neutrogin) was marketed worldwide to treat leukopenia.
2010 World’s first closed colony of marmosets directly connected with regenerative treatment for spinal injuries and myocardial infarction maintained in the CLEA Japan Inc.
2011 Authorized as a public interest incorporated foundation
New research facilities opened in Tonomachi, Kawasaki.

A Shiverer Mouse cannot stop shivering because of its genetic abnormality. In 1988, CIEA led the world by successfully tracing the cause of this disease. This achievement accelerated CIEA’s R&D activities in the field of molecular biology, allowing its researchers to develop and release a string of the world’s first genetically modified mouse. To note a few of their achievements, the Polio Mouse contributed to evaluate the safety of live Polio vaccines swiftly and accurately, the rasH2 Mouse established a new standard for the carcinogenicity assessment of newly developed drugs, and the super immunodeficient NOG Mouse contributed to AIDS and leukemia research.
More recently, Common marmosets that CIEA successfully turned into a laboratory animal are cultivating new possibilities in the field of regenerative medicine, especially for treating spinal cord injuries and cardiac infarction. On the international level, CIEA is collaborating with other institutions to establish a global standard for laboratory animals through the GALAS (Global Alliance for Laboratory Animal Standardization).

As noted henceforth, CIEA has solidified its foothold as the world leader in laboratory animal preclinical research, by continuing to produce and provide high-quality, uniform-character laboratory animals to the medical arena for many decades.

And now towards the future, CIEA is renewing its determination to exploit a new horizon by preserving its basic stance of resolving the cause of various human diseases, developing better ways of medical treatment, and improving the health and welfare of all mankind.

Working on the Genes

◯Polio Mouse
From 1991 until around 1999, CIEA concentrated to develop the Polio Mouse. At the same time, it worked to establish the safety evaluation of the live Polio vaccine, by using the Polio Mouse it developed. This was an exceptionally meaningful step on a global level, since live vaccines produced from the attenuated Polio virus are used for immunization, and the safety of the vaccine must be carefully checked to prevent it from accidental Polio caused by contamination of non-attenuated Poliovirus: A disease that leaves behind a serious after-effect of paralyzing the extremities. In the past, the above safety checking process was conducted by using monkeys. However, requests were rising for a substitute laboratory animal, together with the growing demand in animal protection.
In 1978, Dr. Akio Nomoto of the Tokyo Metropolitan Institute of Medical Science succeeded in establishing Japan’s first Polio Mouse. Approached by Dr. Nomoto, CIEA took over his research, and turned the Polio Mouse into an experimental animal.

日経 1993年2月3日版に掲載されたポリオマウス記事の要約
The feature article of CIEA’s Polio Mouse in the Nikkei newspaper issued on February 3, 1993

Activities at the genetic level

In 1993, the World Health Organization (WHO) conducted a comparative test on the Polio Mice and monkeys, to evaluate their efficacy on measuring the safety of the live Polio vaccine. This test confirmed the superiority of the Polio Mouse over a monkey, both in terms of test result accuracy and cost. The test also noted the significant meaning of substituting monkeys with mice, thus saving the precious mammal that delivered only one or two babies per pregnancy. Acknowledging the WHO’s test results, medical institutions around the world started replacing their monkeys with Polio Mouse whenever they checked the safety of their own live Polio vaccines.

ポリオ撲滅の状況
Aiming for Polio Eradication

◯rasH2 mouse
The rasH2 Mouse is another mouse species that CIEA created in 1986, after about eight years of trial and error. Embedded with the ‘ras’ human cancer gene, this mouse was specifically developed for the “carcinogenicity assessment test”: a compulsory examination process that is implemented during the “safety evaluation test” of a newly developed drug. In the past, this compulsory process was extremely unpopular for being expensive and time-consuming. The dilemma was that it required an observation period of over two years after the chemical substance in a new drug was continually administered to healthy mice and rats to check whether the substance caused cancer or not. Furthermore, even if that substance developed cancer in mice, it was very difficult to make a correct judgment on whether or not it would also cause cancer among human beings.
Although the above shortcomings of the testing process were argued for many years, no effective measures existed. CIEA therefore created a big sensation in 1995 by announcing the rasH2 Mouse at the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use).
Cutting down the required time of carcinogenicity assessment tests from over two years to just six months, the advent of the rasH2 Mouse even led the ICH to review its safety assessment process for new drugs.
Following the rasH2 Mouse, other genetically modified mice, such as the p53 Mouse, the TgAC Mouse and the XPA Mouse, were released in succession from various research laboratories in the US and Europe. But a comparative test of the four different kinds of mouse conducted by the respective new drug approving administrative organizations in Japan (Ministry of Health, Labor and Welfare), the US (Food and Drug Administration: FDA) and the European Union (Committee for Proprietary Medicinal Products: CPMP), evaluated the rasH2 Mouse most highly. As such, the worldwide demand for the rasH2 Mouse in 2010 reached 23,000, turning it into the most popular laboratory animal for carcinogenicity assessment even in the US that is controlled by the FDA.

rasH2マウス
Comparative test results of the four different mouse species conducted by the new drug approving administrative organizations in Japan, the US and the European Union (summarized by MacDonald et al)

◯NOG Mouse
Almost fully eliminating the immune functions of a healthy mouse, the super immunodeficient NOG Mouse was created for the first time in the world by the Mamoru Ito Research Team in 2002: another remarkable achievement by CIEA.
In the natural environment, the Nude Mouse was the first immunodeficient mouse discovered in 1962. The Nude Mouse suffered immunodeficiency as it had no thymus gland which produces T-cells. This discovery was followed by another mouse with even more severe combined immunodeficiencies (SCID) in 1983. Named the SCID Mouse, this mouse had no T- and B-cells, a distinctive feature that allowed easy transplantation of human lymphocyte cells. Hence, the SCID Mouse soon became a popular experimental animal for studying HIV that infects and grows in lymphocyte cells.
CIEA imported the SCID Mouse breeding stock in 1985 from the US, and tried to produce a mouse with no immune function. In doing so, the Ito Team discovered that a more immunodeficient mouse could be produced by crossing over the SCID Mouse with a NOD (Non Obese Diabetic) Mouse. But the SCID-NOD Mouse still retained a relatively large number of NK (Natural Killer) cells that are responsible for some immune functions.

Nogマウス
The comparative test results of the NOG Mouse and NOD/SCD/D2mnull Mouse (Source: CIEA)

By the mid 1990s, the significant progress in the gene engineering technique allowed the normal immune functions of a healthy mouse to be artificially “knocked out.” Eventually, it also becomes possible to define which genes should be knocked out to reduce the immune functions to almost nil. Dr. Masataka Nakamura of the Tokyo Medical and Dental University used this technology to produce his NK cell knocked out genetically modified mouse. But his mouse still had a large number of T- and B-cells.

Human hematopoietic cells differentiated from CB CD34+ cells in NOG mice

It seemed logical then for Dr. Nakamura, former member of Sugamura Group at Tohoku University who had transferred himself to Tokyo Medical & Dental University, to approach the Ito Team at CIEA and suggest that by collaborating with each other, the probability of producing a more perfect immunodeficient mouse would increase greatly.
The outcome was the NOG Mouse, which is being praised globally today as the “ultimate form of an immunodeficient mouse.” Recording an astonishing 40% to 70% survival rate of human hematopoietic cells, the NOG Mouse production by CIEA already reached 10,000 per year in 2006. But in spite of such remarkable achievement, Mamoru Ito, the leader of the NOG Mouse Development Team, humbly says “we had the luck and chance.” Ito continued to state that “the laboratory animals we produce would be worthless if our clients don’t use or value them.”

◯Marmosets
During the 1960s, CIEA already started studying monkeys, and tried breeding the South American marmoset in 1973. But having no idea on how they ate or lived, the 17 wild marmosets died within a month after being brought over to Japan. Though another 10 years were spent to turn it into an experimental animal, no demand rose for them for a long time in Japan, since they were an uncommon monkey species among the Japanese.
Compared to other monkeys, however, marmosets are quite small like a rat and weigh only around 200 to 400 grams. Furthermore, they offer the advantage of being much more fertile than macaque monkeys. Having two to three babies per delivery after a six-month gestation, each mother can deliver around 50 babies in roughly 10 years. As such, they started to be actively used in the regenerative medical field from around 2000.

マーモセット
Marmosets

Today, marmosets are most commonly used for studying spinal cord injuries and cardiac infarctions. As for the former, marmosets are used for developing the stem cell transplant method that recovers and reproduces paralyzed lower body functions caused by spinal cord injuries. As for the latter, research is conducted to ultimately reproduce the human cardiac muscle damaged by cardiac infarction, through new cardiac muscle cell transplantation using marmosets. As of 2010, CLEA Japan Inc., CIEA’s related company, maintained the world’s largest colony of marmosets comprising of 500 males and 500 females.

◯GALAS (Global Alliance for Laboratory Animal Standardization)
In order to standardize the quality of laboratory animals, GALAS was collaboratively established by laboratory animal producing companies and institutions throughout the world, according to the call from CIEA. In the autumn of 1998, CIEA joined hands with four experimental animal producing companies in Japan, the US and Europe, and signed a contract to regulate and standardize the quality of rats for laboratory use. In the future, CIEA intends to expand the activities of GALAS to standardize the quality of many other laboratory animals including marmosets.

GALASのロゴ
GALAS logo

Opening a new laboratory in the summer of 2011, in the coastal area of Kawasaki City across the newly re-internationalized Haneda Airport, CIEA will take a progressive step forward to nurture a new industrial foundation based on medical/new drug creation technologies, by collaborating with pharmaceutical companies, medical equipment-related industries, health/foodstuff-related corporations, venture businesses, and so on.

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