Ryuzo Yanagimachi

Ryuzo Yanagimachi
Yanagimachi in 2014
Born	(1928-08-27)August 27, 1928 Ebetsu, Hokkaido, Japan
Died	September 27, 2023(2023-09-27) (aged 95) Honolulu, Hawaii, U.S.
Alma mater	Hokkaido University
Scientific career
Institutions	Worcester Foundation for Biomedical Research John A. Burns School of Medicine University of Hawaiʻi at Mānoa

Ryuzo Yanagimachi (柳町隆造, Yanagimachi Ryūzō, August 27, 1928 – September 27, 2023) was a Japanese-born, American-based scientist. He made numerous key contributions to the study of mammalian fertilization, and he was also a pioneer in the cloning field. Accordingly, he assisted in fertilization technologies such as in vitro fertilization and direct sperm injection into the egg (commonly called intracytoplasmic sperm injection or ICSI), which are widely used today in human infertility clinics throughout the world. In 1997, his laboratory at the University of Hawaiʻi at Mānoa successfully cloned mice using the Honolulu technique.

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Cloning 101 The ability to create a clone used to be science fiction. Dr. Ian Wilmut's group changed that in 1997 with the creation of Dolly the sheep. Since then the debate on applying the technique to clone human beings has been ongoing. Based on all the discussion, it may sound like cloning, human or otherwise, is an easy process. Find out what is actually involved in the cloning process by viewing our short animation. What are clones? Simply put, clones are organisms that have identical genetic material. In other words, the sequence of bases in their DNA is exactly the same. Long before the birth of Dolly the sheep, clones had been observed in both nature and in the laboratory. When a couple has identical twins (or identical triplets, etc.), the children are clones of one another. A plant cutting can also be used to generate a clone. Prior to 1996, it was thought that cloning an entire animal could only be done with embryonic cells; cells present in the early stages of an organism's development. In the 1950's, scientists generated entire frogs from embryonic frog cells. After a small number of cell divisions, embryonic cells start to change into the different types of cells that an organism needs, including cells that form muscle, blood, liver, etc. This process is called differentiation. Although each of these cells has the same genetic material, each cell can only access the genes needed for its particular function. Before the experiment at the Roslin Institute, it was thought that once cells differentiated, they could not be used to generate an entire organism. For instance, in a sheep, udder cells could generate other udder cells, but not an entire sheep. The scientists at the Roslin Institute solved this problem by growing sheep udder cells under starvation conditions. This put the cells in a state similar to embryonic cells. This is called the G0 state. An egg cell was taken from another sheep. The nucleus, which contains the genetic material, was removed from the egg cell using a very fine needle. They then used electric shock to fuse one starved udder cell with one nucleus-free egg cell. They made 277 of these fused cells. Although the egg cell came from a black-faced sheep, notice that the nucleus with the genetic material came from the white-faced sheep. These fused egg cells were then inserted into several different sheep. These surrogate mothers were also black-faced. Of the 277 fused cells, only one progressed to form a developed lamb. Dolly was born on July 5, 1996. Scientists found that Dolly had the same DNA as the udder cells she came from. She is a clone of these udder cells. Dolly has given birth to a lamb named Bonnie, produced the natural way. Other lambs have been born at the Roslin Institute through their cloning process; some carry genes that will produced usable human drugs. A laboratory in Hawaii run by Dr. Ryuzo Yanagimachi was the second group to successfully clone an animal from an adult cell. They cloned mice using cumulus cells, a cell type found in the ovaries. The cloning method used by the lab in Hawaii was different in two ways from the method used to clone Dolly. First, the cells used to clone the mice were not grown in culture, but instead were used immediately. Second the nucleus was removed from the cumulus cell and then directly injected into the egg cell. This egg cell's nucleus had already been removed. The Yanagimachi lab used coat color to track genetic heritage. The cumulus cell comes from an agouti (brown) mouse, and the egg cell comes from a black mouse. The egg cell now had the same genetic information as the nucleus donor mouse. The egg cell was then activated and implanted into a white host mother. On October 3, 1997, the host mouse gave birth to Cumulina, named after the cumulus cells she was cloned from. Cumulina is the same color as the mouse that donated the nucleus. DNA fingerprinting confirmed that Cumulina had the same DNA as the nucleus donor. The scientists have taken cells from Cumulina to make more clones. They have successfully made several generations of clones and all mice seem normal. Dolly the sheep died at the age of six. Since the world said hello to Dolly, several other animals have also been cloned. Both Dolly and Cumulina were cloned from cells in the female reproductive system; cows have also been cloned using ovary and cumulus cells with the same method that was used to clone Dolly. Pigs have been added to the cloned animal menagerie. Scientists hope to use cloned pigs to grow organs that can be transplanted into humans.

Biography

Yanagimachi was born in Ebetsu and raised in Sapporo, Japan.^[1] He received a BS in zoology in 1952 and a DSc in animal embryology in 1960, both from Hokkaido University. Being unable to find a research position initially, he then worked as a high school teacher for two years.^[2]

Yanagimachi applied for a post-doctoral position with Dr. M. C. Chang of the Worcester Foundation for Biomedical Research in Shrewsbury, Massachusetts. He got this position and there discovered how to fertilize hamster eggs in vitro. This work led to in vitro fertilization of eggs of humans and other mammalian species.

In 1964, he returned to Hokkaido University as a temporary lecturer, with the possibility of later being appointed to an assistant professorship. However, another person eventually got the position.^[2]

In 1966 Yanagimachi ended up at the University of Hawaiʻi as an assistant professor and became a full professor of the Department of Anatomy and reproductive biology at the John A. Burns School of Medicine. After working for 38 years at the University of Hawaii, he retired at the end of 2005 to become a professor emeritus but kept working with junior fellows. He was married to Hiroko, a former child psychologist. She could not find work in her field when they came to the U.S. due to a language barrier, so she went to work with researchers in his lab as an electron microscopist.^[2]

Ryuzo Yanagimachi died in Honolulu from complications of a fall on September 27, 2023, at the age of 95.^[3]^[4]

Cloning

In July 1998, Yanagimachi's team published work in Nature on cloning mice from adult cells. Yanagimachi named the new cloning technique they had created to do this to work the "Honolulu technique". The first mouse born was named Cumulina, after the cumulus cells whose nuclei were used to clone her. At the time of the publication of this work, over fifty mice spanning three generations had been produced through this technique. This was accomplished by an international team of scientists, including co-authors Teruhiko Wakayama, Tony Perry, Maurizio Zuccotti and K.R. Johnson.^[5]^[6]

The Yanagimachi laboratory moved from the warehouse which had housed it for over thirty years into the newly created Institute for Biogenesis Research in the Biomedical Sciences Tower of the John A. Burns School of Medicine. Money and renown from the opportunities opened up by the Nature article made the institute possible.

The Yanagimachi laboratory and his former associates continued to make advances in cloning. The first male animal cloned from adult cells was announced in 1999. In 2004 the laboratory participated in the cloning of an infertile male mouse. This advance may be used to produce many infertile animals for use in research on human infertility.^[7]

Mice cloned by the Honolulu technique were displayed at the Bishop Museum in Honolulu, Hawaiʻi, and the Museum of Science and Industry in Chicago, Illinois.

Major work before and after 1960

As a graduate student of Hokkaido University in Japan, Yanagimachi studied fish (herring) fertilization and the sexual organization of rhizocephalans (parasitic barnacles). In fish, he discovered calcium-dependent, chemotactic movement of spermatozoa into the micropyle through which the fertilizing spermatozoon enters the egg. This was the first discovery of sperm chemotaxis in vertebrate animals. In rhizocephala, he found that adults are not hermaphroditic as generally thought, but bisexual. The so-called "testis" in an adult animal is a receptacle of cells from larval males. This discovery revolutionized biological studies of rhizocephalans and related animals.

While he was at the Worcester Foundation for Biomedical Research as Dr. M.C. Chang's postdoctoral fellow (1960-1964), he witnessed and recorded the entire process of sperm penetration through the zona pellucida and fusion with the egg proper in a living (hamster) egg, which was the first in mammals. He was one of few who began to study the process and mechanisms of mammalian fertilization using in vitro fertilization technique.

Throughout his career he has made numerous, fundamental contributions to our understanding of mammalian fertilization and to the development of assisted fertilization technologies such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) which are widely used today in human infertility clinics throughout the world. His comprehensive review of the basic biology of "Mammalian Fertilization" published in 1994 (In: Physiology of Reproduction, Knobil & Neill eds, Ravan Press) is classic.

Yanagimachi himself considered "cloned mice" to be byproducts of fertilization study and that the production of cloned animals in various species triggered/accelerated the research on the genomic reprogramming of adult somatic (body) cell nuclei as well as the production of pluripotent stem cells from adult cells for therapeutic purposes. He retired in 2005, but continued working on natural and assisted reproduction.

In 2014, he had an interview with The Prism in which he was quoted saying:

Unlike people, nature never lies.^[8]

Awards and honors

Fulbright Scholarship, US-Japan, 1960 and 1964
Lalor Foundation Scholarship, US, 1964–1966.
Zoological Society Prize, Japan, 1977
Research Award, Society for Study of Reproduction, US, 1982
University of Hawaii Regents' Medal for Excellence in Research, US, 1988
Recognition Award, Serono Symposia, US, 1989
Marshall Medal, Society for the Study of Fertility, UK,1994
International Prize for Biology, Japan, 1996
Honorable Degree of Philosophy from the University of Rome, Italy, 1997
Distinguished Andrologist Award, American Society of Andrology, US, 1998
Induction to the Polish Academy of Sciences, Poland, 1998
Carl G. Hartman Award, Society for the Study of Reproduction, US, 1999
Honorable Degree of Philosophy, University of Pavia, Italy, 1999
Honorary Member, European Society of Human Reproduction and Embryology, 1999
Pioneer Award, International Embryo Transfer Society, 2000
Induction to the National Academy of Sciences, US, 2001
Honorable Degree of Philosophy, Hokkaido University, Japan, 2002
Induction to Hall of Honor, National Institute of Child Health and Human Development, US, 2003
Donald Henry Barron Lecture, University of Florida, US, 2003
Pioneer Award in Reproduction Research, US, 2012
Lifetime Achievement Award, Society of Reproductive Biologists and Technologists, US, 2014
Kyoto Prize in Advanced Technology, Japan, 2023^[9]