Column

Column

Researchers for the future

To realize preclinical trials using human disease models in primates

Dr. Erika Sasaki

Dr. Erika Sasaki, Central Institute for Experimental Animals, is the first who successfully modified genes of marmosets, a small primate species, and generated transgenic marmosets. Transgenic animal is an animal in which foreign genes are introduced by genetic engineering techniques. She is working on establishing human disease models in transgenic marmosets that will serve for preclinical trial systems for examining the safety and efficacy of drugs and treatments in a highly accurate manner. It is her strong will since her teenage that she wants to study transgenic animals that pushes her to work in this field.

Interviewer :
Before you began to study transgenic marmosets, you were dealing with other animals, weren't you?

Photo:Dr. Erika Sasaki

Dr. Erika Sasaki

Sasaki :
When I was a student of the fourth grade at University of Tsukuba, I was studying hormonal regulations of the sexual cycle in a small goat species called "shibayagi". When I was a graduate student, I was always in the same lab, but I could not help but think about studying transgenic animals, and began to work on generation of transgenic chickens with a professor at an Institute under the Ministry of Agriculture, Forestry and Fishery, whom I met by chance. When I was a high-school student, I was inspired by lectures given by my professor of biology at high school and TV documentaries on transgenic animals, and was interested in studying these animals. I find now that it was a really selfish way of working that I was doing research at the Ministry's Institute while enrolled in the lab at University of Tsukuba, and the professors allowed me to do it.
We were the first to successfully generate transgenic chickens, but this work was not so much paid attention to at that time. It was a study for improving the breeding efficiency or resistance to diseases in chickens from the standpoint of food production, however, consumers do not like to eat such chickens because they see these animals as something like GM soybeans.

Interviewer :
You were working in Canada as post-doc fellow. What were you doing there?

Sasaki :
I was working always on transgenic chickens in Canada. In the mean time, in one year and a half from the start of my study there, my professor left the university and his lab broke up. And I had to find a new post within 6 months. It was lucky for me that there was a Japanese professor in a building just in front of ours and said to me that I could come if I had no place to work. So I came to his lab to work. However, the situation changed and I had again to move to another lab. Then I asked advice to another professor at the university, and he said, "OK, come to our lab". In this way, I moved from one lab to another. In the mean time, my husband got a job in Japan and I looked for my job there. Then I found in the recruitment pages in the Journal "Saibo Kogaku"(Cell Engineering) a call for "somebody who is interested in molecular biology, cell biology, and developmental biology". Though I did not have any idea about what I would be doing, I was interested in these fields of study, and I applied for the post. It was a post offered by The Institute of Medical Science, The University of Tokyo, which is to develop preclinical studies for treatment of blood diseases using ES cells in the framework of the JSPS Research for the Future Program. I met marmosets for the first time in this project.

Interviewer :
Why do you use marmosets?

Sasaki :
There is a large distance between the mouse and the human, and we cannot always extrapolate human events from experimental results obtained in mice. If we are able to use marmosets that are closer to humans in preclinical trials, this will allow us to examine more accurately the safety and efficacy of the treatment. Marmosets have higher reproductive rate and are smaller than other primate species, so they are easier to handle. As for the sensitivity to diseases, there are differences between mice and humans. For example, mice are not susceptible to hepatitis virus infection, and we do not use mice but marmosets for developing drugs or studying disease mechanisms for hepatitis treatments.

Interviewer :
After coming back from Canada, you began to work on generating marmoset ES cells, didn't you?

Sasaki :
James Thomson who first generated human ES cells had generated marmoset ES cells before. In the beginning, I used the ES cells supplied by Prof. Thomson, for which it is provided in the supply contract that the introduction of the ES cells into embryos are restricted. If we do not introduce ES cells into embryos, we cannot generate transgenic animals. Then we decided to generate our own marmoset ES cells.
We have to get fertilized eggs for generating ES cells, and we started the work by trying to find a way to collect fertilized eggs from marmosets. We found an article indicating a method to collect the eggs without surgical operation, but we could not obtain the same results. We went to visit the lab to which the author was affiliated, but unfortunately it was after the author left the lab, and any other member of the lab did not know the method. In this situation, we tried to establish our own technique to do it, and it took about one year to successfully collect fertilized eggs. And it took another one year to generate ES cells.

Interviewer :
How did you create transgenic marmosets?

Sasaki :
To create transgenic animals, we have to transplant ES cells into embryos to create chimeras. But so far we cannot create chimeras with animals other than mice. I knew it but did not tell it to my colleagues. I thought that ES cells themselves would be useful for research in regenerative medicine, and if the ES cells would not serve to create transgenic marmosets, it would be OK. After we got marmoset ES cells, I said to my colleagues "we cannot create transgenic marmosets with these ES cells", and they criticized me for it.
There is another way of creating transgenic marmosets. It is a technique using virus vectors carrying the target genes to be introduced into fertilized marmoset eggs. We introduce the virus vectors into the gap between the egg surface and the transparent membrane covering the egg, and the question was that the gap was too small to inject the vectors.
Then an idea came across my mind that we could enlarge the gap by shrinking the eggs in a sucrose solution. Using this technique, we tried to introduce the green fluorescent protein (GFP) gene into five marmoset fertilized eggs, and obtained four pups expressing green fluorescence in their hairs, skins and treads, that is to say, the GFP gene was integrated, and we confirmed that the gene was passed to the next generation.

Chart:pre-clinical study using common marmosets
pre-clinical study using common marmosets(large view(PDF))

Interviewer :
What is your current research subject?

Sasaki :
We know now how to create transgenic marmosets, and I am trying to establish human disease models in transgenic marmosets, using this technique. I am now in the course of establishing Parkinson's disease models. And, in order that we will be able to treat the animals when they develop the disease, I am also working on regenerative medicine using ES and iPS cells. I am aiming at realizing preclinical trials for treatment of Parkinson's disease, using these techniques.
On the other hand, there are diseases that are not reproducible by means of gene modification using virus vectors. There are two types of pathogenicity at the level of genes. In one type, a mutation in the responsible gene causes abnormal shape of the protein expressed that is harmful to surrounding cells and triggers the disease. In another type, a mutation causes destruction of the protein itself to lose its functions and cause the disease. We can reproduce diseases of the first type using virus vectors, but not the second type. For example, in muscular dystrophy, a protein called dystrophine is destroyed and the patients cannot maintain their muscles. This disease we cannot reproduce with virus vectors. I am working on how to solve the problem.

Interviewer :
Do you have any dream that you wish to realize in your research?

Sasaki :
My dream is to establish a higher position of marmosets as experimental animals, after mice. It was said several years ago that marmosets did not represent a primate species suitable for experimental animals. We organized an international symposium on marmosets for the first time in Japan, and many people were interested in this field. I was very happy to hear that the president of an institute for primate research in USA was willing to introduce marmosets.
I am also interested in studying basic questions like why we cannot produce chimeras in animals other than mice, or what the pluripltency is.

Interviewer :
I suppose that you may feel pity for the marmosets you are dealing with?

Sasaki :
We are taking care for not injuring the animals, and if they have severe symptoms, we ask a veterinarian to treat the animals and try to prolong their lives. The ways to deal with marmosets are different from those for mice. There are researchers who are to deal with marmosets just like mice when they make experimental plans, and it will be one of our missions to enlighten those people about the differences.

Interviewer :
Would you give advice to younger scientists?

Sasaki :
You must persist in your efforts to follow what you are interested in. I can say from my experience in Canada where the lab was broken up, that if you will be working in a lab for earning the salaries and not for doing research of your interest, you will not be very happy. It will be important to organize your career based on what you want to study.


Interviewer :
Chisato Hata
Interview date : March 7, 2012

Dr. Erika Sasaki

Director of Applied Development Biology Department, Central Institute for Experimental Animals

1989 Graduated from Institute of Agriculture and Forestry, University of Tsukuba
1995 Finished the doctoral course and received a doctor's degree at the Graduate School of Agriculture, University of Tsukuba
1995 Researcher at Research Development Corporation of Japan (National Institute of Animal Health under the Ministry of Agriculture, Forestry and Fishery)
1996 Post-doc fellow at University of Guelph, Canada
2001 Research Associate at The Institute of Medical Science, The University of Tokyo
2002 Research Associate at Medical Institute of Bioregulation, Kyushu University
2003 Senior Researcher at Foundation of Biomedical Research and Innovation
2003 Researcher at Animal Experiment Center, Central Institute for Experimental Animals
2004 Assistant Professor at School of Medicine, Keio University (concurrently with the above post)
2004 Researcher at Primate Laboratory, Biomedical Research Department, Central Institute for Experimental Animals
2007 Senior Researcher at Marmoset Research Department of the same Institute
2007 Associate Professor at Research Center for Human Metabolism Systems Biology, Keio University (concurrently with the above post)
2010 Director of Applied Development Biology Department, Central Institute for Experimental Animals

Movie

See more

Page top

Movie

Movie

  • MEXT
  • Japan Science and Technology Agency
Page top