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″I think living creatures are works of art.″ Makoto Asashima Head Researcher, Dome Gene Life Science Experiment Research professor at the University of Tokyo, Director of the Research Center for Stem Cell Engineering at the National Institute of Advanced Industrial Science and Technology

Studying Frogs to Learn About Human Evolution

Q. Tell us about your Dome Gene experiment.

Xenopus laevis
Xenopus laevis

Developmental biologists study the process by which organisms grow and develop - how cells become tissues, organs, etc. In the Dome Gene Experiment, we cultivated Xenopus A6 kidney epithelial cells in space, and studied how their form, function and genetics would change in space.
Xenopus laevis, commonly known as the African Clawed Frog, is one of the model organisms used by developmental biologists throughout the world. Millions of years ago, when this frog left the water for land, its kidney cells were the ones that changed the most. So now we would like to see how these cells would function in space. We also plan to conduct a similar study on this frog’s liver cells.
For the 3.8 billion years that there has been life on Earth, we have been subject to gravity. Our body has many genes that are stabilized by gravity. By comparing cell function on Earth and in space, we can see what role gravity plays, and we can understand better how the cells work. I think studying the changes these cells undergo in the zero gravity environment of space gives us a new sense of the power of life.

Q. Why did you choose kidney cells from frogs?

Dome structure of Xenopus A6 kidney epithelial cells
Dome structure of Xenopus A6 kidney epithelial cells

Microscopic images: kidney cells cultivated in microgravity environment (top), kidney cells cultivated in artificial gravitational environment (middle), and kidney cells cultivated on Earth (bottom). Red circles indicate dome structures. (Courtesy: JAXA/University of Tokyo)
Microscopic images: kidney cells cultivated in microgravity environment (top), kidney cells cultivated in artificial gravitational environment (middle), and kidney cells cultivated on Earth (bottom). Red circles indicate dome structures. (Courtesy: JAXA/University of Tokyo)

When it comes to space experiments, I think you can only make comparisons when you have a large amount of baseline data from Earth to compare with the data you collect in space. I have been studying cultured kidney cells for more than 20 years, so I have a plenty of knowledge on the subject. In 1989, I discovered the activin protein, which induces cell differentiation. I was the first in the world to successfully create organs such as hearts and kidneys from undifferentiated cells in test tubes. Through this research, we have come to understand how organs are created, and how genes are expressed. So for all these reasons, I chose the kidney.
Why the frog? Human history dates back only about 2 million years, but frogs originated 300 million years ago. Their bodies adapted so they could come out of the water and live on dry land, so there must be some sort of mechanism that either doesn’t exist or is invisible in humans, who have always lived on land. I believe that if you look at the frog, you can find the prototype for humans.

Of course, I understand very well that there are big differences between humans and frogs. But when you compare the kidneys of a frog and a human, the genes required for organ formation are very similar. For example, the basic structural unit of the human kidney is the nephron, which produces urine. Each human kidney has about a million nephrons. On the other hand, the kidney of a tadpole, which will grow into a frog, has only one nephron. You may say having one nephron is completely different from having a million of them, but if the genes and the original genetic agent used in kidney formation are the same, I would say they are essentially similar. For this reason, I’d love to research kidney formation in space using cultured kidney cells. If we can understand in detail how frog kidneys are formed, we may be able to find some sort of clue to curing human kidney-disease patients who need dialysis. Q. What are the results from the experiment so far? When you cultivate Xenopus A6 kidney epithelial cells on Earth, they look like little domes - they have a hemispheric convex shape. But when we did our experiment in space, the cells didn’t form that shape very well in the zero-gravity environment. So we need to investigate why the gene that controls the formation of the cell structure didn’t work in space.
So far, our analysis of the space experiments shows the following:

  • the genes that control shapes didn’t work well
  • the cancer gene was very active
  • in metabolic systems, different genes than we expected were active, including some never seen on the ground
These findings are the focus of our research right now, at the molecular level and at the morphologic, or structural, level.

It’s particularly interesting that some of the genes that were dormant on the ground were activated in space. These genes may not normally be active in frogs today, but they might have been in the past. And because they got activated, it’s possible that newer genes that normally do the same work on Earth worked differently in space. When you decode a genome, you always find some "junk genes" that don’t seem to do anything. As a result of our experiment, we now know that these genes do in fact have a purpose.
In this experiment, we also brought a centrifuge to space to create an artificial 1G environment, and cultivated cells in it in order to make a comparison. In this artificial 1G environment in space, dome-shaped cells were created, but many of them were smaller than those created on Earth. That means even with the same 1G environment, there is some kind of difference between space and Earth. We are trying to verify this at the moment, and I’m looking forward to more discoveries. At the same time, we are also doing analysis on liver cells.
This is just one of the life science experiments performed on Kibo. There are many other great results in plant science and radiation science.

The International Space Station is the Common Property of Humanity

Q. What are your thoughts after performing experiments in Kibo?

Dr. Asashima conducting microscopic observations on cells during a Dome Gene Experiment at Tsukuba Space Center.
Dr. Asashima conducting microscopic observations on cells during a Dome Gene Experiment at Tsukuba Space Center.

There is a device called a clinostat that can simulate microgravity on the ground, and I have used to cultivate frog kidneys in many experiments. Some people say we don’t need to do this experiment in space because we have such devices on the ground, but the space experiment actually gave us different results than clinostat experiments on the ground. There were some similarities, of course, but still there are many things that we could not have understood if we hadn’t done this in space. That’s what we learned after our first space experiment. Even though we could use high-tech devices to perform these experiments on the ground, there are better systems and environments in space.
Also, we learned from this experiment that a frog’s kidney cells do not take on a dome shape in space. What is causing this? If the cell cytoskeleton isn’t functioning properly, then what’s needed to make it work? One question after another has appeared in my head, and I have more things to study. If we continue our research, we will gain new knowledge and wisdom about the nature and origins of life. The ISS is the common property of humanity, and so it is very important that we use this new knowledge wisely and responsibly. Q. How do you think we should use Kibo in the future? I’d like the ISS to be operated as long as possible, and I want more people using the Kibo module. Although, to make that happen, it is important to create an environment for easier participation. For example, in my case, it took me 15 years from the public offering to perform this experiment. During this period, there was a Space Shuttle accident and the construction of the ISS was delayed, but to be honest, it was difficult for me to wait to carry out space experiments. Of course, those 15 years were not wasted. Technology moved forward a great deal, and experimental methods and analysis improved a lot. But if the process were simplified and scientists would have to wait only three or four years, there might be a lot of interest form various fields in using Kibo. In addition, we need to think about broadening the range of utilization of Kibo, such as collaborations with other Asian countries. Q. Why do you think people are saying that specific results from experiments on the ISS are slow to emerge? The Kibo experiments have just started. It takes time to analyze data, to find out what that data means, and then to verify whether or not the data is correct. Everyone also thinks that samples are returned to us right as soon as the experiment is finished, but the Space Shuttle can only carry so much on its return from the ISS, so most of the time the return of the samples is delayed. The samples from the Dome Gene Experiment came back to me six months after the experiment was completed in March 2009. Until then, I couldn’t even start to analyze them.
Many things about the Dome Gene have only recently been understood, so I think a lot of interesting results will emerge from other experiments. We have already achieved great results from experiments on gravisensivity element analysis; and on the process through which radiation causes cancer, loss of bone mass, and, reduction of muscle mass; but soon we’ll be getting more and more results from the ISS experiments. Instead of demanding immediate results from experiments that have only just begun, we need to focus on how we can accumulate these results for the benefit of Japan.

  
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