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Enhancing Quality of Life through Deep Understanding of Protein Structure Masaru Sato Supervisor, High Quality Protein Crystal Growth Experiment Associate Senior Engineer, Space Environment Utilization Center, Human Space Systems and Utilization Mission Directorate, JAXA

Significance of Applied Research

Q. Tell us about the objective of the applied research experiments on Kibo.

In applied research, we aim to conduct experiments that have an "exit." In other words, our goal is to make concrete achievements by applying the results of the experiments to the development of medicine and new materials on Earth, and to the improvement of our quality of life. For example, we are conducting experiments on protein crystal growth and nano material, such as nano skeletons and nano templates. In addition to experiments selected through public invitation, we have a framework for running paid experiments, where the results are proprietary, to encourage the participation of business and university researchers.

Q. What is your responsibility in this project?

Protein Crystallization Research Facility
Protein Crystallization Research Facility

As a supervisor for protein crystal growth experiments on the Japanese Experiment Module "Kibo", I work as a liaison between JAXA’s internal staff and various external organizations. For these experiments, JAXA prepares the facility to crystalize the proteins and provides integrated support, from receiving and selecting samples, to examining conditions for crystallization, conducting experiments in space, observing crystals after their return to Earth, and supporting X-ray diffraction data collection. We can execute all the operations, from preparation to results, in a short period of time, around five months before launch.
The protein crystal growth experiments are performed in the Protein Crystallization Research Facility "PCRF", which is installed in the Ryutai Rack aboard Kibo. It can store six crystallization cell units, each of which can contain up to 144 kinds of proteins. These cell units are very compact: 15 cm x 10 cm x 7 cm. Protein crystals are so small, they offer the advantage of allowing us to carry out a number of experiments simultaneously in a limited space. In addition, the cell units are reusable, so you can run many experiments with different objectives just by changing the contents. This has allowed us to schedule six protein crystal growth experiments in total, one every six moths, from 2009 to 2012. My responsibility is overall coordination to ensure that all the experiments are carried out smoothly and successfully.

Understanding the Origin of Life - Protein Structures and Functions

Q. What is the advantage of conducting protein crystal growth experiments in microgravity?

Ground-grown protein crystals forming in cluster (crystals are attached to each other)
Ground-grown protein crystals forming in cluster (crystals are attached to each other)

Space-grown protein crystals are cleanly and discretely crystallized
Space-grown protein crystals are cleanly and discretely crystallized

Proteins are assembled from amino acids based on information encoded in genes, and each protein has a unique function. The human body contains more than 100,000 kinds of proteins; about 10 billion kinds exist in nature. Proteins are the basic building blocks of life.
Everyone has heard of DNA. DNA is mere information, synthesized with nucleic acid (the smallest molecules that make up DNA). Simply put, DNA is the blueprint of life. The blueprint dictates the types, number, and arrangement of molecules that make up proteins. It tells various proteins, such as keratin for hair and collagen for skin, how to function in our bodies. Proteins have a three-dimensional structure, and their shape plays a critical role in their function. So, to understand protein function, it is essential to study protein structure. With today’s technology, the three-dimensional structure of a protein can be revealed by collecting protein molecules to form a crystal and observing it by X-rays diffraction.
A protein does not work in isolation; it only carries out its characteristic function when a chemical reaction takes place. This is why, to understand protein functions, it is critical to look at what type of chemical reaction is happening, and locate the carbon and hydrogen that are causing that reaction. High-quality crystals are essential to pinpointing these locations with accuracy and detail. If each molecule is like a face, high-quality crystals are crystals with all their faces beautifully aligned and looking in the same direction. This is why the microgravity environment of space is attractive.
In space, protein molecules can align beautifully because there is no convection, where aqueous solution moves vertically or horizontally due to a difference in concentration, nor sedimentation, where a heavy substance sinks due to the influence of gravity. So it is possible to form high quality crystals and observe protein structures in substantial detail.

Q. How are protein crystal growth experiments on Kibo expected to benefit our life on Earth?

A reactive site in a protein is a keyhole. and a compound that stops a chemical reaction is a key
A reactive site in a protein is a keyhole. and a compound that stops a chemical reaction is a key

First of all, they will contribute to the development of new medicine. I mentioned earlier that a protein does not function in isolation, but only when a chemical reaction takes place. We call the location where that chemical reaction occurs the active site. If we can add a compound to the active site that blocks the chemical reaction, the protein can’t function, and - for example - a disease stops progressing. You could explain this phenomenon with the analogy of a keyhole and key: the reactive site in a protein is the keyhole, and the compound that stops the chemical reaction is the key.
By studying the protein structure, we try to figure out the precise shape of the keyhole. If we can do that, we can make a key that will fit, and plug the hole. Under normal circumstances, when the keyhole is open, something gets in there and causes a chemical reaction that allows the protein to function. And the protein allows the disease to progress. But if we plug the hole, then nothing can get in to cause that reaction, and the protein stops working. And when that happens, the progress of the disease stops, too.
The key I’m referring to is a compound to inhibit the function of a protein that causes disease - in short, a medicine to cure a disease. If we can find a key that perfectly fits the keyhole, it becomes possible to develop medicine with few side-effects.
Also, protein crystal growth experiments can contribute to the development of environmentally-friendly waste disposal. Plastics don’t decompose naturally, but there are proteins that can dissolve them. If we can learn how to use these proteins correctly, we will find the key to environmentally friendly waste disposal.
Furthermore, the protein crystal growth experiments on Kibo can contribute to the development of bioenergy without the use of food. There is a type of protein that accumulates sugars by breaking down grass or straw, which are not used for food by humans, and that protein can be used to produce energy. If this becomes feasible, it is expected to help solve the problem of Japan’s food self-sufficiency and aid in the development of renewable energy. Another potential application is using proteins as catalysts for fuel cells. So protein crystal growth experiments have so much new potential to benefit our life.

Applications for Protein Crystal Growth Expriment in Space

Q. What kind of results have the Kibo experiments produced in the field of medicine?

Protein involved in muscular dystrophy, and muscle atrophy reduced by the protein (courtesy: Dr. Yoshihiro Urade, Osaka Bioscience Institute)
Protein involved in muscular dystrophy, and muscle atrophy reduced by the protein (courtesy: Dr. Yoshihiro Urade, Osaka Bioscience Institute)

Protein involved in inhibition of cancer proliferation (courtesy: Prof. Yuriko Yamagata, Kumamoto University)
Protein involved in inhibition of cancer proliferation (courtesy: Prof. Yuriko Yamagata, Kumamoto University)


Protein expected to be used in bioenergy production (courtesy: Dr. Koji Inaka, Maruwa Foods and Biosciences, Inc)
Protein expected to be used in bioenergy production (courtesy: Dr. Koji Inaka, Maruwa Foods and Biosciences, Inc)

Protein that degrades nylon oligomer (courtesy: Prof. Yoshiki Higuchi, University of Hyogo)
Protein that degrades nylon oligomer (courtesy: Prof. Yoshiki Higuchi, University of Hyogo)

The closest to practical application is the research of Dr. Yoshihiro Urade of the Osaka Bioscience Institute. An effective treatment for muscular dystrophy is expected to be developed soon. Muscular dystrophy is a disease that weakens muscles to the point where they lose their function, and it had been thought to be incurable. However, by using the Kibo facility to form and analyze protein crystals connected with the progress of the disease, Dr. Urade’s team was able to learn some crucial new information. They have detected water molecules involved in the function of the protein. That is, they discovered not just the shape of the active site in the protein (the keyhole), but also the shape of the compound that binds to it (the key). I think this achievement was possible because the experiment was conducted in space, where high-quality protein crystals are easier to create.
In collaboration with the pharmaceutical industry, Dr. Urade has developed a compound that is an effective drug candidate for muscular dystrophy. The compound was administered to a dog that had been induced to develop muscular dystrophy, and the result was very favorable. Dr. Urade’s research continues, and he hopes to have the compound certified as a new medicine as soon as possible.

Other than this, Prof. Sam Yong Park of Yokohama City University is working on a protein involved in DNA replication, with the aim of developing breakthrough medication effective for influenza. Influenza outbreaks happen every winter, and so it is essential to have the right vaccine available that will target the prevailing type of influenza virus. Also, there is the increasing emergence of drug-resistant influenza viruses that are resistant to current medicines. Prof. Park has figured out the structure of the protein the causes DNA information to be replicated in various types of influenza virus. Studying the structure of the protein in detail will allow scientists to develop new medicine that inhibits the function of influenza viruses regardless of their type.

Finally, Prof. Yuriko Yamagata of Kumamoto University is studying the protein involved in cancer proliferation. The hope is that inhibiting the function of the protein could stop the proliferation of cancer, and reduce the size of cancer cells. Growing these protein crystals in space, Prof. Yamagata has been able to learn the details of their three-dimensional structure. Now, scientists are trying to find a compound (key) that will fit that keyhole.
Many other medical experiments are being carried out on Kibo, with growing hopes for practical application. Q. What other kinds of results have come out from experiments on Kibo? Dr. Koji Inaka of Maruwa Foods and Biosciences, Inc. has conducted research on bioenergy production. He has looked at the structure of an enzyme called cellulase, which breaks down plant cell walls and a protein that’s a main ingredient of fiber. Recently, there has been a focus on environmentally friendly bioenergy. However, the most common form, bioethanol, is made of chemically processed food crops, such as corn. Energy production with the cellulase enzyme does not require the use of food crops; instead it involves dissolving the plant fiber of grass, straw, timber and waste. If this becomes feasible, I think it will help solve Japan’s problem of food self-sufficiency. Instead of using food crops to produce energy, we’ll be able to use them as actual food. Dr. Inaka is aiming for practical application of the enzyme in three to five years.

Prof. Yoshiki Higuchi of the University of Hyogo is studying an enzyme that helps break down by-products of nylon (plastic) manufacture. These by-products, known as nylon oligomers and monomers, have conventionally been thrown away. In our daily life, we use a lot of artificial fiber and plastics, but they degrade naturally only with great difficulty, and result in a lot of waste we have to dispose of. If it becomes possible to make an enzyme that can efficiently break down this waste and turn it once more into a raw material, it will be a great contribution to the environment. The development of such an enzyme is currently underway not only for waste disposal purposes but also for industrial applications.

  
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