Studying things that nobody else studies
“Although my grandmother seemed fine, she came down with an illness in the winter when I was a third-year student in high school. We were told that she had only a week to live,” says Uchiyama, reflecting on the incident that stimulated him to become a researcher. “The doctor said to us, ‘I am sorry, but very few cases of this disease have been reported. At present, there are no curative drugs, because pharmaceutical companies are reluctant to create new drugs for which there are few patients because it is not profitable.’ I remember how upset I was. I thought I would become a researcher and try to study things that nobody else would attempt to study, and make a contribution to society in that way.”
Uchiyama went on to join the faculty of pharmaceutical sciences, and later, a chemical laboratory at the faculty. First he wanted to study in a biological laboratory because he was interested in life phenomena, but changed his mind on realizing that chemistry is absolutely central to understanding life phenomena. He decided to pursue computational chemistry and theoretical chemistry, which take advantage of spectroscopy and computers, as well as synthetic chemistry. At that time, few researchers in the faculty of pharmaceutical sciences took this approach. However, although in those days biological phenomena were observed from the perspective of proteins or at the genetic level, Uchiyama thought that the day would surely come when biological phenomena would be investigated at the atomic level from the perspective of hydrogen and carbon atoms and electrons.
Metal elements as cheap as vegetables
In 1995 Uchiyama took a position as an assistant professor at a chemical laboratory at Tohoku University. “We were running short of research funds because the laboratory had just started when I joined it. We could not afford to buy expensive rare metals and precious metals. So I was asked to conduct research with inexpensive base metals such as zinc that are available anywhere. In those days, few chemists expected that base metals had no potential for new functions, and consequently little attention was being paid to zinc. I was fortunate, however, because I had learned in a class at the faculty of pharmaceutical sciences that zinc has various important roles in the body. I officially decided to study chemical reactions using zinc, and started my research life as an assistant professor, making efforts to answer the question, ‘why is this low-profile zinc necessary in the body?’”
Zinc is an essential metal in the body and is second only to iron in abundance there. For example, the body of a person weighing 70 kg contains on average about 2.3 g of zinc. Essential metals such as zinc can combine with proteins to fulfil important functions as enzymes, which promote chemical reactions in the body. “In the body, just seven metals—including iron, zinc, and cobalt—cause the chemical reactions that support biological phenomena. These base metals are inexpensive, safe, and available anywhere.”
In contrast, many kinds of rare and precious metal are used in present high-technology products. For example, fuel cells, which are predicted to become one of the keys to saving energy, require platinum as the catalyst. “Per unit weight, the price of platinum is as expensive as a jet fighter, whereas many metal elements in the body are as cheap as vegetables.” Rare and precious metals are expensive, and some people are concerned about their depletion. Thus, the “element strategy” started as a national project, seeking to develop new molecules that can substitute for rare metals and precious metals.
“It is only recently that attention has focused on research into methods of deriving the same functions from base metals, which are cheap and available anywhere.”
Combining organic molecules and metal elements
How do we derive these functions from base metals? “In the body, enzymes cause various chemical reactions by a ‘hybrid method’ that combines the functions of organic substances such as proteins with those of metals.”
On the basis of the mechanism of enzymes, Uchiyama and his team members have pursued their research by focusing on hybrid molecules (so-called ate complexes), which are a combination of two different metals and organic substances. Their research method involves mainly synthetic chemistry, spectroscopy, and computational chemistry. “Whenever we try to observe chemical reactions in the body, we end up finding that they cannot be separated from the body. We depend on spectroscopy and computational chemistry to a large extent: spectroscopy uses light to explore the essence of substances, and computational chemistry, which is based on computer technology, helps us to make a precise estimate of the behavior of molecules and electrons.”
Uchiyama and his team members used the advantages of computational chemistry, predicting the possible emergence of a new function if zinc and lithium elements were surrounded by four bulky organic molecules (Fig. 1). “The molecule differs in shape from others because the metal at the center is completely surrounded by organic substances. We attempted to synthesize the molecule, expecting something special to happen.”
The synthesized molecule was used as a catalyst, and it proved to be a special polymer with new functions. A polymer is a long chain of units (monomers) connected together. This new functional polymer has a unique structure that consists of a hydrophobic organic substance as its main chain and a hydrophilic organic substance as its side chain; it changes from hydrophilic to hydrophobic at a temperature of 31 °C (Fig. 1). The polymer is now attracting wide attention in various fields of science, including biotechnology.
“So far, no method has been reported that can synthesize these polymers in one step.” Conventional catalysts used in polymer synthesis are so active that they can activate several portions of a monomer that should not be activated. The chemical reaction is therefore always accompanied by a step to introduce protecting groups that can block these portions, and by another step to remove them from the polymer when polymerization is complete. However, when thousands, or tens of thousands, of monomers are connected together, it is almost impossible to remove all the protecting groups from the polymer.
The new molecule that Uchiyama and his team members have developed by combining zinc and organic molecules is capable of activating special portions of a monomer without the use of protecting groups. Furthermore, the molecule has allowed the synthetic reaction to be developed effectively even in water, although conventional reactions are always performed in a organic solvent. “Unlike in a test tube, there are many molecules of different kinds in the water of body cells. In addition, enzymes that can activate various molecules are considered dangerous for the body. What the body needs is enzymes that can activate specific portions of a specific molecule to create what is needed when certain conditions are satisfied. The molecule we have developed can serve as an enzyme that behaves in this way.”
Conventional chemistry has sought to develop ‘highly active’ catalysts that can activate various kinds of molecules (functional groups). Such catalysts, however, may cause violent chemical reactions to happen unless the temperature is properly controlled. This reaction may accidentally lead to a fire or produce harmful by-products, and in some cases it requires much energy. “I believe that in future society will require ‘highly selective’ catalysts such as enzymes that can cause specific reactions only when certain conditions are satisfied.”
Direct absorption of zinc by the affected part
Uchiyama and his team members are also advancing research into the use of zinc to create therapeutic agents. Lack of zinc in the body is known to be a cause of various diseases. For example, it impairs the ability of the tongue to detect taste stimuli. “When you have a cold, you often lose your sense of taste. The lack of zinc ingested by your body contributes to your loss of appetite.”Zinc is effective in treating hepatitis, glaucoma, and skin cancers. “Nobody has yet conducted a study involving enabling metals such as zinc to be absorbed directly by the affected part of a patient. Zinc is an inorganic, ionizable material, and it can be absorbed by the body only with difficulty, because our cells are enclosed in lipophilic (fat-containing) membranes. By surrounding zinc ions with organic substances, we think we will be able to develop an agent that can enable zinc to be absorbed effectively by the affected part in the form of eye drops or skin ointment.”
Getting closer to the mystery of the blue color in flowers
Uchiyama and Atsuya Muranaka, a contract researcher, are also pursuing studies to chemically analyze the mechanism of highly functional molecules working in the body. “Recently we have seen the color blue used in various things from traffic lights to illumination devices. Producing a natural color blue, however, is still difficult. Why can flowers produce such beautiful blues? We are exploring the mystery chemically.”
Uchiyama and his team members focused on a certain molecule among the components extracted from a blue flower by an agricultural researcher (Fig. 3). Analysis by spectroscopy has shown that the molecule absorbs orange light. When orange light is removed from sunlight, what is left is a beautiful blue color. Thus, the molecule is producing the blue in the flower.
Now, how does the molecule absorb the color orange? “The molecule consists of two metals at the center and six organic molecules around the center. The six molecules are arranged with overlaps in the same way as a pinwheel. We separated these elements by computer simulation and attempted to investigate how individual elements absorb orange light; we found that they did not absorb light. This suggests that the six organic molecules can absorb orange light, leaving blue, only when they are all connected to a metal at the center and arranged around the metal like the six petals of a flower.”
Chloroplasts, which are responsible for photosynthesis, include pigment molecules that absorb sunlight efficiently. The pigment molecule has 18 flat molecules with slight overlaps, forming a large circular molecule (Fig. 4). “Using chemical synthesis, we tried to connect similar flat molecules with a slight overlap and found that these molecules absorb light of a longer wavelength. This pigment molecule is known to be able to absorb light from short to long wavelengths efficiently because of the overlaps between the flat molecules. I believe that chemical analysis of the functional mechanism of these natural molecules will lead to a modification of the mechanism and the designing of molecules with new functions.”
Exploring functions from electrons
“In the days when I started my study of zinc, I had to present papers at conventions in rooms with few participants because almost no researchers showed any understanding of, or interest in, my studies. I feel most stimulated, however, while I am trying something that nobody has ever attempted, or studying something that is considered very difficult,” says Uchiyama.
His motto is: “I want to be a researcher who will not be easily forgotten rather than a researcher who earns a name in the record of literature publication.” “We can write lots of research papers if we study popular research themes, and I think that many researchers are happy to choose these research themes. Instead, I would rather actively work on low-profile themes that few researchers are interested in and themes in which study results are not expected quickly. Basic chemical research is one of these themes. I want to establish a unique discipline of basic chemistry on my own, and expand the discipline to every field of research surrounding basic chemistry by faithfully following my own curiosity.”
One of his curiosities is the mystery of the functions of elements. “Why do elements have specific properties? Chemistry has not succeeded in explaining this mystery.” The chemical functions of matter are considered to depend on the state of the electrons in the atoms. “For example, we can combine organic molecules and the metal element into a molecule with new functions. This is because electrons in the organic molecules are attracted to the metal element, resulting in a change in its electronic state. Furthermore, two elements in a similar electronic state, such as Cu(I) and Zn(II), show different properties. I want to take advantage of synthetic chemistry, spectroscopy, and computational chemistry to explain the functioning of electrons from their electronic states. I think this will lead to an understanding of biological phenomena at the molecular, atomic, and electron levels.”
Now a completely new chemistry of elements is being explored through basic research into the roots of chemistry. The new chemistry will lead to the creation of new molecules having functions that can support our society in the future, and the creation of therapeutic agents for uncommon diseases.
About the researcher
Masanobu Uchiyama was born in Saitama, Japan, in 1969. He graduated from the Faculty of Pharmaceutical Sciences, Tohoku University, in 1993, went on to the Graduate School of Pharmaceutical Sciences, the University of Tokyo, and obtained his MSc in 1995 from the same university. He was appointed an assistant professor at Tohoku University in 1995, and then received his PhD in 1998 from the University of Tokyo. He moved to the Graduate School of Pharmaceutical Sciences, the University of Tokyo, as an assistant professor in 2001 and was promoted to lecturer in 2003. From 2001 to 2004 he served concurrently on a three-year project of ‘Synthesis and Control’, PRESTO (Precursory Research for Embryonic Science and Technology), Japan Science and Technology Agency. He has been Associate Chief Scientist at RIKEN since 2006, as director of his own research group. His research interests are in the area of synthetic organic chemistry based on organometallic chemistry, physical chemistry, and computational chemistry.
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