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Knowledge Co-Creation - Profiles of researchers

Examining the Deep Relationship between the Effect of Medicine, Dietary Habits, and the Biological Clock

Shigenobu Shibata
Professor, Waseda University Faculty of Science and Engineering
Vice-Research Representative, Center for the Consolidated Research on Medical, Life Science and Engineering(*)
(*)Part of the Private University High-Tech Research Center Project funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT)

Proving the existence of biological clock nervous centers

My area of expertise is the discipline of pharmacology, which involves examining the system of the effects of pharmaceuticals. Pharmacology can be divided into two main categories. In the first category, clinical pharmacology, research is performed through the administration of pharmaceuticals to actual human patients. In the second category, fundamental pharmacology, examination of fundamental systems is performed while performing work such as animal experiments in a laboratory. I specialize in the latter, the field of fundamental pharmacology.

My work started in the pharmaceutical research of emotional nervous centers which control feelings, with a focus on mental symptoms such as depression and Alzheimer's disease. I then proceeded to study in the laboratory of Professor Yutaka Omura (Professor Emeritus at Kyushu University), an expert in the field of cerebral physiology. While I was researching the relationship between the secretion of hormone and nervous centers for appetite/satiation, I learned that an area called the suprachiasmatic nucleus of the hypothalamus possessed the function of controlling the biological clock. This took place in the early 1980s.

In the laboratory, I performed an experiment in which I sliced the brain of a rat and then inserted electrodes in order to measure the action potential. I found that the suprachiasmatic nucleus was unique in that there were high levels of activity when sliced and measured in the morning, but low levels of activity when sliced and measured in the evening. However, subjects that were calm in the morning gradually became vital and active with the coming of morning and the afternoon. I realized that biological rhythms were the only explanation for this phenomenon. If, even when the transmission of information from other areas of the brain is cut off, the suprachiasmatic nucleus alone acts autonomously to fulfill a clock-like function, then the suprachiasmatic nucleus must be the brain center of the biological clock.

At that time, 3 different research groups from Germany, USA, and Japan had developed similar theory and were involved in experimentation. There was fierce competition to prove this theory. As the result of repeated experimentation, we were able to obtain good data and make a presentation that received global recognition.

At that time, I was still a graduate student working towards my doctoral degree. However, due to my involvement in this research, I encountered the new research field of examining the relationship between biological rhythms and pharmacology-a field which is recently attracting great attention under the name of "chronopharmacology". Beginning from that encounter and continuing to this day, I have continued to work in this field.

New medicine created from chronopharmacology

There are many types of medicine for which effects are improved and side-effects are decreased when attention is based to the rhythm of ingestion. For example, people with hyperlipidemia are prescribed with medicine that reduces the formation of cholesterol, and this medicine is best taken in the evening. The enzymes which form cholesterol have a higher value in the evening but decrease in value in the afternoon. Therefore, it is best to conform to this body rhythm by taking more of the medicine in the evening.

Currently, I am involved in joint research with the University of Yamanashi Faculty of Medicine to examine the relationship between the biological clock and allergies such as asthma and hay fever. Itchiness, a symptom of allergies, tends to be more pronounced at night rather than in the afternoon. However, the mechanism behind this phenomenon is not yet understood. Another example is that asthma attacks occur more often at dawn. By examining the combination of the rhythm of asthma symptoms and the rhythms of medicinal effectiveness, I believe that we can understand the appropriate form of treatment to reduce the severity of symptoms.

In 2007, through joint research with the National Institute of Advanced Industrial Science and Technology and the University of Tsukuba, it was discovered that medicine (fibrate medicine) for the treatment of hyperlipidemia acts to alter the biological clock. When such medicine was administered to a laboratory mouse, the time that the mouse was active became earlier. Therefore, there is the possibility to link these findings to the development of medicine for "delayed sleep-phase syndrome (DSPS)", a sleep disorder in which the biological clock becomes fixed to a pattern of late-night activity and late awakening in the morning. Until now, the only treatment available for sleeping disorders was symptomatic treatment such as sleeping medicine, so there are high expectations for the development of new types of medicine.

The above are just a few examples. In actuality, I believe that the effectiveness of many types of medicine can be improved through attention to the relationship with the biological clock. I also believe that new medicine and methods of treatment can be developed. There are great expectations for contributions to medicine from chronopharmacology.

Even healthy people experience respiratory stenosis at night (upper graph). / When the suprachiasmatic nucleus is destroyed in an experiment using mice, biological rhythms for day and night are lost and respiratory stenosis occurs (lower graph).

Approach towards "chrono-nutrition"

Measurement of lifestyle rhythms using an actigraph

Recently, I am involved in research regarding nutritional intake and the biological clock, based on reasoning similar to chronopharmacology. This new field is known as "chrono-nutrition". There is a high level of interest from the general public regarding this field, and we are involved in a variety of projects.

Through research aid given by JAXA (Japan Aerospace Exploratory Agency), our laboratory performed research to compare "morning people" and "night people" in terms of the relationship between the biological clock and lifestyle rhythm factors such as mealtime, exercise, and sleep. The Waseda University Women's Lacrosse Team participated in the experiment as the "morning people" group, due to their habit of waking at the same time every morning to engage in morning practice. The difference between this "morning people" group and other types of people was then examined. All participants in the experiment wore an actigraph, a wristwatch-type measurement device that costs \100,000 per device, and activity amounts throughout the day were measured in detail.

As a result of this experiment, it became clear that the greatest influence on the biological clock was exerted by mealtime, rather than by exercise. This means that it is easier to maintain the biological clock by having meals at a set rhythm, rather than by adjusting the time and amount of exercise. Methods for maintenance of the biological clock are an important issue in an outer space environment. If the knowledge gained from our research can be skillfully applied, it will become easier to control the biological clocks of astronauts.

Although one day consists of 24 hours, people are active according to a biological clock with a 24.5 hour rhythm. In order to lead a well-regulated daily life, it is necessary for people themselves to adjust for this 0.5 hour discrepancy everyday. However, this is a difficult task. Even when viewing the data of students from the laboratory, the students are not able to skillfully adjust for this discrepancy.

Actually, my personal actigram (a graph of data for activity amount) shows a 24 hour cycle that is surprising in its accurateness. This is something that I can be proud of. I suppose this means that my personal lifestyle is an embodiment of the mealtime and sleep rhythms that I research. The MEXT (Ministry of Education, Culture, Sports, Science and Technology) is promoting a public campaign for "Early to Bed, Early to Rise, and a Good Breakfast", and I am often asked to lend them my lifestyle data as an example!

By using a high-capability actigraph (upper graph), rhythms for sleeping and awakening can be measured in detail from the time a person enters sleep until the person rises in the morning. Temperature of feet was also simultaneously examined (lower graph), and it can be seen that release of heat occurs together with going to sleep.

Construction of an evaluation library for herbal medicine

Chronopharmacology for herbal medicine is an area that I would like to enter in the future. As is widely known, herbal medicine consists of a combination of various medicines and has a fundamental philosophy of making prescriptions that match the constitution of the patient and that improve the patient's constitution while performing treatment. This differs from Western medicine, which is based on symptomatic treatment. Prescription of herbal medicine has relied on the accumulation of experience throughout its long history, and a formal pharmacological evaluation has not been performed. Japanese manufacturers of herbal medicine conduct strict examinations regarding the safety of ingredients, but they do not have much excess resources to engage in pharmacological evaluation. Herbal medicine is attracting increased attention from Europe and USA, and has the possibility to spread on a global level if strict evaluations are established and standardization is performed.

I believe that the concept of chronopharmacology, which is based upon rhythms of the biological clock, is a good fit for evaluating the effectiveness of herbal medicine, which seeks to improve the user's constitution while working in the body over a long period of continued use. It can be thought that, in terms of herbal medicine, a disrupted constitution is akin to a disruption in rhythm, and that improvement of the constitution is achieved through adjustment of rhythms.

Prescriptions of herbal medicine use delicate combinations of medicine. However, when conducting a pharmacological evaluation, it is necessary to delve one level deeper when evaluating, from the level of medicine to that of chemical compounds. It is also necessary to construct a library regarding these compounds. This library should contain profiling of combinations used in prescriptions for herbal medicine. I envision an evaluation database of herbal medicine constructed using the two pillars of a "compound library" and "profiling".

Towards the next step of research through the fusion of medicine, science, and engineering

Operation on a mouse and view of the laboratory

Another theme which I would like to become involved in is the development, through a fusion of medicine, science, and engineering, of research for biological rhythms at a cellular level. My laboratory is part of TWIns (Tokyo Women's Medical University / Waseda University Joint Institution for Advanced Biomedical Sciences), and there are researchers from Tokyo Women's Medical University who are working in advanced regenerative medicine engineering. I am currently planning joint research to bond cells into a variety of forms and to examine the functions of biological rhythms through the relationship with forms. This research will be performed through a partnership with the cell sheet engineering possessed by researchers of Tokyo Women's Medical University. Form and function are in a deep relationship, and functions are often discovered by creating types of forms.

Among researchers from Waseda University at TWIns, there are several researchers, including myself, whose work relates to biological rhythm research. There has been discussion about creating a tangible summary of the knowledge gained by each of these researchers. As a result of these discussions, a new lecture course in "chronobiology" will be opened in 2010 for undergraduate and graduate schools. Researchers will cooperate to hold the lectures. I am looking forward to seeing what kinds of lectures are developed.

Mouse room

I enjoy myself the most when I am having discussions with students. We can freely develop theories on a variety of topics, such as the types of lifestyles that lead to obesity. Experiment work is very tedious and methodical. For this reason, it is important to hold discussions so that researchers can step back and review their objectives from a objective point of view, and so that excitement can be infused into the work.

Shigenobu Shibata
Professor, Waseda University Faculty of Science and Engineering
Vice-Research Representative, Center for the Consolidated Research on Medical, Life Science and Engineering(*)
(*)Part of the Private University High-Tech Research Center Project funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT)

Graduated from the Kyushu University School of Pharmaceutical Sciences, Department of Pharmaceutical Sciences in 1976. Completed his Doctorate Degree at the Kyushu University Graduate School of Pharmaceutical Sciences in 1981. Doctor of Pharmaceutical Science. Served as Research Associate and Associate Professor at Kyushu University and then as Research Fellow at the State University of New York. From 1995, served as Associate Professor and then Professor at the Waseda University School of Human Sciences. In 2003, assumed the position of Professor at the Department of Electrical Engineering and Bioscience in the School of Advanced Science and Engineering. Major research themes include pharmaceuticals which act upon the biological clock, as well as molecular biology research and pharmacological research regarding body rhythms. Received the PSJ Award from The Pharmaceutical Society of Japan in 1994. Has served various positions including Vice-Chairman of the World Federation of Societies for Chronobiology and Director of the Japanese Society for Chronobiology.

Shigenobu Shibata Laboratory

http://www.waseda.jp/sem-shibatas/

Related Article (Introduction of TWIns)

http://www.waseda.jp/rps/information/magazine/front/front_080722.html

WASEDAWASEDA UNVERSITY Research Promotion  http://www.waseda.jp/rps/