Interdisciplinary fusion of medicine and pharmacology

I am visiting the Global COE “Global Center of Education and Research for Chemical Biology of the Diseases” to interview Prof. Takashi Kadowaki, project leader, and Prof. Shoji Tsuji and Prof. Masakatsu Shibasaki, who are core members. I have heard that this Center is a combination of three Centers developed under the 21st Century COE Program: two in the medical field and one in the pharmaceutical field.

Professor Kadowaki：

Yes, that’s right. One of the three was the “Study on Diseases Caused by Environment/Genome Interactions” led by Prof. Ryozo Nagai. Researchers participating in this Center in the medical field were mainly from the Division of Internal Medicine at the Graduate School of Medicine, and I was one of them. The second was the “Center for Integrated Brain Medical Science,” also in the medical field. The Center was led by Prof. Tsuji and consisted mainly of researchers from the Division of Neuroscience at the Graduate School of Medicine. The third was the “Strategic Approach to Drug Discovery and Development in Pharmaceutical Science,” established in the Department of Pharmaceutical Chemistry at the Graduate School of Pharmaceutical Science. Prof. Shibasaki played an important role in this Center. These three Centers were combined and developed into a Global COE project under the concept of “promoting integrated research on disease and drug discovery by combining interdisciplinary expertise in medicine and pharmacology, and providing training for future cross-disciplinary and internationally-oriented researchers.” This is how our Center was established.

What achievements have been made by these three Centers under the 21st Century COE Program?

Kadowaki：

All three Centers have yielded significant results. The Center for internal medicine has identified key molecules involved in clinically important diseases such as diabetes, metabolic syndrome, cardiovascular disease and hematologic malignancy. With regard to diabetes and metabolic syndrome, for instance, it was elucidated that a decrease in adiponectin secretion from adipocytes in obesity is an underlying pathology of these diseases. Based on this elucidation, researchers of the Center identified the adiponectin receptor, a key target molecule for the treatment of these diseases, for the first time in the world.

The Center for neuroscience focused their efforts on neurodegenerative diseases, particularly on Alzheimer's disease. Researchers have made pioneering achievements, including full elucidation of the essential cofactors for gamma-secretase, a key molecule in Alzheimer’s disease. In the Strategic Approach to Drug Discovery and Development in Pharmaceutical Science project, researchers have made considerable pioneering achievements in the fields of organic synthetic chemistry and signal transduction. One example of this is the world’s first successful completion of a synthesis of oseltamivir phosphate (Tamiflu).

With these three Centers being integrated into one, the concept of a fusion of medicine and pharmacology was presented, with the aim of building the future of medical science in the 21st century to include major disease areas and important organs. I think that the phrase “the Chemical Biology of the Diseases” is being used for the first time in the world to clearly express this concept.

The term “chemical biology” does not sound that new to me, as a layman.

Kadowaki：

This has already been used in the basic concept of drug discovery in pharmaceutical and medical research but has never been used by medical researchers in the context of disease science where the mechanism of a disease is identified, based on which a therapy is discovered.

While researchers in internal medicine deal with diseases of the peripheral organs such as the heart, liver, fat and blood, researchers in neuroscience, which Prof. Tsuji specializes in, deal mainly with CNS diseases such as neurological and psychiatric disorders. In the last few years, it has been revealed that there are very close networks and communications between the peripheral and central nervous systems. In response to this finding, interdisciplinary fusion has been encouraged with the main objective of elucidating more precisely the role of these networks of nervous systems and peripheral organs in maintaining the normal functions of the body in order to understand how failures in these networks result in various diseases.

It seems that we can expect significant achievements in the next five years.

Kadowaki：

In the United States, business entities, universities, and government agencies have become more cooperative and integrated than before in their efforts to discover innovative new drugs. There are more drugs developed using university-originated patents in the United States than in Japan. While there have already been systems allowing university spinoff ventures to play a leading role in drug discovery in the United States, the large Japanese pharmaceutical manufacturers do not yet regard academia as a strategic partner in drug discovery.

My understanding has been that medicine and pharmacology are very closely related, but it seems that they are not.

Kadowaki：

It may be difficult for non-professionals in these fields to imagine and understand but, although medicine and pharmacology seem to be the closest to each other, researchers in the two fields have had scarcely any interaction or communication. Those involved in medicine are responsible for treating patients, but are far behind in an education and understanding of pharmacology. Specialists in pharmacology have expertise in drugs, but are far behind in learning about diseases for which drugs are administered. There have been these fundamental flaws in both approaches. For this reason, we recognized the need for a fusion of the two disciplines.

Screening Core Lab and Imaging Core Lab

Please give us a detailed descriptions of your research methods.

Kadowaki：

At our Center, we use disease model animals and cells derived from lesions to identify pathological pathways and target molecules by making full use of genomics, epigenomics, transcriptomics, proteomics and metabolomics. A Screening Core Lab is currently being established by the Graduate School of Pharmaceutical Science with the aim of identifying a number of lead compounds that regulate the functions of molecular targets for diseases using chemical libraries that are generated based on totally new principles and concepts.

The Graduate School of Medicine is now building an Imaging Core Lab. Our plan is to evaluate in vivo pathologic conditions using lead compounds identified by the Screening Core Lab and also to evaluate lead compounds based on the evaluation results of the pathologic conditions. Researchers at the Graduate School of Pharmaceutical Science will participate in the projects of the Imaging Core Lab and researchers of the Graduate School of Medicine will participate in the projects of the Screening Core Lab. Through concerted efforts between the two core labs, researchers will first evaluate pathologic conditions and then generate lead compounds useful for regulating the functions of key molecules.

It’s a trial and error process, isn’t it?

Kadowaki：

Yes, it is. An ideal lead compound can rarely be identified in the first step. We need to find a compound that most strongly controls the key molecule among those identified in the first step, by making the best use of conformational analysis and organic synthetic chemistry. This process will lead to the identification of compounds that control a specific target molecule, eventually enabling us to identify a highly effective compound that causes no adverse reaction. The optimization of a lead compound is thus achieved.

The next step is particularly important. Our Global COE project aims to discover an agent that regulates the activity of the key molecule involved in a disease. If such an agent is discovered, you can accurately evaluate the function of the key molecule in the disease and the in vivo role in the pathologic condition by administering the agent in a model animal. Our goal is to identify a first-in-class agent?“first in class” in the sense that you can use it as a tool to analyze the function of the key molecule in a disease so as to elucidate and discover the principle of the disease. We also hope to develop an identified compound into a promising novel drug in collaboration with pharmaceutical companies. If successful, the drug will be the “best in class.”

Education at the Center: early and intensive exposure

Will you please tell us about the education on the doctoral courses?

Kadowaki：

Students have received and are still receiving a mono-disciplinary education, where medicine and pharmacology are taught separately. Students with a single major in medicine will become doctors or medical researchers who do not understand pharmacology, and those with a single major in pharmacology will become pharmacists or pharmacology researchers who do not understand diseases. This is, unfortunately, the actual situation. Our ultimate goal is to provide multi-disciplinary education and increase double-major students so that they will become medical researchers who understand chemical biology or pharmacology researchers who understand the science of disease. With this in mind, we first of all focus our efforts on establishing a system that enables students to take a major-minor combination.

Could you provide us with a more detailed explanation?

Kadowaki：

We will take full advantage of the achievements and experiences of the three 21st Century COE Centers in their five-year activities. For example, the Neuroscience Center held regular retreats for the entire members of the Center. The number of participants at these retreats was about 150. The Center also provided educational opportunities for young researchers to attend symposiums and conferences held abroad so as to broaden their perspective internationally. At the Pharmaceutical Science Center, students in doctoral courses under the COE support program organized symposiums mainly for young researchers. The Neuroscience Center too had a program designed to support young researchers: They accepted young researchers based first on an assessment of their academic performance.

9 with about 250 participants, inviting the world’s most prominent researchers in chemical biology with whom participating students engaged in insightful discussion.

So, through such opportunities, researchers will be able to understand both medicine and pharmacology, with a focus on chemical biology, in a well-balanced manner.

Kadowaki：

Exactly. We need to produce doctors and medical researchers who understand the chemical biology of the diseases, and pharmacology researchers who understand clinical problems and pathologic conditions. If we offer programs to train students to enhance their abilities to discover innovative therapies on their own and play a leading role in medical science in the future, there are many countries and fields in which these researchers can play an active role.

What kind of support systems are available for training young researchers?

Kadowaki：

The primary focus is on early and intensive exposure of students to cutting-edge and interdisciplinary research. This is the basic concept of the interdisciplinary programs in medicine and pharmacology and cross-disciplinary lecture series that I mentioned earlier. An international symposium and a retreat to which we invite researchers from abroad are each held once a year with the aim of exposing students to international research.

Chemical libraries, research focused on the prevention of pathologic conditions, and other issues

Professor. Shibasaki, would you give us your comments from the pharmacological standpoint?

Professor Shibasaki：

There is a clear reason why universities in Japan, particularly the University of Tokyo, can offer programs to promote integrated research on disease and drug discovery by combining interdisciplinary expertise in medicine and pharmacology and to train cross-disciplinary and internationally-oriented researchers. In the United States and Europe, colleges of pharmacy are specifically designed to provide vocational education for pharmacists. In Japan, over the last century, pharmaceutical departments of universities have provided education to students to become researchers engaged in drug discovery.

For this reason, many Japanese pharmacists have expertise in organic chemistry, biological science and physical chemistry. Under these circumstances, it may not be easy to integrate medicine and pharmacology in the United States and Europe but, thanks to the unique system of pharmaceutical departments in Japanese universities, it is relatively easier for them to provide such interdisciplinary programs. I believe these programs will produce successful outcomes. I hope young undergraduate and master’s program students understand this well.

Please also tell us about chemical libraries.

Shibasaki：

There have been discussions in various media about chemical libraries, mainly focusing on how many libraries there are, or basically, about the number of chemical compounds contained in a library.

A chemical library may contain a large number of compounds if its target compounds can be easily synthesized. There may be some promising compounds included in such a chemical library but the possibility of this leading to an innovative discovery may not be very high.

Our catch phrase is “research to improve the quality of chemical libraries.” We want to generate a large number of chemical libraries, within our Center at the University of Tokyo, that only contain chemical compounds that have been extremely difficult to synthesize or that have been given up on due to the difficulty of synthesis. It is our hope to generate a collection of chemical libraries with distinctive characteristics.

Professor Tsuji, would you also share your comments, including issues about research and education?

Professor Tsuji：

Before joining this Global COE project, I was involved in the 21st Century COE project, with its main focus on neuroscience. Our efforts have always been directed toward improving graduate education, including improving lectures and more exposure of students to international experiences. In addition to retreats and international symposiums, we have provided students with opportunities not only to participate in scientific meetings and symposiums held abroad, but also to stay in a foreign country to conduct experimental research. Some of them produced outstanding research results in a short period of time. When students have gone overseas for a short period or we have invited lecturers from abroad, we have arranged opportunities for student discussions in a closed, half-day session.

Another issue I would like to mention is that the field of neuroscience covers from basic to clinical sciences. We provide education designed in such a way that students can understand a wide range of neuroscientific research from basic to clinical. In this Global COE project, researchers are talking about key molecules. By dealing with a disease on a molecular scale, you can now discuss brain diseases, internal diseases and life-style related diseases on the same level. Additionally, neuroscientists can now be connected with pharmacologists via chemical biology, expanding our research capacity much more widely than before. Adding these two new core approaches, I believe, will improve graduate education significantly.

In your field, integration with pharmacology was essential as well.

Tsuji：

In the medical field, there is an expression, “physician scientist.” I think it is our mission to produce researchers who are very familiar with medicine, clinical science, and diseases and, at the same time, know how to fight the disease. This point tends to be forgotten, but it is one on which we all want to place more emphasis.

In regard to chemical biology, there has recently been a significant move toward the application of chemical biology to research into therapy in international academia. In treating neurodegenerative diseases?for example, Alzheimer’s disease and Parkinson’s disease?therapeutic drugs currently available for these diseases are useful for improving associated symptoms but do not cure the pathological condition. Symptoms can be mitigated by supplementing neurotransmitters, but the progress of the disease cannot be stopped. So there is some limitation to these treatments. In contrast, therapy focused on preventing pathologic conditions, as with the targeted therapy of key molecules mentioned earlier, is desirable in the sense that the pathologic condition is identified and attacked so as to treat it directly.

In future, more researchers in academia may be engaged in research on therapy focused on preventing pathologic conditions because it is often difficult for mega-pharmaceutical manufacturers to conduct this kind of research. On this point, I think it is significant that researchers in academia perform such research.

How about awareness of the interdisciplinary fusion of medicine and pharmacology among students?

Shibasaki：

After earning a doctorate degree in pharmacy at a graduate school of pharmaceutical science, most students take a job in the laboratory of a pharmaceutical company or an academic institution. At our Graduate School of Pharmaceutical Science, despite our efforts to provide students with education on diseases, this is by its very nature limited. In the United States and Europe, there are quite a large number of medical graduates working in laboratories at pharmaceutical companies.

Is that so? The difference may reflect a cultural difference.

Shibasaki：

In Japan, on the contrary, there are hardly any medical graduates in pharmaceutical companies. In this regard, the cross-disciplinary education and research promoted at the Global COE Center should have a significant impact on the Japanese drug discovery industry, which is regarded as one of our key industries in the 21st century. Students do have a great interest in learning about diseases. In determining the area of research, knowledge of diseases affects their decision significantly. They are a collection of people who aim to be leaders in drug discovery research. To fulfill their goal, an interdisciplinary education is essential and it should have already been provided, but unfortunately has not.

Kadowaki：

In Japan, both the undergraduate system and the graduate system, which was added to the traditional undergraduate system, are based on classical disciplines that have a long history. In contrast with these time-honored disciplines, science is advancing rapidly. If you want to output something new or pursue innovation, you need to create new values, but without an effort to transcend traditional disciplines and boundaries, you are not able to do so.

Tsuji：

Another thing I would like to emphasize is that research on diseases takes time of the order of seconds or minutes inside a test tube, or of the order of days when cells are used, or of the order of months and years when animal models are used. Researching a disease in humans requires a time span of 50 to 60 years. Without understanding them all in a comprehensive manner, you cannot understand the disease correctly. It would be difficult for institutions other than universities to provide the place and opportunities for researchers to be engaged in this kind of research. There are hospitals as well as laboratories for basic science research in universities. It is necessary to see things comprehensively and more research organizations that allow researchers to do so should be established.

Thank you all for today.

(Interviewer: Masaharu Yano, COE Program Promotion Office)