Manager
Clinical Development Planning and Management Mochida Pharmaceutical Co., Ltd.
Visiting Professor Tohoku University
Kazumi Nishijima

■The success rate for development of new drugs is only one part per 25 thousand.

━ From the s t andp oint of promoting research and development in the pharmaceutical industry, Mr. Nishijima has been involved in various leading-edge research bases.

●Nishijima （dispense with the Mr.）　Firstly, I was involved in Spring-8. In order to make shared use of exclusive beam line (BL) by the Japan Pharmaceutical Manufacturers Association (JPMA), a consortium for the analysis of protein structure by the JPMA was launched by 22 companies (19 companies due to merger, etc., at present). All the Japanese pharmaceutical companies are among the medium-sized businesses in the world. It is quite difficult for one such company to construct an exclusive BL in a world's top level public institution. Therefore, the industry attempted to launch the consortium for use by all the companies in this industry. Thereafter, moreover, many drug discovery companies also came to use the NMR (nuclear magnetic resonance) facility of RIKEN (Yokohama Laboratory), J-PARC (Japan Proton Accelerator Research Complex) in Tokai Village and the radiation light facility PF of the High Energy Accelerator Research Organization (Tsukuba City), and 8 companies joining the consortium have already sent samples to the experimental module “Kibo” of the International Space Station. Finally, the ten quadrillion speed computer “Kei,”and the XFEL (X-ray free energy laser) in Harima Science Park City (Hyogo Prefecture) were promoted in the fourth Basic Program for Science and Technology, and we will also promote an approach to use these facilities for drug discovery in the all-Japan organization.

━ Proactive utilization of such leading-edge research bases will have an important significance for the pharmaceutical industry, won’t it?

●Nishijima Absolutely yes. According to the latest data of the JPMA, there were about 610 thousand types of synthetic (extracted) compounds produced for drug discovery in Japan in 5 years from 2004 to 2008. Among them, there were only 24 compounds approved as new drugs. They are so few in 5 years. The probability is 1 : 25,482. It is just like a miracle. The expenditure of research and development for a new drug is about 70 billion yen per new drug. I think there are less than 10 pharmaceutical companies in Japan that can do the development alone from start to finish. This is because it is difficult to secure the development cost, so there has been an increase in cases in which the development project was changed into a joint development with another company in the middle of the project. Even if the profit is less, the most important purpose is to launch the drug. About 70% of this development cost is spent in clinical studies and the stage thereafter. The cost for nonclinical studies is about 30% , that is, the budget that we aim at exploratory drug discovery utilizing leading-edge research bases accounts for about 30 % of the whole. Of course, the assertiveness of divisions involved in clinical studies inside and outside the company may become bigger. However, I think that the part in which corporate efforts are sufficiently reflected is before clinical studies, that is, the upstream part of drug discovery. For example, in the structural analysis and screening test of proteins to discover new compounds, the parts described as searching sources are very important. The upstream flow is very weak despite being important, but since we are doing research and development while imagining that this flow will run into the ocean, we have a high motivation and are very proactive, although money is limited, so there is a considerable possibility that the flow will dry up in mid-course. Even so, it is necessary to address the issue of drug discovery while promoting efficient searching of candidate compounds for development. Therefore, proactive utilization of leading-edge research bases is required.

■For overcoming the disease of a low degree of contribution of drugs

━ Is the method of creating new drugs changing from day to day?

●Nishijima In Japan, it has largely changed from the time when the consortium for structural analysis of proteins was established by the JPMA. Until then, drug discovery consisted of first searching the cause of the symptoms of a disease, but the target was completely based on guesswork. We conducted so-called random screening of a lot of compounds and natural products thinking they might be related to diseases. We searched for new drugs in this manner. The difference of new drug discovery is as follows. First, it became possible to identify receptors and enzymes, the targets of a drug, by structural and functional analysis instead of guesswork, and searching for new drugs can be carried out in a rational manner. It also became possible to adjust the expression of a protein based on genome information, and to verify whether or not it is involved in a disease or is the target of a drug. Therefore, it became possible to design new drugs to treat disease in a rational way. By using molecular imaging, moreover, it is also possible to confirm the action and therapeutic effect of a drug in the body. It can be said that the time has changed from the era of symptomatic drug discovery to that of rational drug discovery aimed at fundamental treatment. Therefore, it is essential to carry out rational drug discovery by integration of leading-edge research bases.

━ For what diseases will rational drug discovery be promoted in the future?

●Nishijima Here is data summarizing the degree of satisfaction with the treatment of various diseases, and the degree of contribution of drugs to the treatment (Figure 1). This data shows that diseases treated very well with surgery and drugs have already been differentiated from diseases which heal poorly and for which there is no good drug. It can be understood that there have already been good drugs for hypertension, hyperlipidemia, peptic ulcers, tuberculosis, etc. On the other hand, although there are various drugs for dementia, complicated diseases like diabetes mellitus, various cancers, etc., the degree of satisfaction is very low. For example, this is because we barely inhibit the progress of dementia and cannot cure it. For diabetes mellitus, moreover, treatment must be continued indefinitely once it occurs. That is, since we cannot heal them, it is natural that drugs do not contribute essentially. Therefore, rational drug discovery in the future will be performed for overcoming diseases in which the degree of contribution of drugs is low.

━ In the molecular imaging research strategy promotion program (Phase 2 program) of the Ministry of Education, Culture, Sports, Science and Technology, it was shown that we will address the 2 fields of refractory cancers and dementia.

●Nishijima This is the first reason for specialization in cancer and dementia. Inotherwords, the target site of the drug is not clear in these diseases. In order to overcome this, it is necessary to implement drug discovery by integrating leadingedge research bases instead ofconventionalmethods. For example, this requires a breakthrough in brain science, deepening and integration of the understanding of the brain and nervous system, and progress in nerve and brain cell simulation utilizing supercomputers and the contribution of molecular imaging to diagnosis and drug discovery. We believe that all citizens want to introduce leading-edge research bases into this field for which doctors, patients and pharmaceutical companies ne e d assis t ance. Moreover, it can be said that this is just where the performance of the ten quadrillion speed computer “Kei” comes in. The mindset of the general public is more important than the pull of future science technology or being top in the world. For example, when you or your family members undergo examination, it takes 2 weeks until the result of diagnosis is obtained by precise image processing, a huge amount of data processing and comparisons, etc. with a conventional computer. If the ten quadrillion speed computer is used, however, it may take 30 minutes to obtain the result. If you are asked which do you choose, anxiously waiting out the 2 weeks or acquiring the result quickly on site, everyone would choose getting the result quickly. I think that the general public will understand that this needs money. In a brain science such as dementia, moreover, the dimension of the drug discovery process is different from lowering blood pressure or killing bacteria invading the body. Because of the problem of recognition, all the problems cannot be tackled by using experimental animals, neither is it easy to open the human brain to try drugs. If so, there is no other way than simulation utilizing supercomputers. As an extreme case, if you were asked, “May I open your head or may I use a supercomputer?”, your answer would be obvious (laughing). Actually, there is a field such as dementia, in which it is necessary to perform simulation.

■It is important to cultivate human resources to open up the next generation.

━ Are high-level calculation tools such as supercomputer very important for the practice of rational drug discovery carried forward by the pharmaceutical industry?

●Nishijima If Spring-8 is used, for example, the amount of data increases 10- or 20-times in comparison with the X-ray analysis which was done by our company. The more precise, the clearer the image, so the amount of data does not decrease but increases. Then, we may of course have to consider choices like upgrading the computers in our company, use of supercomputers owned by national research organizations, or cooperation with a university which can use a supercomputer.

━ For the pharmaceutical industry, the 2 main reasons for using a supercomputer are processing of a huge amount of data and simulation as described previously.

●Nishijima Of course, simulation of the structure of proteins, drug design and disease models will become more important in the future. As concerns diseases with a low degree of satisfaction with the treatment and contribution of drugs, such as dementia, complicated diseases like diabetes mellitus and some cancers, described previously, in particular, research by simulation may become important. Moreover, the processing speed will also be important. A demand for the fastest computer, if possible, is common in government, industry and academia. If possible, moreover, it is important to develop an environment in which other leading-edge research bases and supercomputers are integrated, and everything can be used together. If the user can use a supercomputer without recognizing it as a supercomputer, it may be better. For example, it will be wonderful if an environment could be developed so that data can be collected with SPring-8, a structural and functional analysis is immediately performed with a ten quadrillion speed computer, and virtual screening is also carried out. This is because future drug discovery is not possible with individual leading-edge research bases alone. It is necessary to address this problem by bringing everything together nationwide. In the future, there is no doubt that supercomputers may be involved in the most important part. Since the data obtained in leading-edge research are all precise, the high processing performance of supercomputers is required to utilize the data

━ Finally, please give us your opinion about operation of the ten quadrillion speed computer after its completion, if any.

●Nishijima After looking at various leading-edge research bases and their operations so far, the matter I feel the most important is cultivation of human resources. I feel that Japanese facilities have no room to expand. We are good at making facilities themselves, but after starting operation, the budget to expand and improve it is not available. Therefore, cultivation of human resources there is not well implemented. I think that the facilities need room for minimal maintainence, as well as for future evolution. To be specific, we need to cultivate young people more for the next generation. For example, in choosing research projects, we should consider cultivating people who will develop the next generation by creating a fund for young researchers in their 20's and 30's, instead of selecting glamorous projects. As concerns the present ten quadrillion speed computer, it will probably be difficult to develop the next generation computer after this with the same way of thinking. A new breakthrough is required. There is no doubt that young researchers in their 20’s or 30’s may achieve it. We should consider how to cultivate such human resources.