3.3. The Progress of the Genome Project made Japanese Companies Strengthen their R&D

pp. 30-34 in Bioethics and the Impact of Human Genome Research in the 21st Century

Author: Isao Yokoyama (Nikkei B.P., Biotech. Editor)

Editors: Norio Fujiki, Masakatu Sudo, and Darryl R. J. Macer
Eubios Ethics Institute

Copyright 2001, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.
It was announced in June of this year that the international human genome project team completed the draft sequence analysis of human genome. On the same day, Celera Genomics made an announcement that the company had finished connecting their analyzed human genome information. These facts may give an impression that businesses using genomic information may take off in earnest. But genetic information is already causing a revolution in various industries. I have tried visualizing the flow of genetic information usage. I am sorry it is in Japanese.

In the medical field, supply of new drug targets has begun as well as development of tailor-made medicine, gene therapy and antibody medicine. In the diagnosis field, genetic testing services to check the risks of cancer and high blood pressure are beginning to spread not only in the U.S. and Europe but also in Japan. Genetic information is also being used to develop products in the food field, the agriculture field, the chemical field and the new material field. All of these owe to an advancement seen in the technology to analyze genes as well as development of bio-informatics technology to retrieve useful information from gene information.

Now, I would like to elaborate on development of drugs using genome information. Since there are other specialists who will explain in detail the skills and concepts of using genomic information and DNA polymorphism for drug development, I will stick to the general view.

First, I will talk about the bio-related market in Japan. According to a research conducted by Nikkei Biotechnology, the Japanese bio-product market showed a favorable expansion to 976.7 billion yen in 1999. But focusing only on the biopharmaceuticals market, 1999 sales were 371billion yen and growth has been flat for the past several years. This is because sales of pharmaceuticals using genetic recombinant technology have reached the ceiling. Drugs using genomic information are anticipated to be more effective and there is a strong expectation that they will boost the biopharmaceuticals market once again.

Genomic information is especially useful for rapid isolation of genes and proteins when developing new drugs. Information technology is combined with genetic information of the drug target collected through genetic research to date as well as with massive amount of accumulated DNA sequences. Use of IT is said to be speeding up drug target development. Some people even say that development of the assay system, which used to take two years for drug screening, can now be done in just half a year.

Orphan receptor is drawing attention for use in developing new drugs. Orphan receptor is a receptor whose ligand is unknown. Many pharmaceutical companies are trying to isolate orphan receptors and determine ligands for development of new drugs. Why are they all after orphan receptors? The reason is because there are many drugs that act on receptors from which huge sales can be anticipated. Drugs related to receptors occupy about half of the world's top 50 best-seller drugs. Research on orphan receptors is progressing rapidly. For example, Takeda Chemical Industries has already isolated seven orphan receptors and ligands.

Competition is intense especially with G protein coupled receptor (GPCR). Many pharmaceutical companies are engaged with GPCR. For example, SmithKline Beecham has succeeded in isolating a receptor of an exceptionally potent vasoconstricting hormone. Using the common sequence of GPCR, Japanese pharmaceutical companies including Takeda Chemical Industries, Chugai and Yamanouchi are trying to isolate orphan receptors and determine ligands for drug screening. Fujisawa and Taisho have tied up with Arena Pharmaceuticals to screen compounds that act on orphan GPCR. Besides GPCR, enzymes and ion channels are also highly anticipated as new targets that can be obtained from genome information.

Venture businesses focused on genome play an important role in discovering genes and proteins that are the target of new drugs. Many genome ventures have succeeded in isolating disease-related genes and supplied them to major pharmaceutical companies.

Millennium Pharmaceuticals is one of the most successful genome ventures in supplying disease-related genes. The first company with which Millennium tied up was Hoffmann-La Roche. This was in April 1994 and their objective was to search genes related to obesity and type II diabetes. To date, Millennium has tied up with more than twenty companies. If all the research activities proceed as written in the contracts, it is said that Millennium will be funded by over 1.3 billion dollars. Among the tie-up contracts of Millennium, the most notable is the one with Bayer signed in September 1998. The contract is worth a total of 465 million dollars. Under this five-year contract, Millennium is to isolate 225 new drug targets identified as being relevant to cardiovascular disease, cancer, osteoporosis, pain, liver fibrosis, hematology and viral infections. According to the announcement made by Bayer in March 2000, goals of their joint research in 1999 were fully achieved, as a result of which Bayer acquired 26 new drug targets and identified one lead compound that act on a certain drug target.

Myriad is another genome venture that has been successful in supplying many disease-related genes to major pharmaceutical companies. Using ProNet technology, Myriad is identifying many new genes that play important roles in a cell's biochemical pathways. ProNet is a technology based on yeast two hybrid technology. In May 2000, Hitachi and Myriad formed an alliance based on ProNet. Under this arrangement, Hitachi has the right to use ProNet in its service business in Japan. Myriad too has tied up with many pharmaceutical companies. For example, Myriad is working with Novartis in searching genes that are related with cardiovascular diseases, and with Pharmacia to identify the biochemical pathway of three diseases and discover new drug targets.

Although I will refrain from going into details, some Japanese pharmaceutical companies have identified disease-related genes using DNA microarray technology, transgenic technology and so on. Some have formed alliances with genome ventures to identify genes.

The first generation of biomedicine, including human growth hormone and interferon, was developed based on proteins. Researchers first identified and separated proteins that exist in the body in only a small quantity. Then, they determined the amino acid sequence, synthesized the cDNA and produced the biomedicine using genetic recombination technology. Today, however, it is more popular to look for proteinous drugs from genetic information. This trend has to do with advancements seen in the project of analyzing genomic information and isolating cDNAs.

For example, Human Genome Sciences (HGS) announced in June 2000 that the company would start clinical tests of BlyS or the B lymphocyte stimulating protein. Because biological signals are often secreted proteins, HGS scientists studied about 400 human proteins in their database whose DNA sequences suggested that they were secreted. Each protein was purified and tested its ability to stimulate B cell growth. As a result, one protein, BlyS, was found to have a powerful effect on B cells.

There are ongoing projects to analyze cDNA. These projects are anticipated to contribute to the discovery of new drug targets and new proteinous drugs. In Japan, there is a national project progressing to analyze 30,000 cDNAs. In the U.S., the National Institute of Health too has embarked on its cDNA project.

Once a new drug target is identified from the genome and gene information, it can be used for much more than just the conventional drug screening. In recent years, a variety of new biotechnologies have appeared in the medical field. Such new technologies, combined with new drug targets, are anticipated to lead to the development of more innovative medicines.

One of the new biotechnologies is antibody technology. New targets identified from human genome are also targets for antibodies. New drugs using antibody are being introduced on the market one after another in the U.S. and Europe. Examples of such new antibody drugs are platelet inhibitor "ReoPro" of Centocor and anti-cancer drug "Herceptin" of Genentech. Many antibody drugs have been put to practical use over the past few years in such fields as cancer, cardiovascular diseases, infectious diseases and autoimmune diseases. Clinical development is advancing in Japan as well.

The reason why antibody drugs are spreading so rapidly is because technologies to avoid immune reactions against antibodies are also spreading. Progresses seen in technologies related to chimeric antibody and huminized antibody are also a tide running in the favor of antibody drugs. Recently, development is advancing with complete huminized antibodies produced using E.coli bacteria or mice. Future potentials are rising in this field.

As antibody drugs come into practical usage, more and more antibody developers and genome ventures are forming alliances. Their goals are to produce complete huminized antibodies against targets identified through their genome researches. Millennium Pharmaceuticals has joined hands with antibody companies such as Abgenix, Medarex and MorphoSys. Cambridge Antibody Technologies has tied up with HGS and Medarex with Eos Biotechnology, just to give a few examples.

Anti-sense drugs, together with antibody drugs, are medical technologies that recently entered the stage of practical usage. An anti-sense drug is made of a nucleic acid having complementary sequence to the DNA of a protein that triggers a certain disease. It is believed to hinder appearance of mRNA or the process of translation to a protein. The first anti-sense drug was Isis Pharmaceuticals's "Vitravene" that was released in November 1998 in the U.S. Vitravene is a drug to cure cytomegalovirus (CMV) retinitis of AIDS patients. With the progress of genome analysis, more and more genes will be discovered that cause various diseases. Anti-sense discovered against such genes can readily be made into a drug. Clinical development of ribozyme to decompose RNA is also under way, which is also a highly anticipated anti-sense drug.

Convergence of structural biology to study the 3-dimentional structure of protein with genomic information is starting in earnest. The 3-dimentional structure analysis of proteins is used as an essential technology for designing drugs. Structural genome, or the movement to comprehensively analyze 3-dimentional structures based on the massive amount of accumulated genomic information, has begun.

The Japanese and the U.S. governments, on May 2, agreed to embark on the structural genome project as a new international joint project to follow the international human genome project. The Japanese government, in November 2000, will host an international conference on structural genome. During this conference, methods of global role sharing will be discussed.

In the U.S., the National Institute of Health leads the effort regarding structural genome. In September, the organization announced its strategy of determining the structures of several thousand proteins over the next ten years. Japan too is working on devising a national strategy regarding structural genome. The Japan Pharmaceutical Manufacturers Association (JPMA) has its own plan for a joint research project on protein structure analysis among its member companies.

Use of genetic polymorphism is highly anticipated in the use of genomic and gene information. By categorizing patients, it becomes possible to select the more effective treatments while avoiding the risks of side effects. There are some drugs whose development was discontinued mid way, because clinical tests were carried out without distinguishing patients and satisfactory results were not obtained. Among such drugs, some may in fact win the reputation of being an epoch-making new drug.

A progress in the analysis of genomic information and gene information is leading to discovery of numerous disease-related genes and drug targets. By distinguishing patients having these targets and genes, treatment will have greater effects. The act of "choosing patients" is already performed when giving "Herceptin," which is an antibody to cure cancer, or interferon to a hepatitis C patient. This way of thinking is likely to become more popular.

Genetic polymorphism is anticipated as methodologies of categorizing patients in the most detailed and effective manner. Among them, usefulness of SNPs, or single nucleotide polymorphisms, is attracting attention and various projects have been launched. SNPs are a variation of just one base that differs by individual. There are various different types of genetic polymorphism such as RFLP, micro-satellite. The most frequently observed among them is considered to be SNPs. This is why research is advancing to use SNPs as a marker for genomic analysis. The technology of distinguishing patients by the difference of gene type is called pharmacogenomics.

Application of pharmacogenomics is anticipated to happen the soonest with drug metabolization. By studying the polymorphism of drug metabolizing enzymes like cytochrome P450, it becomes possible to choose the most appropriate medicine and decide on the most appropriate amount of dosage for better results and less side effects. It may also lead to development of derivatives that differs little by polymorphisms.

In Japan, the Ministry of Health and Welfare is engaged in the analysis of SNPs of drug metabolize related genes, while JPMA is about to launch a joint project to analyze genetic polymorphisms related to pharmacodynamics. There are also many pharmaceutical companies that are collecting polymorphic information of genes through clinical trials.

SNPs are anticipated to be also useful as markers on a genome to discover disease-related genes. The idea is to isolate such genes by studying the appearance frequency of SNPs between a group of people who are suffering from a certain disease and a group of people who are not. SNPs are also anticipated to be useful for measuring the risks of sufferig from certain diseases.

Glaxo Wellcome is one of the companies that are aggressively promoting SNPs-related research. The company is said to have isolated genes that are related to migraine, psoriasis, diabetes and Parkinson's disease by making full use of SNPs information. For the specific purpose of developing a drug to cure migraine, the company analyzed 100,000 basepairs on a human chromosome using 20 SNPs. Glaxo Wellcome has unveiled that 5 SNPs were actually linked with the disease and that they were all on one gene.

Biotechnology ventures too are aggressively analyzing SNPs. Celera, now famous for human genome analysis, is one of the companies aiming at launching a business using SNPs information. Celera embarked on its business in August 1998. The company plans to analyze the DNA sequence for the human genome of six people who vary in gender and race. By analyzing the DNA sequence of multiple chromosomes, Celera is trying to unveil SNPs automatically. Celera's goal is to create a database of such information for provision to the pharmaceutical companies, while patenting the more valuable SNPs in the industry. GENSET, under contract with Abbott Laboratories, has succeeded in isolating SNPs that distinguish patients who may suffer liver trouble as a side effect of Abbott's Zyflo (5-lipoxygenase inhibitor) used to cure asthma.

While venture businesses such as Celera are tackling enclosure of SNPs information, the leading pharmaceutical companies and genome research institutions in the U.S. and Europe established a non-profit consortium by the name of The SNP Consortium in April 1999. Currently, non-pharmaceutical companies too are participating in this consortium where analysis of SNPs is advancing steadily. In Japan, a major SNPs project has been launched under the leadership of the Ministry of International Trade and Industry, the Ministry of Health and Welfare, the Science and Technology Agency and the Ministry of Education.

So far, I have discussed the basic flow of genomic information usage in new drug development and I must admit that U.S. and European companies are ahead of their Japanese counterparts. But there are some Japanese companies that are aggressively tackling this field with hopes of a rollback. Companies such as Takeda Chemical Industries, Yamaunouchi, Chugai and Eisai have advanced R&D structures of their own to work on discovery of GPCR-related genes and disease-related genes. There are Japanese companies that are screening discovered genes as targets to find lead compounds. A characteristic feature about gene-related research in Japan is that the companies are not trying to cover all the fields. Rather, they are focusing on certain fields where they are strong to in order to promote their development activities. Companies such as Chugai and Kyowa Hakko are advanced in development of antibody drugs.

Companies that have been successful in the field of biotechnology too are starting to tackle drug development using genomic information. They are enhancing their R&D structures with much aggressiveness. Among them, Sumitomo Pharmaceuticals is known for putting Sumiferon, its interferon __, into practical use with its advanced cellular reproduction technology. Sumitomo Pharmaceuticals and Sumitomo Chemical formed a group to concentrate on genomic researches in April this year, and established a research center on genomic science in October. Shionogi tied up with Quark Biotech to put gene discovery technologies in place. Shionogi also has plans to develop new drugs in the fields of inflammation and anti-microbe where the company is strong. Taiso, Fujisawa are examples of companies that are forming alliances with non-Japanese venture businesses to tackle drug development using genomic information.

A characteristic of the Japanese biomedicine industry is that non-pharmaceutical companies are aggressively involved in the business. Many of them in recent years are tackling development of new drugs using gene information. Japan Tobacco, for example, has formed an alliance with Gene Logic of the U.S. to promote development of drugs to cure renal diseases using genomic information. Japan Tobacco is also promoting development of cancer vaccines and antibodies. Kirin Breweries is one of the few companies in Japan that have succeeded in the field of biomedicine. Kirin Breweries has tied up with Hyseq with the aim of discovering genes related to cellular reproduction. In addition, Kirin owns a technology related to mice for generating humanized antibodies. There is a future possibility that the company will form alliances with non-Japanese companies in this arena.

One of the reasons why Japan is far behind the U.S. and Europe in the field of biomedicine has to do with the existence of biotechnology ventures. The number of biotechnology ventures is increasing in Japan owing to the appearance of venture capital companies that invest in biotechnology firms as well as to the government's policy to nurture them. New venture businesses play an important role in the development of drugs using genomic information. GenCom that focuses on functional analysis and Medogene that focuses on gene treatment are examples of such venture businesses.

Now, I would like to refer to the challenges that lie ahead for Japanese pharmaceutical companies in developing medicines that use genomic information. The most serious among them is the lack of bio-informatics talent. Universities are being required to enhance their educational programs.

Other challenges include the problem of patents and ethics. In fact, this is a serious problem that is shared by many countries. Several presentations will be given in relation to this topic during this seminar. In Japan, technology transfer and nurturing of venture businesses are also important.

Next, I will talk about the national budget in Japan. According to a recent reporting put together by Nikkei Biotechnology, the amount of biotechnology-related budget request for the fiscal year 2001 increased by 15.5% against this year to reach 396.3 billion yen. Considering the fact that the amount of budget request was only 289.5 billion yen in 1998, there has been an increase of about 100 billion yen in just two years. This shows how eager the Japanese government is in strengthening the biotechnology industry. Looking at the budget request for fiscal year 2001, the Ministry of International Trade and Industry requested for an increase of approximately 60% with the aim of analyzing the function of proteins and boosting bio-informatics research. The Science and Technology Agency, on the other hand, requested for an increase of 25% to focus on analyzing the 3-dimensional structure of proteins. Next year's budget will be used not only for R&D but also for bringing up competent researchers. The Science and Technology Agency will hire post-graduate students with the aim of training them as young researchers engaged in cutting-edge research themes. Joint research centers of universities will also be enhanced.

Development is under way for a smooth mechanism of transferring technology and university organizations for technology transfer are being established one after another. In the U.S., the Bayh-Dole Act certainly helped the incorporation of many biotechnology ventures. Although the Japanese version of the Bayh-Dole Act was enforced in 1999, the number of patents held by universities is much smaller in Japan compared to the U.S. and technology transfer to industrial circles isn't necessarily smooth. There is a need to revitalize universities and create a mechanism for smooth technology transfer. There are many more problems that need to be solved for Japanese bio-products and biomedicines to survive in the world in such aspects as social acceptance and educational environment. In addition to earmarking budgets, the Japanese government must act urgently in order to put a social framework in place.

Please send comments to Email < asianbioethics@yahoo.co.nz >.

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