1. Selection of a cell based model system

In order to acquire large sets of relevant data, researchers will identify the cells responsible for the development of diseases and establish cell-based model systems.

2. Global analysis of the temporal and spatial profiles of gene expression and protein localization

Using cell-based systems, we are pinpointing changes in the gene expression profile in detail. Time dependent gene expression changes, and changes in the localization of proteins are two major information sets crucial to a systems approach.

3. Creating an integrated database

The data acquired in our various laboratories is integrated into a single database. A large number of novel targets for drug development are emerging from this huge amount of high impact, cross-referencing data.

4. Development of diagnostics and therapeutics as an open laboratory

Drug target genes and proteins are expressed and monoclonal antibodies against these proteins are being generated by an orchestrated effort of both industrial and academic researchers whose various forms of expertise have been chosen especially for how they complement each other and this multidisciplinary process.

Systems biology and medicine - beyond the science of the genome and on to the post-genomic sciences.

The Progress of genome science indicates that at the best current estimate there are approximately 39,000 human genes. Proteomics, which is the key to post-genome science, is faced with the challenge of not only solving more than 100,000 proteins structure encoding by these genes, but also interpreting the function of these proteins and their role in pathogenesis.

LSBM (The Laboratory for Systems Biology and Medicine) is the worldﾕs first laboratory dedicated to the analysis of complex living systems by the integration of 4 basic technologies: genomics, proteomics, transcriptomics,and the study of cell-cell interactions.

From individual gene research to the research of biological network.

Why is systems biology needed to understand life, health and disease? From genome analysis, it has become understood that many genes function not in isolation, but redundantly and/or in interelation with one another. Accordingly, there are many phenomena which can not be solved by either knockout or transgenic technology, as valuable as these approaches are. At LSBM, we have been able to successfully compile a very large amount of data obtained from a comprehensive analysis of gene expression profiles. Using these data we have developed methods for systematic information analysis. As a result, we have been compelled to the recognition that individual genes are not regulated randomly or as singular units apart from one another, but, on the contrary, are regulated by the overlap of many feedback loops in the system. By integrating systems biology and medical science LSBM aims at the elucidatation of this complex network of interactions.

Cancer and atherosclerosis as targets for genome based drug development

As the system under study complexifies, the amount of comprehensive analysis data increases substantially, and significant resources, e.g. manpower, and funding are therefore needed for construction and maintenance of the corresponding database. However, on the other hand, systems biology and medical science working together are uniquely able to identify and/or clarify the highest value targets for the pharmaceutical, environment, food, cosmetics and other industries. For example, in the pharmaceutical industry, this multidisciplinary approach is able to develop drugs for target proteins at the greatest speed and at the lowest cost. We provide the technological solution for bridging the in-parallel progress of life science and information technology for the industry.

Diseases frequently arise out of an impairment of the most vulnerable feedback loop in a biological organism

Human systems are maintained at equilibrium, called Homeostasis. Homeostasis is maintained by a set of complex feedback mechanisms. For example, blood pressure and plasma cholesterol levels are maintained in a fixed range by the following mechanisms. Sensor proteins of a cell detect changes in the biological milieu, and a signal transduction mechanism transmits this information to the nucleus, where it will modify the expression pattern of genes, and hence their protein products. These proteins function as effector agents in the restoration of the original homeostasis.

Cancer and atherosclerosis are complex diseases which develop from the most vulnerable sub-systems among the many overlapping regulatory pathways. The triggering steps can originate at various points in the system landscape, and then ramify from there into the destabilizing pathology. Systems biology and medicine together are able to elucidate where the specific triggering events take place. This kind of information is priceless when it comes to pointing out the fundmanetal targets for a specifically effective drug which has minimal or no side effects.

Time dependent changes in gene expression and spatial changes in protein shape during signal transduction

The human body consists of approximately 60 trillion cells. These cells are regulated by two distinct patterns of changes. The first is the time course of the expression of those 39,000 genes in the genome which have been activated. The timing of one of these expressional events is controlled exquisitely. The second critical regulatory step is the transfer of a protein and the formation of a membrane microdomain. Proteins inhabit only delimited domains of a cell, and biological signals are transmitted by the translocation and conformational change of proteins. LSBM is investigating these two critical changes at a very fine level of detail by means of DNA microarray analysis of gene expression patterns, and an antibody-based identification of the localization and conformational changes in the effector proteins.

A new and an epoch-making drug development target: orphan receptor genes

The Human genome encodes for many chemoreceptor genes. Because of the specificity of these pre-established pathways, chemicals which bind to these receptors can deleteriously affect the human body even at very low concentrations. Genome science now leads us to believe that there are about 5000 chemoreceptor genes in humans.

Although currently the number of proteins used for therapeutics is only 500, there could well be ten times this number among the proteins which bind the large number of as yet unidentified orphan receptors which exist. Because of its ablity to discover and functionally elucidate such receptors, LSBM enables the development of completely new therapeutics directed at previously unavailable targets.

The Incomparable Speed of genome-based antibody therapeutics

In this era of hyper-intense global competition, it is said to take at least 20 billion yen and ten years for the development of a new drug. Some estimates are considerably higher. LSBM is pursuing the development of genome-based antibody therapeutics to reduce this cost in time and money by one third, making full use of the technology advantage provided by the unification of systems biology and medicine.

We express functional chemoreceptor proteins which serve as a target for novel drugs, make functional monoclonal antibodies, and develop them for clinical use.

Conventionaly, drug are selected individually through a series of multiple, refining steps. Using budded baculovirus technology, we can express functional proteins encoded by genes from the total genome sequence and select the functional monochlonal antibodies which interact with them. Antibodies are contructed from human genes and then modified by the technology for humanizing antibodies so as to make them less immunoreactive and hence prone to side-effects.

This method is able to reduce eight steps of conventional drug discovery into just three. We can also reduce the risks associated with going forward with a single candidate early in drug development by making many slightly different antibodies against the same target so the one of greatest utility can be selected for further testing at the right time.

The world standard for systematic analysis of a chemoreceptor

In drug development, the most important targets are (1) the receptors on the cell membrane, the so-called G-protein coupled receptors (GPCR), and (2) the nuclear hormone receptors. LSBM is a world leader in the systematic analysis of these two classes of receptors. First of all, we have achieved the technological feats of expressing the GPCR on the surface of an insect virus, and then in reconstituting the functional complex.

LSBM also has access to the intellectual property of The University of Montreal, and formed a global alliance for the exchange of intellectual property with a number of institutions. We are working together with scientists at the Pasteur Institute in France, and the Howard Hughes Medical Research Institute at the University of Texas. To date,

LSBM has expressed most of the known 48 nuclear receptor proteins, on which we have filed intellecutal property claims, and are in the process of establishing 48 monoclonal antibody drug candidates which bind these targets.

LSBM has established a world-class technical method for the analysis of orphan chemoreceptors.

(1) Comprehensive gene expression profile analysis

In our system we determine the RNA expression level for almost all the genes in the human genome. Currently, two dimensional DNA chips can not detect approximately half of these genes, for example, those genes for which the expression levels are relatively low. In collaboration with Combimatrix, we have developed DNA chips with much higher sensitivity which employ three dimensional systems.

Genes for GPCR and Zinc finger proteins, including the nuclear hormone receptors, have been identified and novel DNA chips for these genes are under development.

(2) Datamining of the gene expression data

At the LSBM web site, one can access a comprehensive gene expression database of more than 1000 human tissues and cells, including 40 of normal human tissues. Genes involved in human cancers and other disorders have been and continue to be analyzed intensively. We are now deep into developing the sophisticated bioinformatics tools needed for identifying disease related genes.

(3) Expression of a functional membrane protein on the surface of an insect virus

Membrane proteins are critical targets for drug development, but for technical reasons also the most difficult proteins to functionally express. At LSBM, we have developed a novel method which utilizes an insect virus, known as budded baculovirus, for the expression of the functional membrane complex. We are the world leader in this field and possess the critical BV patents which cover many aspects of this technology.

(4) Systematic establishment of antibodies & the generation of functional antibodies

Antibodies are one of the very most powerful tools we have for protein analysis. At LSBM we are creating monoclonal antibodies for all the nuclear hormone receptors. Based on our BV-patented technology we are also developing a method for the generation of functional monoclonal antibodies against GPCR. Systematic antibody generation has enabled us to study the temporal and spatial changes which occur in protein complexes.

The virus which expresses the GPCR signaling complex

GPCR is the most important protein family for the recognition of many chemical substances at the cell surface. They are the target of many drugs. At LSBM, we have succeeded in establishing the functional expression of GPCR on the surface of insect baculovirus (BV). Three different kinds of G proteins, α, β, and γ, have also been expressed along with GPCR on baculovirus and created a comlex, the ligand for which can be recognized at 1/100 the concentrations required in other systems.

Ligand binding can be indicated by luminescent insect virus

We are developing a virus which will change the range of emitting fluorescence by means of FRET technology. In this system, ligand binding causes the dissociation of the Ga protein from GPCR and binding of Ga to the effector molecule. We are developing a FRET system which operates on the virus surface, and this technology will be a key for the development of GPCR protein chip technology.

An artificial smell sensor

We can detect 10,000 or more odors and have about 500 known odorant GPCRs in our nose. Our brain can recognize a smell from the pattern of signals from these receptors. In LSBM, we have succeeded in the expression of an odorant receptor on an insect virus. We are now developing an artificial smell sensor using all of the 500 known GPCR in insect virus systems.

A Diagnosis of cancer can be performed from a single drop of blood.

Cancer is one of the greatest causes of death and suffering the world today.

At LSBM, the expression profile of the more than 30,000 genes involved in liver and stomach cancer has been determined by means of DNA chip technology. We are expressing the genes most highly induced at the various stages of cancer from transformation to metastasis, and generating monoclonal antibodies against these proteins. We are also actively developing a novel method for the simultaneous measurement of these multiple protein levels in patientsﾕ blood using monoclonal antibodies. This method will enable a rapid and accurate diagnosis of cancer from only one drop of blood.

Monoclonal antibodies which can kill a cancer cell

The monoclonal antibody SP-3 has been generated against a membrane protein the expression of which is induced during malignant transformation. SP-3 kills cultivated liver cancer cells and has attracted attention as a potential new anti-cancer agent. At LSBM we are comprehensively profiling molecular targets on the surface of cancer cells. LSBM provides the technological platform for genome-based antibody development which will allow novel treatments for diseases currently thought to be intractable.

Monitoring the development of atherosclerosis in a test tube.

Atherosclerosis is for the most part a silent disorder until it erupts in a stroke or heart attack. At LSBM, we have developed a novel system which allows the generation of vascular lesions in vitro. This interactive pathology model enables us to much more easily study the process of atherosclerosis and to determine the specific intervening effect of potential or established drugs.

Drug development for lipid and glucose metabolism

At LSBM, we are analyzing the effect of drugs on gene expression in conjunction with our work on membrane and nuclear chemoreceptors. Many such chemoreceptors have been identified as drug targets in hyperlipidemia and diabetes, and by studying changes in gene expression profile by the administration of drugs, we will get a much more precise understanding of the optimal treatment mechanisms.