The Life Sciences Project Bulletin

   

 

New Projects in

 

GENE DISCOVERY and FUNCTIONAL GENOMICS

 

from Israel and the Netherlands

 

No.18 – February 2004

                                            www.optin.nl

 

Projects

 

1.      A Novel Gene Essential for Brain Formation

 

2.      Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data

 

3.      Applying Functional Genomics For The Development Of Novel Therapeutic Reagents (Genes And Their Derivatives) For The Treatment Of Cancer And Other Human Pathologies

 

4.      Recombinant Antibody Arrays for Functional Cancer Genomics

 

5.      A New Technology for Constructing Drug Targets and Developing New Drugs in Silico

 

6.      Signature Algorithm For Analyzing Large-Scale Gene Expression Data

 

7.      Identification of Anticancer Drugs for Patients with Aggressive Breast Cancer: The Synthetic Lethality Screening Approach

 

8.      Micro-array technology and cluster algorithm for characterizing receptor-ligand interactions

 

9.      Development of Novel Potassium Channel Openers for Neuroprotection, Neuropathic Pain and the Treatment of Epilepsy

 

10.   Human DNA Repair in Medical Diagnostics

 

11.   Functional Polymorphisms in Olfactory Receptor Genes

 

12.   Recombinant Fragments Of the Human Acetylcholine Receptor: Application for the Treatment of Myasthenia Gravis

 

13.   Diagnostic method for early detection and follow-up of Schizophrenia

 

14.   Genetic Testing for Usher Syndrome Type 3

 

15.   A Novel Erythrocyte Differentiation Factor

 

16.   Nucleic Acid Fragmentation in Millisecond Time Scales By Conventional X-Ray Machine: Application To Protein-Nucleic Acid Footprinting

 

 

 

Advertorials

 

1.      The Cuppen research group

 

2.      Functional genomics of the antigen presenting DC

 

3.      Programs that integrate the proprietary AFLP® and cDNA-AFLP technologies

 

4.      Evogene: accelerating natural evolution processes 

 

 

 

In the News

 

1.    Gene Discovery Through Est and Genomic Data Clustering and Assembly

 

2.    Technion researchers develop 'glue' to support broken bones

 

3.    Who's afraid of biotech? 

 

 

 

 

 

Events

Nanotechnology Conference

Guest of honour and keynote speaker:

Shimon Peres

 

Presentations by Israeli Companies and Universities.

 

Mach Making Event: Investors, Business Development, R&D and Academic Cooperation.

Contact Optin for more information.

15 April 2004, SciencePark Amsterdam, The Netherlands

 

Plant Biotechnology Symposium
19 March 2004,  Wageningen, The Netherlands

 

 

8th European Symposium on controlled Drug Delivery

7-9 April 2004, Noordwijk aan Zee, The Netherlands

 

 

Biotech Israel 2004

4-6 May 2004. David Intercontinental Hotel, Tel Aviv, Israel

 

One year subscription to the Life Sciences Project Bulletin  including all contact information for € 95

 

Publish your projects in the Life Sciences Project Bulletin

 

Projects from the previous Bulletins

 

For more information contact Optin’s Director Drs. Jennifer Peersmann or call +31-(0)70-3643260

 

For  background and contact information per project contact: Optin’s Life Sciences Manager Drs. Eli Guetta

 

 

 

Coming up in the next Bulletins:

New projects in Gene & Cell Therapy

 

 

 

Sponsors

 

Health Invest

 

The Embassy of The Netherlands

 

The Embassy of Israel

Matimop

 

MXCard: Profetional Marketing and Customer

Relations Tools

 

DSM Venturing

 

IBM Life Sciences

 

Tel Aviv University

 

Teva Pharmaceutical Industries Ltd

 

Eden’s Creations/ Hoekert

 

Holland Biotechnology

 

WFIA / Israel Office Delft

 

Rad-Biomed Incubator

 

CIDI

 

 

Announcements

 

·     EOI'S for the Sixth Framework

 

Projects

A Novel Gene Essential for Brain Formation

To unravel the mysteries of brain development and function, one possibility is to utilize functional genomic techniques as follows.  A gene can be specifically increased or turned-off to evaluate functional outcome.  In many cases there will be a compensatory mechanism and other genes will take over.  However, there are essential master genes that are vital for normal development and function.  Utilizing advanced molecular engineering techniques, our research team discovered a gene that codes for activity-dependent neuroprotective protein (ADNP) and showed that it is essential for brain formation.  Turning this gene off resulted in the inability to form a brain in a developing mouse embryo.  This finding led to the hypothesis that ADNP regulates other important genes and to the demonstration that a gene associated with stem cell multiplication increases when ADNP is decreased and a gene associated with brain maturation decreases following decreases in ADNP.  ADNP is regulated, in part, by the neuropeptide vasoactive intestinal peptide (VIP).  Neuropeptides are short proteins that transmit information between nerve cells and between nerve cells and their environment.  In this family of molecules, VIP is intimately involved with the development and proper function of the brain.  However, blocking VIP function is not lethal, while a blockade of ADNP expression leads to a lethal outcome.  As many diseases are associated with embryonic malformation, mental and motor retardation and high risk pregnancies, unraveling gene function will open new horizons in our understanding of brain activity and will pave the way to new therapeutics alleviating brain damage and deterioration.  To this end, functional fragments of ADNP were discovered, among them a short peptide NAP that keeps nerve cells alive against conditions that normally lead to their demise; this breakthrough is now poised for clinical development.  A new start-up company was founded - Allon Therapeutics, Inc.- which aims to bring NAP to the clinic.

 

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Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data

Much of a cells activity is organized as a network of interacting modules: sets of genes coregulated to respond to different conditions. We present a probabilistic method for identifying regulatory modules from gene expression data. Our procedure identifies modules of coregulated genes, their regulators and the conditions under which regulation occurs, generating testable hypotheses in the form regulator X regulates module Y under conditions W. We applied the method to a Saccharomyces cerevisiae expression data set, showing its ability to identify functionally coherent modules and their correct regulators. We present microarray experiments supporting three novel predictions, suggesting regulatory roles for previously uncharacterized proteins.

 

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Applying Functional Genomics For The Development Of Novel Therapeutic Reagents (Genes And Their Derivatives) For The Treatment Of Cancer And Other Human Pathologies

Researchers at the Weizmann Institute have developed a unique screening method for identifying genes involved in cell cycle arrest, apoptosis, and cellular senescence.  The method is based on functional approaches of cloning genes including gene inactivation and selection of growth resistant clones. The isolated genes may have enormous importance in developing anti-cancer therapies since their malfunction is likely to have a key role in cancer progression. Using this method the researchers have succeeded in isolating several novel apoptotic genes, which are currently being investigated for their potential oncogenic activity.

 

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Recombinant Antibody Arrays for Functional Cancer Genomics

The group is developing a strategy that will allow for human single-chain antibodies (scFvs) to be used as endeavors for the study of newly discovered cancer-associated gene products, and in particular to elucidate their intracellular location and primary interacting partners. The human genome project has revealed a vast number of gene sequences and expressed sequence tags, many of which are still un-annotated. Thus, the main goal in the post-genomic era, so-called “functional genomics”, is to identify and characterize a multitude of gene products and to understand their function within the intracellular milieu. This overwhelming task calls for the development of novel high capacity technologies to be used as “tools of discovery”. Currently, the routine use of DNA microarrays for the analysis of gene expression profiles at the mRNA level and improved informatic tools to organize and analyze such data.  However, protein arrays, in particular antibody arrays, as tools for functional genomics or proteomics studies are still in their infancy. The group has constructed a very large human synthetic antibody-phage display library from which they can  isolate human antibodies that specifically recognize the products of newly discovered genes (for example, we are now studying putative prostate cancer-associated proteins). The scFv isolation platform is the recently developed DIP selection approach - a high-throughput method allowing the rapid isolation of scFvs against any particular target, combined with arrays of immobilized scFv-CBD (cellulose-binding domain) fusion proteins. These arrays will be screened simultaneously with recombinant gene products decorated with different fluorescent dyes, allowing parallel isolation of antibodies against many target molecules in a short time. The isolated scFvs can be used for studies of their cognate antigen expression and intracellular location by flow cytometry and immunofluorescent staining of cancer cell lines and tissue sections, and for co-immunoprecipitation of their antigens in complex with interacting proteins followed by chromatographic separation and MALDI-TOF analysis. The results should demonstrate the utility of scFv antibodies and fusion proteins as invaluable reagents for functional genomics and for cancer detection.

 

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A New Technology for Constructing Drug Targets and Developing New Drugs in Silico

This novel computerized technology provides a basis for a multitude of solutions to the most complex problems of Structure-Based Drug Design, such as the construction of identified protein targets from their sequence, flexible docking of drug candidates, protein-protein interactions, de novo construction of drug candidates from fragments, molecular comparisons, construction and analysis of combinatorial libraries, analysis of structure activity relations, ADME/Tox properties and construction of “drug like” libraries, as well as others. It is capable of considerably reducing the amount of time required to develop new drugs or to improve drug leads, at all phases of drug development, thereby decreasing time to market. The core of this new technology is a novel stochastic search method that has no roots in any previous method and can be applied to problems of complex combinatorial nature. In addition to finding the best solution, it identifies many alternatives (“many needles in a haystack”) that are close to that best solution, i.e., a “population” or “ensemble” of best solutions. The algorithm is highly efficient and parallelizable, thus enabling to solve ever-increasing sizes of complex combinatorics. This technology seems to be unique in its generic ability to find both the optimal solution and a large set of best solutions or alternatives. Thus, it could produce “libraries” of drug candidates with optimized, “drug like” properties. There is currently no similar generic technology known to us.

 

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Signature Algorithm For Analyzing Large-Scale Gene Expression Data

Signature Algorithm For Analyzing Large-Scale Gene Expression Data

Technologies that monitor genome-wide expression data are becoming a central tool in biological research and drug discovery. Researchers at the Weizmann Institute have developed an algorithm for extracting transcription modules from large-scale data. This method offers a novel and more informative approach for analyzing large-scale gene expression data, which enables identifying gene clusters, which are co-regulated under specific conditions.

 

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Identification of Anticancer Drugs for Patients with Aggressive Breast Cancer: The Synthetic Lethality Screening Approach

The classical mechanism-based anticancer drug target identification approach aims at understanding the molecular alterations that drive the malignant process, and developing selective drug therapies accordingly. Thus, the current search for cancer therapeutics focuses on either inactivating the identified cancer-causing oncogenes or reactivating cancer fighting, tumor suppressor genes. In contrast, the synthetic lethality screening approach addresses the possibility that some activated oncogenes and mutated tumor-suppressor genes may sensitize cellular targets that do not necessarily have abnormal expression in the tumor context. Compounds inhibitory to such ‘secondary targets’ are specific to a particular tumor because they become lethal only when linked to the previously defined primary alteration in the cancer cells. Synthetic lethality screens are unbiased in the sense that no prior knowledge of the identity of the secondary target is necessary. This is in contrast to the mechanism-based approach that prejudges the identity of the ‘best’ drug target. Therefore, synthetic lethality screens are likely to broaden the range of drugs and drug targets that one can find, and shorten the time required to identify such drugs. Previously, we established the principles of a chemical synthetic lethality screen in cultured human tumor cells, and in mouse embryo fibroblasts derived from knockout mice. We have also established a methodology for a genetic synthetic lethality screen in cultured human cells.  Over the past two years, we have applied the chemical screening methodology to human breast carcinomas. This has resulted in the identification of compounds that (at the sub-micro molar range) specifically kill cells derived from aggressive human breast carcinomas. Currently, we are seeking investment and/or collaboration for further development of these potential anticancer drugs. Keywords: anticancer drug discovery; chemical and genetic synthetic lethality screens; drug targets; cancer therapy; breast carcinoma.

 

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Micro-array technology and cluster algorithm for characterizing receptor-ligand interactions

Arrays of genes have been characterized and studied using "DNA chips" designed to detect hybridization between defined probes and unknown ligands. Researchers at the Weizmann Institute have extended the concept, technology and analytical tools to deal with arrays of additional binders, such as antibodies-antigens, lectins-ligands, and so forth. By applying a particular cluster algorithms developed by the scientist, It is now possible to classify the state of health or disease of persons, or the identity of unknown molecules on the basis of the global patterns of interactions between test ligands and arrays of probe molecules.

 

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Development of Novel Potassium Channel Openers for Neuroprotection, Neuropathic Pain and the Treatment of Epilepsy

We are developing a platform for new highly targeted and genotype-specific therapies. Our aim is to develop specific drugs (openers) that will enhance KCNQ potassium channel activity, with therapeutic impact on epilepsy, neuroprotection and cardiac long QT syndrome (LQTs). Previously, we succeeded in rescuing the loss of channel function produced by specific LQT mutations by means of KCNQ1 potassium channel openers (Abitbol et al., 1999). Recently, we have found that openers activate KCNQ2/3 channels, by causing a profound leftward shift of the voltage activation curve and slowing the deactivation kinetics. This opener action leads to increased KCNQ2/3 current amplitude at physiologically relevant potentials and as such these compounds constitute anti-epileptic and neuro-protective drug candidates. Using rationalized targeted chemistry and high throughput technology, our drug development strategy is to design and screen for KCNQ channel openers that will protect from LQTs and epilepsy. A rational structural chemistry and mutational analysis should facilitate the design of openers that will correct efficiently genetic abnormalities produced by specific potassium channel mutations as well as non-inherited cardiac and neuronal defects of various etiologies. Exploiting the tremendous power of genetics and structural chemistry, this strategy offers new therapeutic perspectives in the treatment of epilepsy, ischemic stroke and inherited and drug-induced LQTs, as well as in the treatment of neuropathic pain.

 

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Human DNA Repair in Medical Diagnostics

DNA damage interferes with the essential function of DNA by causing it to issue incorrect coding instructions or by stopping the decoding process. These problems are usually avoided by DNA repair, a housekeeping process by which the damage is recognized and repaired by a large battery of repair proteins. Failure of DNA repair has serious consequences on health causing cancer, immunodeficiency, infertility, neurodegeneration, and aging. The Weizmann Institute of Science group has developed a human blood test for a particular type of DNA repair. This accurate and highly reproducible test measures the enzymatic activity of the DNA repair in white blood cells. It provides means to predict the patient’s response to certain treatments and thus aids in selecting and tailoring the appropriate therapies for malignant diseases, neurodegeneration diseases and infertility treatment.

 

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Functional Polymorphisms in Olfactory Receptor Genes

It is well known that human beings exhibit high variation in their olfactory faculties. This phenomenon is mainly reflected in inter-individual differences of threshold sensitivity towards specific odorants and variability in odorant perception. These differences originate from the genetic polymorphism within the population. Researchers at the Weizmann Institute have identified a family of Olfactory Receptor (OR) genes and pseudogenes which display a very diverse repertoire in each individual. This repertoire is greatly influenced by the ethnic background. The researchers propose a DNA chip of the complete human functional OR gene repertoire in order to identify specific receptors for specific odorants for rational design of odors, flavors and perfumes.

 

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Recombinant Fragments Of the Human Acetylcholine Receptor: Application for the Treatment of Myasthenia Gravis

Myasthenia gravis (MG) is a human autoimmune disease characterized by muscle weakness and fatigability. In this disease, antibodies against the acetylcholine receptor (AChR) bind to the receptor and interfere with the transmission of signals from nerve to muscle at the neuromuscular junction. A diagnostic test for anti-AChR antibodies in MG has been developed by researchers at the Weizamnn Institute, that employs recombinant fragments of human AChR as the test antigen. Such a test would avoid the need to extract the antigen from human tissue, could yield anti-AChR titers that are well correlated with disease severity, and may enable to evaluate additional antibody specificities that are involved in myasthenia.

 

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Diagnostic method for early detection and follow-up of Schizophrenia

Schizophrenia is a neuropsychiatric disorder afflicting about one percent of the population. It is characterized by delusions, hallucinations, disorders in organizing thoughts logically, and emotional withdrawal. To date, a definitive diagnosis of schizophrenia requires six-month duration of symptomatology and there is neither an effective biological marker for identifying schizophrenia nor an accurate and rapid diagnosis to ensure more optimal management at an early stage in the illness. Researchers at the Weizmann Institute have developed a method for early detection of Schizophrenia, which is based on measurements of mRNA levels of D3 dopamine receptor and of α7 nicotinic acetylcholine receptor (α7 AChR) in peripheral blood lymphocytes (PBLs). The researchers have shown that individuals suffering from Schizophrenia disorder have significant elevation of D3 dopamine receptor mRNA and decreased levels of α7 AChR mRNA compared to normal individuals. This method can serve as an efficient tool for diagnosis and follow-up of Schizophrenia and other neurodegenerative disorders. Technology 

 

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Genetic Testing for Usher Syndrome Type 3

Researchers at the Weizmann Institute of Science have located three new mutation linked to Usher Syndrome Type 3 (USH3), a genetic disorder which causes a postlingual progressive hearing loss. These mutations are located in the coding region of a newly identified transcript of human USH3A. The USH3A protein is a member of a new four trans-membrane domain (4TM) vertebrate- specific protein family. Based on sequence similarities to stargazing, a well studied member of this hyperfamily, the researchers have suggested a role for the novel protein in the hair cells synaptic junctions.

 

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A Novel Erythrocyte Differentiation Factor

Researchers at the Weizmann Institute have identified a gene encoding for a novel erythrocyte differentiation factor designated Codanin-1. The protein was shown to be involved in the differentiation of red blood cells. Mutations in the differentiation factor are associated with Congenital Dyserythropoietic Anemias (CDA), a group of inherited red blood cell disorders associated with dysplastic changes in late erythroid precursors.

 

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Nucleic Acid Fragmentation in Millisecond Time Scales By Conventional X-Ray Machine: Application To Protein-Nucleic Acid Footprinting

Mapping the interaction between protein and nucleic acid in physiological buffers and in a dynamic way provides means for rapidly screening DNA-drug interactions, RNAi interactions, and protein-DNA interactions. Researchers at the Weizmann Institute have developed simple, inexpensive procedures of conducting X Ray footprinting to produce protein-DNA protection portraits at sub seconds time scales. These procedures could replace high-resolution footprints produced by Synchrotron Radiation which are expensive and demand complicated logistics.

 

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Advertorials

Health-Invest: The New Dutch magazine for Life Sciences

Health-Invest is a new magazine with popular scientific articles about the newest developments in Life Sciences in The Netherlands: health, new medicine and food. The magazine also includes fashion, carrier and financial business. Health-Invest wil highlight various subjects through combining Life Sciences and Life Style. Attention wil go to  stormy developments in the medical sciences, for innovative medical research and company profiles, as wel as developments in the general health and prosperity of society. Health-Invest is a Dutch language, internationaal orientated magazine about health and prosperity made for a large audience: from starters in Life Sciences, to those interested in health-care, the food sector, students, and especcially investors and eveyone interested in his own health. The next issue of Health-Invest will come out in January 2004 and wil focus on:  Nanotechnology Nanotechnology is today seen as the most important industrial revolution of the 21st century. In the next 25 years an enormous market will develop for products made with the help of this technique. Besides the information technology the medical profession wil also profit from nanotechnology. Our body is made up of cells and a technology that works on that level is much beter suited for treating sick cells than the treatments now available. The Netherlands has in this area a very good starting position in order to become an important  partner in this enormous nanotechnology market.  Health-Invest will focus further on this issue.

For more information contact: www.health-invest.nl  E-mail: info@health-invest.nl

 

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Functional genomics of the antigen presenting DC

Dendritic cells (DC) are the professional antigen presenting cells (APC) of the immune system that instruct and control the activation of B and T lymphocytes, the mediators of specific immunity. Their extremely potent capacity to initiate and modulate immune responses is currently exploited by many groups to fight infectious diseases, cancer as well as autoimmune diseases. Although much progress has been made in understanding the DC’s ability to initiate and modulate immune responses, surprisingly little information is available regarding its molecular basis. In the past 5 years we have conducted a major effort to identify a panel of novel DC specific molecules. We selected novel DC antigens based on two main criteria; I: their preferential expression by DC and II: their conservation in higher eukaryotes, indicative for an important function in DC immuno-biology. These novel antigens include a transcription regulator, DC-SCRIPT; a multi-membrane spanning receptor, DC-STAMP; and a novel adhesion receptor, DC-SIGN.  We have generated a DC yeast two hybrid library using both mature and immature DC as a source of RNA to detect potential DC-specific partners. Several interesting partners have now been defined. These and novel antigens defined in additional yeast two hybrid screens are the topic of the current research project. Next to assigning the molecular partners to a given molecular pathway, the focus will be to unravel their  function in DC immunobiology.

For more information please contact  dr G.J. Adema or prof.dr. C.G. Figdor, phone 024-3617600. E-mail: g.adema@ncmls.kun.nl  and c.figdor@mailbox.kun.nl.

 

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The Cuppen research group

The Cuppen research group is part of the Netherlands Institute of Developmental Biology also known as the Hubrecht Laboratory. The institute falls under the auspice of the Royal Dutch Academy of Arts and Sciences (KNAW) and is located on the campus of Utrecht University in Utrecht, The Netherlands.

The research in the Cuppen lab is focussed on the functional analysis of animal genomes (functional genomics), using both bioinformatics and biological experiments in model organisms.

For more information please contact  Dr. Edwin Cuppen ecuppen@niob.knaw.nl or tel. +31 30 2121969

Functional Genomics Group, Netherlands Institute for Developmental Biology / Hubrecht Lab, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.

Fax: +31 30 2516554,  Web: www.rat.niob.knaw.nl

 

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Programs that integrate the proprietary AFLP® and cDNA-AFLP technologies

During the last 14 years, Keygene has been very successful in developing the AFLP(r) molecular marker system and a wide range of related services for (plant) breeding companies. Their shareholders and main customers have become market leaders in several high-yielding vegetable crops the last years.

 

Most of Keygene services are based on AFLP(r), the most cost effective marker technology available. For many crops Keygene executed large programs and assisted in the development of extensive genetic knowledge for their customers. For instance; in Capsicum, Barley, Corn and other species large integrated genetic maps are build.

 

Keygene can be divided into two major departments, the first, Gentics, is specialised in services like identification of varieties, marker assisted back cross programs, marker development projects (mono- and polygenic traits), genetic (fine) mapping, allele / chromosome haplotyping and development of specific breeding tools like mentioned in our article "Breeding by Design(tm)" which describes the potential possibilities of markers in breeding.  Please contact Keygene  to receive more information regarding this revolutionary concept.

 

Keygene Genomics, the second department, is specialized in innovative contract research. With in-depth vision and extensive research facilities Keygene Genomics provides state of the art contract research programs with emphasis on structural and functional genomics.  Programs that integrate the proprietary AFLP® and cDNA-AFLP technologies with a broad spectrum of other genomics tools, Keygene Genomics offers total genomics solutions to its customers. Application of the powerful technology platform in many different sized programs is now targeted towards the generation of marker (AFLP®/SNP) sets, gene isolation and the elucidation of complex (QTL) biological questions.

 

In summary Keygene offers companies in the life science industry a wide range of services for the development of specific breeding tools, genetic software packages and genetic contract research for more complex genetic problems.

For information please contact Arjan van Steekelenburg avs@keygene.com or tel: +31 317 466 866

 

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Evogene: accelerating natural evolution processes

Evogene is an agro-biotechnology company specializing in the development of superior crops through genome remodeling.  Evogene’s core technology platform mimics and accelerates evolutionary processes and can address issues associated with transgenic plants. The company has demonstrated its technological capabilities in Arabidopsis and the tomato and is currently expanding its platform to other economically significant crops such as cotton. With a growing base of intellectual property and collaborative agreements, Evogene’s goal is to emerge as a leading developer of plant-based products and technologies that have the potential to accelerate discovery processes.Integrating genomics tools and advanced breeding to bring plant genomics to the crop in the field. Directing evolution to generate new genetic diversity. Accelerating the development of high-value crops and plant-derived compounds. Accelerating and Directing Natural Evolution: Evogene’s central concept is to develop a platform that mimics, directs and accelerates evolutionary processes in plants to circumvent the limitations of genetic variation occurring in classical breeding techniques.

 

The Evogene Process: By applying computational and biological tools to public or private plant genome databases, Evogene predicts, isolates and prioritizes genomic component candidates associated with specific functions or traits and validates them in-plant. Evogene believes and demonstrates that optimizing gene regulation is essential to successful agro-biotechnology development and develops a strong position in gene regulation and in the optimization of coding region expression. Evogene uses molecular tools and techniques, with unprecedented efficiency, generating novel INTRAGENIC genetic diversity within the gene pool of a targeted crop. Advanced high throughput breeding techniques are used to bring superior traits to the final plant, successfully addressing the classical bottleneck between plant genomics and the field. Advanced Predictive Computational Genomics Skills: Based on the technology used by Compugen’s pharmaceutical customers in human genomics, Evogene has developed advanced computational genomics skills to predict and isolate sets of high quality gene and promoter candidates that address customer-specific problems.  This capability provides a solution for what is currently a major bottleneck slowing product development timetables.

 

ProMine “Promoter Mining” Focusing on Gene Regulation Optimization: First applied to Arabidopsis, ProMine, a unique promoter mining tool, was used to generate a library of thousands of predicted DNA Regulatory Elements (DREs).  Hundreds of these DREs are already biologically validated.   By defining partner-driven queries, Evogene is capable of generating highly targeted sets of DREs to jointly optimize the expression of a specific coding region.  Evogene is developing similar promoter assets in other economically important crops. “EvoXellerator”: Creating novel INTRAGENIC Genetic Diversity: The “EvoXellerator” (Evolution Accelerator) technology is a novel approach to creating new genetic diversity by mimicking and accelerating natural evolutionary processes while addressing concerns regarding transgenic GMOs and avoiding limitations inherent in sexual reproduction.  HTP: High Throughput Breeding: Initially implemented in the tomato and currently being expanded to other crops, Evogene uses miniature plants and other advanced breeding tools to increase the output of classical breeding techniques.  Evogene applies its High Throughput Breeding to rapidly identify desirable traits generated by its Evolution Accelerator technology.   In addition, Evogene’s High Throughput technology can deliver breeding projects in a shorter time and at lower cost than via traditional techniques.

 

In order to implement its fully integrated approach, Evogene has created a proprietary Information Management System to track and enhance the vast amount of data generated when merging computational biology, molecular biology, plant transformation, plant genetics and classical breeding. This database manages the knowledge created in the development process, from the DNA sequences in-silico and all the way to the plant in the field.

These products, as well as others in the company’s development pipeline, are available for licensing, R&D collaborations and strategic partnership opportunities.

For more information please contact Julien Meissonnier julien.meissonnier@evogene.com  or tel: 00 972 8 9311900

 

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In the News

Gene Discovery Through Est and Genomic Data Clustering and Assembly

Of the estimated 150,000 human genes, only a fraction are currently known, and an even smaller fraction is well annotated (i.e. significant information is known about the gene function). On the other hand, a lot of low quality, fragmented data about many of the genes has been collected in the past few years in EST (Expressed Sequence Tags) databases. Compugen has developed a unique technology to identify as many new genes as possible, out of this data, and annotate them in a comprehensive manner, revealing information about their function, expression patterns, location in the genome and interactions with other biological entities. Clustering and Assembly: This vast amount of data is obviously a valuable source of information for life science researchers. However, the poor quality is a significant hurdle for potential users. It is first necessary to process the data, bringing together different ESTs which represent the same gene, and creating a better picture of this gene.

Detect SNPs (Single Nucleotide Polymorphisms): Map gene structure (exons, introns, alternative splicing)

In order to achieve all this, two different tasks must be performed. The first, clustering, is a division of the body of ESTs into many different groups, each representing one gene. The second task, assembly, is using the sequences in each of these groups to build a comprehensive picture of what is known about this gene. From multiple ESTs spanning the same region one can then detect and correct sequencing errors and polymorphisms, and build a gene map. The resulting sequences are much longer than the input ESTs, and their number is significantly reduced. Processing the data in this manner makes the resulting database much more suitable for data mining and annotation. However, both clustering and assembly pose a significant challenge in algorithmic development. In clustering one should in principle compare every two ESTs to each other, in order to decide whether or not they originate from the same gene. On a 2.5 million EST database, this task literally takes years on a general purpose computer, even if one chooses to use a heuristic approach such as BLAST. The assembly problem is different: here the difficulty is in modeling correctly the underlying biological processes, so that the algorithm will produce relevant biological information. A good example is alternative splicing. This biological phenomena, now believed to occur in 30% of all human genes (see http://hattrick.lbl.gov:8888/alt ), means one gene can elicit several transcripts, made out of different exon combinations. An assembly program which neglects to model this phenomenon will be unable to create one parent sequence which explains multiple ESTs arising from the same gene but diverging into different variant EST sequences, and will have to classify them into different genes, yielding a wrong biological answer, and resulting in significant loss of information.

Compugen has developed novel algorithms for both clustering and assembly, using the expertise accumulated in the company from years of research into sequence alignment, biological modeling, and hardware development. The New algorithms developed allow for the clustering and assembly of millions of ESTs within a few days, while correctly modeling a wide variety of biological phenomena including alternative splicing, chimeric sequences, repeats and contaminations of many types.

Compugen has pioneered the integrated analysis of genomic and expressed data, as well. Genomic data is clustered together with EST and mRNA data, often providing the missing information for the discovery of new genes. The algorithms are run on a periodical basis and allow for reclustering and assembly from scratch of the full database. The resulting gene database then undergoes a series of annotation processes, including sequence homology searches, profile searches, alignment to the available genomic sequence, detection of ORFs, and then detection of signal peptides and transmembrane domains in the resulting protein. More than 4,000 new genes were discovered this way. The validity of the predicted genes has been confirmed experimentally for more than 90% of the cases in Compugen's molecular biology lab, by PCR and sequencing, and in many cases through protein expression. Primers were designed to "fish out" the predicted transcripts, and PCR was run on cDNA from tissue samples, followed by sequencing the resulting products

 

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Technion researchers develop 'glue' to support broken bones

Researchers at the Technion - Israel Institute of Technology in Haifa – have developed "a bone glue," a material that combines biological and synthetic components that when mixed together, supports broken bones and allows them to grow new bone tissue. After the broken bone has fused, the material is broken down in the body. The material was developed in the Technion's Department of Biomedical Engineering by Dr. Dror Seliktar and Liora Almani-Levy, a master's degree student. According to Seliktar, it is common practice in orthopedic medicine today to use various types of screws and steel pins to fix broken bones in place and thereby help them to fuse; sometimes, he says, a material known as "bone cement" is also used.

"These materials," Seliktar continues, "only give the bone the structural-mechanical support it needs, and do not facilitate the

regeneration of bone tissue at the damaged site. Seliktar says that although biological materials used today to rehabilitate

damaged tissues encourage tissue regeneration, they do not provide the regenerated tissue with the physical strength. "The material we have developed," he says, "does both." The new material, known for now as Gelrin, is comprised of Fibrin and the

polyethylene, Glycol. Fibrin is a protein produced in blood plasma and serves as a central element in the blood clotting process; the Glycol is a transparent plastic material.

The Technion researchers have found a way to bind the molecules of the two substances to form a new material that has biological characteristics and can also be adjusted to different strengths. The cells of the body identify the new material as "a friendly substance," on which regenerated tissue that supplements boneless areas can be grown. "In fact, the bone tissue grows within the Gelrin; and as soon as the tissue fills the space, the material breaks down and washes out in the urine," Seliktar explains, adding that one of its advantages is that it can be injected into the damaged area without need for surgery. Till now, tests with Gelrin have been conducted on cells grown under laboratory conditions, with trials on rats to begin within the coming days. Seliktar says both substances that make up the Gelrin are used in medicine today and both are approved by the U.S. Food and Drug Administration. "I believe the FDA will not have a special problem with the fact that we have combined the two substances; hence, if the material proves itself as effective, it will receive the FDA's approval." The Technion has registered a patent on the development of Gelrin, and Seliktar says that the institute is currently in talks with an entrepreneur who has heard of the material and is interested in establishing a start-up that will develop applications for it. In the United States alone, some one million bone-replacement operations are conducted each year.

http://www.haaretz.com/hasen/spages/385113.html

By Yuval Dror, Haaretz Correspondent

 

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Who's afraid of biotech?

Virtually everything good that you've heard about biotechnology is true. It's making inroads against killers such as cancer, heart disease, and stroke. It's stopping other diseases for which until recently the best treatment was an aspirin. Biotech crops will provide malnourished peoples with enough calories to turn them into American-sized butterballs. But to many, biotech has a dark side. They fear cloning humans to rip out their organs as replacements, turning our offspring into ubermenschen, and distorting the whole concept of what it is to be human. Happily, though, almost all of the bad about biotech would be senseless, scientifically impossible, or far more readily done through alternative technologies such as bionics. Or the developments actually don't seem very unusual - much less scary - when considered in a broader context. Consider the idea of growing human clones for replacement organs, with some terrifying scenarios depicting headless bodies connected to life support until the organ is required. But already biotechnology is fabricating organs such as bladders and even relatively complex ones such as penises. The immorality of murdering a human aside, why grow and sustain a whole person for an organ you may never need when you can buy an individual organ "off the rack" or have it specially made for you?

Not all controversial applications of biotech lie in the realm of fantasy, though. A real scenario is the use of stem cells from human embryos, which many see as violating the sanctity of human life. Even those who don't feel that way must recognize that others do, and thus it leaves biotech with a black eye. But it's often the case with biotechnology that new advances eliminate older problems. In the last two years, three different US labs have found evidence that three different types of non-embryonic stem cells - those taken from adults, umbilical cords, or placentas - appear to be able to mature into any cell in the body. Even if all three labs fail, so many different non-embryonic stem cells have been found that can be converted into so many different types of mature tissue that there should be no need for "one-size-fits-all" stem cells. Researchers whose reputations are built on embryonic research and require funding to keep their labs going often insist that non-embryonics are

overrated or even worthless. But non-embryonics have actually been used therapeutically since the 1980s for limited purposes such as treating leukemia, even as embryonics are only now moving into animal testing.

WHAT ABOUT what is called "germ-line" gene-alteration to "improve" the human race as a whole or at least your line of descendants? Research will eventually allow changing such genetic attributes as intelligence or appearance. Johns Hopkins University political science professor Francis Fukuyama devotes many pages to this in his book Our Posthuman Future: Consequences of the Biotechnology Revolution. But most of Fukuyama's fears have already come to pass through other technologies, albeit ones that cannot be passed down genetically. Improving your child's looks is as easy as something called "cosmetic surgery." Improving his or her IQ is as simple as flicking off the TV and putting away the video games. The argument that the rich will have better access to germ-line therapy also falls flat; the rich have better access to everything. For example, wealth can promote higher intelligence even as the child is in the womb by providing better nourishment. After that it can be used to pay for the best pre-schools, schools, and tutors. In any event, the most efficient way to create super-humans will never be with biotech. The technology is inherently limited by the genes that God and nature have provided us.

You can turn them on or off or move them from one organism to another, but a gene can never do what it wasn't intended to. But bionics, the use of implanted computer chips and electronic or electro-mechanical devices, has no such limits. Bionics has already brought us "neuroprostheses" such as the cochlear implant that popular American talk show host Rush Limbaugh received. First approved back in 1984, these bypass the normal hearing mechanism to provide artificial hearing to deaf people. Next stop: superhuman hearing. Implanted retinal chips are providing limited vision to those who were completely blind but will surely eventually bring superhuman vision. Then there are implantable computer brain chips. These are already used to control the tremors of Parkinson's and the seizures of epilepsy. But again the therapeutic will lead to the super. Already monkeys have been given the ability to move a robot arm and a computer cursor with their thoughts alone. The same signals that enable a small arm to pick up food could just as easily move a wrecking crane. Chips being tested in animals will soon increase people's range of senses beyond hearing and seeing. Through wireless connections such as the already-ubiquitous WiFi (80211.x ), they will allow invisible communication with others directly to and from the brain and thus bypass the eyes, ears, and mouth. They will enable consistent and constant access to information where and when it is needed, with no annoying pop-up ads. Fukuyama also frets over the likelihood that biotech will allow us to live to be 150 and beyond; but, illustrating the problem of a social scientist suddenly turned life science commentator, he speculates we will live those last 50 years bedpan-bound and drowning in drool. Yet of the incredible array of such therapies under development that would slow, stop, or even reverse aspects of aging, all would extend not just life itself but also the period before decrepitude. Moreover, probably before any of these therapies is available, biotech will have cured some of the cruelest diseases of aging, such as Alzheimer's.

Dr. Leon Kass, chairman of the President's Council on Bioethics, urges us to "resist the Siren song of the conquest" of death. But he sets up a straw man. Even reversing aging cannot confer eternal life. There are organisms that appear genetically programmed to live indefinitely, such as certain trees and turtles. But something catches up to them eventually, be it a chainsaw or somebody hungry for turtle soup. Likewise, biotech cannot confer immortality. But Kass is on firmer ground when he questions lifespan extension, if only because he does so with non-scientific arguments. The best of them might be

summarized as Why give people more years when they seem so intent on wasting the ones they have, plopped in front of the tube for hours on end watching other people's "reality" because they don't have one of their own? The only answer is that just as a knife that can be used for slicing or for stabbing, biotechnology is a tool; nothing more. What can be accomplished with that

tool is literally miraculous. What will be is up to us. The writer, a senior fellow at the Hudson Institute in Washington, DC, is

author of BioEvolution: How Biotechnology Is Changing Our World. His website is www.fumento.com.

Jerusalem Post, Jan. 15, 2004

By MICHAEL FUMENTO

 

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