Genomics researchers know many disorders are caused by a complexcascade of interrelated genetic events, but tracking a series ofdisease-related gene expressions, as opposed to seeking one mutatedgene at a time, has been a major challenge.
Gene Logic Inc., of Columbia, Md., is among a new group ofcompanies launched recently with technology aimed at comparinggene expression patterns in disease cells with those in normal cells tofind abnormalities.
As Gene Logic President and CEO Michael Brennan points out, inany one cell 10,000 genes are expressed out of a total of 100,000 to150,000 genes in the genome. And the keys to making drugs are thetranscription factors, which are the proteins responsible for turningthe genes on or off.
With sequences for 20 percent to 25 percent of all genes sitting inpublic data bases, Brennan said identifying genes is becoming easier.If the company's scientists do find new genes, such as thoseexpressed at low levels of frequency, they sequence them. Most DNAfragments already sequenced, Brennan noted, are those expressedwith high frequency in abundant amounts.
Brennan has positioned Gene Logic, which started operations inNovember 1995, as a next generation genomics company set up todecipher the function of genes being discovered by randomsequencing of the genome and positional cloning of specific diseasegenes.
He said Gene Logic is a complementary business, not competitive,adding that one of two potential collaborations currently innegotiations is an alliance with a positional cloning company.
Brennan described random sequencing companies such as HumanGenome Sciences Inc., of Rockville, Md., and IncytePharmaceuticals Inc., of Palo Alto, Calif., as first generationgenomics firms formed to generate DNA sequences as rapidly aspossible.
Second generation companies, such as Sequana Therapeutics Inc., ofLa Jolla, Calif., Millennium Pharmaceuticals Inc., of Cambridge,Mass., Myriad Genetics Inc., of Salt Lake City, Darwin MolecularCorp., of Bothell, Wash., and Mercator Genetics Inc., of Menlo Park,Calif., target specific disease genes using positional cloning.
In both cases, finding genes is an initial step. Figuring out what theydo and how they interrelate with other genes are crucial to makingdrugs.
A gene sequence, Brennan said, does not tell you what the gene does.Identifying a disease gene, he added, provides a linkage between themutated gene and the frequency with which it occurs in certainfamilies, "but you don't know what other genes are involved and howthey are regulated."
Gene Logic, Brennan said, can determine how genes are expressed inparticular cell types under disease conditions and under othersituations, such as the influence of drugs.
Another recent start-up, La Jolla, Calif.-based Digital GeneTechnologies Inc., also is among those marketing expertise indecoding gene expression patterns. (See BioWorld Today, March 20,1996, p. 1.)
Gene Logic completed its first major round of financing in April1996, raising $8.6 million from a group of venture capital investorsled by Hambro America Biosciences, of New York. Other backersinclude Oxford Bioscience Partners, of Los Angeles, which alsoprovided $1.2 million in seed capital; Altamira Ltd., of Montreal; andGIMV Investment Corp., of Antwerp, Belgium.
Gene Logic was founded with technology developed by ShermanWeissman, of Yale University School of Medicine in New Haven,Conn.
Brennan joined the company after four years as senior vice presidentand head of worldwide business development for Corange Ltd., ofBermuda. He guided the pharmaceutical company's move intoAmerican biotechnology by forging deals between Corangesubsidiary, Boehringer Mannheim GmbH, of Mannheim, Germany,and such firms as Sequana and GeneMedicine Inc., of TheWoodlands, Texas.
Gene Logic, he said, expects to expand its 12-member staff to 17 bythe end of the second quarter of this year and 25 by the end of 1996.
"We're in the late stages of negotiations for a couple ofcollaborations," Brennan observed.
In describing Gene Logic's approach to genomics, he usedosteoporosis as an example, a disease the company has beenresearching. The disorder is linked to an imbalance in the naturalprocess of bone deterioration and repair. When the former occursfaster than the latter, bones weaken. Osteoblasts are cells responsiblefor building up damaged bone.
"We would take osteoblasts from normal individuals," Brennan said,"and osteoblasts from diseased individuals and compare the patternsof gene expression."
From the comparison, he added, Gene Logic can identify specificcascades affected by the disorder.
Families Gone Awry
"There is not a single gene that underlies the disease," he said."There are families of genes that go awry."
After analyzing the different gene expression patterns, Brennan said,the next step is to determine the transcription factors that are eithersending a signal they should not or are standing silently by while theyshould be working.
"Some transcription factors are more important than others," heobserved. "The critical part is to determine the right transcriptionfactor."
Achieving that goal, he added, requires going as far upstream in themisguided cascade as possible.
Brennan used the example of a military chain of command. "If youfind the sergeant, you may only influence a platoon, but if you canget to the lieutenant colonel you can control a whole company," hesaid.
Gene Logic's science has two components: Restriction EnzymeAnalysis of Differentially-Expressed Sequences (READS) andMultiplex Selection of Transcription Factors (MuST).
READS is used to detect gene expression patterns and MuSTidentifies transcription factors, cataloguing all the interaction sitesbetween the regulatory proteins and DNA in a target cell. Theinformation generated by the two systems is collected in GeneLogic's Gene Express data base, which stores the genetic profile ofthe cells and can be integrated with DNA sequence data basesmaintained by the public sector or the company's clients.
Gene Logic, Brennan said, can identify a cell's complete geneticexpression profile in 10 days _ a speed which he said distinguisheshis company from others in the same field. n
-- Charles Craig
(c) 1997 American Health Consultants. All rights reserved.