Company: CuraGen Corporation, New Haven, Connecticut
Business: Genomics technologies
Number of Employees: More than 300

Although much of your destiny may lie in your genes, don't forget about your proteins. They may hold the key to overcoming any harmful activity of those genes.

The importance of proteins has been made abundantly clear by CuraGen Corp., a New Haven, Conn., company that has created a novel set of protein-focused biotechnologies to help explain, prevent, and treat complex diseases such as cancer. The new technologies are based on strategies, hardware, and software developed in two projects co-funded by NIST's Advanced Technology Program.

Proteins are made by genes, so CuraGen's work is only a couple of steps removed from more conventional genetic studies. Instead of focusing on the chemical structure or mutations in genes themselves, CuraGen delved into the then-unfashionable and complicated issue of gene expression, or how cells use the genetic information in DNA to make proteins, and what the proteins do after that. The research not only broke new ground but also has led to important benefits for the nation:

• The ATP-funded research has led to three new processes, about 5 patents, and more than $100 million worth of research collaboration and technology access deals with five companies.

• One new process boosted scientific power to analyze gene expression from 100 genes simultaneously to 50,000 genes, according to CuraGen.

• The technologies already have provided new clues to the process and possible treatment of human cancer and crop diseases.

The reaction has been swift and enthusiastic, both from the public--which bought more than $45 million in stock during the company's initial public offering in early 1998--and from the biotechnology community. The "outstanding" technology is expected to "significantly accelerate drug discovery and development," a spokesman for Biogen, Inc., told BioWorld Today. Biogen is both investing in and collaborating with CuraGen.

Much of this success is attributed to the ATP, which was the only source of substantial support for gene expression research in the early 1990s, according to Jonathan Rothberg, CuraGen's founder, president, and CEO. The program provided more than half of the company's early funding, which was founded in 1993 and had just 17 employees when it won the ATP awards. The staff now numbers more than 300.

"We are extremely grateful to the ATP," Rothberg says. "We think that when people look back in 50 years, they will see that ATP's support for gene expression analysis was the most efficient, cost-effective investment the government ever made in any technology."

The two ATP projects, both of which spanned 1995 to 1998 (a third ATP project is now under way), led directly to three automated processes, each consisting of an enabling technology used to generate data, software, and a database. The processes now are being commercialized through research collaborations, internal programs, and database subscriptions. They are designed to provide an integrated platform for gene discovery, validation of potential target sites for drugs, and screening of potential drugs.

When a gene is expressed, the genetic information is copied to a complementary molecule--sort of a chemical mirror image--called messenger RNA (or mRNA), which then makes a protein. The amount of mRNA expressed reflects the gene's activity and the number of protein molecules produced. In the first ATP project, a joint venture with Soane Technologies, Inc., CuraGen developed the capability to detect 95 percent of the genes expressed in any cell, including novel genes and those expressed at very low levels (e.g., one copy of mRNA)--without prior knowledge of the identity or sequence of the genes.

A key advance was the development of a process to label mRNA from a sample with 200 complementary pairs of tags. After the sample fragments are separated using standard techniques (i.e., electrophoresis), the original gene is identified based on the chemical sequence of the tag and the distance between the pair after separation. The new process and software have been used to generate 100 million data points so far, creating gene expression profiles that can be compared to sample tissues in varying disease states.

The overall challenge was to design a process offering both high yield and high sensitivity. The large number of tags increased the accuracy of the process for complex expression profiles and large numbers of expressed genes. In addition, miniature hardware was designed with micromachined channels to separate rapidly fragments using very small sample amounts. Process advances included the development of robots to mix reagents and an improved fluorescent tagging system.

In the second ATP project, a joint venture with American Cyanamid Co., CuraGen used molecular biology methods, structural physics, and computational statistical mechanics to determine how proteins interact and identify structures likely to bind to (and thus interfere with) disease-related proteins. The resulting process and software test simultaneously for interactions between billions of combinations of proteins and assemble them into a database of biological pathways of genes whose protein products interact. A second process resulting from this research screens the identified genes against libraries of molecules that might be candidate drugs.

CuraGen is developing new hardware in its third ATP project and with separate funding from the National Institutes of Health. Meanwhile, the new processes are already paying off. CuraGen and one collaborator, Pioneer Hi-Bred International, Inc., recently announced they had cloned a gene that degrades a toxin produced by a mold that often develops in corn. "This is the first solution in the industry using new technologies and will take us a step closer to eliminating the harmful toxins that threaten the health of livestock," says Pioneer's Jon Duvick.

CuraGen also uses its new technologies in internal research on cardiovascular disease, stroke, cancer, and metabolic disorders and has discovered 13 disease-related genes. One study published in Digestive Disease Week revealed that substances produced by the bacterial fermentation of dietary fiber altered the expression of 1 percent of 3,000 random genes in colon cancer cells. The data may help identify genes that influence the activity of dietary fiber in protecting against colon cancer, according to the researchers.

Ultimately, CuraGen hopes to reduce the high costs associated with uncured diseases and high failure rates in the development of new drugs. The company has estimated that its technologies might save the nation more than $1 billion annually by reducing the time and cost involved in identifying promising drug compounds and eliminating poor candidates from preclinical and clinical studies.

April 2000