|The development of such critical new life science technologies as novel types of arraying and RNA interference relies strongly on collaborative efforts.|
|by Peter Gwynne and Gary Heebner
DNA microarrays, based on the principles of semiconductor technology
American Type Culture Collection (ATCC)
Carl Zeiss [Germany]
Carl Zeiss [USA]
Elsevier Science [The Netherlands]
Elsevier Science [USA]
Takara Bio, Inc.
IN THIS ISSUE:
|•||Protein and peptide arrays|
|•||Peptide based drug discovery|
In recent years a huge variety of powerful new tools and technologies has become available for life scientists, enabling them to make key advances and discoveries in biotechnology, drug discovery, and other industrial and academic fields. Tools such as DNA and protein arrays, short interfering RNA (siRNA), stem cells, and methods of transferring genes from one species to another, combined with high throughput instruments and other systems for laboratory automation, have increased productivity in many laboratories. "The field is moving incredibly quickly," says David Brown, senior scientist at Ambion about siRNA. "it's hard to keep up with but it's exciting to do so."
Advances in life science involve more than technological development, however. The economic picture plays a strong role in determining which new products make it to market for the R&D community. Here, life scientists have seen significant change. "Compared with three years ago the market is very different," says Mike Evans, vice president for marketing and strategy at Amersham Biosciences. "Pharmas, industrial biotechnology companies, and the academic sector had so much money washing around them then. Now people are much more cautious with their money and everyone's thinking about their own productivity in R&D."
That doesn't mean that fewer products are on the way to the market. Rather, vendors have started to take more economical approaches to developing those products. One effort expands an already existing trend - to buy or license intellectual property rather than develop it entirely in-house. Today, industrial research teams routinely set out to acquire the intellectual property needed to develop new tools. "One aspect of my job is being a talent scout for new technology in small companies," says Neil Cook, chief scientific officer and vice president, global R&D at PerkinElmer Life and Analytical Sciences.
Calls for Collaboration
Financial considerations aren't alone in forcing firms to consider licensing or buying intellectual property. Companies that develop new products and tools for life science increasingly find themselves working in new fields in which they have scant experience. In those circumstances, collaboration with academic groups, promising startup firms, or even competitors becomes essential.
Regular customers also provide significant help in product development and improvement. Clients given early access to new tools and technologies provide significant help in tweaking the products to make them more marketable and in finding and developing new applications for them. Overall it is hard today for a successful company to go it alone. Such new tools and technologies as DNA arrays, protein and peptide arrays, kits and reagents for studying RNA interference, stem cell methodologies, and transgenic techniques have come to fruition as a result of the efforts of many scientists in different departments, companies, and even continents working together.
Similarly, academic departments and research institutions rely on cooperative projects to take research findings from the laboratory and start the process of converting them to usable, marketable products. "I don't think that any research organization can be an island any more," says Harry Griffin, acting director of the Roslin Institute, the Scottish research center best known as the home of Dolly, the late cloned sheep.
Increasingly the partnerships cross national boundaries. As biotechnology clusters spring up in new locations, pharmaceutical firms from outside those locations move rapidly to take advantage of the expertise of their research institutions and small firms. The Roslin Institute takes part in several cooperative projects. "Our biggest industrial collaboration right now is with Geron in the United States," says Griffin. That collaboration involves nuclear reprogramming, stem cell research, and gene targeting. Another American firm, Viragen, cooperates with the institute on a project designed to produce human antibodies in the eggs of laying hens.
Major Advances in Microarrays
Microarrays have emerged as key tools for research in all sectors of life science, including large and small pharmas, biotechnology firms, and academic departments. "One of the major advances we've seen in the last couple of years is the move from microarrays being a very specialized research tool applied only in top academic labs and a few large corporate centers to being a very robust, high quality tool that scientists can use to get answers," says Trevor Hawkins, senior vice president, development for Amersham Biosciences.
Microarrying comes in two flavors: do-it-yourself and off-the-shelf. Patrick Brown's laboratory at Stanford University led the way for the do-it-yourself array makers. Starting about 10 years ago, Brown and his colleagues developed several protocols for fabricating DNA arrays, which he made available through the Internet for researchers who wanted to prepare their own.
Since then several companies have developed the tools and systems that scientists need to build their own arrays. Users who want to make their own miniature laboratories on a slide can buy nylon membranes and coated glass slides, colony pickers and array spotters, hybridization chambers, scanners, and analytical software from such suppliers as Amersham, Genetix, and Millipore. "As arraying has become more widespread, particularly in the academic community, there's been a need to offer good, low-cost equipment for users," says Mark Truesdale, senior applications specialist at Genetix. "A few years ago, the average arrayer for customers to spot their own arrays cost about $80,000. That cost has plummeted in the past 12 to 18 months."
Customers also seek complete packages for their do-it-yourself arrays. "We offer a complete spotting and scanning package at a list price of about $75,000," says Truesdale. "We have also developed the mechanics of print heads for our spotter and new chillers for samples held in the arrayers. Customers have driven a lot of those developments."
Customers have also begun to move from spotting their own slides to buying prearrayed systems. Affymetrix was the first company to develop off-the-shelf DNA microarrays, adapting the photolithographic process used to make semiconductors to manufacture high-density oligonucleotide arrays. In 1994, the company began to market its GeneChip products. Since then, the line has evolved into a broad offering of both ready-to-use probe sets such as its U133 Human DNA microarrays and its CustomExpress services for researchers who want probes customized for their areas of research.
Affymetrix has recently extended its branding in RNA analysis to develop a market niche in DNA analysis. "Our GeneChip Mapping 10K array, released in early access late last year, is used to genotype about 10,000 single nucleotide polymorphisms [SNPs] spread evenly across the whole genome," says Greg Yap, Affymetrix's senior director of marketing for DNA analysis. "The primary application is genetic linkage analysis. Many of our customers want to use the product to look in family populations to find genes or regions associated with significant genetic disease." Also in early access now is CustomSeq, a product designed for custom sequencing. Both products will have their formal launch later this year.
Power of Scotland
Now Scotland has created its own biotechnology sector. In 1999 Scottish Enterprise, the organization that promotes the member nation of the United Kingdom, announced a plan to double the country's biotechnology community within four years. "The four years is about to end and we've achieved our goal; we have 477 organizations," says Ken Snowden, the organization's acting director of biotechnology. In addition, the country's biotechnology industry now employs more than 25,000 people, up from about 12,000 in 1999. And the current rate of growth of Scotland's biotechnology community is double the European average of just over 15 percent.
Scotland has several natural advantages as a center of biotechnology. The country of about five million people produces twice as many life scientists as the rest of the United Kingdom, whose total population approaches 60 million. Scotland boasts scientific quality as well as quantity. For example, life sciences professor Sir Philip Cohen of the University of Dundee, who carries out research on the role of phosphorylation in human health and disease, emerged as the second most cited life scientist in a recent citation survey. Another study showed that 9 percent of worldwide patents relating to stem cells came from Scottish institutions.
Scotland's government encourages the application of that research. "We are developing the Scottish Stem Cell Network to bring together researchers working at the bench with other interested parties, including clinicians," says Harry Griffin, acting director of the Roslin Institute, located near the Scottish capital of Edinburgh. "There's a great opportunity for us to build on the effort in stem cells already in the region and the country, and to take advantage of funds from Britain's Medical Research Council and the Biotechnology and Biological Sciences Research Council, both of which have identified stem cells as a research priority." Adds Snowden: "We have real strength and depth in stem cells in Scotland."
Amersham offers a microarray platform that it acquired recently from Motorola, called CodeLink, for applications that range from gene expression to SNP analysis and ADME (absorption, digestion, metabolism, and excretion) studies. The technology uses a proprietary three-dimensional aqueous gel matrix to which presynthesized oligonucleotide probes are attached. "We offer three human ±bioarrays' - two human 10Ks with 10,000 genes on each and a 20K with 20,000 well-characterized human genes," says Sam Raha, Amersham's vice president for CodeLink. "We also have two rat offerings and one mouse. And to address SNPs we have a p450 array."
Echoing the experience of Genetix, customers help makers of prepared microarrays to tweak their new products. Clients intrigued enough to try out new technology as soon as it emerges become particularly valuable sources of help and advice. "For our new DNA analysis products we look to the early access model to find commercial customers to work with," explains Yap of Affymetrix. "Customers will help us to see the best applications and how best to use our products for them." Amersham Biosciences takes a similar view. "We tend to work with our customers a great deal to help define what they need and develop products with market potential," says Hawkins. "No company should forget that it's the customer who drives markets."
An Emerging Market
The introduction of DNA microarrays quickly sparked the idea of using this miniaturized platform with other biomolecules. Companies such as Biacore and Ciphergen developed systems for the analysis of proteins using different proprietary technologies. Jerini and PerkinElmer, meanwhile, came up with other arrays for different applications. "The protein array market is obviously emerging," says PerkinElmer's Cook. "we're starting to see protein and peptide arrays. There's quite a lot of interest in putting small subset arrays inside microtiter plate wells."
PerkinElmer's Protein Array Workstation is an automated system for high throughput, in-gel digestion, sample cleanup, and MALDI spotting. It provides walk-away liquid handling capabilities by automating labor-intensive tasks such as manifold assembly and disassembly. Like other instrumentation that has reached the market recently, it stemmed from a collaboration. "The product was largely developed at NextGen in the United Kingdom and transferred here for applications and manufacturing," says Cook. "We like working with inventive small companies like NextGen because, through a collaborative approach, we can apply the best mix of talent and resources to product development, and then to manufacturing, distribution, and service."
Jerini's Peptide Technologies unit offers its unique peptide microarrays to accelerate crucial steps in drug discovery programs. "We are able to automatically synthesize peptides in a high throughput format," says Mike Schutkowski, director of Jerini Peptide Technologies. "Subsequent to printing on chips or membranes, these libraries enable profiling of both enzymes' activities and protein-peptide interactions." Life scientists can use the company's pepSTAR platform, developed in collaboration with the protein phosphorylation unit of the Medical Research Council in Dundee, Scotland, for ultrafast substrate identification and for profiling kinases and proteases. "Some years ago customers asked if we could use our spot technology for kinases," recalls Jerini's CEO Jens Schneider-Mergener. "Customers came up with the applications."
In addition to providing ready-to-use and custom peptide arrays, Jerini has an in-house drug discovery program advanced by its second business unit, Jerini Pharmaceuticals. The process starts with preparation of massive peptide arrays to identify bioactive peptides. Selected peptides are rapidly converted into peptidomimetics that mimic the activities of bioactive peptides. The process generates exhaustive structure-activity relationships that lead the direct, nonstepwise transformation of selected peptidomimetics into small molecules with drug-like properties by using pepMED, a medicinal chemistry platform.
Focus on Drug Discovery
New items this year include separate four-day programs on informatics issues and business issues in drug discovery, new therapeutic sessions on applications of new drug discovery technologies to cancer and cardiovascular disease, and free presentations to visitors registered only for the exhibit hall. Keynote speeches will focus on Massachusetts as a center for the pharmaceutical and biotechnology industries, R&D productivity in the pharmaceutical industry, and speeding up the development of new drugs.
Two parallel science tracks at the event will focus on advances in basic and applied life science, covering such areas as disease-associated targets for drug discovery, cell imaging technologies, links between genomics and chemistry, and case studies of drug discovery projects. The new informatics track will cover such issues as dealing with the huge amounts of data generated by drug discovery technologies, making that information available throughout large organizations, and applying data to effective decision making in drug discovery. And sessions on business issues will examine methods of finding sources of funds and appropriate partners, evaluating licensing opportunities, protecting intellectual property, managing alliances, and negotiating deals that represent a win for all participants.
The congress will also feature several workshops. Topics include biochemical and cell based assays, clinical genomics, high throughput synthesis and purification, and knowledge management.
To learn more about the event, you can check the website, www.drugdisc.com. Alternatively, call Michael Keenan at 508-616-5550, extension 288 or write to IBC Life Sciences, One Research Drive, Suite 400A, P.O. Box 5195, Westborough, MA 01581.
A Silencing Mechanism
Another hot topic in life science laboratories is RNA interference (RNAi), the process that introduces double-stranded RNA into a cell to inhibit gene expression in a sequence dependent fashion. Scientists have observed RNAi in cells from many organisms, including mammals. They believe that it participates in antiviral defense and regulation of gene expression. RNAi is usually described as a posttranscriptional gene-silencing mechanism in which the double-stranded RNA triggers degradation of homologous messenger RNA in the cytoplasm.
Scientists know that siRNA can induce gene silencing in mammalian cells. Thus exogenous siRNA holds great promise as a new tool for mammalian functional genomics. "The industry is focusing on development of siRNA as a functional genomics tool," says Stephen Scaringe, CEO and chief scientific officer of Dharmacon. "The use of siRNAs in animals as opposed to cultured cells is a big focus in many groups," adds Ambion's Brown. "There's also the use in gene discovery. People would like to develop functional assays and use siRNAs to identify genes in the pathways they're interested in." That line of research may lead to applications for siRNA in gene-specific therapeutics.
Several vendors, including Ambion, Dharmacon, and New England Biolabs, offer kits for gene expression studies with siRNA. "it's not cheap and hence not a commodity, but it's becoming a robust technology that people can start using as soon as they open the box," Scaringe points out.
In this arena also, cooperative R&D plays a key role in the development of new products. "We've developed probably 20 percent to 30 percent of our products in collaboration with academic researchers," says Brown of Ambion. "The others we have developed with the help of collaborators in alpha or beta tests. For many of our products, we find that it is beneficial to work with researchers who have expertise in areas where we lack expertise. Matching our strengths with theirs, we are able to develop very effective products very quickly." Scaringe takes a similar view. "We are working on antibodies for protein detection with Upstate Biosciences, " he explains. "We also do testing with academic collaborators to check that our products truly work."
Transgenics and Stem Cells
Antibodies also play a role in significant transgenic research under way at Scotland's Roslin Institute. "One project in our transgenic program aims to develop the idea of transgenic chickens that produce human antibodies in their eggs' whites," explains Griffin. "The idea is to produce human antibodies in quantity at a reasonable price." The need for appropriately priced antibodies arises from the fact that about 250 treatments for disease under development throughout the world use human antibodies as their targets. "The bottleneck is that when any of these therapies are proven effective and become licensed, there's a need to obtain human antibodies in quantity," Griffin explains. Roslin's approach, undertaken in collaboration with American firm Viragen, is one of many aiming to solve that problem.
Another transgenic project at the institute focuses on mice. "Many of the major pharmaceutical companies are trying to develop mice as reporters of drug toxicity," says Griffin. "If they are successful, the projects would reduce the numbers of mice needed for toxicity testing or would increase the sensitivity of the tests. Our idea is to generate reporter genes in the mice that will provide a readout, and thus report the toxicity, on a continual basis."
The Roslin Institute also has a collaborative program on stem cells with American biopharmaceutical firm Geron Corporation. Here, political geography represents a key factor. Stem cell research is severely restricted in the United States. "But here in the United Kingdom," Griffin says, "the whole area is strongly supported by the government. Since 1990 it's been allowable to do research on human embryos. That includes deriving stem cells from human embryos for therapeutic use." In addition to the Roslin Institute, the nearby University of Edinburgh has collaborative projects on stem cells with Geron and Australian company Stem Cell Sciences.
Collaborative efforts in the life science industry take several forms. The simplest and most natural is the use of early adopters of new products and technologies to tweak and improve those products. Beyond that, life science companies increasingly rely on a strategy of acquiring intellectual property from other firms through licenses or other cooperative agreements as a major factor in their technical development. "If an area is worth getting into, it's likely to have a lot of intellectual property associated with it," points out Evans of Amersham Biosciences. In his view, two principles control the decision to take a partner or partners. "You can't do all the R&D you want by yourself," he explains. "And your marketing position can be bolstered by forging an alliance with another company."
Amersham exemplified the collaborative approach recently when it announced that it will link up with Thermo Electron Corporation in a joint effort to market and sell mass spectrometry based proteomics solutions for protein scientists. The two companies will first comarket Amersham's Ettan MALDI-ToF Pro mass spectrometer and Thermo Electron's Finnigan line of ion trap mass spectrometry systems, which include the ProteomeX integrated proteomics work station.
Choosing the right partners involves balancing business and technical considerations. "We wouldn't collaborate with direct competitors, but we do collaborate with competitors who have common interests," explains Genetix's Truesdale. Thus Genetix worked on protein arrays last year with British firm Sense Proteomic. "We developed the instrumentation to make the product viable," says Truesdale.
PerkinElmer's Cook sees an emerging pattern in which small, nimble life science companies come up with ideas for new technology that they then hand off to larger, more established firms for development into marketable form. Sequencing the human genome, he notes, "relied on technology invented by many small, innovative companies. But it took large companies and teams of researchers and resources to bring it together." At PerkinElmer, he continues, "we know how to bring together all the innovative components for protein arrays and build a high value system capable of delivering them."
Corporations aren't the only members of the life science community to need and benefit from collaborations. The Roslin Institute provides an example. "The institute deals with basic and strategic science," explains acting director Griffin. "We will collaborate with individual firms and groups of companies to take our ideas to market." In the past, the companies have typically started the process by suggesting collaborative projects. But early this year Roslin won a five-year Faraday partnership, a British government initiative that tries to address ±the perennial problem for the UK of not being as successful as we should be in taking research to the market," in Griffin's words. "We see this as an important new vehicle to increase our understanding of what the livestock breeding industry needs," he adds. "It will also give the industry an appreciation of what science can and cannot deliver."
The future of the life science industry plainly promises more partnerships between smaller biotechnology companies whose very existence is driven by innovative ideas and larger corporations that have the infrastructure to do what small firms can't - integrate different facets of technology to enable marketable applications. "The large players that have the global reach will enable small companies to get into the marketplace fully deployed," Cook explains.
As researchers from across the world work together in extended teams, so do individuals in the companies that develop the tools to support life science research. With the world continuing to grow smaller through the Internet and other innovations, the power of partnerships in the laboratory and in businesses continues to expand, to the benefit of everyone.
Note: Readers can find out more about the companies and organizations listed by accessing their sites on the World Wide Web (WWW). If the listed organization does not have a site on the WWW or if it is under construction, we have substituted its main telephone number. Every effort has been made to ensure the accuracy of this information. The companies and organizations in this article were selected at random. Their inclusion in this article does not indicate endorsement by either AAAS or Science nor is it meant to imply that their products or services are superior to those of other companies.
This article was published
as a special advertising section
in the 13 June 2003 issue of Science