Nature Biotechnology
22, 1203 – 1205 (2004)
doi:10.1038/nbt1004-1203
A taste of the future
Cormac Sheridan
Dublin
Flavor-enhancing molecules provide a fast track to market and to an IPO, at least for Senomyx, the first ‘flavor’ biotech out of the block. Will others follow? Cormac Sheridan investigates.
At first glance, Senomyx’s entry into the ranks of public biotechnology companies this past summer was nothing very remarkable. The La Jolla, California-based firm has established a series of cell-based assays to screen combinatorial libraries for novel compounds that modulate G protein−coupled receptors (GPCRs) and ion channels, and it has signed a clutch of licensing deals with large corporations that will develop and commercialize molecules generated through these discovery programs. Two have already entered the regulatory approval process and, says Senomyx CEO Kent Snyder, could be on the market by 2006.Table 1
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What makes this company noteworthy is the particular class of targets on which it is focused. Senomyx is the first company to apply the high-throughput screening methods developed for drug discovery to the hunt for novel molecules that modulate the activity of taste receptors. If it’s successful, it could have a profound impact on the flavor ingredients industry and on the wider food and beverage industry by enabling food producers to radically alter the nutritional profile of their products without having any impact on taste.
Warp speed taste testing
Until now, flavor technologists have stuck to an unavoidably low-throughput approach to screening, combining analytical chemistry techniques, including gas and liquid chromatography, mass spectroscopy and NMR spectrometry, with the expertise of human taste specialists. By introducing an automated approach to screening, Senomyx has achieved orders-of-magnitude gains in efficiency, pushing up the number of compounds that can be screened annually from around a thousand to over a hundred thousand. It can also hope to fish out potentially valuable molecules that would escape the notice of even the most experienced human taste testers.
Taste receptors evolved to enable humans—and other organisms—to find carbohydrates, proteins and other nutrients, and to avoid harmful substances. The molecular biology of taste is now well understood, at least at the periphery, where that first encounter between our taste buds and the flavor compounds found in natural and processed foods occurs. Our taste perception system recognizes five distinct taste sensations—sweet, sour, bitter, salt and umami, a savory taste imparted by monosodium glutamate (MSG)—that are triggered by binding interactions between tastant ligands and taste receptors expressed on the surface of taste cells. Senomyx cofounder Charles Zuker, of the University of California, San Diego (UCSD), is one of the scientific leaders in the identification and characterization of taste receptors1,
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The sweet, bitter and umami tastes are all mediated by GPCRs. Receptors for salt and sour have yet to be definitively characterized, says Senomyx chief scientific officer Mark Zoller, although evidence suggests that the epithelial sodium channel (ENaC), an ion channel protein, functions as a salt receptor. The diuretic drug amiloride hydrochloride blocks ENaC and reduces sensitivity to salt.
The sweet and umami tastes each appear to be mediated by a single receptor com-posed of two subunits. Each receptor type is expressed uniquely by specialist sweet or umami taste cells. In contrast, some 25 bitter receptors exist, all of which are expressed within the same cell. Senomyx has established screening programs to find sweet, salt and savory (umami) enhancers. It has a library of some 200,000 compounds, from which it has filtered out structures not typically found in food. The most potent hits it identifies are then assessed in the traditional manner—by a panel of taste experts who conduct ‘swish-and-spit’ tests before selecting the most promising compounds for lead optimization.
Technically, the company does precisely what many biotechnology firms involved in drug discovery do. But the characteristics of what it is looking for are different. “The hurdles for a drug are so much higher,” Zoller says. “Here the delivery is so much easier. There isn’t any bioavailability problem. The compounds can be a lot simpler.”
First out of the blocks
Zuker established Senomyx (the company was initially called Ambryx) in 1998 along with Roger Tsien, also of UCSD, and Lubert Stryer of Stanford University, just as the first papers detailing his group’s discoveries in taste receptor research started to appear1,
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4. The company underwent three successive venture capital rounds and netted $34.4 million this summer from its initial public offering (IPO), which was priced at $6.00, below its published range of $13 to $15.
Even though it is still very much a small-cap biotech, with a market capitalization of around $160 million, the company has grabbed the attention of the incumbent players in the sector. “It’s new technology for the flavor industry, and I do believe that Senomyx was the first one to say: ‘let’s go build taste-receptor assays’,” says Clint Brooks, senior vice president of R&D at New York-based International Flavor & Fragrances (IFF), the second largest company in the field. “They’re the most visible and also probably the most capable right now,” says Boris Schilling, vice president of bioscience at Givaudan, the Geneva-based market leader.
The company’s potential influence goes beyond that of forcing a technology transition on the sector, however. Senomyx also aims to recast the economic model on which it is based, by mimicking the kind of deal structures that biotechnology companies and big pharma have created to develop and commercialize new drugs. It licenses the compounds it identifies to partners, which, once regulatory approval has been obtained, incorporate them into processed foods. “When we grant a license to use one of our flavor enhancers, it’s an exclusive license in a defined field, which is expected to provide our collaborator with a competitive advantage in the marketplace,” says Snyder. This arrangement also allows the company to seek additional deals with the same compound in noncompeting product categories.
Flavor ingredients companies usually manufacture the compounds themselves and sell them on to the food processors, taking a profit on the margin. Senomyx will earn its income through royalties, clocking up revenue on the sale of every can of soup or beverage that contains its chemistry. It also collects R&D funding and milestone payments during the discovery phase of its collaborations.
Flavor attraction
The model may be new to the food industry but it has already found favor with some of the biggest names in the business. Senomyx has signed licensing deals with Campbell Soup, of Camden, New Jersey; Coca-Cola, of Atlanta, Georgia; Kraft Foods, of Northfield, Illinois; and Nestlé, of Vevey, Switzerland. “That’s very unusual—for food companies to do that,” says Elise Wang, senior biotechnology analyst at New York-based Smith Barney, the equity research arm of Citigroup, which underwrote Senomyx’s recent IPO. Senomyx’s collaboration with Nestlé has yielded two candidate flavor compounds that are currently undergoing the regulatory approval process (Box 1).
The carrot for these companies is the prospect of finding compounds that would enable them to improve the nutritional or health profile of their products by reducing levels of sugar, salt or monosodium glutamate, while maintaining or improving taste. In terms of ambition, this represents a step-change from the industry’s usual R&D goals of finding molecules with incremental performance or manufacturing improvements. It could potentially rewrite the economics of the flavor ingredients industry and of the fragrance ingredients sector, which, structurally and scientifically, are very closely related. In addition to Givaudan and IFF, the market leaders include Firmenich of Geneva, Symrise of Holzminden, Germany, and Quest International, of Naarden, the Netherlands. All are active in both sectors, which generate combined annual sales of around $15 billion.
For the existing players, the value of their chemistry lies in complex flavor formulas containing multiple components rather than in individual molecules. An artificial strawberry flavor, for example, could contain 70 to 80 critical molecules which, collectively, mimic the taste of a real strawberry, which contains around 400 flavor compounds. According to Clint Brooks, the molecular biological approach could yield individual molecules that would generate significant value in their own right. A safe, naturally occurring salt enhancer that worked at parts per million and enabled a food processor to slash salt levels by 50%−75 % would be a “blockbuster,” he says. Brooks says that w hatever molecules Senomyx may come up with will still have to be incorporated into complex flavor formulas, a capability that the company has not developed internally. “I don’t think that would be a failure hurdle. It is something that would require extra expertise and extra effort.”
Follow the leader
IFF is itself following Senomyx’s lead into automated screening, by establishing a partnership with Chromocell, of North Brunswick, New Jersey, which has proprietary technology for establishing highly stable cell lines. The plan is to build robust assays that can function in the presence of plant digests. “We’re going to give these assays plant goop,” says Brooks.
 The carrot for these companies is the prospect of finding compounds that would enable them to improve the nutritional or health profile of their products by reducing levels of sugar, salt or monosodium glutamate, while maintaining or improving taste.  |
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The stakes are, potentially, very high. According to a report by Smith Barney’s Wang, Senomyx’s current collaborations could potentially generate between $310 million and $1.2 billion in royalties, based on disclosed royalty rates of between 1% and 4%. “The primary risk is technical risk. Are they going to be able to find something?” she asks.
John Leffingwell of Leffingwell & Associates, a consultancy based in Canton, Georgia, says another critical factor is how well a company of its size can work the relationships it has established with such big partners. The Nestlé deal is “probably the most serious”, he says. “They have been involved in doing work on testing taste receptors and have a number of patents in the area,” he says. In contrast, Coca-Cola, he says, is currently in a state of flux. “It will be another year or two before that shakes out with the new management.”
Although Senomyx is the leader in this newly emerging field, it does not have the space entirely to itself. In the US, Linguagen, of Cranbury, New Jersey, is the other specialist biotechnology contender. The company was founded by Robert Margolskee, a Howard Hughes Investigator based at Mount Sinai School of Medicine in New York, who identified gustducin, a component of the taste signal transduction chain over a decade ago5. The company has already obtained approval for one compound, adenosine monophosphate (AMP), discovered while building a prototype assay, and it has obtained a utility patent on its use as a bitter blocker. AMP—and other bitter blockers—could potentially be used as a replacement for masking agents and encapsulation approaches currently employed to offset the bitter taste of certain medicines. They also provide another means of reducing fat, sugar and salt levels in processed foods. The latter ingredients are often added to offset the bitter taste associated with certain products of the Maillard (or browning) reaction, which occurs during cooking or processing.
Linguagen only finalized its series A funding round within the past year, so the company is still at an early stage in its development. In the meantime, Senomyx appears to have closed off much of the territory by amassing an extensive patent estate comprising 29 issued US patents, 18 issued overseas patents plus over 170 pending applications. “We’re focused on approaches we feel are completely free of encumbering IP,” says CEO Ray Salemme. “There’s a lot of ambiguity about what the ultimate strength of their IP portfolio is going to be.”
Although Linguagen has not divulged full details of its in vitro and cell-based assay systems, the company is looking beyond tastant-receptor interactions to the other components of the signal transduction chain (Fig. 1). “We’ve got a number of tools, which we’ve developed that don’t involve the use of cloned receptors,” Salemme says. Informatics is as important as molecular biology, he says, as the size of chemical space will always be greater than the scope of any screening system. “In our view it is much more important to use intelligence than blind screening.”
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Apart from the taste receptors themselves, it is not yet clear what other targets may be addressable in the taste signaling system. Some of its components appear to be nonspecific and are shared across several taste modalities. The ion channel protein transient receptor potential M5 (TRPM5) and phospholipase C beta are two signaling elements that are downstream from all three classes of GPCR taste receptor. “Knockouts of either of these two genes result in a complete loss of sweet, bitter or umami taste,” says Nicholas Ryba at the National Institute of Dental and Craniofacial Research, in Bethesda, Maryland, a coauthor on Zuker’s taste receptor papers.
The actual experience of flavor results from a highly complex interaction between our taste- and odor-sensing systems in the brain. “What most of us think about taste—everything we enjoy about it—is to a large extent olfaction,” Ryba says. The task of characterizing olfactory receptors is at an earlier stage of development, however, and it is a far more onerous undertaking. Several hundred (estimates vary from 350 to over 400) olfactory receptors are expressed in the olfactory receptor cells found in the nasal cavity. However, capturing the interactions between these proteins, which are also GPCRs, and their ligands, which are generally small volatile compounds, is technically challenging. Different receptors exhibit varying sensitivities to a given odorant, says Givaudan’s Schilling, so the perception of a particular compound depends on its concentration. At higher levels, different receptors may be fired, triggering an unpleasant sensation. Moreover, excessive levels of particular odorants can be toxic for cells, further complicating analysis. Even obtaining functional expression of cloned olfactory receptors has been difficult. “The biggest hurdle is to identify a robust screening platform,” he says.
Christian Van Osselaer, CEO of ChemCom, a privately held company based in Brussels, says it hopes to implement such a system in two years, drawing on the Aequorine GPCR assay technology of one of its shareholders, the biotechnology company Euroscreen, also of Brussels. “Our platform will integrate a multivariate ‘image’ of the odors of different compounds,” says Van Osselaer. Each ‘image’ will hold a record of the binding interactions and binding affinities between a given odorant and the full panel of olfactory receptors. It will calibrate the system by screening with known compounds and then search for novel molecules that exhibit similar interaction patterns. “We don’t need to have all the answers to have an industrial tool,” Van Osselaer says.
For the present time, though, olfaction remains a far riskier proposition than taste. The science is more complicated whereas the potential rewards may not be as lucrative. As the fragrance industry has no ‘killer application’—such as a salt or a sweet enhancer—the main opportunities lie in identifying molecules with desired performance attributes that are cheaper to produce than existing fragrance chemicals. The first products of this emerging niche in biotechnology are more likely to act on the tongue than the nose.
REFERENCES
- Hoon, M.A. et al. Putative mammalian taste receptors: a class of taste-specific GPCRs with distinct topographic selectivity. Cell 96, 541−51 (1999). | Article | PubMed | ISI | ChemPort |
- Adler, E. et al. A novel family of mammalian taste receptors. Cell 100, 693−702 (2000). | Article | PubMed | ISI | ChemPort |
- Chandrashekar, J. et al. T2Rs function as bitter taste receptors. Cell 100, 703−711 (2000). | Article | PubMed | ISI | ChemPort |
- Nelson, G. et al. An amino-acid taste receptor. Nature 416, 199−202 (2002). | Article | PubMed | ISI | ChemPort |
- McLaughlin, S.K. et al. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature 357, 563−569 (1992). | Article | PubMed | ISI | ChemPort |
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