Two Firms Race To Derive Profits From Mussels' Glue

Despite gaps in their knowledge of how the mollusk produces the adhesive, scientists hope to re-create it GAITHERSBURG, MD. -- "Nature didn't make mussel glue for man's instant gratification," says Herbert Waite, the marine biochemist who first isolated adhesive protein from the foot of the common blue mussel. But man certainly intends to make use of and profit from this novel material. Last month, Genex Corp. - a Maryland biotechnology company - introduced its first glue based on the mussel adhesive. A second firm, BioPolymers Corp. of Farmington, Conn., has just gotten a patent on a synthetic version of the glue. But, Waite feels, neither firm will be able to take full advantage of this new glue until it better understands how the mussel makes the adhesive in the first place. It took years for Waite, at the University of Delaware, to obtain the natural protein. And it may take years more for scientists to master its structure. For instance, Genex and BioPolymers, taking different scientific approaches, are ignoring his message as they hasten to get products to market. "It's not known how nature [makes the adhesive] or how the structure and function of the glue relate," says Robert Strausberg, a Genex geneticist who considers that information not to be vital at present. "The product does what we want." Only time will tell whether these firms will get stuck with short-term gains rather than long-term advances. "Just looking at the product is like smashing a watch open to understand how it works," says Mike Marron, manager of the molecular biology program at the Pentagon's Office of Naval Research, which has funded much of the research in mussel adhesives. "We need to go into the mussel. The next major direction will be to understand the biological processing. In the long run it will lead to more products." Like buoys bobbing on the sea's distant horizon, applications for man-made versions of the glue - whether a genetically engineered protein churned out by yeast or a polymer-protein mix fashioned by a computer - are guiding its development. Scientists at Genex and Bio-Polymers envision such uses as a medical adhesive for repairing torn knee ligaments, sheets of resilient elastic for skin grafts, material for filling dental cavities, a sealant paint that can be applied underwater to naval equipment, or even an adhesive that conducts electricity. In March Genex sold its first four bottles of AdheraCell, a recombinant version of the adhesive extracted from the foot of the mussel. The Gaithersburg bioengineering firm's customers - two government groups and two pharmaceutical firms that the company declines to name - will use the protein-based adhesive as a surface support for cell and tissue cultures. In the same month, Bio-Polymers obtained a patent for a unique synthetic form of the mussel adhesive. BioPolymers first put its own laboratory mussel glue, Cell-Tak, on the market four years ago. Biopolymers had almost 300 customers for its laboratory adhesive last year, according to the distributor. Both companies caution, however, that the medical applications are only now going through animal trials, and it may be years before they reach market. "When the products appear on the market depends a fair amount on whether the Food and Drug Administration classifies the adhesive as a drug or a device," says Strausberg. "The safety requirements for both are the same, but it's easier to prove efficacy for a device, so obviously we'd prefer that." Since the ancient Phoenicians first cast their boats into the Mediterranean, mussels have been the curse of the mariner. Today, the sea-going mollusks attach tenaciously to the sides of navy ships and freighters. In 1987 mollusks cost the Navy more than $200 million in such areas as hull scraping and excess fuel consumption. Six years ago the Office of Naval Research began to support research by marine biologist Herbert Waite, then at the University of Connecticut, to analyze the mussel's glue. The National Institutes of Health, reasoning that such a biologically friendly adhesive might have medical uses, was also sending money the biochemist's way. It was a sticky problem for Waite, now at the University of Delaware. Scientists had tried without success for almost 80 years to analyze the gooey substance that mussels squirt onto rocks and ships. The very structure that makes the glue so strong - a repetitive cross-linking of protein strands - also makes it resistant to chemical analysis. It took until 1981 and several years of sloshing around in tidal pools along the East Coast collecting mussels before Waite was able to spell out the chemical makeup of one mussel protein. And that protein was just a chemical precursor to the glue. Nonetheless, the vision of endless uses for a biocompatible protein that would stick and harden even in a wet, salty environment caused two biotechnology companies to leap into action. Waite, as well as scientists at BioPolymers in Connecticut and Genex in Maryland, readily acknowledge they still don't understand the complex molecular structure of the final adhesive. Nor do they know how the adhesive is processed inside the mussel. This lack of understanding has already led to one major problem in the development of a glue, says Waite. In his early work, Waite had extracted the precursor to the glue from the mussel's storage sack and mapped out its amino acid sequence. Now, to make an adequate synthetic version of the glue in the laboratory, scientists have to add mushroom or bacteria enzymes or sodium ascorbate to the precursor material they have created. But enzymes and ascorbate don't do the job as well as the mussel's own chemicals do, according to Waite. As a result, the laboratory-prepared product is not as strong as the original material. Until scientists figure out how the mussel activates the precursor protein, however, they'll have to make do with second best. --D.M. The mussel squirts the adhesive onto hard surfaces to anchor itself under water. Its chemical structure is so complex that Waite still doesn't understand it, even though he has studied it for 10 years. The two companies chose different methods to tackle the difficult task of synthesizing a man-made version of the marine bioadhesive. The future success of each route may be determined by the ways the researchers at the two companies do science today. Nonindustry scientists like Waite say it may also be up to him and other academic researchers to tackle the basic biology questions that may provide the answers the biotech firms are looking for. BioPolymers makes Cell-Tak, its tissue culture adhesive, in what many scientists now consider to be the old-fashioned way. Its scientists extract the adhesive directly from a gland in the mollusk's foot. In a laborious and expensive process, 30,000 mussels are shucked to make one gram of the pure protein that goes into Cell-Tak. It is not surprising, then, that Cell-Tak sells for $90 a milligram, twice what Genex charges for AdheraCell. But with their new computer-formulated biosynthetic glues, BioPolymers scientists envision an endless array of products, each tailored to the firm's specifications. The polymer chemists construct their hybrid adhesive by grafting amino acid sequences onto a polymeric backbone. The researchers first decide on what qualities they want the adhesive to have. Then they use a computer program in a peptide synthesizer to determine and attach the right sequence of amino acids. The finished product resembles a baby-bottle brush, with amino acid bristles jutting from a central wire handle. "I can change the programming and the next morning have a new product," says Christine Benedict, chief scientist and cofounder of BioPolymers. "I define the properties I want and then plug in the amino acid sequences I think will give me that." Genex has taken a different tack in producing AdheraCell, its adhesive. After seven years of research, Robert Strausberg and his lab genetically engineered a protein that differs 60 percent from the mussel glue's natural amino-acid sequence in a yeast system that allows them to produce relatively large amounts. Strausberg alters the gene sequences and tests the resulting protein for qualities such as strength and stickiness. That's not always easy, of course. The higher the molecular weight of a protein, the more cross-linking there is between protein strands. Cross-linking appears to make the glue both strong and sticky. The glue produced by a mussel has a molecular mass of about 130,000 daltons. "When we first started, we couldn't get above 25,000," says Strausberg. "It was a real stumbling block." Building up the size of a protein and its molecular weight was a key factor in determining how each company would try to build its adhesive. Each firm started with the basic knowledge that Waite had garnered through his early research. When Waite had finally teased out the molecular structure of the mussel glue he was surprised by its simplicity. He found it to be a repeating sequence of 10 peptides; each of the 75 to 80 repeats had slight variations. At the time, Waite expected that such a simple sequence would be easy to construct artificially. Yet when he and others tried to string together more than a few sequences, the substance seemed to lose its ability to be a glue. The sequences failed to maintain the structure needed for adhesive properties. Benedict thought she saw a way around the problem. A postdoctoral student of Waite's at the University of Connecticut in the early 1980s, the young biochemist and her businessman husband, Tom, founded BioPolymers in 1985. With Waite at their side as a consultant and investor the couple hired a group of polymer chemists and plunged into biomimetics, the science of developing synthetic analogs of natural materials. The idea was simple. They would use a synthetic backbone for stability. To the backbone they would attach in parallel arrays the polypeptides important for adhesion - it would look a bit like a comb - until they had reached the right molecular weight. "It was a business judgment based on the likelihood of success within a reasonable time frame," says Benedict, who thought biomimetics was likely to be the quickest and most efficient method to produce an adhesive. "BioPolymers has taken the short-cut approach," says ONR's Marron. "Instead of reproducing nature, they incorporate the essential features of the biological product they want into an artificial device." BioPolymers' approach also allowed them to avoid a problem that stymied for years the scientists at Genex, who were trying to genetically engineer an adhesive by manipulating the mussel's gene sequence. "When I came to [Genex] in 1984, it seemed like a perfect genetic engineering project," says research leader Strausberg. "Here was a protein with useful qualities and we had a way to make it in large quantities. With protein engineering you can make changes in the genes and see the effect in the protein. Then you go back and tweak some more." Nonetheless, like the scientists at BioPolymers, he still had to contend with the adhesive molecule's natural reactivity. The molecular weight of his protein appeared stuck at 25,000 daltons. Eventually he discovered that by focusing on one specific sequence of amino acids that is then made over and over, the adhesive protein could be built up to 100,000 daltons. The result, he says, is a tough, flexible glue. In response to Waite's charge that more basic work is needed to reach the full commercial potential of the mussel glue, officials at both companies stress that they comprehend the science well enough to do applications-oriented research. "Sure, everyone would like to understand the natural process better," says Strausberg. "But we don't think it's necessary for our products." On one hand, Marron understands the short-term approach. "Biotechnology companies are interested in the product. They've got to feed people today if they want to stay in business," he says. But both Marron and Waite have problems with that kind of industry thinking. By continuing to study the mussel, the companies can devise more rational strategies for product development. "The Benedicts have an obsession with trying to market this stuff as an adhesive, which I think is throwing them on severe financial difficulties," says Waite, who contends that adhesive research is stymied by the missing links in the understanding of the mussel's physiology. "[The Benedicts] would be smarter, for instance, if they explored the fact that mussel glue appears to have a high affinity for metals. It might be possible to develop anticorrosives and compounds that bind with heavy metals in water." Waite says that each of the hundreds of different species of mussels produces a different kind of adhesive depending on its environment. And each one, he notes, has developed a different kind of glue with a slightly varying molecular structure. "The crux of the problem is that mussels don't use chemicals in a vacuum," he says. "They've evolved sophisticated strategies for storage and processing that allow them to use a very reactive molecule." If the industry scientists want to turn their visions of endless new products into reality, Waite says, they must turn back to the lowly mussel. But neither he nor the scientists in pursuit of profits expect that to happen anytime soon.

Two Firms Race To Derive Profits From Mussels' Glue

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