NEWS FEATURE

Mussels’ sticky feet lead to applicationsThe remarkable adhesive powers of the mussel are being harnessed fordiverse applications, ranging from medical adhesives to climate-changeresearch.

Stephen OrnesScience Writer

J. Herbert Waite was a graduate student inbiochemistry in the 1970s when he began towonder how mussels cling to rocks in theturbulent intertidal zone, where they slurpnourishing plankton from the water. So insummers and fall, Waite donned Wellingtonboots and rubber gloves and headed for theConnecticut shore near Rocky Neck StatePark to pluck bivalves from the water.Despite initial skepticism from his peers

about the research, Waite is now considereda pioneer in the field of bioadhesives, a thriv-ing interdisciplinary endeavor that connectsmarine biology to materials science. “Natureis a bottomless treasure trove, as far as adhe-sion strategies go,” says Waite, now at theUniversity of California at Santa Barbara.“Adhesion is often a survival mechanism,

but to my surprise very few strategiesare the same. Barnacles and mussels havecompletely different strategies, differentarchitectures.”Understanding these strategies is more

than a basic problem in biology. Materialsresearchers would like to develop adhesivebandages that can match a mussel’s abilityto stick underwater, for example. “If I havea fundamental understanding, it’s going tomean that if you cut your hand on a brokenglass while washing dishes, you’re going to beable to put a Band-Aid over that injury whileit’s soaking wet,” says Waite.The biochemistry behind the mussel’s leg-

endary grip is also being used to seal surgicalincisions, and is shedding light on the impactof global warming. Those applications are

taking Waite’s curiosity-driven researchabout the pure science of mussel stickinessto places he never dreamed of during thoselong sojourns along Connecticut’s coldbeaches.

Protein SoupWhen he began his research, Waite knewthat the molecular secrets of the mussel’ssticking ability must lie in the proteins of itsbyssal threads, the golden, leathery tethersthat attach the shell to a rock. The threadsare produced in the byssal gland buried in agroove in the mussel’s foot, and are largelymade from collagen, the same protein thatgives skin its stretchiness. The liquid ingre-dients produced in the gland solidify quicklywhen they hit seawater, forming a threadwith a hard, protective outer skin and anadhesive plaque at the end.These threads combine strong adhesion

with strong cohesion—the material holdstogether under the relentless pounding ofthe ocean’s waves—making them unlikeany commercial glues. Although some med-ical adhesives, such as those using a proteincalled fibrin, adhere well to wet surfaces,they tend to lose their cohesive strength aswater degrades the sticky molecules.Working through his copious mussel har-

vests, Waite broke down the sticky byssalproteins into their component amino acids.Then he looked for those amino acids insidethe mussels themselves. In 1980, he foundthat a rare amino acid called L-dopa, betterknown as a treatment for Parkinson disease,showed up in every tissue the mussel neededto produce the sticky byssi (1). L-dopa was inthe threads themselves, it was in the adhesiveplaque, and it was in the mussels’ living tis-sue. Since then, Waite and other researchershave identified at least 10 different musseladhesion proteins that contain DOPA (2).DOPA contains a chemical group called

catechol, made from a benzene ring bearingtwo adjacent hydroxyl (-OH) groups. Thereis evidence that these hydroxyl groups formchemical bonds with rocks and other sub-strates that help to stick the mussel in place

A cold day in January 1988 found biologist J. Herbert Waite collecting mussels from theConnecticut coast. Image courtesy of Herbert Waite.

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(3). From the late 1990s, researchers alsobegan to find that the threads containedhigh concentrations of transition metals,like iron and manganese, which interactwith catechol groups to cross-link thebyssal proteins and make them more co-hesive (4). In July, researchers reportedthat the particular blend of hard and softmaterials in the byssal threads helps themussels to withstand dynamic forces thatare nine-times as great as the staticstrength of the threads (5).Although the composition of the threads is

now fairly well understood, what happensinside the byssal gland itself is a completemystery. “You’ve got all the ingredients, buthow do you mix them together, cook them,allow them to come together to make thefinal form? Those steps are still not un-derstood,” says biologist-turned-materi-als scientist Phillip Messersmith at North-western University in Evanston, Illinois. “Wewant to know the tricks of how the musselprocesses this soup of proteins and transitionmetals into a beautiful, high-strength, robustmechanical adhesive we know as themussel byssus.”

Inspired by NatureMessersmith is using synthetic analogs of thesticky proteins to explore the chemistry of the

byssal threads, and to produce new, bio-inspired adhesives. Messersmith’s team has

produced a glue based on long molecules ofpolyethylene glycol that are capped withDOPA. When the catechol groups are oxi-dized with sodium iodate, the polymerstrands join up to form a strong adhesivehydrogel. Messersmith and his colleaguesfound that the glue successfully bonded pigtissue, and was several times stronger thana fibrin-based glue (6). The researcherssubsequently used the glue to permanentlyclose surgical incisions in mice withouttriggering an adverse immune response. “Itsolidifies on tissue in anywhere from fiveseconds to a minute,” Messersmith says.In a laboratory study on human fetal

membranes, Messersmith’s nontoxic gluecould also repair an incision in the tissue,performing better than commercially avail-able adhesives, including Dermabond, His-toacryl, Tissucol, and fibrin (7). Messersmithhopes that the glue could be used to seal theamniotic sac after prenatal surgery on a fetus,for example. Fetal membranes have poorhealing capacity and suturing is not alwayseffective. “If amniotic fluid leaks or there’sa poor seal, that can induce premature labor,”he says.Messersmith and his colleagues have also

combined the mussel’s sticking power withthe adhesion strategy of the gecko, whichuses tiny hair-like structures on its feet tocling to almost any dry surface. Dubbed

Byssal threads and adhesive pads are clearly visible in this photo of a mussel attached toa pane of glass. Image courtesy of Phillip B. Messersmith.

Biologist Emily Carrington from the University of Washington visits a mussel farm near Vigo,Spain, one of the top mussel-producing regions in the world. Work by biologists like Carringtonmay point to more efficient and environmentally friendly ways to cultivate mussels for con-sumption. Image courtesy of Kenneth Sebens.

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“geckel,” the novel adhesive is made fromfibrous silicone coated with Messersmith’ssynthetic mussel-inspired glue (8). Pro-mising studies showed that geckel wasextremely sticky in both wet and dryconditions, but Messersmith is no longerworking on the material. “It turned out tobe very hard to manufacture on a largescale,” he explains.In contrast to Messersmith’s synthetic ap-

proach, chemical engineer Hyung Joon Chaof Pohang University of Science and Tech-nology, South Korea, is trying to developa medical adhesive using the mussel’s ownadhesive proteins. Harvesting the glue is notan option—it would take 10,000 individualmussels to isolate just one gram of adhesiveproteins—so Cha and his colleagues havegenetically engineered Escherichia coli tomake the proteins (9). “Messersmith’sapproach is more practical and economi-cal because chemical synthesis and conju-gation can be easily done on a large scale,”says Cha. “But his materials may have lim-itations in terms of toxicity, biocompat-ibility, and biodegradability.”Cha is currentlytesting his adhesive on animal models forsafety and effectiveness, and says he hopes tocommercialize it in 5 to 10 year’s time.

Gas AttackThemussel’s protein glue may be tough, but ithas an Achilles’ heel: acid. That makes themussel vulnerable to the effects of climatechange.The growing quantities of carbon dioxide

in the atmosphere are also dissolving in theoceans to create carbonic acid. As a conse-quence, average ocean pH has dropped from8.2 to 8.1 in the past 100 years. The In-tergovernmental Panel on Climate Changeestimates that it could drop by another 0.3 or0.4 pH units before the end of the century

(10). Laboratory studies on marine organismssuggest that many species could face a dra-matic decline as the pH continues to drop.Acidic seas tend to have a low concentrationof carbonate ions, for example, which shellfishuse to build their shells.Acidification is also bad for byssal threads,

says marine biologist Emily Carrington at theUniversity of Washington in Seattle. “Thefibers are extrusions of mussels, not unlikeour hair,” she says. “If you’re nutritionallystressed, one of the first things that happensis your hair falls out.” She believes that dra-matic declines in mussel populations, as inother organisms, could be a bellwether forhow vulnerable coastal ecosystems are react-ing to ocean acidification. Her research hasalready shown that byssal threads change onseasonal cycles, becoming stronger in thewinter andweaker in the summer. Carringtonis now trying to pin down how ocean chem-istry and temperature affect those cycles.In laboratory experiments, Carrington has

been testing the strength of byssi in water withdifferent concentrations of carbon dioxide. Asthe researchers ratcheted the carbon dioxideload in the water, the pH dropped from 8.0 to7.5, within the range found in commercialmussel beds. However, at pH 7.5, individual

threads began to break at shorter extensionsunder smaller loads. In June, the researchersreported that this was caused by a breakdownin protein cross-linking rather than a loss ofadhesion (11). For wild mussels, that couldmean they are unable to attach to rocks inwater that is too acidic.Monitoring mussels’ sticking power could

help researchers develop better models of howclimate change will affect complex coastalecosystems, says Carrington; most oceanacidification models currently focus on theopen ocean. A better understanding of howmussels respond to water chemistry could alsoimprove the mussel aquaculture industry,which was worth $1.5 billion in 2009. Musselfarms, where mussels are grown in denseclusters on long underwater ropes, could useCarrington’s research to tweak the tempera-ture, composition, and flow of water pumpedthrough the hatchery.The study of bio-adhesion has come a

long way since Waite’s first mussel-gath-ering trips. The humble mollusc is joiningtogether disparate fields, promoting fruit-ful interdisciplinary science with poten-tially important applications. “It’s verygratifying for those us that started as biol-ogists,” says Waite.

1 Waite JH, Tanzer ML (1981) Polyphenolic substance of Mytilus

edulis: Novel adhesive containing L-Dopa and hydroxyproline.

Science 212(4498):1038–1040.2 Silverman HG, Roberto FF (2007) Understanding marine mussel

adhesion. Mar Biotechnol (NY) 9(6):661–681.3 Lee H, Scherer NF, Messersmith PB (2006) Single-molecule

mechanics of mussel adhesion. Proc Natl Acad Sci USA 103(35):

12999–13003.4 Monahan J, Wilker JJ (2003) Specificity of metal ion cross-linking in

marine mussel adhesives. Chem Commun (Camb) 2003(14):

1672–1673.5 Qin Z, Buehler MJ (2013) Impact tolerance in mussel thread

networks by heterogeneous material distribution. Nat Commun

4:2187.

6 Burke SA, Ritter-Jones M, Lee BP, Messersmith PB (2007) Thermalgelation and tissue adhesion of biomimetic hydrogels. Biomed Mater2(4):203–210.7 Bilic G, et al. (2008) Injectable candidate sealants for fetalmembrane repair: Bonding and toxicity in vitro. Am Journal ObstetGynecol 202(1):85.e1–85.e9.8 Lee H, Lee BP, Messersmith PB (2007) A reversible wet/dryadhesive inspired by mussels and geckos. Nature 448(7151):338–341.9 Hwang DS, Gim Y, Yoo HJ, Cha HJ (2007) Practical recombinanthybrid mussel bioadhesive fp-151. Biomaterials 28(24):3560–3568.10 Orr JC, et al. (2005) Anthropogenic ocean acidification over thetwenty-first century and its impact on calcifying organisms. Nature437(7059):681–686.11 O’Donnell MJ, et al. (2013) Mussel byssus attachment weakenedby ocean acidification. Nature Climate Change 3:587–590.

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