It starts with a chicken, not an egg.
The red combs of roosters and hens turn out to be some of the best sources for the sugar molecule hyaluronan, a compound that some doctors are calling the next big thing after Botox.
It is already used to protect the eye during surgery, reduce inflammation in arthritic knees and prevent postsurgery scar tissue. Most recently, hyaluronan has become known as the latest treatment for plumping up facial wrinkles.
Hyaluronan, formerly known as hyaluronic acid, may have many more applications, researchers and doctors hope, as they search for ways to harness its potential to manipulate cells.
Hyaluronan was discovered in 1934 by Karl Meyer in an ophthalmology lab at Columbia University. Meyer found the substance in cows' eyes and determined that it helped the eye retain its shape. The substance was very viscous, leading Meyer to suspect that it might have some therapeutic use.Continue reading the main story
But extracting cows' eyeballs was neither appetizing nor feasible commercially. Along came Dr. Endre Balazs, a Hungarian scientist who also ended up at Columbia. Using Meyer's procedures, Dr. Balazs figured out in the early 1940's how to extract and purify hyaluronan from rooster combs.
The combs were already known ''as one of the world's richest sources of hyaluronan,'' said Dr. Vincent Hascall, a researcher at the Cleveland Clinic Foundation who has studied the molecule. And the combs are plentiful, Dr. Hascall noted, because they are usually thrown away after slaughter.
In roosters, the comb, essentially a big flap of skin, swells with hyaluronan in response to testosterone, Dr. Hascall said. Hens have hyaluronan in their combs, too, but not as much.
In humans and other mammals, the compound is primarily found in connective tissue, in the eyes, the umbilical cord and in joint fluid, where it acts like a cushion.
Since the 1970's, hyaluronan has been injected into the arthritic knees of racehorses to reduce inflammation, and it is used in veterinary eye surgery.
But the compound was not used on humans until 1980, after Dr. Balazs sold his patents and methods to Pharmacia, the Swedish drug company. That year, Pharmacia introduced Healon, a product used in cataract surgery to protect the cornea while a new lens is installed.
Healon is now owned by Pfizer, but the hyaluronan continues to be produced in Sweden, building on Dr. Balazs's method.
Pfizer has selectively bred roosters to have superhuge combs. At one point, the combs grew too big, said Dr. Rolf Bergman, a professor of physical chemistry at Uppsala University, north of Stockholm, who helps oversee the hyaluronan operation.
''We stopped getting it bigger and bigger because all of the sudden the rooster couldn't keep his head up,'' Dr. Bergman said.
Pfizer rigorously cares for its Swedish white leghorns, in keeping with Swedish ethics laws, he said.
Plus, fine care makes for a better product. ''If the roosters are doing well,'' he said, ''we get a higher quality hyaluronan.''
To extract the product, Pfizer and another major manufacturer, Genzyme, follow essentially the same process.
Genzyme, of Cambridge, Mass., starts with garden variety chickens from Northeastern farms. The combs are removed after slaughter (the chickens are sold for food), frozen and shipped to the manufacturing plant. Freezing helps destroy bacteria. But when the combs arrive at the plant, they are raised to room temperature and sliced into chips. The chips are dumped in a huge vat where they are washed to remove remaining bacteria, feathers, blood or other contaminants.
At Genzyme, about 1,300 pounds of combs are processed in a single vat. The vat is drained, and water is pumped in. Hyaluronan is water soluble, so it leaches into the water.
The water-hyaluronan solution is pumped into a clean tank and neutralized. The liquid is put through a series of filters to strain viruses, bacteria and proteins, and then it is pumped into another tank. Alcohol is added to form a slurry that can be dried into the final product, powdered hyaluronan.
The end product from chickens has a high molecular weight, which makes it so useful. Hyaluronan is also extracted from streptococcus bacteria, but that source provides a smaller molecule. The bigger and heavier the molecule, the more viscous it is and the longer it lasts, officials said.
That is why Pfizer sticks with rooster combs and why Genzyme chose them for its joint treatment Synvisc and for the Hylaform wrinkle-filling gel, which is awaiting approval from the Food and Drug Administration, said Dr. James Burns, senior vice president for biomaterial research and development at Genzyme.
To create the gel, Genzyme uses a process called cross-linking to tie together hyaluronan strands. Dr. Balazs also invented that technique. The hyaluronan lasts longer in the body in gel form, Dr. Burns said. ''With time,'' he said, ''the body's natural processes will eventually allow breakdown and clearance of the gel.''
The gel, which Inamed plans to market, is intended to be injected into wrinkles like those around the nose and chin. The treatment is expected to last six months to a year.
Another product, Restylane by Medicis, was already approved for wrinkle treatments this year. It also uses hyaluronan, not from animals, but from bacteria.
The effectiveness of hyaluronan for knee joints was called into question this month in The Journal of the American Medical Association by researchers who said it worked no better than a placebo. Other scientists think the molecule, whether from chickens or bacteria, has excellent potential.
''It's going to make a big splash in research over the next 10 years,'' Dr. Hascall said.
Scientists used to think hyaluronan had just a physical, structural role. But researchers have found that it influences the way that cells act, said Dr. Bryan Toole, a professor of cell biology and anatomy at the Medical University of South Carolina.
At a conference in October held by Dr. Balazs and Dr. Hascall at the Cleveland Clinic, 300 researchers presented data on hyaluronan's potential to heal wounds, prevent scarring and deliver slowly released drugs to precise areas.
Some early studies, including a few by Dr. Toole, have shown that hyaluronan may help cancer cells migrate through the body. Scientists are trying to figure out how to manipulate the molecule to stop that action. Dr. Toole said he was talking to a company about this area of research, but was unable to say more about it yet.Continue reading the main story