LBL, biotech firm sign CRADA to develop tendon-repair drug

December 11, 1992

By Peter Weiss

A cellular substance discovered at LBL could lead to a new drug that would improve how quickly, and how sturdily, injuries to tendons and ligaments heal. No drug currently exists that aims specifically at this notoriously slow, and often incomplete, healing process.

LBL recently signed a million-dollar Cooperative Research and Development Agreement with Amgen, Inc., the nation's largest independent biotechnology company. Amgen, which is based in Thousand Oaks, Calif., will purify, test, and manufacture the substance. Under the terms of the agreement, $492,000 will be provided over the next three years by the Department of Energy, and $570,000 will come from Amgen.

The potential drug has been dubbed Cell Density Signal-1, or CDS-1, by its discoverer -- cell biologist Richard Schwarz of the Life Sciences Division. Schwarz found the drug in the tendon cells of chicken embryos. In those cells, CDS-1 acts as part of a chemical switch that turns on procollagen production.

Procollagen is a protein which embryonic tendon cells pump out in large amounts, and which is transformed outside the cell into collagen -- the basic building block of connective tissues. Collagen molecules in connective tissues such as tendons, ligaments or bones twist together into rope-like strands. In bone, those strands are also hardened by other processes.

Embryonic tendon cells stimulate procollagen production in themselves and their neighbors by secreting small quantities of CDS-1, Schwarz says. Because adult tendon cells make very little procollagen, he postulates that they produce almost no CDS-1.

Current theory holds that when adult tendons or ligaments are injured, cells come from outside the tissue to make a repair. Invading fiber-secreting cells, called fibroblasts, secrete new collagen threads that knit together the damaged area, but often not very well.

"Instead of rope," Schwarz says, "you get a patchwork pattern as if you mended something. As (San Francisco 49ers quarterback) Joe Montana can attest, tendons heal slowly and don't heal very well. Usually, the tendon never heals to its former strength."

If CDS-1 works as expected, it will stimulate adult cells themselves to produce larger amounts of procollagen, as if they were embryonic cells. That would be a first for cell biology, Schwarz says, since scientists have never before, by design, reversed cell development. It would also mean a sturdier repair, at a faster pace : "Then Joe could go out and throw for another 10 seasons."

As CDS-1 induces cells to produce procollagen, it also prevents them from growing. That growth-inhibiting action may prove effective against connective tissue cancers, Schwarz says. "Most cells have very strong cell-density effects: they stop growing when they reach a certain density. Cancer cells lose that." If, however, connective-tissue cancer cells respond to the inhibitory effect of CDS-1, they might produce gobs of collagen instead of malignant growth.

Connective tissue cancers are rare. Osteosarcomas, or bone cancers, which are slightly more common than those of tendons or ligaments, most often strike teenagers. The treatment of choice frequently is amputation. If CDS-1 works against osteosarcomas, limbs may be spared -- "you would get bone tissue where you once had a tumor," Schwarz says.

Besides its potential practical benefits, Schwarz's discovery promises to shed light on basic questions about cell growth and differentiation. Experiments that he is conducting with CDS-1 may help explain how cells detect that other cells are nearby. This cellular awareness exerts a strong influence on the rate at which cells grow and divide, and it affects the amount of collagen they produce, Schwarz says.

So far, more is known about what CDS-1 does than what it is. Schwarz has developed techniques, however, for figuring out the material's structure. He is also collaborating with Amgen scientists to isolate pure CDS-1 from cell cultures for further analysis.

Once the substance has been chemically analyzed, Amgen will use genetic engineering to mass-produce it.