New Alchemy: Bone and Cartilage From a Snippet of Skin

URL: www.nytimes.com/library/national/science/health/062000hth-body-skin.html

Date accessed: 15 July 2000

June 20, 2000

          By GREG WINTER

               Taking a less traveled path in the quest

               to replace damaged organs with parts

          grown in the laboratory, a professor at the

          University of California at San Francisco

          reports that he has changed human skin and

          gum cells into bone and cartilage.

          "Sounds like science fiction, doesn't it?" said

          the researcher, Dr. Rajendra Bhatnagar, who

          is head of the university's graduate

          bioengineering group.

          "But that's what we do."

          Dr. Bhatnagar's findings, detailed in the latest

          issue of Cells and Materials, a peer-reviewed

          journal, provides one of the first alternatives

          to researchers' widespread reliance on stem

          cells, the primordial cells from which all

          others emerge.

          For several decades, researchers have tried

          to find a source of living cells to coax into

          new tissues. Most are focusing on stem cells,

          because, in theory, they can be manipulated

          to form any organ in the body.

          But they are difficult to harvest. Stem cells

          are found in bone marrow, but make up only

          one out of every 10,000 cells, or even fewer as patients age, making

          them extremely difficult, not to mention painful, to excavate and isolate

          through biopsies and other means.

          Human embryos offer another source of stem cells, but the prospect of

          mining biological matter from fetuses has raised objections. In 1994,

          President Clinton banned the use of money from the National Institutes of

          Health for experiments that either create or destroy embryos, a policy

          Congress later adopted.

          Using embryonic stem cells also has immunological complications. Just as

          the body rejects transplanted organs from donors, it can reject tissues

          grown from donated cells.

          Skin, however, is not only the largest organ in the body, providing

          researchers with a seemingly unlimited number of cells, but it is also the

          most accessible. Within the dermis, the middle layer in the folds of human

          skin, are fibroblasts, the cells that Dr. Bhatnagar and his researchers

          convert into bone and cartilage. So it is with gums as well, where

          fibroblasts are plentiful and, Dr. Bhatnagar reports, equally pliable.

          From a snippet of skin or gum tissue no more than a few cubic

          millimeters in volume, Dr. Bhatnagar says he can generate enough tissue

          to fill a hole in bone or cartilage many hundreds of times that size.

          And because the fibroblasts come directly from the donor, there is no

          risk of rejection.

          "This will have enormous impact in the field," said Dr. Antonios Mikos,

          vice president of the Tissue Engineering Society and editor of Tissue

          Engineering, which published a paper by Dr. Bhatnagar last year on

          converting a type of fibroblast found in gums into bone. "There are many

          technologies trying to isolate stem cells from bone.

          The problems of those technologies may be solved if one can use dermal

          fibroblasts."

          Dr. Bhatnagar's newest paper describes the transformation of a different

          type of gum cell, the gingival fibroblast, into bone.

          In November, CeraMed Dental, a small company owned primarily by

          Dentsply International, got approval from the Food and Drug

          Administration to sell a product based on Dr. Bhatnagar's research for

          patients with advanced periodontal disease. CeraMed paid the university

          for the rights to use the research; Dr. Bhatnagar says he has no financial

          interest in the company.

          Inserted wherever teeth have eroded, CeraMed's product, Pepgen P-15,

          works by transforming fibroblasts in the gums into bone, CeraMed

          officials say.

          In clinical trials required for F.D.A. approval, the product proved 38

          percent more effective than current methods of plugging holes in teeth,

          and generated new growth over roughly three-fourths of deteriorated

          areas.

          In one test, a middle-aged man whose jaw had become too dilapidated

          to bear false teeth had his gums packed with the pasty substance.

          After six months, he had grown what amounted to a new jaw, somewhat

          crudely formed, but solid enough to withstand drilling and support fake,

          screw-in teeth.

          Dr. Bhatnagar hopes the technology can be adapted to eliminate the need

          for costly operations for other degenerative diseases.

          Osteoarthritis, characterized by a breakdown in the joint's cartilage, is the

          principle cause of nearly half a million knee and hip replacements each

          year, according to the American Association of Orthopedic Surgeons.

          Of course, fibroblasts are not supposed to turn into bone or cartilage.

          Biologists have long believed that cells do not change course once they

          fully differentiate.

          But Dr. Bhatnagar pays them no mind. After spending more than 40

          years tinkering with the laws of nature, he has learned to be irreverent.

          "There is no dogma that has any true basis," he is fond of saying.

          His skeptics disagree.

          Dr. Arnold Kaplan, a founder of Osiris Therapeutics and one of the first

          scientists to isolate the stem cells found in bone marrow, said he was not

          familiar with Dr. Bhatnagar's work but speculated that the professor was

          unknowingly experimenting with another type of stem cell, called a

          pericyte, which also inhabits blood-rich tissues like skin and gums.

          Pericytes, virtually indistinguishable from fibroblasts, are as flexible as

          their counterparts within bone marrow, and may explain how Dr.

          Bhatnagar's findings seemingly throw the developmental process into

          reverse. "We don't know that you can take one type of tissue cell and get

          it to back up," Dr. Kaplan said.

          "In the cases that have been looked at with some rigor, that isn't how it

          happens."

          But Dr. Bhatnagar said his years of experimenting left him certain that it

          was the fibroblasts that were changing their properties, and as he

          publishes more findings he is convincing a growing number of his peers.

          His work with fibroblasts began in the late 1980's. Dr. Bhatnagar sent his

          graduate students to the university's medical clinic, where they collected

          the discarded foreskins of just-circumcised babies. Then he extracted the

          fibroblasts and placed them on a matrix that closely mimicked the

          properties of bone.

          Surrounded by minerals, held fast by P-15, a string of sticky amino acids

          that allowed them to interact, the skin cells conformed to the new

          environment as if they always belonged there. Within three weeks, the

          cells began producing proteins found only in bone. The same was done

          with more fibroblasts, this time from gum tissue, with the same results.

          Then the researchers packed fibroblasts tightly together and deprived

          them of oxygen, imitating the conditions of cartilage.

          Once again, the cells responded, as if they knew the lines of different

          characters and delivered them as soon as the set was changed. "They

          completely forgot how to be skin cells," said Dr. Bhatnagar.

          "We played mind games with the cells.  We made them think of home."

Category: 1. Advances in Science/Scientific Discoveries