By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
From the Stone Age to the Bronze Age to the Iron Age, mankind has come a long way in the tools and materials that set its adeptness off from lower forms of life. But those forms keep fighting back. Right now, fungal organisms are ganging up on plastics, especially medical devices.
The Plastics Age began in the early 1900s, with the invention of bakelite and cellophane. Now, more sophisticated formulations go into catheters, replacement heart valves, artificial hip and knee joints, contact lenses, dentures - even teeth. But fungal infection, especially by Candida albicans, is proving every bit as sophisticated in rendering these plastic products useless.
Besides C. albicans' devastating infection of skin, oral cavity, esophagous, gastrointestinal tract and genitalia, that ubiquitous fungus destroys the functioning of medical devices by smothering them with an intractable coating called biofilm. These resilient sheets and globs resist traditional chemical attack.
"Particularly vulnerable," observed microbiologist Todd Reynolds at the Whitehead Institute for Biomedical Research, in Cambridge, Mass., "are people who are neutropenic - with weakened immune defenses - who are undergoing cancer therapy, organ transplantation, various procedures where they're going to have a diminished immune system, and probably also have a lot of catheterization.
"Also," he pointed out, "there is a relationship between having antibiotic treatment and an increase in such biofilm fungal infections." Every year, thousands of deaths can be traced to fungal infections around medical implants. Lack of an informative model system has hampered studying this mounting menace.
A paper in Science dated Feb. 2, 2001, describes a way around that roadblock. Its title: "Bakers' yeast, a model for fungal biofilm formation." Reynolds is its first author, and Whitehead Director Gerald Fink is the article's senior author.
Yeast, Saccharomyces cerevisae, is the friend of brewers, bakers and biologists. Noting that yeast cells stuck to the bottom of their plastic laboratory plates, the co-authors set out to find a yeast protein that accomplishes this adherence. "The system that initiates the formation of a biofilm in baker's yeast," Reynolds pointed out, "potentially can hold true for pathogenic Candida as well. Once molecules involved in this process are identified," he added, "then we can search for similar molecules in that fungus, with the ultimate goal of finding new drug targets to prevent pathogenic biofilm formation in patients."
Two steps in that direction are their identification of two yeast genes, FLO11 and FLO8. The first encodes a cell surface glycoprotein required for adhesion to agar, a Jell-O-like culture medium substrate. The second gene expresses a protein that turns on FLO11 expression.
The acronym "FLO," Reynolds explained, derives from the term "flocculation" - precipitation from solution of fluffy, cottony or wooly clumps.
This effect in vitro caused the team's yeast cells to radiate out in gauzy floral patterns, as depicted on the cover of Science. Disrupting the FLO11 gene, the co-authors report, put an end to that spreading flower-like mat of cells, which could no longer form biofilms on hard plastic surfaces.
In searching for drugs to curb or abolish biofilms, Reynolds surmised, "The idea would be to find a ligand for this FLO11 gene. If there's a comparable gene in Candida, for example, which, it's well known, has quite a variety of similar flocculin-like proteins, and a competitive inhibitor that would interfere with its ability to bind, that could substantially inhibit the fungus from setting up a biofilm - or even perhaps from adhering to human tissue, in an infectious situation.
Whitehead has licensed its fungal biofilm discoveries in exclusivity to Cambridge-based Microbia Inc., a start-up biotech company of which Fink is a founder, and chair of the firm's scientific advisory board.
Hair Follicle Stem Cells Seen For Wound Healing, Skin Grafting, Cancer Therapy, Baldness, Hirsutism
The skin's stem cells (SCs) are situated mainly in hair follicles, which are located deep within the dermis. French scientists report that the skin of adult mice contains SCs that can give rise to all the cell types needed for reconstituting the epidermis, sebum-secreting sebaceous glands and hair-growing hair follicles. This discovery, they point out, opens up new perspectives for wound healing, and skin grafting in burn injury patients. It also has implications, they point out, in understanding the origins of some skin cancers, and in cosmetology, to deal with both hair loss and excessive hirsutism. (See BioWorld Today, Aug. 22, 2000, p. 1.)
The journal Cell, dated Jan. 26, 2001, carries their findings in a paper titled: "Morphogenesis and renewal of hair follicles from adult multipotent stem cells." The paper's senior author is biologist Yann Barrandon, at the Ecole Normale Superieure, in Paris.
Mice possess some 50 hairs per square millimeter; humans only about five. Each follicle contains 1,000 to 1,500 stem cells. Barrandon's team located these SCs to a small region at the top of the follicle, and traced the pathways by which they migrate and differentiate.
The co-authors pointed out two main potential applications in cancer research: countering the factors causing malignant transformation of hair follicle cells and protecting cutaneous SCs during chemotherapy, to prevent associated hair loss.
Potential applications in plastic surgery and cosmesis, they propose, include the treatment of male pattern baldness by stimulating atrophic hair follicles, and contrariwise, removing unwanted hair by selective stem cell destruction. n