"Ah, sweet mystery of life, at last I've found you!"

So goes the operetta song, which equates that sweet mystery to love.An intimately related mystery is life itself, the presumedconsequence of requited love. Specifically, how does a fertilized eggdevelop into an entire human being?

Renaissance men who dabbled in biology during the 1500s and1600s had an explanation _ preformation: That is, every sperm cellcontains a completely preformed miniature person, a homunculus,who, nourished in utero by its mother's egg, simply grows and growsto become a fully formed newborn baby. These proto-biologists evenprofessed to see the tiny homunculus in the newly inventedmicroscope.

Now, developmental biologists know better, but the mysteries of lifemultiply. Precisely how a single cell proliferates and differentiatesby the process of morphogenesis uncovers new riddles even as itgains new knowledge.

"Over the past 50 years," said structural biologist Gerhard Wagner,"it has been rather enigmatic how an embryo forms out of a dividingegg, and from the first cluster of dividing cells." Besides cell divisionand differentiation, he told BioWorld Today, "there had to be someorganization so that you have dorso-ventral [back-and-front]organization of the cells into organs, and then an entire organism."

From Pure Morphogenesis Toward Drug Discovery

One facet of the puzzle lies at the door of highly specialized, andlittle understood, proteins called CAMs _ cell adhesion molecules.The walls of ignorance surrounding CAMs are beginning to cometumbling down. This trendy area of cell biology is spreading tendrilsof CAM knowledge beyond reproductive biology into a widespectrum of medical indications. (See BioWorld Today, Sept. 8,1993, p.1.)

That news story 17 months ago reported a research and developmentcollaborative agreement between Chiron Corp. and Syntex Corp. todevelop CAM inhibitors. By its terms, Chiron, of Emeryville, Calif.,would have rights to such compounds for fighting infections, cancerand eye diseases; Syntex, of Palo Alto, Calif., for inflammation,asthma, allergy and organ transplantation.

Since then, CAMs have gone big time, with most majorpharmaceutical firms, and numerous more specialized companies,exploring the adhesive molecules' pharmaceutical potential.

As for the Syntex-Roche CAM deal, BioWorld Today has learnedthat since the latter company acquired the former last year (seeBioWorld Today, Aug. 31, p.1), the nuts and bolts of their jointresearch and development program are being reevaluated.

One extended CAM super family consists of some 30 or moreproteins called cadherins _ calcium-dependent adhesion proteins.Most vertebrates express at least one type of cadherin in order toform solid tissues (by an unknown mechanism), with the help ofcalcium.

Wagner, who is on the faculty of Harvard Medical School'sDepartment of Biological Chemistry and Molecular Pharmacology,has written an editorial in the current Science, dated Jan. 20. Itcomments on a paper in that issue titled "Solution structure of theepithelial cadherin domain responsible for selective cell adhesion."

Its senior author is structural biologist Mitsuhiko Ikura, of theOntario Cancer Institute and University of Toronto. He and his teamdetermined the 3-D structure of mouse E-cadherin bymultidimensional heteronuclear magnetic resonance spectroscopy.

The significance of Ikura's feat, Wagner said, "is that this is one ofthe first macromolecules for which a structure has been found ofimportance to the development of organisms in a certain shape."

Ikura told BioWorld Today, "There has been a major lack ofstructural information in this area. I think that's the impact our paperhas." Besides being "critical in tissue formation and organization ofthe multicellular organism," he said, "this epithelial cadherinmolecule is known as a cancer metastasis mediator."

He explained: "If this CAM's protein structure is affected somehow,if the cancer cell loses E-cadherin expression, it could becomedetached from the primary tumor and go somewhere else."

Ikura added: "Perhaps one could think of designing drug inhibitors,based on the structural knowledge of this molecule, that couldprevent such cancer metastasis. But we are at just the very beginningof such a long-time effort."

E-cadherin, Ikura said, "is a huge molecule, measuring about 120kiloDaltons. The portion for which he and his group determined thethree-dimensional structure, which spans amino acids one to 104,includes only one-tenth of it, about 12 kD, but it's the tenth that'sknown to contain the cellular adhesion specificity and the calcium-binding sites.

Cell adhesion, as Wagner put it, "is a way cells can choose theidentity of their neighbors." To do so, he explained, "in the case ofthe cadherins, a single polypeptide strand goes through the cellsurface and exposes the extracellular part of the CAM. You canimagine this receptor glycoprotein as a sticky blob on the cellsurface. One face of this blob makes specific interaction withhomologous counter-receptors on other cells. Then these two cometogether and fix the two cells relative to each other."

Fixation is based on the complementarity of the two CAM-connectedcells. Their adhesive surfaces have a very fine relief, which match upor dovetail. "Only these two receptors fit together," Wagnerobserved. "It's a very specific interaction, mediated by calcium."

This molecule recognizes only itself, or a self-like copy, Ikurapointed out. "Thus, neurocadherin adheres only to neurons, kidneycadherin only to kidney cells. That's why kidney cells can organizeto form a kidney organ."

Formation of this adhesion complex between receptor and counter-receptor triggers signals inside both cells, and leads to further stepsin organism development. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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