When a new protein slides off the tiny molecular assembly line within the cell, it is nothing more than a droopy string of amino acids, not yet fit for its designated profession.
Only upon being coiled and pleated and braided into its proper three-dimensional conformation will a protein burst to life, seizing up oxygen if it is hemoglobin, shearing apart sugars if it is an enzyme or lashing cells together if it is a stout twine of collagen.
Until recently researchers had scant idea how a simple chemical strand manages to fold up into a working protein, with all its knobs, clefts, sheets and curves arrayed in vivid harmony, able to mingle with other molecules around it.
The problem is no mere academic exercise but a question of central importance to biology. Proteins perform every one of the tens of thousands of tasks needed to keep the body alive, and only a perfectly folded protein is up to the relentless demands made upon it.
Many scientists believed that folding happened spontaneously, and that a newborn protein, or polypeptide, would spring into its correct three-dimensional shape on its own, driven solely by the repellent or attractive electrical and chemical forces of its individual amino-acid building blocks.
As they tried to calculate what those enormously complicated interactions might be, they made little headway in cracking the folding conundrum.
But now the theory of how a protein folds in the cell is being dramatically overhauled.
Much to their astonishment, scientists have discovered that nature does not let proteins fold up by themselves but has created a whole family of proteins whose sole purpose is to help other proteins crinkle and furrow.
The detection of the handmaiden proteins, called chaperones, means that the traditional theory of spontaneous folding is mistaken and that the forces inherent in a polypeptide's sequence of amino acids are not enough to sculpture and knead a protein into its correct, muscular form.
Instead, researchers are learning that protein folding, like so much of what happens in the body, is done by committee. They have found that as the amino-acid chain rolls forth from its birthing chamber in the cell, folding must begin immediately to avoid any missteps.
To that end, a series of chaperone midwives rush over and gently embrace the flat polypeptide at hundreds of key spots, shielding it against the hostile environment of the cell.
The chaperones allow amino acids that are destined for the interior of the active protein to curl in on themselves, while encouraging those regions meant for the protein surface to turn and confront the outside world.
They help twist some stretches into corkscrews or pummel others into flat sheets. The chaperones also prevent the fragile chain from becoming impossibly ensnarled with other infant peptides floating in the cell, as it would if left unattended.
Nor does the job of the chaperones end once the initial folding is through. Should the cell suffer a perilous shock from extreme heat, oxygen cutoff or any sort of trauma that threatens the structural integrity of the thousands of proteins within, the chaperones will toil mightily to prevent protein disintegration, latching onto the wilting molecules and helping to bend them back into shape.
So indispensable are the folding molecules to growth and survival that cells experimentally shorn of their chaperones rapidly die.
"There's been an explosion of interest lately" in chaperones, said Dr. Mary-Jane Gething of the University of Texas Southwestern Medical Center in Dallas. "For cell biologists, finding them was just like pulling a blind up." In a recent issue of the journal Nature, Gething and a colleague, Joseph Sambrook, wrote an extensive review about protein folding, with particular emphasis on chaperones.
"They're wonderful and neat and exciting things," said Dr. Jane S. Richardson, a professor of biochemistry at the Duke University School of Medicine in Durham, N.C. "They change one's attitude about what's going on in the cell and the sort of things you need to take into account when thinking about new problems."
The knowledge researchers are gathering about chaperones could yield insights into many human diseases. After a heart attack, for example, large patches of cardiac muscle tissue end up dying as a result of temporary oxygen deprivation.
Some doctors are exploring the possibility that if the chaperones in heart tissue could be manipulated right after a heart attack, the restorative molecules could shore up collapsing proteins in the heart cells and perhaps prevent tissue death.
Other scientists suspect that certain genetic disorders, like muscle-wasting diseases, may result from mutations that slightly weaken the cell's chaperones, leaving many proteins in disarray.
Biotechnology companies would like to use chaperones to help them generate vital human proteins in mass quantities. With current recombinant DNA techniques, many human proteins end up gumming together into worthless aggregates after they have been synthesized in bacterial cells.
The addition of the proper cocktail of chaperones could allow the proteins to assume their active shape.
Pharmaceutical companies are also desperate to understand the rules of protein folding to allow them to design better drugs, which are often based on natural proteins.
If they could learn why a particular amino acid prompts a vital protein to twirl up rather than down, and why the protein works better in one shape than in another, they could mix and match components to improve on nature's offerings.