Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
Designer molecules that prevent protein misfolding, in which stringy proteins collapse into globs of extracellular gunk called amyloid, promise new therapies for literally hundreds of diseases. Protein misfolding contributes to illnesses ranging from Alzheimer's and Parkinson's diseases to cystic fibrosis, adult-onset diabetes and bovine spongiform encephalopathy (mad cow disease).
Such amyloid misbehavior occurs when proteins misfold into structures that lead them to cluster together, forming microscopic fibril plaques made up of hundreds of these misfolded proteins. The plaques deposit in internal organs and interfere with their normal function, sometimes lethally.
Chemical biologists at the Scripps Research Institute in La Jolla, Calif., trained their crosshairs on hereditary amyloidosis, a rare disease affecting the heart and nerves, which is caused by misfolding of a liver protein named transthyretin (TTR). Their report in Science, dated Jan. 31, 2003, is titled "Prevention of transthyretin amyloid disease by changing protein misfolding energetics."
The paper's co-authors designed small molecules that bind to the protein and increase the amount of energy needed to break it down, thus stabilizing its normal shape.
Familial amyloid polyneuropathy (FAP) is a collection of more than 80 rare amyloid diseases caused by misfolding of the transthyretin protein. The liver secretes TTR into the bloodstream to carry thyroid hormone and vitamin A. Normally, TTR circulates in the blood as an active tetramer, made up of four separate copies, or protein subunits, that bind to one another.
These tetramers come from two different genes. When one of them sustains a heritable defect, hybrid tetramers form, composed of mutant and normal subunits. The mutants make the four-part molecule less stable, and its four subunits easier to separate. Once free, they misfold and reassemble into the hair-like amyloid fibrils. These cause FAP by building up around peripheral nerves and muscle tissue, disrupting their function and leading to numbness, muscle weakness, and - in advanced cases - failure of the autonomic nervous system, including the gastrointestinal tract. Current treatment for FAP is nothing less than a liver transplant, which replaces the mutant gene with a normal copy.
An analogous disorder called familial amyloid cardiopathy (FAC) causes fibril formation in the heart, which leads to cardiac dysfunction. About a million African-Americans carry the gene that predisposes them to FAC. A separate amyloid disease that fatally clogs the heart is senile systemic amyloidosis (SSA). It afflicts an estimated 10 percent to 15 percent of all Americans over the age of 80.
Some previously tried therapeutic approaches involved administering drugs that inhibit the growth of fibrils from the misfolded state. However, this strategy often failed because fibril formation is strongly favored once an initial, misfolded "seed" fibril forms. Instead of preventing the misfolded protein subunits from conglomerating to form plaques, the Scripps team is attempting to prevent them from becoming abnormal monomeric subunits in the first place - by stabilizing the tetrameric "native state" of the protein.
"Encouraged by tests on animals and in healthy human volunteers," the New York Times dated Jan. 31, 2003 reported, "the researchers are about to begin clinical trials on patients with the two [cardiac] ailments, [FAC and SSA]."
Designer Molecule Spawns Subunits That Abate Swelling, Mucus In Asthmatic Mouse Models
Asthma has reached epidemic proportions, with some 200 million individuals affected worldwide. To capture the therapeutic value of the data derived from the recent sequencing of the human genome, and translate this information into pharmaceutical agents for treatment of various disease states, this information must be converted into small-molecule chemistry to pharmacologically validate a new molecular target.
Toward this goal, scientists at the Pacific Northwest Research Institute in Seattle have designed a novel molecule that reduces the inflammation associated with asthma. They report this work in the Proceedings of the National Academy of Sciences (PNAS), communicated Dec. 23, 2002. Their paper is titled: "Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma.
Asthmatics experience a complex inflammatory response in the lungs that produces swelling and mucus, reducing the ability to breathe. The co-authors describe a synthetic molecule, named PNRI-299, which inhibits a protein that leads to inflammation. They used an automated chemical process to develop and test a series of designer molecules that might inhibit production of AP-1, a protein that has a high activity in the bloodstream of some asthmatics. They constructed a pool of special-purpose molecules, each with a slightly different structure, and tested the ability of each construct to inhibit AP-1 inside living cells.
Despite Concerns, Genetically Modified Crops Seldom Worm Their Way Into Pollen
They don't do it very often, but foreign genes in genetically modified plants can hop from a cell's chloroplast into its nucleus. This finding, published online in a letter to Nature dated Feb. 5, 2003, suggests that foreign genes can theoretically make their way from chloroplasts into pollen grains - and therefore into wild flowers and weeds. A chloroplast, the site of photosynthesis, is the part of a plant that makes energy from light.
The Nature paper is titled "Direct measurement of the transfer rate of chloroplast DNA into the nucleus." Its authors are at the University of Adelaide in Australia.
Early in the history of genetically modified (GM) crops, there were concerns that foreign genes introduced into plants could jump into their wild relatives via pollen. Sequences in the nuclear DNA of many plants suggest that this has happened a few times throughout evolution. To prevent this, some GM plants have foreign DNA inserted into the genetic machinery of their chloroplast. Whereas DNA in a cell's nucleus is incorporated into pollen as cells divide, chloroplast DNA stays put, the Australian plant scientists report.
They inserted a marker gene into the chloroplasts of tobacco plants, then hunted it in 250,000 of their offspring. In about 1 in 16,000 of the seedlings, the gene had jumped from chloroplast to nucleus, and was being heritably expressed.