From Watson and Crick, the discoverers of DNA structure in 1953, we know that DNA takes a double-helix (spiral) form, like a slinky, winding around what Allis calls a "tuna can" shape of two each of four histone proteins, sometimes called an octamer. This wrapped can forms the nucleosome core particle. Such proteins are extremely conserved (i.e., remaining constant through biochemical changes), stable, common to almost every living thing in nearly identical form. 

From the work of Allis and others, we now know that there is a mechanism in the cell that opens and closes the slinky (decondensing and condensing the chromatin) to initiate and halt a wide range of cell processes—among them, protein synthesis and replication. DNA has to be unlocked to get its information read and produce an RNA, which in turn "has to get out of the nucleus and become ‘translated’ into a protein product, one of the genetic workhorses that make us what we are and determine everything from eye color to cancer. The process," says Allis, "is called gene expression." Finding what turns genes on and off in their natural chromatin package could provide a dramatic insight into disease processes.

For some years it’s been known that the tail-ends of histone proteins which "wag" outside the nucleosome "in the cellular breeze" are marked with certain modifications that occurred after RNA translation. Allis theorized that there must be an enzyme—a catalytically active molecule that performs a chemical reaction—which puts the modification on the tail, as well as an enzyme which takes it off. In 1996 at the University of Rochester, he found the on-enzyme which activates gene expression, at least for some genes. A month later, a group at Harvard University independently isolated the off-enzyme, a gene repressor. Allis explains: "We had an immediate connection that resonated through the field, showing there was something that positively regulated gene expression by ‘tickling’ the histones in certain ways." They had found the on/off switch.

The two labs discovered how two chemical modifica-tions— acetylation and phosphorylation—open up the slinky and permit expression to occur. Right now the UVa lab is working on acetylation, phosphorylation and methylation—all of which add small chemical groups to the tail of the histone. What these modifications actually signify and what they do are the big questions. In a new paper, "The Language of Covalent Histone Modifications," Allis and co-author Brian Strahl, Ph.D. (UVa Postdoctoral Fellow in Biochemistry) suggest that the tails contain a kind of Morse Code that somehow tells the cells what to do next.

Allis describes the on-off enzymes as operating "like a little switch, a molecular machine switch, which is beautiful because it’s so elegant. Think of it like a balance, a see-saw going on in the cell; the cells learn how to tweak that balance by regulating the enzymes. DNA is the central player, packaged in this chromatin tuna-can coat, and the cell has to learn to open it and close it, pull the slinky, close the slinky, and it’s found real cool switches to do it."

All this has enormous consequences for medicine, therapy and drug design. Both the on-enzyme and the off-enzyme have been found to be defective in a large variety of human tumors. In a group of leukemic children, it was found that the switching process doesn’t operate. To inhibit the on-off enzymes, clinics have already developed anti-leukemia drugs that have proven very effective in helping regress the activity of leukemia in children in the last stages of disease.

In Strasbourg, France, at the Insititut de Génétique et de Biologie Moléculaire et Cellulaire, a group under Paolo Sassone-Corsi working independently of Allis found that children suffering from Coffin-Lowry syndrome (characterized by mental retardation and deformities) had mutations in the enzyme pathway Allis was studying. In a collaborative effort, the two labs proved that the mutation did indeed interfere with histone phosphorylation and was the most likely cause for the growth defects. Recently the French group has engineered the human mutation in mice, finding that they clearly showed retarded behavior. In the hippocampus, that part of the brain responsible for long-term memory, researchers found that the mutant mice were not appropriately signaling the chromatin.

Allis calls the ramifications for human biology and human disease "absolutely staggering." Manipulating these enzymes has clear connections to controlling cancer, which fact has not been lost on the big pharmaceutical drug companies. Allis reports that he gets regular calls from some of them, as they are making significant investments in new enzyme programs. It also turns out that there are chromatin effects in spermatogenesis which may have consequences for male fertility. The same, he is finding, is true in neurobiology. All owing to the discovery of nature’s elegant little switch—a pair of enzymes that work one against the other.

Chromatin: A complex of nucleic acids and proteins in the cell nucleus serving as the structural organizer of DNA, binding DNA into higher order structures and ultimately forming the chromosome itself.

DNA or 
deoxyribonucleic acid: Two very long chains of nucleotides twisted into a double-helix shape and joined by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. DNA initiates the synthesis of proteins, needed for all cell development. DNA also replicates itself, separating its two strands before forming a new DNA molecule and a new chain.

Histones: Composed of a globular domain (or head) and an N-terminal "tail," these four varieties of highly stable, basic proteins control the opening and closing of chromatin to permit gene ex-pression to occur. The tail is "modified" in various ways to control chromatin behavior.

Nucleosome: The funda-mental unit of chromatin, consisting of the DNA strands wrapped around the four-histone (times 2) "tuna can," or octamer.

RNA or 
ribonucleic acid: a long, single-stranded chain of phosphate and ribose units, whose structure and base sequence determine protein synthesis and the transmission of genetic information.