A Focus on Heredity and Development

Photo: Coriell Institute for Medical Research

The Division of Genetics and Developmental Biology supports studies of how genes are inherited and how organisms develop from single cells. The eventual goal of these studies is to improve the diagnosis, treatment, cure, and prevention of human genetic and developmental disorders.

The Division also supports the Human Genetic Cell Repository (http://locus.umdnj.edu/nigms/). This cell bank houses an enormous collection of human cell cultures and DNA samples. The resource enables researchers to study the genetic basis of hundreds of diseases, including cystic fibrosis, Huntington's disease, a severe form of manic depression, and the eye disease retinitis pigmentosa.

The Cycle of Life
Just like a living creature, an individual cell has a life made up of stages. It is "born" (usually when its parent cell divides in two); it carries out its biological functions; it reproduces by dividing, often dozens of times; and it dies.

Underlying these milestones are regular cycles, which can last from less than an hour to years or even decades. Progress through each cycle is governed by a precisely choreographed biochemical cascade involving a repertoire of molecules with names like maturation promotion factor, cyclin, and cyclin-dependent kinase.

For the past several decades, NIGMS-supported researchers have conducted detailed studies of these molecules, methodically unraveling their biochemical identities and properties. The scientists have examined the molecules' ebb and flow throughout the cell cycle and their eventual demise as they are chemically chewed up when their job is done — until they are made again for the next cell cycle.

As for most life processes, when the biochemical choreography goes awry, the result can be disastrous. Glitches in the cell cycle can lead to a host of diseases, most notably cancer, which can be defined simply as uncontrolled cell division.

Scientists are poised to take advantage of the wealth of basic research on the cell cycle. They are testing scores of potential anticancer drugs that aim to bolster or block cell cycle molecules. Researchers are also harnessing their knowledge of the cyclical fluctuations in cell cycle molecules to predict the aggressiveness of a cancer and to tailor treatments.

Biology by the Clock

The cell cycle is by no means the only bit of biology controlled by the orchestrated fluctuation of many molecules. Another key example is the daily, or "circadian," rhythms of creatures as diverse as flowering plants, bread mold, fruit flies, and humans. The circadian rhythms of all of these organisms rely on light, which activates an array of genes that control each organism's biological "master clock." These genes, many of them first identified in the fruit fly Drosophila melanogaster, are playfully given names like timeless, clock, frequency, and double-time.

Photo: Woody Machalek

In humans, the master clock regulates sleep-wake cycles, the release of various hormones, and a host of other biochemical activities. A better understanding of the inner workings of this clock promises to aid the treatment or prevention of sleep disorders, certain types of depression, and jet lag. The ability to manipulate the circadian rhythms of plants and animals could also have broad applications in the biotechnology and agricultural industries. Farmers could control when plants flower or go to seed, or they could breed drought-resistant plants by adjusting when leaf pores open and close.

Protecting Chromosome Tips
NIGMS-funded researchers are not only interested in what genes and chromosomes do, but also in what they look like and how they behave at various times throughout a cell's life cycle or an organism's lifetime.

At each end of every chromosome is a long chain of repeated DNA sequences called a telomere. Just as the plastic tips on shoelaces protect the laces from fraying, telomeres protect the ends of the chromosome from wearing away. Even so, telomeres in normal human cells become progressively shorter each time the cells divide. If the telomeres become too short, the cells either stop dividing and die, or they become vulnerable to genetic damage that can lead to cancer. This suggests that telomeres serve as molecular hourglasses that track how old a cell is and when it should die.

In some cells, an enzyme called telomerase helps maintain telomeres at a proper length by adding special DNA to the chromosome tips. Telomerase was first described by Elizabeth Blackburn, now at the University of California, San Francisco, and her former graduate student Carol Greider, now at The Johns Hopkins University. They discovered the enzyme in a single-celled creature called Tetrahymenathermophila, whose telomerase is always active.

In most adult human cells the enzyme is inactive, but it is turned on again in some cancer cells, allowing these cells to continue dividing even if they contain damaged DNA. Scientists are investigating whether shutting off telomerase in these cells could lead to new anticancer therapies.

Fingerprinting Anthrax
Paul Keim, an evolutionary biologist at Northern Arizona University, studies how genomes evolve. He's investigated genetic variation in species ranging from microbes to endangered birds. But what he is now best known for is his group's technique to genetically fingerprint organisms that could be used as bioweapons, including those that cause plague, tuberculosis, and anthrax.

Keim and his coworkers study the evolutionary relationships among anthrax strains so they can trace a specific strain's lineage, even if it is subtly different from that of its ancestor. These studies aid investigations of bioterrorism by suggesting whether different attacks are carried out by the same person or group and revealing clues about the source of the bacteria.

The Keim technique was catapulted into prominence when it was harnessed by the FBI in the fall of 2001 to identify the strain of anthrax spores mailed in envelopes. The approach relies on slight genetic differences between the hundreds of known strains of anthrax. Keim's team detects these differences using a type of DNA fingerprinting technique related to that used in criminal and paternity cases.

The researchers also used this technique to analyze the strain of anthrax released in 1993 by the Japanese cult Aum Shinrikyo. Their study showed that the attack failed because the cult members used a veterinary vaccine strain of anthrax that is not dangerous to humans.

Like the work of many other NIGMS-supported scientists, Keim's research initially appeared to have little immediate medical significance. Now, it directly addresses a serious public health threat.

Using microarray technology, Shapiro's group discovered that the activity of 553 of the nearly 3,000 genes in the Caulobacter crescentus bacterium fluctuates throughout the cell cycle. The microarray read-out of these 553 genes is shown here, organized by when they are "on" (in yellow) and "off" (in blue). Photo: Lucy Shapiro

Microarrays Light Up Gene Activities
Now that scientists have at their fingertips the complete genetic sequences of a number of organisms, the next step is to figure out what all those genes do. One way to get this information is by using DNA microarray analysis. When a gene is "on," it lights up fluorescently on the microarray. This relatively new technology provides an instant visual read-out of the activity of thousands of genes — in some cases, an organism's entire genome.

By using microarrays to learn which genes are expressed differently in normal tissues and in diseased tissues, researchers can diagnose a disease, reveal its molecular basis, or discover targets for drugs to treat it. Similarly, they can identify which genes change to transform a benign strain of bacteria into a deadly one.

Already, NIGMS grantees have used microarrays to analyze which genes in an organism are "turned on" at different developmental stages, in different tissues, or in response to drugs or other environmental factors. Lucy Shapiro of Stanford University, for example, uses microarrays to investigate which genes vary in their expression during the cell cycle. Her research team conducts its studies using the bacterium Caulobacter crescentus, which is harmless but is related to microbes that cause diseases in livestock and plants. This work may lead to new antibacterial drugs for use in medicine and agriculture.

Photo: lower right - ZFIN,  the zebra fish model organism database.

Often, scientists conduct their research using cells from a variety of well-studied creatures, including a harmless strain of E. coli bacteria, yeast, a tiny worm nicknamed C. elegans, zebrafish like those found in aquariums, fruit flies, and mice. Using such "model organisms" allows scientists to control their experiments tightly and to build on existing knowledge about the organisms. Because the basic biology of model organisms is very similar to that of humans, these studies teach us, in molecular detail, how our bodies work.

Take the fruit fly. To most people, it is merely a tiny, annoying insect that buzzes around overripe bananas. To a geneticist, it is a window into human biology.

Research on fruit flies, much of it supported by NIGMS, continues to reveal insights into areas of human genetics and behavior that range from genes that control the intricate branching patterns of blood vessels to the neurobiology of cocaine addiction.

Studies of model organisms reveal how malfunctions in cellular activities or components can cause disease. They also allow scientists to do preliminary tests of new therapies.

Photos : upper right - Todd Reynolds, Whitehead Institute
lower left - Bill Branson