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.
Anthrax colonies isolated from the 1993
Aum Shinrikyo bioterrorist attack in Kameido, Japan.
Photo: Paul Keim
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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.
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