New
findings in yeast may reveal why growing older is the greatest carcinogen
in humans
By Kristen Lidke Woodward, Fred
Hutchinson Cancer Research Center via Eurekalert
September
24, 2003
Graduate student camped out in the lab,
sleepless in
Seattle
, to collect the data.
Scientists at
Fred
Hutchinson
Cancer
Research
Center
have made a landmark discovery in yeast that
may hold the key to revealing why growing older is the greatest
cancer-risk factor in humans. Their findings appear in the Sept. 26 issue
of Science.
Senior author Daniel Gottschling, Ph.D., a
member of Fred Hutchinson's Basic Sciences Division, and first author
Michael McMurray, a graduate student in Gottschling's laboratory, have
found striking similarities between humans and simple baker's yeast with
regard to the changes their genes undergo as they age.
"While yeast don't get cancer, they do
have one of the major hallmarks of malignancy, which is genetic
instability," Gottschling said. "We found a similar thing in
yeast that has been seen in humans: genetic instability shoots up
dramatically in the middle to late stage of life."
When yeast cells hit the equivalent of
late-middle age, the Fred Hutchinson researchers discovered they
experience a sudden, 200-fold surge in the production of genetic changes
typically manifested as loss of heterozygosity, or LOH, a condition
characterized by missing or mutated chromosomes. This finding suggests
that the yeast Saccharomyces cerevisiae, a simple, single-celled organism,
may be an ideal model for understanding the complexities of age-related
cancer development in humans.
"Yeast gives us, for the first time, the
potential for not only understanding the principles of what's going on
mechanistically but also which molecules might be relevant to the process
of age-related cancer development," Gottschling said.
Aging indeed is a potent carcinogen. Consider
these statistics from the American Cancer Society: Nearly 80 percent of
cancers are diagnosed after age 55. After reaching late-middle age, men
face a 50 percent chance of developing cancer and women have a 35 percent
chance. No one knows why cancer typically surfaces later in life, although
a multitude of scientific theories abound. "This finding may provide
scientists with a new tool to test those theories," Gottschling said.
To determine whether yeast could be used as a
model to help explain the abrupt increase in human-cancer risk, the
researchers tracked the life cycles of multiple yeast strains. Most yeast
cells survive for about 30 or 35 generations of cell division. Each
generation is represented by a mother cell's production of a new daughter
cell, or yeast bud. The yeast cells were genetically manipulated to turn
color if they started showing genetic instability. In every strain of
yeast studied, genetic mistakes started happening at the equivalent of
late-middle age.
"In following the life history of the
cells, we found it takes about 25 generations, or cell divisions, to see
an LOH event," Gottschling said. "After that, the genetic
instability just starts happening like crazy. We think a switch of some
kind is being thrown, because it's happening in virtually all of the new
offspring at the same time."
Even among the longest-lived yeast that were
genetically manipulated to go through 50 to 60 generations of cell
division before dying, the evidence of DNA damage surfaced, like
clockwork, right around the 25th generation. "This tells us that life
span operates on its own clock; it is independent of genetic instability.
Living longer doesn't necessarily mean you have fewer genetic mistakes. It
just means you somehow live longer with more of them," Gottschling
said.
As such, the researchers surmise that genetic
instability isn't related to how close cells are to death, but how far
they are from birth - how many times they've divided.
The discovery that an age-dependent switch is
somehow activated to trigger genomic instability could have major
scientific consequences, Gottschling said. "This helps us to
simplify. It gives us a place to focus to try and understand the causal
event at the onset of cancer development." If researchers can
determine the molecular mechanics that trip the switch, they one day may
be able to develop drugs or gene-replacement methods to prevent the switch
from being thrown in the first place.
The researchers' findings also may lead to a
better understanding of the role of stem cells in cancer development, a
subject of intense scientific interest. In tracking the life span of the
mother-yeast cells, which are largely analogous to stem cells in humans,
they found that the mothers retained their genetic integrity as they aged
- only their daughters inherited chromosomal defects.
"If you think of mother cells as stem
cells, then the discovery that the offspring of aging mother-yeast cells
have an increased rate of genomic instability fits with the idea that
age-associated effects on stem cells could relate to the age-associated
increase in cancer," McMurray said. "The theories about
mutation, stem cells and cancer that have been floating around for years
may now have some correlates in the microbial world. This might point to a
fundamental relationship between cellular aging and genomic instability
and, in particular, how aging cells manifest that instability."
The fact that aging mother cells are
protected from age-induced genetic instability also has evolutionary
implications, McMurray said. "In yeast genetics, people historically
have thought of the mother cell as being the trash bin that accumulates
all the genetic bad stuff so that the daughters could be protected. But we
found the opposite. The mother remains protected, which preserves her
chance to produce more normal daughters."
If this evolutionary process is biologically
conserved in human stem cells, Gottschling said, "It could explain a
lot of the age-induced diseases that happen in people."
So if cancer is an inherent consequence of
aging, are lifestyle interventions to prevent the disease - such as eating
right, not smoking and getting enough physical activity - merely an
exercise in futility?
"People should still keep eating their
broccoli," Gottschling said. "Our yeast were on a diet
equivalent to steak and potatoes. We had the mother cells growing in a
very rich, nutrient-dense environment. They were, in essence, pigging out
the whole time. We'd like to do similar experiments in which we put the
yeast on a 'lean and mean' diet to see if we could delay the switch that
triggers the genetic instability," he said. "Yeast promises to
be an excellent model system for testing various environmental factors,
such as caloric restriction, to get at the mechanisms of cancer
initiation."
Yeast also has been an indispensable
scientific tool for unraveling the mysteries of how cells divide. The
lowly microbe, best known for its supporting role in baking bread and
brewing beer, in 2001 gained new respect when Fred Hutchinson's president
and director, Lee Hartwell, Ph.D., received the Nobel Prize in physiology
or medicine for using brewer's yeast to uncover the genetic mechanisms of
cell division. He shared the award with British researchers Timothy Hunt
and Sir Paul Nurse.
"Yeast cells have been an informative
model system for human cells, revealing many conserved aspects of cell
biology. If this discovery - a genetic instability that accompanies
mother-cell aging in yeast - turns out to apply to human stem cells as
well, it would revolutionize our concepts of how cancer arises and how
aging occurs," Hartwell said.
Gottschling's work was funded by a four-year
Senior Scholar grant from the Ellison Medical Foundation Aging Program.
Established by Larry Ellison, president of Oracle software, the foundation
supports basic biomedical research on understanding aging processes and
age-related diseases and disabilities. McMurray's work was supported by
training grants from the National Science Foundation and National
Institutes of Health.
"Sleepless in
Seattle
" isn't just a movie. For the past few
years it's been a frequent way of life for graduate student Michael
McMurray. To gather the data upon which the Sept. 26 Science
paper's findings are based, he spent many bleary-eyed weeks camping out in
the laboratory of his mentor, Daniel Gottschling, Ph.D., and taking
catnaps on a couch in his office at
Seattle
's
Fred
Hutchinson
Cancer
Research
Center
.
"He knew what he was getting into but he
did it anyway, because he was curious," Gottschling said of
McMurray's unique experiment, which was elegantly simple from a scientific
perspective but, admittedly, somewhat grueling to execute.
To see if yeast could be used as a model
organism to help explain the abrupt, age-related increase in human-cancer
risk, McMurray needed to closely track the life spans of 40
"mother" yeast cells that were arranged in pairs within 20 petri
plates.
He kept the round, shallow plates stacked in
an incubator and brought them out every couple of hours to check them
under a microscope for the emergence of new "daughter" cells, or
buds. Most mother cells produce 30 to 35 daughters before expiring. The
whole process, from birth to death, takes about five days.
"When I began I really didn't know how
long it would take - how fast or slow the yeast mothers would divide
before finally pooping out," McMurray said. "Toward the end of
the life cycle the yeast started slowing down and so I'd get longer
breaks, which allowed me to go home and shower and come right back."
As the buds sprouted, McMurray would gently
pull them away from the mother cells with a needle-like instrument and
line them up in a row in another area of the petri plates so he could
easily keep track of each new generation. The buds, which soon grew into
small colonies, were genetically manipulated to turn bright red or dark
brown if they started showing signs of genetic instability.
About three-quarters of the way through the
life of each mother cell, colored colonies appeared, signaling the
presence of genes gone awry.
"At first it was a shot in the dark to
see if we'd see anything this way. We didn't have any expectations that it
would work, but it was definitely worth it to go through the whole
process," said McMurray, who had to repeat the experiment multiple
times on various strains of yeast to collect enough data for analysis,
resulting in many near-sleepless days and nights.
"It takes a lot of practice to be able
to do this kind of work under sleep-deprivation conditions," he said.
"But the crucial information easily could have been missed if we
hadn't done it this way."
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