Researchers led by Ronald DePinho of the Dana Farber Cancer Institute and
Harvard Medical School in Boston were studying mice engineered to lack the
enzyme telomerase. The enzyme normally occurs in stem cells, such as those that
give rise to eggs, sperm or blood. It helps to maintain the special sections of
DNA, called telomeres, that are usually found at the ends of chromosomes. Most
human cells do not have telomerase, and the telomeres erode each time the cells
divide.

Mouse telomeres are about five times as long as human telomeres, so telomere
loss is unlikely to be a factor in normal mouse ageing, even if it is in human
ageing. So DePinho’s team genetically engineered telomerase-deficient mice in
the hope of producing animals that might model the ageing process in humans.

The researchers found that after three or more generations without
telomerase, the mice turned grey as they grew old and developed bald spots. They
were also unusually thin, and their wounds took 50 per cent longer than normal
to heal. After six generations without telomerase, the mice lived on average for
just three-quarters of their normal life span. Having short telomeres seems to
collude with as yet unknown aspects of ageing to reduce fitness, DePinho
concludes.

The mice with shortened telomeres were also four to six times as likely to
develop cancer, particularly cancer of the reproductive system, blood and skin.
These organs “walk the telomere plank more quickly”, DePinho says, because their
cells divide rapidly. He calls this result “mind-bending” because until now it
was believed that tumour growth was promoted by the presence of telomerase, not
its absence. In DePinho’s mice, it seems that the genetic chaos caused by
telomere loss, including fusion and loss of chromosomes, provoked the onset of
cancer (Cell, vol 96, p 701).

But it is still not clear whether telomere loss is a normal cause of human
ageing. The telomerase-deficient mice did not show any predisposition toward the
symptoms observed in human premature ageing syndromes, such as cataracts,
osteoporosis or cardiovascular problems. “A huge burden of proof remains,” says
Leonard Guarente, a molecular biologist who studies ageing at the Massachusetts
Institute of Technology. He suggests that mice without telomerase could simply
be showing symptoms of disease because of general unhealthiness.

“Telomere shortening isn’t the whole story,” DePinho admits. “But the results
will drive a productive discussion about what to look for.”

Researchers in Berlin found that people who are unusually sensitive to
particular drugs can be identified by a few simple DNA tests. In their detailed
study, Ivar Roots and his colleagues at the Humboldt University in Berlin have
linked variations in almost 600 people’s capacities to break down drugs with
specific mutations in a gene responsible for the production of a key enzyme
known as 2D6.

Although researchers have known for a long time that this enzyme is important
for drug breakdown, they have never before been able to pin down the effects of
each mutation in such a large population.

The 2D6 enzyme is a member of the family known as the cytochrome P450s, which
has more than 60 members. Many of the genes that encode the cytochrome P450s
have several different forms, or alleles, so there may be hundreds of different
variants of the enzymes in a single population. About a fifth of the common
drugs we take, including painkillers and antidepressants, are broken down by
2D6. Some five other cytochrome P450s between them break down most other
drugs.

Researchers have known for two decades that variations in some of these
enzymes affect the rate at which people break down drugs. In the 1970s Robert
Smith, a researcher at St Mary’s Hospital in London, discovered that up to 1 in
10 Caucasians is a “poor metaboliser” for debrisoquine, a drug commonly used to
treat high blood pressure, because of mutations in the 2D6 gene. Such people
break down the drug between 10 and 200 times more slowly than those with normal
forms of the enzyme. But the complexity of the cytochrome P450s daunted
researchers. Unfortunately, Smith and his colleagues could not solve a
fundamental problem: how to identify the poor metabolisers before they suffered
bad reactions to drugs.

Roots and his colleagues have now shown that the solution is easier than
anyone expected. The team took samples of blood from each participant to
identify which alleles of the gene encoding the 2D6 enzyme they were carrying.
The researchers also tested each individual’s ability to break down one of two
drugs: dextromethorphan, a cough suppressant, or debrisoquine. They found that
they could link specific alleles of the 2D6 gene with variations in the
efficiency with which people broke down the drugs.

Better still, just four DNA tests were enough, between them, to identify the
dozen or so mutations that make people poor metabolisers. The researchers report
their results in the current issue of The American Journal of Human
Genetics (vol 60, p 284).

Roots says more studies should be done to confirm the findings in Berlin.
“Other populations—maybe in the south of Germany or in
Switzerland—may have unique mutations,” he says. And in non-Caucasians,
there may be greater variation. Despite these caveats, other researchers are
enthusiastic. Joyce Goldstein, a pharmacologist at the National Institute of
Environmental Health Sciences in Research Triangle Park, North Carolina, says
that the study is significant because of its size and thoroughness.

Roots believes blood tests may soon be available to allow people to find out
their cytochrome P450 “profile”. Those who find out that they are poor
metabolisers should then know to avoid certain drugs.