Possible New Treatment Found for Serious Liver Disease
February 18, 2000
By NICHOLAS WADE
A possible new approach to treating cirrhosis of the liver,
the seventh-leading cause of death in the world, has
emerged from studies of telomerase, a recently discovered
agent that indefinitely prolongs the life of human cells grown
in the laboratory.
So far the treatment has worked only in mice that have
artificially been given cirrhosis. If it works in people, too, it
would offer a new way of tackling a major, intractable
disease, as well as of averting liver cancer, the leading cause
of cancer cases worldwide, 80 percent of which originate
from liver cirrhosis.
The research is the work of Dr. Ronald A. DePinho, a
mouse geneticist at the Dana-Farber Cancer Institute, and
colleagues, and is reported in today's issue of Science.
Dr. Irwin A. Arias, a liver expert at Tufts University, said
that the work was "brilliant" but that any treatment was "a
long, long way off."
Cirrhosis is the scarring of the liver that results when toxins
like alcohol or hepatitis viruses B and C kill the liver cells
and exhaust the organ's usual capacity to regenerate itself.
The scarring blocks blood flow and the liver's ability to
function properly, leading to symptoms that can be
postponed but not reversed.
The mechanism by which the various liver toxins cause
cirrhosis is unknown, but Japanese scientists recently noticed
that liver cells from cirrhosis patients had an anomaly in their
chromosomes, the giant DNA molecules in which the cell's
programming instructions are encoded. Specifically, the end
sections of the chromosomes, known as the telomeres, were
unusually short. Each time a cell divides, its telomeres get
shorter, as if counting off some permissible number of
divisions, until at a certain minimum telomere length the cell
is thrown into crisis and dies.
Telomeres are kept long in egg and sperm cells by the
enzyme telomerase. But the telomerase gene is suppressed in
most normal cells, and as people age, their telomeres
decrease.
Scientists supported by the Geron Corporation of Menlo
Park, Calif., discovered recently that human cells grown in
glassware could be made to divide indefinitely -- becoming in
principle immortal -- if given an active copy of the
telomerase gene that builds their telomeres back to youthful
length.
Telomeres in general do not seem to place a limit on human
life span. Their purpose seems to be as a last ditch defense
against tumors, zapping malignant cells after they have
reached their quotas of divisions.
But some biologists believe short telomeres may be a
drawback in diseases where a cell type is forced to divide
unusually often. When Dr. DePinho heard of the Japanese
finding of short telomeres in cirrhosis, he decided to test the
idea in mice by seeing if insertion of the telomerase gene into
liver cells could prevent the development of cirrhosis.
Mice have very long telomeres, so to obtain animals with
telomeres as short as those of elderly people, he took a strain
that lacked the telomerase gene altogether and bred the mice
through several generations.
Cirrhosis was induced in the short-telomere mice by injecting
them with a liver-poisoning chemical. In addition, one group
of mice was injected with a virus carrying a copy of the
mouse telomerase gene.
In these mice, development of cirrhosis was blocked,
presumably because the telomerase rescued certain
short-telomere cells from crisis, enabling them to regenerate
the liver.
Because of this finding, Dr. DePinho and colleagues
conclude, "It is reasonable to anticipate that activation of
telomerase could inhibit the development of liver cirrhosis or
terminal liver failure in humans."
If the telomere-shortening system protects against cancer, an
artificial lengthening of the telomeres might raise a cancer
risk.
In their article, the authors suggest the telomerase treatment
could be tested in patients awaiting a liver transplant, since
the liver was due for removal anyway.
Dr. Calvin Harley, scientific director of Geron, the company
developing telomerase-based therapies, said Dr. DePinho's
work was "a pretty important first step in establishing that
telomere loss can be the trigger of chronic disease." Geron
has also been working on telomere-based treatments for
cirrhosis, but any clinical tests of a treatment are "certainly
not less than two years away," Dr. Harley said.
Dr. Arias, the Tufts liver expert, interpreted Dr. DePinho's
work more cautiously, saying it was too early even to be
sure that short telomeres were the trigger for cirrhosis.
Because many questions remain about the timing of telomere
shortening and the types of cirrhosis in which shortening
occurs, "It is not a good idea to speculate about the
therapeutic aspects or suggest that a clinical trial can be done
instantly," Dr. Arias said.
Dr. DePinho inserted the telomerase gene into mice by
piggy-backing it onto a disabled adenovirus, one of the
causes of the common cold. Though the virus itself is
considered pretty harmless, its use in gene therapy has fallen
under a cloud after the death of Jesse Gelsinger, a patient
being treated for a rare metabolic disease at the University of
Pennsylvania.
Dr. DePinho and Dr. Harley said there were many other
methods besides adenovirus for delivering both the
telomerase gene and the telomerase protein itself.
Besides cirrhosis, several other diseases are thought, though
not yet proved, to be caused by telomere shortening and the
depletion of critical cell types. This include AIDS, ulcerative
colitis and various skin and immune-system disorders.
In another report in Science, a team of Japanese and
American scientists describe a method for growing enough
liver cells in glassware to regenerate the organ when the cells
are injected back into rats. The method depends on first
infecting the cells with tumor gene that makes them divide.
The tumor gene can be completely excised from the cells
after they have divided. |
