Three Win Nobel for Work on Suicidal Cells

By LAWRENCE K. ALTMAN

An American and two Britons won the Nobel Prize
in Physiology or Medicine yesterday for their discoveries
of how healthy cells are instructed to kill themselves.

The discoveries, made largely in studies of a tiny worm,
involved a process called programmed cell death,
or apoptosis, which is necessary for proper tissue
and organ development but also plays a role in many
diseases.

The winners are Sydney Brenner, 75, a British
citizen who founded the Molecular Sciences Institute
in Berkeley, Calif., and who is a professor at the
Salk Institute for Biological Studies in San Diego;
H. Robert Horvitz, 55, a professor at the Massachusetts
Institute of Technology in Cambridge and a Howard
Hughes Medical Institute investigator;
and Sir John E. Sulston, 60, of the Wellcome Trust
Sanger Institute in Cambridge, England.

The three, who worked together in Cambridge, England,
in the 1970's, will share a $1 million prize. The prize
honors their collective work, in the last 30 years,
on C. elegans, a 1-millimeter soil worm or nematode.

The investigations of programmed cell death have given
scientists better insights into cancer and the way some
viruses and bacteria invade human cells, according
to the Nobel Assembly of the Karolinska Institute
in Stockholm, which selected the winners. The body
uses cell suicide in immune cell development
and function, and for removing unnecessary
or damaged cells.

Malfunction of cell-death genes is a hallmark of a number
of diseases. For example, in AIDS, heart attacks,
stroke and degenerative diseases of the central nervous
system, cells are lost from excessive apoptosis,
the institute said in its citation.

Other diseases, like autoimmune conditions and cancer,
are characterized by a reduction in cell death, leading to
the survival of cells normally destined to die.

Biologists who study the development of the embryo
were the first to describe programmed cell death.
They noted that cell death was necessary for embryonic
development, as when tadpoles metamorphose to become
frogs, and in the process that eliminates tissue that forms
in human fetuses between fingers and toes. Apoptosis
also shapes brain development, in that a vast number
of neuronal cells present in the early stages
is gradually eliminated.

The research on the way cells are programmed to die
began in the 1970's when Dr. Brenner, a native
of South Africa was working in Cambridge, England.

Dr. Brenner, who has a trenchant wit and enjoys stirring up
the scientific world, had earlier worked on basic principles
of how DNA instructs cells to make proteins. Together
with his colleague Dr. Francis Crick, Dr. Brenner did
basic work on the nature and workings of genes.

Looking for new peaks to conquer, he chose the working
of the brain but felt the project required a new experimental
animal with a simple brain. He chose C. elegans. Its brain
turned out to be too complex to analyze, but the worm
nonetheless served as a wonderful model to study
development of the animal embryo.

Dr. Brenner's team could look through a microscope
at the translucent worm to follow cell division and other
biological processes as it grew rapidly from a fertilized egg
to form muscle, blood, heart, the nervous system
and hundreds of other tissues. That process requires
cells to specialize in a correct manner and at the right time
during development in a way that allows the specialized
cells to cooperate and make the body function
as an integrated unit.

The embryo and fetus produce huge numbers of cells.
But even an adult human forms more than a thousand
billion cells each day. As cells are created, an equal
number die through cell suicide both in the fetus
and adult. Maintaining the appropriate number of cells
in the tissues requires a fine-tuned balance between
cell division and cell death.

The single-cell organisms like bacteria and yeast that
scientists often use in other studies are unsuitable
for understanding how the complicated processes
of cell suicide are controlled. And the enormous
number of cells in mammals make them too complex
for such basic studies.

Dr. Brenner's worm, multi-cellular yet relatively simple,
became the most appropriate model system.

In 1974, Dr. Brenner broke ground by using the chemical
EMS, or ethyl methane sulphonate, to induce mutations,
or genetic changes, in the genome of C. elegans.
Additional studies showed that mutations could be
linked to specific genes and to specific effects
on organ development.

In later studies, the three scientists discovered that
specific genes control the cellular death program in
C. elegans. Other studies showed that the deaths
of 131 of the worm's original 1,090 cells are under
the control of a particular set of genes. Corresponding
genes exist in higher species, including humans.

Dr. Sulston was honored for extending Dr. Brenner's
work with C. elegans. Dr. Sulston developed
techniques to study all cell divisions in C. elegans,
from the fertilized egg to the 959 cells in the adult.

The process by which a single fertilized egg undergoes
repeated divisions to create the many distinct cell types
of an adult animal is known as cell lineage. In 1976,
Dr. Sulston described the cell lineage for part of the
developing nervous system.

Dr. Sulston also showed that every nematode
underwent exactly the same program of cell division
and differentiation, and that programmed cell death
is an integral part of the normal differentiation process
for certain cells. He identified the first mutation
of a gene participating in cell death.

These findings led him to the important discovery
that specific cells in the cell lineage always die
through programmed cell death and that this process
could be monitored in the living organism. Dr. Sulston
described the visible steps in the cellular death
process and demonstrated the first mutations
of genes participating in programmed cell death,
including a gene known as nuc-1. Dr. Sulston
also showed that the protein whose production
is governed by the nuc-1 gene is required
for degradation of the DNA of the dead cell.

Dr. Horvitz, who was born in Chicago, was honored
for continuing Dr. Brenner's and Dr. Sulston's work
on the genetics and cell lineage of C. elegans.
He received the news while vacationing
in the French Alps.

"It was quite enjoyable to have Champagne
before lunch in France," Dr. Horvitz said
in a phone call to a news conference
at M.I.T. yesterday.

In a series of experiments beginning in the 1970's,
Dr. Horvitz used C. elegans to determine the existence
of a genetic program controlling cell death. In 1986
he published what the Nobel committee called
pioneering research that identified the first two
bona fide "death genes," known as ced-3 and ced- 4.

Dr. Horvitz showed that functional ced-3 and
ced-4 genes were essential for cell death.

Later, Dr. Horvitz showed that another gene,
ced-9, protects against cell death by interacting
with ced-4 and ced-3. Dr. Horvitz also identified
a number of genes that direct how a dead cell
is eliminated. Further, Dr. Horvitz showed that
the human genome contains a ced-3-like gene.

Dr. Horvitz's team has found a new function for cells
known as phagocytes that engulf foreign agents.
In the past scientists believed that phagocytes
acted only as part of a cleanup crew to get rid
of dying cells so that harmful byproducts would not
hurt the body. Now Dr. Horvitz's work has shown that
phagocytes actually play a role in helping cells die.

Working with colleagues at Harvard, Dr. Horvitz
has found a new type of receptor in C. elegans that
responds to the chemical serotonin. The finding
could help explain how drugs like Prozac, which
manipulate brain levels of serotonin, work.

"We have identified a new mechanism of signaling
in the nervous system, whereby serotonin can
rapidly turn off, instead of turn on, the actions
of nerve cells," M.I.T. quoted Dr. Horvitz as saying.

Dr. Horvitz said that the body's abnormal control
of cell suicide "can play a central role in certain
cancers, autoimmune diseases and neurodegenerative
diseases." He said better understanding
of programmed cell death might lead to development
of treatments for cancer and other diseases.

"Knowledge of what makes cells die and of what can
block the cell-death process in the nematode may
help lead to the identification of agents that
can regulate the cell deaths involved in a variety
of human disorders, such as cancer
and neurodegenerative diseases," Dr. Horvitz said.

SOURCE: The New York Times
http://www.nytimes.com/2002/10/08/science/08NOBE.html?ex=1034740800&en
=e19c23ec4aecbb57&ei=5062&partner=GOOGLE

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