X-Message-Number: 23364
From: "Basie" <>
Subject:  Window into the state of the human brain at the moment a person dies
Date: Mon, 2 Feb 2004 18:30:34 -0500

Genetic analyses should take into account cause of death.
2 February 2003

Patterns of gene activity are different depending on how patients died.

Researchers have opened a window into the state of the human brain at the
moment a person dies. The findings call into question previous reports based
on brain autopsy tissue.

Richard Myers of Stanford University in California and his colleagues found
that a coma patient fires up a different set of genes in the brain than one
who dies quickly from a heart attack. The group stumbled on the discovery
when studying preserved human brain tissue.

Using a chip carrying thousands of genes, the researchers analysed which
ones are active in the brains of 40 people with depression, bipolar
disorder, schizophrenia or none of these. They were searching for genes that
were activated abnormally and therefore might underlie the disorders.

Instead, they noticed that the patterns of active genes fell into two
distinct groups - depending on how the patients had died. "The statistics
were screaming at us," Myers says. "It was pretty remarkable."

Those who suffered prolonged deaths over hours or days, such as by
multi-organ failure or coma, showed one type of genetic profile. Those who
died suddenly from a heart attack, accident or suicide showed another1.

Myers thinks his group has inadvertently taken a snapshot of dying brain

During a prolonged illness, the brain might be starved of oxygen and sugars,
triggering it to switch on a whole suite of genes that help cells survive.
The dying brain also seems to dampen down genes involved in energy
metabolism, perhaps because the cells are deprived of essential nutrients.

Patients who suffered a prolonged death also seem to have more acidic brain
tissue. This might be because cells deprived of oxygen churn out acidic
by-products, such as lactic acid, as they make energy. "Brain death probably
occurs when the pH threshold is crossed," suggests team member Jun Li.

Out of kilter

Myers' results will affect other researchers doing gene-chip analyses on
post-mortem brain tissue. These studies are aimed at identifying genes that
are out of kilter in sick people's brains when compared with healthy ones,
and so pinpoint those that trigger disease.

We think we've touched on a big problem in this area
Jun Li
Stanford University

Some of the genes isolated in these studies might have cropped up because of
the way a patient died, rather than because of their specific disease,
Myers' group suggests. "We think we've touched on a big problem in this
area," says Li.

Researchers already use statistical methods to check that they are not
confusing a gene involved in disease with one that has been activated for
other reasons, says psychiatric researcher Eric Nestler of the University of
Texas Southwestern Medical Center at Dallas. But in some cases, old data
might be re-analysed to take into account how patients died, he says.

The researchers speculate that their results might point to the proteins or
metabolic molecules that are switched on in the brains of dying patients and
then filter into the blood. This might help doctors predict when a patient
is heading towards a medical crisis.

Li, J. Z. et al. Systematic changes in gene expression in postmortem human
brains associated with tissue pH and terminal medical conditions. Human
Molecular Genetics, published online, doi:10.1093/hmg/ddh065

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