Technology that allows investigators to quickly determine the
genome sequence of the suspect microorganism is helping doctors pin
down the sources and causes of infections and viruses.
It was Tuesday evening, June 7. A frightening outbreak of food-
borne bacteria was killing dozens of people in Germany and sickening
hundreds. And the five doctors having dinner at Da Marco Cucina e
Vino, a restaurant in Houston, could not stop talking about it.
What would they do if something like that happened in Houston?
Suppose a patient came in, dying from a rapidly progressing
infection of unknown origin? How could they figure out the cause and
prevent an epidemic? They talked for hours, finally agreeing on a
strategy.
That night one of the doctors, James M. Musser, chairman of
pathology and genomic medicine at the Methodist Hospital System,
heard from a worried resident. A patient had just died from what
looked like inhalation anthrax. What should she do?
"I said, 'I know precisely what to do,"' Dr. Musser said. "'We
just spent three hours talking about it."'
The questions were: Was it anthrax? If so, was it a genetically
engineered bioterrorism strain, or a strain that normally lives in
the soil? How dangerous was it?
And the answers, Dr. Musser realized, could come very quickly
from the newly available technology that would allow investigators
to quickly determine the entire genome sequence of the suspect
microorganism.
It is the start of a new age in microbiology, Dr. Musser and
others say. And the sort of molecular epidemiology he and his
colleagues wanted to do is only a small part of it.
The first bacterial genome was sequenced in 1995 -- a triumph at
the time, requiring 13 months of work. Today researchers can
sequence the DNA that constitutes a microorganism's genome in a few
days or even, with the latest equipment, a day. And the cost has
dropped to about $1,000 per genome, from more than $1 million.
In a recent review, David A. Relman, a professor of medicine,
microbiology and immunology at Stanford, wrote that researchers had
now published 1,554 complete bacterial genome sequences and were
working on 4,800 more. They have sequences of 2,675 virus species,
and within those species they have sequences for tens of thousands
of strains -- 40,000 strains of flu viruses, more than 300,00
strains of the AIDS virus, for example.
With rapid genome sequencing of microbes, "we are able to look at
the master blueprint of a microbe," Dr. Relman said in a telephone
interview last week.
Mathew K. Waldor of Harvard Medical School said the new
technology "is changing all aspects of microbiology -- it's just
transformative."
One group is starting to develop what they call disease weather
maps. The idea is to get swabs or samples from sewage treatment
plants or places like subways or hospitals and quickly sequence the
genomes of all the microorganisms. That will tell them exactly what
bacteria and viruses are present and how prevalent they are.
Others are sequencing bacterial genomes to find where diseases
originated. To study the Black Death, which swept Europe in the 14th
century, researchers compared genomes of today's bubonic plague
bacteria, which are slightly different in different countries.
Working backward, they were able to create a family tree that placed
the microbe's origin in China, 2,600 to 2,800 years ago.
For Dr. Musser and his colleagues, the real-world test of what
they could do came on that June evening.
The patient was a 39-year-old man who lived about 75 miles, or
120 kilometers, from Houston in a relatively rural area. He had been
welding at home when, suddenly, he could not catch his breath. He
began coughing up blood and vomiting.
When he arrived at a nearby emergency room, his blood pressure
was dangerously low and his heart was beating fast. Doctors gave him
an intravenous antibiotic and rushed him to Methodist Hospital in
Houston. He arrived on Saturday night, June 4. Despite heroic
efforts, he died two-and-a-half days later, on Tuesday morning.
Now it was Tuesday night. From an autopsy, the cause looked like
anthrax, in the same unusual form -- so-called inhalation anthrax --
that had terrified the United States in 2001.
"We knew we had to get this solved in a hurry," Dr. Musser said.
"We had to know precisely what we were dealing with. That's when we
put into play a plan to sequence the genome."
A few days later they had their answer. The bacteria were not
anthrax, but were closely related. They were a different strain of
Bacillus: cereus rather than anthracis.
The bacteria had many of the same toxin genes as anthrax bacteria
but had only one of the four viruses that inhabit anthrax bacteria
and contribute to their toxicity.
The conclusion was that the lethal bacteria were naturally
occurring and, though closely related to anthrax, not usually as
dangerous.
Dr. Relman, meanwhile, is focusing on the vast bulk of microbes
that live peacefully in or on the human body. There are far more
bacterial genes than human genes in the body, he notes.
Bacterial genes help with digestion, sometimes in unexpected
ways. One study has found that bacteria in the guts of many Japanese
people have a gene for an enzyme to break down a type of seaweed
that wraps sushi. The gut bacteria apparently picked up the gene
from marine bacteria that live on this red algae seaweed in the
ocean.
But if these vast communities of microbes are as important as
researchers think they are for maintaining health, Dr. Relman asked,
what happens when people take antibiotics? Do the microbial
communities that were in the gut recover?
Using rapid genome sequencing of all the microbes in fecal
samples, he found that they did return, but that the microbial
community was not exactly as it was before antibiotics disturbed it.
And if a person takes the same antibiotic a second time, as late as
six months after the first dose, the microbes take longer to come
back and the community is deranged even more.
Now he and his colleagues are looking at babies, taking skin,
saliva and tooth swabs at birth and during the first two years of
life, a time when the structure of the microbe communities in the
body is being established.
"We wait for the babies to be exposed to antibiotics -- it
doesn't take that long," Dr. Relman said. The goal, he says, is to
assess the effects on the babies' microbes, especially when babies
get repeated doses of antibiotics that are not really necessary.
"Everything comes with a cost," he said. "The problem is finding
the right balance. As clinicians, we have not been looking at the
cost to the health of our microbial ecosystems."
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