The New Generation of Microbe Hunters

Annie Tritt for The New York Times

ECOSYSTEMS Dr. David A. Relman of Stanford studies the microbes that live peacefully in or on the human body.

By GINA KOLATA

Published: August 29, 2011

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.

This week: The microbe hunters, candid camera for endangered animals and trying to plan a graceful exit.

Michael Stravato for The New York Times

DETECTIVE Dr. James M. Musser, second from right, put DNA sequencing to work in a Houston case involving lethal bacteria that looked like anthrax. The culprit turned out to be a closely related strain of Bacillus.

What would they do if something like that happened in Houston? Suppose a patient came in, dying of 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 newly available technology that would allow investigators to determine the entire genome sequence of the suspect micro-organism.

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. New methods of quickly sequencing entire microbial genomes are revolutionizing the field.

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 micro-organism’s genome in a few days or even, with the latest equipment, a day. (Analyzing it takes a bit longer, though.) They can simultaneously get sequences of all the microbes on a tooth or in saliva or in a sample of sewage. And the cost has dropped to about $1,000 per genome, from more than $1 million.

In a recent review, Dr. David A. Relman, a professor of medicine, microbiology and immunology at Stanford, wrote that researchers had 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 300,000 strains of H.I.V., for example.

With rapid genome sequencing, “we are able to look at the master blueprint of a microbe,” Dr. Relman said in a telephone interview. It is “like being given the operating manual for your car after you have been trying to trouble-shoot a problem with it for some time.”

Dr. Matthew 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 it calls 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 micro-organisms. That will tell them exactly what bacteria and viruses are present and how prevalent they are.

With those tools, investigators can create a kind of weather map of disease patterns. And they can take precautions against ones that are starting to emerge — flu or food-borne diseases or SARS, for example, or antibiotic-resistant strains of bacteria in a hospital.

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.

Still others, including Dr. Relman, are examining the vast sea of micro-organisms that live peacefully on and in the human body. He finds, for example, that the bacteria in saliva are different from those on teeth and that the bacteria on one tooth are different from those on adjacent teeth. Those mouth bacteria, researchers say, hold clues to tooth decay and gum disease, two of the most common human infections.

A Real-World Test

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 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. He had a headache and pain in his upper abdomen and chest.

In the emergency room, his blood pressure was dangerously low and his heart was beating fast. Doctors gave him an IV 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. On autopsy, the cause looked for all the world like anthrax, in the same unusual form — so-called inhalation anthrax — that terrified the nation in 2001. Even before the man died, researchers had been suspicious; washings from his lungs were teeming with the rod-shaped bacteria characteristic of anthrax. Investigators grew the bacteria in the lab, noticing that the colonies looked like piles of ground glass, typical of anthrax but also other Bacillus microbes.

“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. And they lacked a miniature chromosome — a plasmid — found in anthrax bacteria that also carries toxin genes.

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The conclusion was that the lethal bacteria were naturally occurring and, though closely related to anthrax, not usually as dangerous. So why did this man get so ill?

He was a welder, Dr. Musser noted, and welders are unusually susceptible to lung infections, perhaps because their lungs are chronically irritated by fine metal particles. So his fatal illness was most likely due to a confluence of events: welding, living in a rural area where the bacteria lived in the soil and happening to breathe in this toxin-containing species of bacteria.

Dr. Waldor and his colleagues asked a slightly different question when Haiti was swept by cholera after last year’s earthquake. Cholera had not been seen in Haiti for more than a century. Why the sudden epidemic?

The scientists quickly sequenced the genome of the bacteria in Haiti and compared them with known cholera strains from around the world. It turned out that the Haitian strain was different from cholera bacteria in Latin America and Africa, but was identical to those in South Asia.

So the researchers concluded that the earthquake was indirectly responsible for the epidemic. Many relief workers who came to Haiti lived in South Asia, where cholera was endemic. “One or more of these individuals likely brought cholera to Haiti,” Dr. Waldor said.

Charting Disease Maps

One of Dr. Waldor’s collaborators in that study, Eric Schadt, wants to take the idea of molecular forensics one step further. Dr. Schadt, the chairman of genetics at Mount Sinai School of Medicine and chief scientific officer of Pacific Biosciences, wants to make disease weather maps.

He began with pilot studies, first in his company’s offices. For several months, the company analyzed the genomes of microbes on surfaces, like desks and computers and handles on toilets. As the flu season began, the surfaces began containing more and more of the predominant flu strain until, at the height of the flu season, every surface had the flu viruses. The most contaminated surface? The control switches for projectors in the conference rooms. “Everybody touches them and they never get cleaned,” Dr. Schadt said.

He also swabbed his own house and discovered, to his dismay, that his refrigerator handle was always contaminated with microbes that live on poultry and pork. The reason, he realized, is that people take meats out of the refrigerator, make sandwiches, and then open the refrigerator door to return the meat without washing their hands.

“I’ve been washing my hands a lot more now,” Dr. Schadt said.

The most interesting pilot study, he says, was the analyses of sewage.

“If you want to cast as broad a net as possible, sewage is pretty great,” Dr. Schadt said. “Everybody contributes to it every day.”

To his surprise, he saw not only disease-causing microbes but also microbes that live in specific foods, like chicken or peppers or tomatoes.

“I said, ‘Wow, this is like public health epidemiology,’ ” he said. “We could start assessing the dietary composition of a region and correlate it with health.”

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. One study that looked at stool samples from 124 healthy Europeans found an average of 536,122 unique genes in each sample, and 99.1 percent were from bacteria.

Bacterial genes help with digestion, sometimes in unexpected ways. One recent studyfound that bacteria in the guts of many Japanese people — but not in the North Americans tested as control — 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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