A New Kind of Genomics

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http://www.nytimes.com/2003/10/21/science/earth/21GENE.html?th

 

October 21, 2003A New Kind of Genomics, With an Eye on EcosystemsBy ANDREW

POLLACK

 

Determining the complete DNA sequence of a single species has become almost

commonplace. It has been done for humans, mice, rice plants and a host of

microbes, among others. Now some scientists are moving to a more audacious

challenge, sequencing " metagenomes, " the DNA of entire ecosystems.

 

The new efforts seek to read all the DNA in the bacterial communities found in a

patch of soil or seawater or even the lining of the human gut. Deciphering the

genetic blueprint of all of the microbial species may help tell scientists which

species are present and how they work together. Thousands of previously unknown

micro-organisms may be unearthed, as well as new drugs, chemicals and ways of

harnessing bacteria to fight pollution.

 

" We think this is a window on biology that is really unprecedented in its

implications, " said Dr. Jo Handelsman, a professor of plant pathology at the

University of Wisconsin, who coined the term metagenomics to refer to the new

field. Others call it community genomics, environmental genomics, or microbial

population genomics.

 

By whatever name, the task will not be easy. There can be thousands of different

microbial species in a spoonful of soil. " A milliliter of seawater, in a genetic

sense, has more complexity than the human genome, " said Dr. Edward F. DeLong, a

senior scientist at the Monterey Bay Aquarium Research Institute in California.

 

Besides soil and seawater, scientists are trying to read all the DNA of a

bacterial community that contributes to acidic runoff from a former California

mine, and of another community of seabed-dwelling microbes that can be used to

produce electricity. Other projects are looking at microbial communities in the

guts of termites and gypsy moths, since microbes play a role in the way these

pests wreak their damage.

 

Among those entering the field is Dr. J. Craig Venter, the maverick scientist

whose biotech company, Celera Genomics, defied skeptics and determined the human

genetic sequence in a scant three years. Dr. Venter, who now runs nonprofit

research institutes in Rockville, Md., is trying to determine the genomes of all

of the microbes in the Sargasso Sea, an area of the Atlantic Ocean near Bermuda

known for its floating seaweed.

 

That area of the ocean is considered relatively devoid of life. Nevertheless,

Dr. Venter said, " Just from the Sargasso Sea alone, we've discovered more new

genes than in the human genome. "

 

The project is being done by Dr. Venter's Institute for Biological Energy

Alternatives, which seeks to harness microbes to make clean-burning hydrogen

fuel and reduce global warning. Another of his research centers, the Institute

for Genomic Research, is trying to sequence the genomes of all the organisms in

the human intestinal tract. The information could lead to new ways to diagnose

and treat diseases.

 

Until now, scientists have started with a known species, be it humans or anthrax

bacteria, and sequenced the genome to learn more about it. But metagenomics

works in reverse. It starts with the DNA of unknown organisms and then tries to

figure out what the organisms are.

 

More than 99 percent of bacteria cannot be grown in laboratory cultures, so

scientists know almost nothing about them. But it is possible to extract DNA

from a sample of soil or seawater without knowing the identities of the

creatures that are the DNA sources. " We don't know what the species even look

like, " Dr. Venter said. " All we know of them is their genetic code. "

 

This DNA will consist of fragments from all the species present. The challenge

is to sort out which fragments come from the same organism and then to arrange

them in the correct order to determine the complete sequence of each species.

Such genetic blueprints could then provide clues about what species are present

and what their roles are.

 

The payoff could be vast. Bacteria constitute more than half the living matter

on earth and play essential roles in numerous environmental cycles. They turn

nitrogen in the air into a form usable by plants, produce about half the oxygen

on the planet, break down minerals and clean up pollution.

 

" Microbes are kind of the master chemists of our planet, " said Dr. DeLong of the

Monterey Aquarium. Bacteria are also the source of most antibiotics and of some

other drugs and industrial enzymes and of the genes that confer pest and

herbicide resistance to genetically modified crops.

 

There have already been some discoveries from sampling environmental DNA. Dr.

DeLong, sampling microscopic plankton from the surface of the Pacific Ocean,

discovered certain bacteria that could convert sunlight into energy, a role

normally played by plants.

 

" It's a whole new class of light-driven energy generation that exists in a

category of microbes that's really abundant, " he said. " It remained invisible

until we applied these genomics techniques. "

 

Diversa, a company in San Diego, bases its business on extracting DNA from

creatures that can survive in extreme environments, like super-hot deep-sea

vents and the highly alkaline soda lakes of Kenya. It then searches the DNA for

genes that provide the code for novel enzymes. One enzyme, found from sampling

DNA in the soil of the tropics, is expected to cut in half the cost of a

critical step in manufacturing the cholesterol-lowering drug Lipitor.

 

Community genomics got its start in the 1980's, when scientists began sampling

microbial DNA from the environment and studying a single gene that coded for

part of the ribosome, the cell's protein-making machinery.

 

Virtually every creature on earth is thought to have this gene, though it has

changed through evolution. So looking at it could tell scientists how many

different types of microbes were present and into what broad categories they

fell. But it did not tell them more about the way the bacteria functioned.

 

In the 1990's, scientists began to analyze larger fragments of DNA, looking for

genes of interest. This was how Dr. DeLong found the photosynthetic bacteria and

Diversa the enzyme to be used in making Lipitor.

 

Now, to get even more information, scientists are trying to determine the

complete genome sequences of all the bacterial denizens of a community.

 

The technique they use is called shotgun sequencing, which was used by Celera in

sequencing the human genome. Because gene-sequencing machines can handle only

small stretches of DNA, the DNA to be sequenced is broken into random fragments.

After the sequence of each fragment is determined, powerful computers assemble

the pieces in the correct order by looking at overlapping sequences.

 

It is like shredding multiple copies of a book into tiny pieces and then trying

to figure out the text.

 

But while this has been done for individual species, doing it for hundreds or

thousands is expected to be much harder, like shredding and reconstructing

multiple copies of multiple books. Dr. Venter says computer simulations indicate

that it should be possible, at least for the Sargasso Sea.

 

Many scientists still doubt that. But success is already being seen on more

narrow communities. Dr. Jill Banfield, professor of earth and planetary science

at the University of California at Berkeley, is studying the microbes found 400

feet underground at Iron Mountain, an abandoned mine in Northern California. The

microbes contribute to the highly acidic runoff that has made the mine a major

hazardous waste site under the federal Superfund program.

 

Dr. Banfield, who is working with the Department of Energy's Joint Genome

Institute in nearby Walnut Creek, says there are probably just seven different

species in the sample, either bacteria or archaea, another type of microbe that

tends to inhabit extreme environments. The full genomes of the two organisms

have already been determined. " As far as I know, it's the first time a genome

has been recovered from a truly environmental sample, " she said.

 

There are some obstacles to overcome before even trying to put the DNA fragments

together into the correct order. Extracting DNA fragments from the environment

can be difficult, particularly from soil, which contains acids that break down

the genetic material. And one or two species may dominate in an environment,

outnumbering other species by as much as 100,000 to 1. So the DNA fragments will

be mainly from the dominant species.

 

" When somebody says they are going to sequence all the bacteria in a soil

sample, well, that's rubbish, " said Dr. Julian Davies, an emeritus professor of

microbiology and immunology at the University of British Columbia.

 

Dr. Davies started a company to find new antibiotics by extracting genes from

soil bacteria that could not be cultured in the laboratory. But antibiotic

production is often governed by many genes, not just one, and it was impossible

to extract DNA fragments large enough to contain all the necessary genes, he

said.

 

Still, sampling techniques are improving. Diversa has a method, based on the

relative density of DNA's chemical units, to prevent rarer species in a sample

from being overlooked.

 

There is still debate about how valuable it will be to reconstruct the genomes

of all members of a community. That alone will not necessarily tell which genes

are active or how the bacteria interact with one another. " What you get is a

catalog, " Dr. Davies said. " You get unnamed organisms. The question is how can

you tell what they do. "

 

But Dr. Steven R. Gill, a microbiologist at the Institute for Genomic Research,

countered that if a creature's genetic blueprint was known, " we can go back and

reconstruct its metabolism. "

 

Besides providing clues about the roles organisms play, such information may

pinpoint nutrients they need, allowing previously unculturable organisms to be

grown in the laboratory. And once all the genes in an organism or community are

known, it will be possible to make gene chips to study which genes are turned on

or off as environmental conditions change.

 

Some scientists think ecosystem genome sequencing may eventually be used to

monitor the health of environments or to predict environmental impacts. That

could apply not only to the external environment but also to the ones inside

people.

 

Dr. David A. Relman, an associate professor of medicine and microbiology at

Stanford who is collaborating on the project to read the DNA of the bacteria in

the human digestive tract, said changes in those bacterial communities

contributed to diseases like colitis.

 

It may be possible to find patterns in the bacterial population that will

predict when someone is about to get sick. The human gut metagenome project

" will be the first step in identifying these patterns, " Dr. Relman said.

 

Copyright 2003 The New York Times Company |

 

 

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