Packard Foundation grant boosts a dirty hunt for DNA

The dirt beneath your feet holds many secrets, not the least of which may be the next miracle drug.

A pinch of soil is home to millions upon millions of microbes, mostly bacteria that routinely secrete chemicals that are the keys to an elegant signaling system through which microbes communicate with friend and foe alike.

Those same chemicals, however, can be transformed into lifesaving antibiotics when tamed by science. The problem, though, is that scientists can successfully culture in the lab only a small fraction of the bugs that thrive in the soil, making the chemicals they produce inaccessible to modern medicine.

But now the David and Lucile Packard Foundation, through a nearly $1 million grant, has come to the aid of scientists who may have found a way to bypass the problems of raising microbes in captivity by going straight to the genetic instructions that bacteria and other soil microbes use to synthesize their chemical arsenal.

“The tremendous diversity of microbes is likely to be reflected in the diversity of the chemicals they make,” said Jo Handelsman, a UW–Madison professor of plant pathology who, with Robert Goodman, also a UW–Madison professor of plant pathology, and Jon Clardy, a distinguished Cornell University chemist, have embarked on a novel quest for new drugs.

The Packard Foundation grant of $960,000 was awarded in support of their work.

To access this untold biological chemistry, all you need, said Goodman, are the long strands of DNA – the genetic instructions – that bacteria use to manufacture chemicals. Some of these chemicals have potent antibiotic activity and have the potential to augment the shrinking pharmacopoeia of lifesaving antibiotics.

By taking soil samples and freezing and thawing the filtered dirt to crack open the bacteria that live in it, the Wisconsin group can retrieve strands of bacterial DNA. By introducing those strands of genes into E. coli bacteria, the lab rat of microbiology, the scientists can sometimes induce the cultured E. coli to produce the chemicals made by the untamable soil microbes. By mixing the modified E. coli with pathogenic bacteria, the scientists can then look for antibiotic activity, a sign that the chemical may be useful as a drug.

“Antibiotic biosynthesis usually requires many genes,” Handelsman said, noting that it is a challenge to obtain the long strands of DNA that may harbor all of the genetic instructions needed to make an antibiotic.

Goodman and Handelsman have begun to assemble libraries of DNA that has been pried from their bacterial hosts, and Clardy has begun to tease out the secrets of the chemicals they make.

The upshot, said Goodman, could be “drugs of all sorts, but antibiotics are at the top of our list since they can be readily screened for in the lab, and soil microbes have previously been a rich source of the antibiotics we use today.”

Moreover, the work could be extended to other realms, the researchers said. For example, insect guts are host to an array of microbes whose genes not only make antibiotics, but play roles in insect development by relaying chemical signals, a phenomenon that may be useful in developing natural pesticides or, in human medicine, mediating the cellular signals involved in cancer.

The point, said Handelsman, is that microbes inhabit an almost endless number of ecological niches and are producing novel chemicals that may have many applications.

Working with soil microbes, she said, is the biggest challenge, but also holds the potential for the biggest payoff.

“Soil, we think, will be the richest source. More drugs come