Right out of high school and pondering a path in life, Sean Brady followed his interest in photography to the storied Na Bolom Institute for Scientific Studies, a scientific and cultural center in southern Mexico. Founded by the archaeologist and adventurer Frans Blom and his wife Gertrude Blom, a documentary photographer, the institute was Brady's base for delving into and documenting the cultures of Mesoamerica.
"My time there was hugely influential," recalls Brady. "It was during this experience that I first really began to appreciate the excitement of scientific discovery and exploration."As a young scientist, Brady's academic interests straddled the fields of chemistry and molecular biology. In graduate school he found that he could apply these two interests to the discovery of new compounds produced by fungi and bacteria.
Today, Brady is a chemist at the Rockefeller University. And like Frans Blom, who helped excavate the ancient Mayan city of Palenque, Brady is sifting the soil for treasure. The riches he seeks, however, reside in the DNA of the multitude of bacteria that make their home in the dirt.
Bacteria, especially those from soil environments, are crucibles of potential drug discovery because the chemicals they make to survive in their native habitats have the potential to be transformed into frontline antibiotics and anticancer agents. Although each spoonful of soil teems with thousands of species of bacteria, scientists have found it difficult to study these organisms because most soil bacteria grow poorly in lab dishes.
To circumvent this problem, Brady extracts vast quantities of raw bacterial DNA pulled from dirt samples gathered from locales as diverse as the African Serengeti and the deserts of the American southwest. "Pretty much anywhere someone from the lab goes on vacation," Brady laughs, "they have to bring back some dirt."
Samples in hand, Brady and his colleagues then compile the DNA into libraries, which can be scoured for the genes that make biologically active small molecules that might be transformed into new medicines. "There is a tremendous amount of DNA in the libraries we create," says Brady, noting that his lab's biggest library contains almost 14 million cloned genes. "The challenge, then, is to generate molecules from information encoded in this DNA."
This is accomplished by introducing genetic sequences back into a strain of bacteria that can be easily grown in the lab, such as Escherichia coli, to see if they will make chemicals of interest. "If you can open up even a small fraction of [the sequence], it should give you new chemistry to look at," says Brady of what scientists call the metagenome or the collection of DNA recovered from an environmental sample. "We hope to use it as a discovery engine for new and useful compounds. It is very much an empirical search-and-find approach."
The field, Brady explains, is a relatively pristine biological frontier, given that unknown bacteria reside in so many different kinds of environments, ranging from soil and seawater to mammalian intestinal tracts. All of these environments are little explored and are amenable to the same techniques he is using in his lab. What's more, there are so few scientists prospecting for the small organic molecules in this way that it is almost impossible to come away empty handed: "I think any sample is going to have something new in it. As long as you can get good DNA out of it, you will probably find something," says Brady.
The quest, argues Brady, is critical. The need for new medicines is acute because bacterial pathogens continue to develop resistance to the antibiotic compounds now in use. Many of our most potent drugs, including antibiotics, were first found in soil microbes, suggesting that there are many more biomedical treasures waiting to be discovered.