Evolution in Medicine

Here's a neat story about a guy who's investigating the evolution of snake venom.

Dr. Fry collects venom from death adders, rattlesnakes, king cobras, sea snakes and many others. He estimates that he handles 2,000 to 3,000 snakes a year.

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His goal is to decipher the evolution of snake venoms over the past 60 million years. Reconstructing their history will help lead to medical breakthroughs, Dr. Fry believes. For the past 35 years, scientists have been turning snake venoms into drugs. Just this February, Dr. Fry and his colleagues filed a patent for a molecule found in the venom of the inland taipan that may help treat congestive heart failure.

Understanding the evolution of snake venoms will speed up these discoveries immensely, Dr. Fry predicted. "You need a good road map to get your research going," he said.

It turns out that venom evolved only once in snakes, and that many snakes we believe are non-venomous actually do produce small amounts of venom.

As Dr. Fry reports in the March issue of Genome Research, the DNA of venom genes goes against this idea. He constructed evolutionary trees of 24 venom genes, searching through online databases for their closest relatives among nonvenom genes. In only two cases did he find that venom genes evolved from saliva genes. In almost all the other cases, venom genes evolved from ones that were active outside the venom gland - in the blood, for example, as well as the brain and liver.

The evidence indicates that the evolution of a typical venom gene may begin with the accidental duplication of a gene that is active in another organ. In a process known as gene recruitment, one of these copies then mutates in such a way that it begins producing proteins in the venom gland.

In some cases, these borrowed proteins turn out to be harmful when injected into a snake's prey. Natural selection then favors mutations that make these proteins more lethal.

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As new lineages of snakes evolved, their venom evolved as well. New genes were borrowed to produce new venoms, while existing venom genes duplicated many times, producing a huge diversity of molecules.

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This rapid evolution has produced a wealth of complex molecules that researchers have barely begun to investigate. Evolutionary trees can serve as guides, speeding the search for new venoms and shedding light on how venoms work. "Just looking by chance is very difficult and not economical," Dr. Kochva said.

The venom molecules that Dr. Fry has isolated from the inland taipan is a case in point. He has established that they evolved from a family of proteins known as natriuretic peptides. In snakes, humans and other vertebrates, these peptides relax the muscles around the heart.

And there's the key. Dr. Fry was looking for molecules that might affect the heart, as a way of treating congestive heart failure. When you have a chart of the family tree of snakes, showing which ones have venoms that evolved from enzymes in the heart, you know where to start looking. And you don't need to waste your time looking at venoms that evolved from liver enzymes.

Understanding the evolution of these venoms helps Dr. Fry and his colleagues figure out how they work. Because they have evolved from proteins that only act on the heart, they probably will not pose a risk to other parts of the body.

"If you want to use a venom for some kind of drug, you'd better look back and see where it came from," Dr. Kochva said.