Brain146;s Darwin Machine

At the Salk Institute for Biological Studies, California, Fred W Gage, 53, saw in the brain8217;s unexpected ability to renew itself the potential for repairing brain damage from maladies such as Alzheimer8217;s disease. Gage, among the most influential neuroscientists of his generation, co-founded Brain Cells Inc in 2003 to exploit his discovery that humans generate new brain cells throughout life. Almost immediately, two staff scientists in his laboratory found that a curious DNA sequence muddled their efforts to discover how neural stem cells produced new neurons.

Scientists called the curious genetic sequence a 8220;jumping gene.8221; It could move up and down the double helix of DNA to insert itself into the genetic structure, like a snake crawling along a branch into a bird8217;s nest. Despite the name, the sequence was not a gene but a primitive precursor8212;called a long interspersed nuclear element, or LINE8212;that struggled for survival inside the microcosm of a cell. The LINE sequence belongs to a mysterious family of mobile genetic elements called retrotransposons.

All mammals contain such LINE sequences. But as species became more intelligent, they retained fewer types. Mice harboured 3,000 different kinds of LINE elements, rats 500. Humans had about 100 types that differed from one person to the next.

Unlike the other molecular relics littering the human genetic code, however, the particular human sequence that cropped up in the Salk laboratory, called an L1 LINE, was still on the move. So many thousands of times had it copied itself into the human genome that it now made up one-fifth of a cell8217;s DNA. Every once in a while, the sequence landed close enough to a gene to disrupt its behavior or change its expression.

But no one had ever heard of these DNA strands reweaving the genetic fabric of individual brain cells. Gage asked Alysson Muotri to look into it. The 31-year-old Brazilian was a cancer geneticist, not a neurobiologist like most of the researchers in the Gage lab.

Muotri and Gage wanted to know whether the L1 sequence was actually moving around in developing brain cells. Normally, the sequence copied itself into reproductive cells in the testes and ovaries, where a randomly remodelled gene might be passed to succeeding generations. The sequence did not seem active in any other type of cell in the body.

They could not experiment on people, so they inserted the human DNA into a custom-made brood of mice. To make the L1 sequence visible under a microscope, Muotri and his colleagues added to it a molecular tracer8212;a green fluorescent protein that would light up whenever the DNA intruder entered a growing cell.

To search for evidence of brain activity, he sliced each mouse into wafers 40 microns thick and mounted tissue from every organ on slides. If the sequence had jumped anywhere, it should reveal itself, like a firefly at midnight, with a fluorescent glow.

Muotri8217;s wife lent a hand. One day she could see a glow inside the translucent spheres of brain cells. 8220;It was, like, crazy green,8221; she recalled. First one cell, then five, 10, a dozen. She had found the fireflies in the brain. To their wonder, the L1 sequence had left its distinctive mark wherever they looked in the mouse brains8212;throughout areas devoted to memory, learning, emotion, motor control and the senses. They discovered the sequence affected only developing brain cells. It also seemed to home in on neural genes, arbitrarily changing their behavior. Every time it affected a gene, it set that neuron apart from its neighbors in the brain and from all other cells in the body.

The researchers were elated but puzzled. From the standpoint of conventional evolutionary theory, any independent genetic change in a neuron was a dead end. The random changes caused by L1 inside a brain cell could never be passed on directly through the genetic shuffle of sex.

At this point, Muotri and Gage had an audacious thought. Perhaps the sequence, striving for its own survival inside the growing neuron, made the brain more responsive to changing circumstances. Had natural selection seized on the one rogue sequence most useful for crafting an infinitely adaptable human brain?

8220;There are subtle differences in everything we do throughout our lives,8221; Gage said. 8220;Maybe this is how we generate a deeper adaptability to deal with the unexpected. We believe the sequence is generating this diversity to fine-tune the brain.8221;

Robert Lee Hotz