Other scientists had moved on. "The boys," as Lynch routinely referred to the neuroscience establishment, turned en masse to the exploration of what genes might be involved. That they were able to find such genes almost at will was read by gene proponents as a reason to stay and look for more. To Lynch, it made no sense. "It's like trying to understand a computer by studying it a transistor at a time. Not only will it take forever, it will never work. You'll never get there unless you understand the programming."
"I asked myself: 'Why am I following you down this alley?' So I didn't."
For The Record
Los Angeles Times Tuesday, August 21, 2007 Home Edition Main News Part Page News Desk 3 inches; 118 words Type of Material: Correction
Chasing memory: An article in Monday's Section A about UC Irvine neuroscientist Gary Lynch's research into memory said nitric oxide was a key element in laughing gas. It is not; nitrous oxide is what makes up laughing gas. Also, the glossary accompanying the memory articles in Sunday and Monday's Section A defined genes as "strings of amino acids that make up an organism's genome, a sort of blueprint from which the organism is built. Individual genes are strings of amino acids; each string contains instructions for building a particular protein." The definition should have said: "Genes: strings of DNA that form a blueprint from which the organism is built. Each gene contains instructions for building a particular protein."
Lynch instead rode out the LTP bet. In January 2005, after decades of studying and teasing out its details, he was in the midst of an experiment to determine once and for all whether LTP was a mere laboratory curiosity or the real thing -- the means by which neurons were wired together to form memories. Lynch, in other words, was about to find out whether he was a candidate to stand Nobel shoulder to Nobel shoulder with Kandel. The alternative? He was Clyde.
Lynch had long ago proposed that the end result of LTP was a micro-scale physical remodeling of neurons that allowed them to communicate better with one another. The lab had just developed a new technique that Lynch thought would allow researchers to visualize this remodeling, in fact, to see the physical trace of memories.
This new technique promised to answer conclusively what had been supposition, and to answer it in such a way you would literally see the result.
Neuroscience comprises many distinct disciplines, or tribes, as Lynch called them, ranging from mathematicians to evolutionary biologists. Eniko Kramar, a senior scientist in the lab, was actually going to run the experiment. Kramar was a neurophysiologist, meaning she studied the function of brain cells. Physiologists, generally, can be thought of as engineers. They're practical people, interested in how stuff works.
At the moment, the stuff in question was synapses in a rat brain. Most brain research labs used animals in their work, the main reason being the lack of human subjects willing to have their brains dissected. Lynch Lab used rats almost exclusively.
Other labs used mice or simpler creatures -- fruit flies and sea slugs. Genes that performed certain known functions in fruit flies did the same or similar work in humans; the genes were conserved, scientists say -- natural selection winners passed up the evolutionary chain. Use of these animal models is a daily expression of unquestioned trust in evolution as a central fact of human history. Even as debates might rage in broader society over the idea that human beings are descended from apes, there was a strong conclusion in biology labs that human antecedents go back way past the apes to the flies and beyond.
Still, Lynch wondered about the practicality of studying memory in nonmammals that, in human terms, didn't have any. "Memory is an emergent phenomenon," he said. "Steam is an emergent phenomenon. If you want to study steam, you better study hot water. You ain't going to get steam out of mud."
Visualizing success
Kramar's experiment began with the death of a rat, which she accomplished using a small guillotine. It took her less than five minutes to decapitate -- or, as she put it, sacrifice -- the animal, cut open its skull, remove the brain and separate the hippocampus, a portion of the temporal lobe thought to be involved in memory, from the rest of its cortex. She then sliced the hippocampus, which in a rat is about the size of a clipping from a thick thumbnail, into five very thin sections.
The slices were transferred to a small, circular Plexiglas chamber centered on a workbench under a microscope. The chamber was fed by separate lines carrying a nutrient-rich warm liquid and oxygen, which together kept the brain alive and in some sense functioning.
The top of the chamber had cutouts that allowed electric probes to be placed into the brain slices, one for stimulating and one for recording. The stimulating electrode could be set to deliver currents of precise timing and duration. Lynch and colleagues had discovered decades before that LTP was optimized when initiated by electric currents that mimicked a naturally occurring rhythm within the human nervous system known as theta rhythm. This coincidence -- that the best way to obtain LTP in the lab was to mimic actual real-world biology -- had, more than anything, convinced Lynch that LTP was real.
"That day -- the day we found theta -- our mouths fell open," said John Larson, who worked with Lynch on the discovery.
Kramar's chamber was situated on a table equipped with shock absorbers to prevent the rumble of a truck or car outside from disturbing the queasy equilibrium of the experiment. Because the electrical measurements needed to be precise, any equipment that might interfere with them was grounded, and connections were shielded with aluminum foil to prevent stray signals from intervening.
