SUPER MOUSE THE THE MEMORY GENES [ back to What's New ]
This September 1999, the media is abuzz with stories about "Doogie" the genetically modified mouse with superior memory created by teams at Princeton, MIT and Washington University led by Dr. Joe Tsien of Princeton. During the 1970s research on sea slugs (withdrawing their siphons  from a mild shock) showed that short term memory involved  the neural encoding of a life experience by means of strengthening the synaptic  connection between two nerve cells, and making it easier for them to "fire" in unison when the learned stimulus is repeated. During the 1980s research on mice (learning to navigate a water maze) and baby chicks (learning to avoid pecking a bead treated with a foul tasting liquid) uncovered the phenomenon of LTP (long term potentiation) in the hippocampal area of the brain. LTP involves biochemical and structural alterations of the cells in the hippocampus which underly the simplest form of memory, the kind of "associative memory" in which one bee sting will make us move away when we next see a bee. It is not equivalent to all forms of memory.  It is one important   segment of the neural process of encoding short term memory en route to further processing for long term storage outside of the hippocampus. LTP occurs when an attention grabbing  stimulus triggers upstream neurons to release  an excitatory neurotransmitter called glutamate, which binds to NMDA receptors on the dendrites of the downstream neurons, causing them to admit an influx of calcium ions into the cells. The calcium ions signal genes in the downstream cell nucleus to "remodel" the synapse by synthesizing new proteins which go to form new dendrites or dendritic spines. The downstream neuron sends nitric oxide back to the upstream neuron to replicate the process, which involves formation of new vesicles for increased storage of glutamate, and  formation of new terminal boutons at the end of the axon. The process also involves the binding of phosphate to proteins in the receptors in the synaptic membrane and the creation of phosphoproteins which change the shape of the receptors, thereby making it easier for calcium to enter and lowering the threshold for nerve cell firing.

What Dr. Tsien and his colleagues did in the late 1990s was to insert a gene called NR2B into the hipppocampal neurons of mice. This boosted the mouse's natural supply of NMDA protein, which in turn increased the number and strength of NMDA receptors to bind with glutamate from the upstream nerve cells, and enhance the vigor of the LTP process. This one tiny change in the mouse DNA produced observable change at the level of the mouse's learning behavior. Mice with the bigger, stronger  NMDA receptors, recalled successful strategies for running a maze better and longer than the untreated mice. This made them learn better and outperform the untreated mice at maze running and other equivalent tests of mouse prowess. There is no evidence this made the new mice smarter or boosted their rodentine IQ. However, it clearly did improve their memory of successful strategies employed in dealing with certain challenging and  complex tasks, like navigating a maze. What are the implications of the results? Undoubtedly this adds to our growing store of useful knowledge about the molecular and cellular processes which underly encoding and storage of memory. Continued extension of our knowledge of these processes may indeed lead to gene therapy for persons with Alzheimer's, and beyond. However, there is need for caution. It is known that too much glutamate and too much calcium can kill brain cells, as happens in stroke. The possibility also exists that a proliferation of NMDA receptors may increase the tendency of some persons to become addicted to narcotics like cocaine and heroin. Finally, boosting memory power by itself, out of sync with other brain capacities, may create a Frankenstein.

In "The Making of Memory, " (1992, Anchor Books) the molecular  neurobiologist Steven Rose of the Open University of London, discusses the tragic cases of two men who both died young from the curse of too much memory. These individuals could not forget anything they had every been exposed to, and were greatly burdened by this excess of memory and the heaps of trivia flashing through their minds. We assuredly do not need to remember every passing detail of our daily experiences. Human memory and animal memory were designed to store long term only those memories which were significant for survival such  as which predators to avoid, and how to avoid them. The massive cognitive machinery in the human brain for analytic   reasoning, creative thinking, and the like could be gummed up by too much memory. Hence the supermouse is controversial, and the scientific and medical communities will have much to debate. Philosopher of science, Stephen J. Gould of Harvard, commented upon Dr. Tsien's research by cautioning us not to equate any single gene with highly complex, multi-factorial systems like intelligence or memory; and instructing us not to search for  short cuts like "smart pills" in the hope of becoming educated without attending school. The content of what we learn and the values that guide how we use it, will always matter a great deal.  Even Mark McGuire will tell you that taking androgens did not by itself let him hit 70 home runs. He still had to train, practice and work with coaches.