Monday, November 27, 2006

Tonegawa   posted by amnestic @ 11/27/2006 09:50:00 PM

Are bloggers more like sharks in a feeding frenzy or vultures on deadmeat?

See the populist rally the mob:

Ah... the Perfumed Class. Our Lords and Masters, the Principle Investigator Princes wandering over their incandescent domains, bestowing upon their peasant postdocs, their servile grad students, their precious beneficence... Don't you love them?
In summary, I am sorry, but I have to say to you that at present and under the present circumstances, I do not feel comfortable at all to have you here as a junior faculty colleague.
Step off Logan Airport, and I'll dip you in tempura batter, fry you in peanut oil and eat you for dinner.

I love that he is able to riff off of Tonegawa's ethnicity with such dexterity.

Oh and here's one who was even more clever with Tonegawa's name. See how she replaced Tone with Toady! So CLEVER! Wish I could pat her on the head for it. "I like to think he was strong-armed into stepping down."

Let's do something besides join the dogpile.

Tonegawa won the Nobel Prize in 1987.

Susumu Tonegawa was the one who finally answered the question how the gene material in B cells could suffice to create the structures of a seemingly endless number of different antibodies. In 1976 he could in a convincing and elegant manner show how different immunoglobulin genes which were far apart in the embryonic cell in the B lymphocyte had been moved in closer contact. Under development from the germ cells (the sperm and egg cell) to an antibody producing B lymphocyte the genes forming the immunoglobulins had accordingly been redistributed. In subsequent experiment Tonegawa could clarify how different pieces of the genome were moved around, recombined and even could be "lost" to finally give rise to the DNA which is found in the mature B lymphocyte.

Since then he has been a leader in the development of transgenic technologies:

Using the phage P1-derived Cre/loxP recombination system, we have developed a method to create mice in which the deletion (knockout) of virtually any gene of interest is restricted to a subregion or a specific cell type in the brain such as the pyramidal cells of the hippocampal CA1 region. The Cre/loxP recombination–based gene deletion appears to require a certain level of Cre protein expression. The brain subregional restricted gene knockout should allow a more precise analysis of the impact of a gene mutation on animal behaviors.

These technologies have become indispensable in the study of memory. You can knockout whatever gene you want in just the portion of the brain circuitry that theory has pointed to as important. One of the first (if not the first) applications was the production of mice lacking NMDA-type glutamate receptors in the CA1 region of the hippocampus. The casual reader or layperson can basically equate NMDA receptors with synaptic plasticity, meaning the changes in neural transmission that underlie memory. These CA1-NMDAR KO mice suck at memory.

But Tonegawa also provides a refined behavioral and theoretical approach. The hippocampus has a strong flow of connectivity from area DG to CA3 to CA1. CA3 has highly recurrent connections and thus has been modeled as a pattern completion module. Knocking out CA3 NMDA receptors doesn't have an obvious effect on memory like the CA1 version. Instead, one has to dig and understand clearly the role of different hippocampal subregions to find the CA3-KOs' specific deficit.

Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.

More recently Tonegawa and colleagues have emphasized the role of regulation of protein synthesis in memory storage, showing that certain pathways many equate with regulation at the level of mRNA synthesis (transcription) also regulate translation factors directly. This short circuits the loop. There is no need for a signal to travel from synapse to nucleus and back in order to make changes in the structure of a synapse. The same group has provided a unique theoretical insight in developing the clustered plasticity model in which changes involved in memory storage are coordinated at neighboring synapses.

The papers in the Arc-stravaganza a couple weeks ago all cited Tonegawa (and other very important PI's: Sur and Majewska) as early empirical evidence that Arc plays a role in reducing noise in synaptic plasticity rather than directly increasing the strength of "signal" synapses as many predicted.

Just some light reading in case you get tired of too much cleverness. As I mentioned at Shelley's blog, I think the peanut gallery could stand to quiet down some until they understand in technical detail the degree to which Karpova and Tonegawa were trying to achieve the same technology. I also agree with the original ad hoc report that we shouldn't be privy to those emails. Unfortunately, we are privy because of some highly unprofessional and noncollegial media wagging performed by somebody besides our latest burning patriarchy effigy.