Posted by SLS on April 18, 2001, at 20:56:20
In reply to Re: Depression, Antidepressants, Life (ramble) » SLS, posted by Cam W. on April 18, 2001, at 11:45:48
Cam.
To continue the dialectic...
> As for the genome thing. I really have to disagree with you on the genome project doing much more than finding genetic links to diseases.
No. It is attempting to discover how the body manages its own functions by reading and understanding the blueprints. Finding genetic links to phenotypes, including diseases, is just one of the steps involved in this process.
> So, what I am saying is that it is not the genome that is determining how you end up.
Neither is it the environment.
The genome surely defines boundaries and potential. It influences the direction of growth in any particular environment.
Both contribute.
I am not focused more on one than the other. I just wanted to express my feelings that the pursuit of the human genome is not without great importance and application. Much will come of it. That is probably an understatement. I think it is counterproductive to describe what it is not without appreciating what it will be. I don't think we can fully understand the potential of deciphering the genome until we do. Its utility will depend upon the cleverness of man to exploit this information. Unfortunately, cleverness is not exclusive to those with good intentions.
> It is the secondary messengers, acting from receptor stimulation, using the genome as a template to put proteins and enzymes where the second messengers say they need to be placed. Yes, introns and exons of genes play a big role in deciding this, but ultimately it is how the cascade of secondary messengers line-up which determine how the template is to be used. If we modify the cascade, we modify the protein, and these modifications will be different for everyone (although there may be some homogeneity across disorders). The protein or enzyme which is malfunctioning may not necessarily be an aberrant genetic mutation, it may be being placed wrong once it leaves the nucleus.
Change the expression of the genes responsible for placement. :-)
> We may be able to eventually tell which proteins and enzymes regulate neuronal plasticity and be able to better target abnormalities causing (let's say) depressive symptoms, but I doubt we will be able to do this by changing the genome.
It is not the genome that is necessarily targeted for change. Decoding the genes and understanding how they function could be used to regulate the expression of those genes within the neuron that serve to regulate membrane and cytoplasmic structure and activity. One example might be to change the sensitivity of receptors. Perhaps this could be accomplished best by bypassing the dysregulated cascade of second messenger events (the communication mechanisms by which the neuron regulates its own gene activity) and establish a new equilibrium by manipulating the genes directly; an equilibrium that might maintain itself once gene manipulation treatment is discontinued.
> It may be better to locally target secondary messenger systems and leave the DNA alone.
Yeah. That sounds better to me too.
> Many different processes will use that enzyme or protein in different functions. If we target the enzyme or protein in the DNA we may be doing more damage other places.
I guess this is sort of like what happens with MAO inhibitors.
However, the relevant genes might be specific for expression in neurons. This is an integral part of cell differentiation. This would take care of your concern. Another perspective might be that if a particular gene and the enzyme it codes for are defective, correcting this one enzyme globally might not do very much throughout the body except to act as it should nominally in a state of good health. I am interested to know if the immune system would react to the "corrected" proteins as antigen.
> I believe that biologic vulnerability is only one of several avenues that need to be explored.
Of course. That's exactly what the human genome project is designed to help accomplish.
> Yes, it is interesting to be able to predict who is vulnerable, but it would be better to be able to fix the end point problem...
As opposed to fixing the starting point?
> ...(with minimal disruption to other systems
This might be an argument in favor of fixing the starting point rather than juggling multiple events pharmacologically at the endpoint and hoping you don't affect adversely the activity of other cells elsewhere in the body. Perhaps we will be capable of localizing gene therapy. Using the strategic placement of genetically-corrected stem-cells might do the job.
> ...and avoid stigmatization in biologically vulnerable people who will never show the disorder).
This will probably be the most potent issue regarding such genetic identification. It is not limited to mental illness.
> I guess you could say that I like epigenetic solutions rather than genetic ones.
Regulating the expression of existing genes is epigenetic, regardless of whether it is accomplished through the manipulation of cytoplasmic or nuclear events. Of course, not all somatic interventions involve gene regulation.
Now, for the record...
I was careful enough to use the phrase "some mental illnesses" when referring to genetic determinants. I purposely did not include the word "depression". I was also careful to include the phrase "psychogenic evolution" as a mode by which a "clinical" (not biological) depression is produced. I am a big believer in the role, and possibly the sole role, that epigenetic influences can produce things like depression and PTSD. I like the way you present neural plasticity and developmental neurological events like pruning. Regarding prominent genetic contributions and the utility of exploiting their identification, I really had in mind bipolar disorder and schizophrenia. However, I don't doubt that many unipolar depressions have a genetic etiology as hard as that of bipolar disorder.
Disclaimer: I am just running off at the mouth. I can't find anything to watch on T.V. 57 channels and nothin' on.
- Scott
poster:SLS
thread:60209
URL: http://www.dr-bob.org/babble/20010417/msgs/60385.html