Science
Gene Therapy
What these guys are thinking will blow you away.
First the bad news. Gene therapy is unlikely to have a clinical application in psychiatry for some time to come. The good news is we're working on it. An article by Robert Sapolsky PhD of Stanford in the February 2003 American Journal of Psychiatry tells us how far we've come and where we need to go. Dr Sapolsky, the recipient of a McArthur "genius" grant and other awards, uses gene technology to import modified genes into the damaged hippocampi of lab animals, and studies baboons in the wild to see how their social behavior affects stress-induced illnesses.
The challenge, he states, is to transfer genes (transgenes) that will have a beneficial effect on cell function into the nervous system. This involves finding effective "vectors," or suitable gene material. There are some problems, however. For one, the neurons in the brain, with some exceptions, do not divide into new cells. This rules out a host of effective gene therapy vectors that exploit cell division to hit their targets. The inaccessibility and complexity of the of the brain pose their own difficulties, while the fragile nature of neurons necessitates a genetic kid glove approach.
To date, gene therapy studies in the nervous system have focused on three techniques. The first involves encasing a transgene in a liposome (fatty) shell, which merges with the membrane of the target neuron and releases its cargo into the cell. The second technique uses a genetically engineered virus as the carrier of the transgene, exploiting the capability of the virus to infect the target cell with its genetic payload.
In the third technique, cells are removed from the body, genetically modified with a retrovirus (a type of gene template), then transplanted into the nervous system. Researchers are working on genetically engineered tissue implanted into the brains of Alzheimer's patients). The drawbacks to all these techniques are these vectors do not migrate very far from their surgical locations, while the blood-brain barrier poses an obstacle to penetrating the brain through the bloodstream..
A future possibility is “antisense” technology, in which a strand of RNA is programmed to attach to (and thereby neutralize) a strand of messenger RNA responsible for switching on disease-causing proteins.
Against neurological damage, gene therapy can work to replace lost cells, reduce damage, or bolster the brain’s natural defenses, say by “overexpressing” neurotrophins, which inhibit programmed cell death. A body of studies have targeted neuron death resulting from global ischemia, seizure, and hypoglycemia. Here, the focus has been on a molecular cascade that begins with an excess of the excitatory neurotransmitter glutamate in the synapse, which results in the accumulation of calcium in the postsynaptic neuron, which leads to an overactivation of calcium-dependent processes, resulting in cellular degradation, the generation of oxygen radicals, and other catastrophes.
Clearly, gene technology opens up a realm of possibilities for the human brain. But Dr Sapolsky cautions: "The biology of a psychiatric disorder is intrinsically subtler than that of global ischemia, a grand mal seizure, or concussive head trauma."
This raises the question: "Can genes be transferred into enough neurons to actually alter [behavior]?"
The answer appears yes. One experiment involving genes engineered to secrete "nerve growth factor" resulted in enhanced spatial learning in lab rats. Another targeting the dopamine pathways decreased the reward properties of cocaine in lab animals. Even the mating habits of prairie voles have been influenced by gene technology.
Nevertheless, "the biology of psychiatric disorders is not about inevitability but is instead about vulnerability and propensity. It is only in certain environments that the disease is likely to emerge."
According to Dr Sapolsky, many psychiatric disorders are based on "if-then" logic, eg "if you are exposed to a stressful life event, then your risk of depression increases," to the more complex, "if you are exposed to a stressful life event and you have a low sense of self-efficacy, then your risk of depression increases.” The genome, Dr Sapolsky states, “represents an informational system of if-then clauses.”
The intermediary between the if of stress and the then of depression appears to be the stress hormone cortisol, which is secreted as part of the caveman fight-or-flight response to a perceived threat. Cortisol, however, has a way of going on a caveman rampage of its own when modern man fails to respond as anticipated. For example, stress can awaken dormant herpes viruses and cause them to replicate. The viral genes responsible for setting this process in motion are controlled by a promoter (gene activator) that contains an element which responds to cortisol. Prompted by these findings, researchers have developed vector (gene material) systems that exploit these promoters. Dr Sapolsky and his colleagues have constructed a family of herpes virus vectors responsive to cortisol introduced into the hippocampus of the brains of lab animals. Their aim is to alter normal hippocampal function during stress so that any number of protective transgenes are switched on, say one that floods tryptophan hydroxylase (which leads to serotonin production) into the brain.
Dr Sapolsky and his team are also working on anxiety and conditioned fear, centering on the amygdala of the brain.
What is especially intriguing about Dr Sapolsky and his fellow researchers' application of if-then logic is that we do not have to identify specific mood genes in order to take advantage of gene technology. Still, gene therapy is more about potential than progress. Disappointments and dead ends tend to be par for the course, and a host of thorny technical issues remain to be resolved. Nevertheless, Dr Sapolsky envisions a day when a few deceptively simple tweaks to our genes are likely to serve as the brain's own internal 911 system, dispatching an array of crisis intervention chemicals to neurons in distress, in response to all those clear and present dangers that have a way of rendering us helpless. Never say never.
April 3, 2003, reviewed Feb 16, 2008
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