If you could look into a crystal ball to find out how your life ends, would you? Yesterday, James Watson (yes, that James Watson) decided that he didn’t want to know. His personal genome was sequenced by 454 Life Sciences and the Human Genome Sequencing Center at the Baylor College of Medicine. Dr. Watson will make his entire genome publicly available with the exception of one gene: apolipoprotein E, the gene most strongly associated with Alzheimer’s disease, which killed his grandmother.

There is no correct answer to the genetic testing dilemma. The children and grandchildren of victims of diseases with much clearer genetic causes have struggled with this question for years. But if Watson’s genome announces the dawn of pharmacogenomics, many more of us will have to decide for ourselves what we do and what we don’t want to know.

Watson is not a man who shies away from controversy. Perhaps that is why I am slightly surprised by such a human decision from such a brazen pioneer.

The use of human embryonic stem cells (hESCs) in research is of course highly controversial, raising ethical questions that for many people amount to serious dilemmas. In our April editorial we didn’t address the moral questions at all, but criticized recent efforts to discredit hESC research.

We’ve received two letters chiding us for the editorial. Though we can’t publish these letters in Nature Neuroscience, we are happy to discuss the matter on Action Potential. We invite the authors of the two letters to join us on the blog, and everyone else of course is also welcome to chip in.

Here are the links to the editorial, and the two pieces we discussed as examples for the new trick of spinning stem cell science against stem cell science. All are available for free:

Nature Neuroscience April 2007 editorial

Maureen L. Condic, “What We Know About Embryonic Stem Cells”, First Things, January 2007

The White House Domestic Policy Council, “Advancing Stem Cell Science Without Destroying Human Life”, January 2007

As the news out of Blacksburg, Virginia continues to unfold, it is difficult not to reflect on the importance of mental health services for young adults. In a sad coincidence, a meta-analysis published today in JAMA suggests that despite earlier reports of increased suicide risk, the benefits of antidepressant treatment in children and young adults outweigh the risks. Bridge et al. report that antidepressants helped young people with major depressive disorder, obsessive compulsive disorder and anxiety and increased their risk of suicidal thoughts or attempts by less than 1%. Improved treatment protocols specific for children and teenagers will hopefully help young adults in need. Unfortunately, we all know that treatments can only help those who seek them.

Just a few weeks can separate a splash from a quiet ripple. On 5 April, Neuron and Nature both published articles reporting genetically targeted silencing of mammalian neurons. In Neuron, Lerchner et al. detailed drug-induced hyperpolarization of neurons expressing a C. elegans chloride channel within hours of treatment. In Nature, Zhang et al. reported light-induced hyperpolarization of neurons expressing an archaea opsin within milliseconds of illumination. The media took note of Zhang’s article, but not Lerchner’s.

To be fair, the two articles are quite different in scope. Zhang et al. reported not just inducible neuron silencing, but a neuron on/off switch. In the same neuron, the authors induced firing with a blue light-activated cation channel and inhibited endogenous firing with a yellow-light induced chloride pump. They turned behaviors on and off with blue and yellow light, respectively, in C. elegans expressing both the cation channel and the chloride pump. The ability to control neuron function is nothing short of stunning and will undoubtedly impact both bench and bedside.

Although their scope was much smaller, Lerchner et al. approached neuronal silencing cleverly. Ivermectin is a chloride channel agonist in C. elegans, but not mammals, making it a potent antiparasitic agent that literally puts worms to sleep, sparing mammalian hosts. The authors silenced mammalian neurons expressing the C. elegans ivermectin-gated chloride channel and suppressed behavior with systemic treatment of ivermectin.

Systemic drug treatment is virtually guaranteed to take longer than illumination to achieve inhibition. And an off switch alone can’t compare to the deluxe on/off model. But I can’t help wondering if I’d be more excited about Lerchner’s article if it came out a few weeks earlier.

There is one interesting postscript to Zhang’s amazing achievement. Han and Boyden reported an identical yellow-light induced chloride pump earlier in the month in PLoS ONE. They examined the properties of blue and yellow light-induced excitation and inhibition in cultured hippocampal neurons. Although Han and Boyden don’t show any in vivo data, their study technically preceded Zhang et al. So, in the grand scheme of things, who will be credited with the discovery? Maybe timing isn’t everything.

We may have to thank body builders for the next big breakthrough in the battle against Parkinson disease. Companies that market powders and potions to those obsessed with their glutes and pecs claim that the dietary supplement creatine changes physiques. However, the NIH National Institute of Neurological Disorders and Stroke (NINDS) recently announced a phase III clinical trial examining the ability of creatine to slow symptom progression in people with Parkinson disease.

Although its body-bulking effect may be caused by simple weight gain, creatine is thought to boost exercise performance. Phosphocreatine donates phosphate groups to ADP, increasing the supply of ATP available in muscle, which allows muscles to work longer and harder.

Creatine is also neuroprotective. Klivenyi et al. reported that creatine prevented neuron loss but did not affect muscle weight in a mouse model of ALS. Zhu et al. reported that ischemia caused smaller stroke volumes in mice treated with creatine relative to vehicle. Ischemia induced less cytochrome c release and caspase activation in creatine-treated relative to vehicle-treated mice.

Creatine performed well in small clinical trials. Now NINDS plans to study 1720 people in the early stages of Parkinson disease in a double-blind study of creatine’s effects. This study, the first of a series of clinical trials called NIH exploratory trials in Parkinson disease (NET-PD), is slated to last five to seven years.

In response to my comments, Juan Carlos Lopez had this reply on Spoonful of Medicine:

Candidate genes? We already have many more candidate genes than we know what to do with. I’d argue that candidate genes are, in fact, part of the “genetic noise” Debra refers to.

What this field needs is, among other things, new animal models that allow us to make more thoughtful experiments on the biological basis of psychiatric disease.

In the absence of good models in which to test the functional relevance of whatever genes the screening process identifies, the massive investment that Apoorva highlighted will bring rather paltry returns.

He makes an excellent point, but I’m sticking to my guns. Groups of genes that are subtly affected (not wiped out entirely) would not have been found in the small populations studied thus far. Furthermore, the absence of good animal models underscores the need for more information on variation in the only disease model we have: the human.

We can agree to disagree. Although I’m a huge, geeky fan of hers, I have to respectfully disagree with Apoorva’s post on Spoonful of Medicine about the Stanley Medical Research Institute’s $100 million gift to the Broad Institute (originally reported in the Boston Globe). The Broad Institute, which is arguably the be all and end all of genomics research, plans to compile genetic and clinical data from thousands of people in order to identify candidate genes that associate with psychiatric disorders, including schizophrenia and bipolar disorder. Apoorva said:

But these are extremely complex disorders, each involving multiple genes. What roles do those genes play in the disease? Without understanding how the different genes interact and what the impact is of the different variations, the data will be all but meaningless.

I would argue that the very complexity of these diseases is the reason that such large datasets (and the bioinformaticians to make sense of them) are necessary. A really good example is in this month’s Nature Genetics. The Autism Genome Project Consortium identified new gene candidates associated with autism from a dataset containing genetic information from nearly 8000 people. Have they poof! figured out what causes autism? No, but they have identified a place to start.

Finding a place to start is really the whole point. These are disorders for which there just isn’t a lot to go on. Apoorva’s concern about understanding the roles of candidate genes in health and disease is really putting the cart before the horse. The molecular interactions between disease-related genes and their roles in psychiatric disorders can only be deciphered once candidates are in hand. With this fantastic grant, maybe the Broad Institute will get that far. That would really be something.

In case you missed it, the New York Times profiled Joseph LeDoux’s rock band, which is appropriately named the Amygdaloids. The band’s fans may be even more impressive than its members, who are all neuroscientists. Nobel prize-winning mathematician John Nash (subject of A Beautiful Mind) describes the Amygdaloids music as “psychoanalytic”.

If you lose your marbles in zero gravity, your fellow astronauts are assigned to catch them. According to the LA Times, NASA has a detailed, if slightly barbaric plan for dealing with an astronaut’s psychotic or suicidal behavior while in space. To prevent a distraught astronaut from harming his colleagues, crewmates are instructed to physically restrain him with bungee cords and administer tranquilizers. Then what? The written plan does not elaborate, but a NASA spokesman quoted in the Times suggests that officials on the ship and on the ground would decide if the mission should be aborted. This report comes in the wake of astronaut Lisa Nowak’s arrest in Orlando for attempted kidnapping.

Although I have no issue with NASA’s concern for the safety of its astronauts in an understandably delicate situation, I am a little uncomfortable with the brutality of its plan. Yes, a suicidal or psychotic astronaut could endanger the lives of his crewmates, and the seriousness of the situation is unquestionable. However, I wonder about the criteria fellow astronauts would use to evaluate a troubled crewmate. Will astronauts be educated about signs of deteriorating mental health, or will they be trusted to ‘know it when they see it’?

Coincidentally, a bill before the US Senate will make it easier for Americans to seek treatment for mental health. The Mental Health Parity Act of 2007 would require health insurance companies to cover treatments for psychiatric and neurological disorders, including substance abuse, comparably to other health disorders.

If you were happy with the level of NIH funding in 2006, you’re in luck! According to the 2008 budget proposed by US President George Bush on Monday, NIH funding will remain flat. Oh sure, the numbers sound good. On paper, the proposal includes a $232 million increase relative to 2006 (Congress has yet to pass 2007’s doozy of a budget). However, $200 million of that is already promised to the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria. The remaining $32 million increases NIH’s budget by 0.1% relative to 2006, far less than the 3.7% yearly inflation rate estimated by NIH. Although the budget includes allotments for new grants, no inflationary increases are planned to increase grant size. That means you, students and post docs with NRSAs: the proposal freezes student and post doc stipends at fiscal year 2007 levels.