Archive for the ‘Pharmaceuticals and Nootropics’ Category


Enhancing memory and learning in mice

Monday, 23 March, 2009

Recently, a review article by Yong‑Seok Lee and Alcino J. Silva was published in Nature Reviews Neuroscience, with the title ‘The molecular and cellular biology of enhanced cognition‘. If you are lucky enough to have a subscription, or know a library that can get this journal article for you, do.

The review lists 33 genetic modifications that lead to some level of enhanced memory and learning in mice. It also discuses the general methods by which these modifications work, focussing on enhancement of a form of neuronal plasticity known as long-term potentiation. NMDA receptors, the role of calcium as a messenger and the various enzymes and transcription factors that are recruited to create the cellular basis of a memory. The review also discusses other mechanisms, like epigenetics, growth factors, the involvement of glia, and also presynaptic signalling. Finally, the review looks at caveats in the current research in cognitive enhancement.

The authors also make a nod in the direction of bioethics, saying:

[I]t is also important to stress that memory enhancing manipulations raise a number of ethical issues that are outside of the scope of this Review, but that merit careful consideration and discussion170,171.

For interests sake, references 170 and 171 are:

170: Rose, S. P. ‘Smart drugs’: do they work? Are they ethical? Will they be legal? Nature Rev. Neurosci. 3, 975–979 (2002).
171. Farah, M. J. et al. Neurocognitive enhancement: what can we do and what should we do? Nature Rev. Neurosci. 5, 421–425 (2004).


Lose weight with gene therapy

Monday, 12 January, 2009

Want to eat fatty food and tell your body to not bother storing that fat all over your body? Well, research recently published in the advanced online publication of  Nature Medicine has done just that, albeit in mice. They created knock-out mice, missing the gene Pla2g16, which codes for the enzyme adipocyte phospholipase A2. This enzyme, abbreviated to AdPLA, and other members of the PLA  (phospholipase A2) family, catalyse the first – and rate limiting – step in the production of eicosanoids, which are signalling molecules. As this enzyme was expressed in adipocytes (which are fat cells), the researchers hypothesised it would be involved in producing molecules that control adipose-specific processes, like lipolysis (fat breakdown).

It turns out they were right. Genetically obese (ob/ob) mice were found to be producing far more AdPLA and diabetic mice increased their AdPLA after receiving insulin. So, this molecules was sure to be involved in metabolising fat somehow.

The researchers made AdPLA-null mice, which lacked the gene to produce this enzyme. They fed these mouse a diet high in fat, and did the same to wild-type mice (which still had the gene). The two groups were not different in weight at weaning, but after 64 weeks of that diet, the AdPLA-null mice weighed an average of 39.1±0.2g in comparison to the average weight of 73.7±0.3g for wild-type mice. But, they didn’t eat any less (in terms of grams of food per gram of body weight). Further, the researchers knocked out the gene in a line of genetically obese mouse, and despite them eating more than any other mouse line, they were only slightly more overweight than wild-type mouse on an ordinary diet. And, the AdPLA mice weren’t exercising any more than the other mice either. A picture is given below:

Shows a genetically obese ob/ob mouse, and one with the same obese genes but with the AdPLA2 gene knocked out

A mouse with a genetic defiency of the appetite-supressor hormone leptin (left), and one with the same leptin-deficiency but with the AdPLA2 gene knocked out (right). From Jaworski et al, 2009

Further analysis revealed that this reduction in body mass was correlated with a reduction in the size of fat cells in AbPLA-null mice. This, in turn, was likely caused by the increased level of lipolysis and increased triacylglycerol production and turnover.  Therefore, the hypothesis is that AbPLA is involved in the regulation of lipolysis by catalysing a key step in the production of prostaglandins, and specifically PGE2. PGE2 has an anti-lipolytic, meaning it promotes fat to be stored rather than released. So, remove the enzyme that produces of PGE2, and the fat just isn’t stored.

In addition, the AbPLA-null mice were more insulin resistant, which makes sense. Insulin is responsible for stimulating the uptake and storage of food, so if mice are eating more and not gaining weight, they must be less sensitive to insulin. The study indicated AdPLA-null mice had 74% reduced insulin-stimulated glucose uptake in adipose tissue. In other words, they were eating lots of food, but it wasn’t being stored as fat. Where is it going? Researchers found the AdPLA-null mice had 37% increased oxidative metabolism, and therefore required more oxygen. This means that the fat cells are using the fat up, burning it rather than storing it. In addition, the researchers hypothesise that the free-fatty acids produced by the higher rate of lipolysis may not be significantly greater, as the fat cells aren’t taking up the fat, even before they get the chance to release it at the faster rate.

So, what does all this mean? The researchers hint at it:

Many questions remain regarding the effect of partial or total PLA2G16 gene ablation in humans

What questions? Well, for one, does this research mean that I can eat fatty foods and yet still not gain weight? I’d say it’s promising. Gene therapy seems a bit drastic at this early stage, so in the near future perhaps RNA interference, or a drug inhibiting this enzyme, will be a useful and reversible treatment for obesity. But, in the future, people will surely be tweaking their genes to ensure they remain at an optimum weight, regardless of how much more than the required intake of food is consumed. Bring on the deep-fried ice cream!

Reference: Jaworski et al, “AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency” Nature Medicine, AOP 11 January 2009 DOI: 10.1038/nm.1904


EPO is a nootropic

Wednesday, 10 September, 2008

Erythropoietin (EPO), a hormone that increases red blood cells and is used as a performance enhancer for athletic performance, has now been shown to enhance memory in normal, healthy mice. Mice that received EPO injections had enhanced memory for 3-4 weeks afterwards, which is longer than the elevation in red blood cell count lasts.

This effect isn’t actually novel, as other researchers had noticed that EPO improved brain function over 18 years ago (Grimm et al, 1990), and research into mental illness has also suggested that EPO has an effect on brain function (Ehrenreich et al, 2004). But it was always thought to be dependent on the change in red blood cells, but more recent evidence has suggested it works independently of effects on blood cells (Miskowiak et al, 2007). This mouse model confirms this.

Of course, the researchers have been focusing on this as a treatment, but anyone can see that this is a promising enhancement too. This mouse research showed that EPO enhanced memory and athletic function in healthy mice. It enhances both athletic and mental performance – how good is that?

Then again, if EPO becomes a common cognitive enhancer, it will mean that few of us normal people would ever be able to compete in the Olympics. It was only in 2004 that caffeine was allowed in professional competition, but pretty soon college students will be doping themselves with EPO as a biochemical study aid. It will be interesting when almost all normal people would not be able to pass an Olympic-level drug test.

The possibility exists, however, that we may want the cognitive boost without increasing our red blood cells too much. And now that we know the cognitive effects of EPO are independent of red blood cell production, this may be possible too. Make a drug that stimulates the brain like EPO does, but doesn’t effect an increase in red blood cells. And this study has gone a long way to unraveling the relevant effects of EPO on neuronal plasticity that underly the enhancement to memory circuitry in the brain, which means that we may be able to find drugs that do so more effectively than EPO or act on other brain functions.


Fidelity enhancements

Wednesday, 3 September, 2008

Surprisingly little has been said about the claim that a ‘monogamy gene’ has been found in people. This is probably because the RS3 334 repeat is in a gene, avpr1a, that is a vasopressin receptor element (Walum et al, 2008). Both oxytocin/vasopressin (pretty much the same peptide, differing at only two residues) have been well known to play a role in pair bonding in all mammals, with oxytocin more relevant in females and vasopressin more relevant in males (Neumann, 2008). I was expecting a bit more of an upset, but I guess the anti-enhancement people aren’t any more shocked than I am about this discovery. But seeing as I haven’t blogged about this, it may be an interesting time to do so now.

First, this research has a real potential to increase our control over our own relationships. If we become worried that we will succumb to temptation and cheat on our partners, we can simply reaffirm our relationship by stimulating the vasopressin receptors. Oxytocin and vasopressin in the brain correlate to acting more trustworthy (Zaket al, 2005). Think of it as biological marriage counselling – it would probably be far more effective too.

One the other hand, if we do not want to be tied down to a single partner, we may be able to alleviate the jealousy felt by loved ones by adjusting the vasopressin/oxytocin system back the other way. It would probably be more complicated in this case, especially if we wanted to ensure that people were just as happy in a non-monogamous group, because these peptides are linked to sex drive and anxiety.

There may be some interesting dilemmas here though. Oxytocin increases the degree to which people trust others (Kosfield, Heinreichs et al, 2005), which creates an environment where cheaters can better prosper (as game theory would indicate). And if a polygamist and a monogamist fall in love, who is expected to change their view with the vasopressin modification?

Of course, these two peptides are not the only things involved in pair bonding behaviour, especially in the complicated brains of human beings. Nonetheless, I think this will be a very useful tool for future relationships. Essentially, this will allow for human relationships to be far less random. Love is blind, but with this knowledge of biology we can take love by the hand and guide it to where we want it to be.


Performance-enhancement in sports with Leon Kass and Eric Cohen

Friday, 14 March, 2008

Leon Kass and Eric Cohen, both former members (former head, in the case of Kass) of the President’s Council on Bioethics, have a piece in The New Republic, somehow from two weeks in the future (28 March), titled “For the Love of the Game“. Have a read, but be warned that it is a prime example of “Kassian sophistry” (although some of it sounds like Michael Sandel, another former member of the President’s Council). Perhaps starting on page 6 may be easier on the brain, and that’s where the good stuff starts anyway. Like this:

In athletics, as in other human activities, excellence has until now been achievable only by disciplined effort.

This is an odd statement to make. It’s pretty obvious that excellence can also be a product of good equipment, good nutrition and, in a major way, natural talent. I know the authors also know this, because they go on to say:

In many cases, of course, no amount of practice can overcome one’s limited natural endowments: nature dispenses her unequal gifts with little regard for any abstract principle of “fairness.” Yet however mysterious the source and the distribution of each person’s natural potential, the individual’s cultivation of his natural endowments is intelligible.

Unfortunately, the authors fail to recognise the problems this fact raises for the rest of their essay. Athletics, like the rest of life, is not fair. In the words of Julian Savalescu:

“sport discriminates against the genetically unfit. Sport is the province of the genetic elite (or freak).” I completely agree with Savelescu, that sport is really just a “very expensive horse race”.

Now, basically the argument of Kass and Cohen boils down to the fact that our enjoyment of sport supposedly comes from being able to put effort into sport and achieve something as a result. In this respect I do agree, and this does separate human sports from animal sports like horse racing. Humans are able to comprehend what they are trying to achieve, and strive to do it. It is precisely this drive that makes many want performance enhancement.

This is why I do not agree that the athlete who opts for enhancement is “cheating himself”. Rather, it is precisely the spirit of sport, and indeed many human endeavours, to want to achieve things through any means necessary. This is why athletes train, this is why they buy top-of-the-line equipment, and why they hire knowledgeable coaches. They have chosen a goal, and want to see that goal realised. Why should we only allow people to compete in a marathon if they were born with qualities of an endurance-runner and trained them to full potential, if we can see that goal realised for any person with the aid of performance enhancement?

Cohen and Kass go on to say:

Precisely because he has chosen to be chemically made into a better athlete, his resulting superior performances are not great athletic achievements. A patient to his druggist, less doer and more done-to, he is dependent on outside agents for “his” performance. His doings become, in a crucial sense, less “his own.”

The first response to this, of course, is to remind ourselves that superior performances are usually not purely athletic achievements. We are all “patients to [our] druggist” in the sense that we are all genetically made into a certain type of athlete by nature. We are already very dependant on outside agents, namely the genetic constitution of our parents, for “our” performances. Not to mention that top athletes were usually trained from an early age, before they could truly consent to it. Another example of external agents contributing to achievements.

Secondly, if we choose to take an enhancement pill, opt to be genetically modified or have a bionic limb, how does that make it less our own achievements. Should we say that drag racers cannot take credit for the speed of their car, or that golf players cannot take credit for their choice of clubs? No, the choice made by the athlete over which enhancement technology to use is no less his own than a choice of what diet to maintain, what training to do or what equipment to use. In fact, as enhancement increases, the influence of natural genetic gifts decreases, arguably levelling the playing field for outcomes to be affected primarily by “our own doings”.

Lastly, I can think of a perfect compromise for those who seek to make sport primarily about effort. If biological enhancements should only be allowed if they represent one’s own performance rather than that of others, then we simply need to get pharmacologists and geneticists into sport. After all, if they make their own enhancement technology, then the fact that they are running the 100m dash in 8 seconds is entirely a result of their own work. Scientist olympics – that would be a great idea.


Genetic Disease Immunity on the Horizon?

Friday, 15 February, 2008

Researchers at McGill University have genetically engineered mice to be immune to viruses. Well, at least four viruses anyway (influenza virus, encephalomyocarditis virus, VSV and SNV).

Still, let us look at how they did it, and then whether I can get it done to myself so that I don’t need flu shots every year. Firstly, they made some knockout mice for the genes 4E-BP1 and 4E-BP2 (meaning, those genes are deactivated in those mice). Those genes are apparently repressor genes, and decrease the production of immune proteins called interferons. Knock out a repressor, no more repression = more interferons. Because interferons, especially type 1 interferons, have antiviral properties, the mice essentially became immune to the viruses tested.

And, the researchers report no noticeable side-effects. However, given that fact that genes have actually evolved to stop interferon production, I still think we can’t rule out side-effects in future trials.

So, where do we sign up for the genetic mods for viral immunity? You can’t. Because we can’t produce knockout humans (technically, we could, but it would take too long and probably be unethical), and somatic gene therapy (especially gene therapy to deactivate a specific gene*) is still a very young science. And germline modification, in case you were thinking about vaccinating your infants before they are even born, is oh so very illegal (although considering the comparison to infant vaccination I just gave, I challenge anyone to tell me why it should remain illegal).

The researchers, being the clever sorts that they are, suggest an alternative:

“If we are able to target 4E-BP1 and 4E-BP2 with drugs, we will have a molecule that can protect you from viral infection. That’s a very exciting idea.” Dr. Costa-Mattiolo said. “We don’t have that yet, but it’s the obvious next step.

I don’t agree that it is the ‘obvious next step’ (I’d say, ‘good near-term compromise’) but still the idea is ok. I’d rather take a pill to become immune to the flu than catch the flu, but I’d still rather be immune to the flu because my parents had be ‘genetically vaccinated’ as an embryo. What if a flu pandemic hits and the stockpile of the drugs runs out? What if I fall on hard times and can’t afford the drugs (assuming they aren’t fully covered by government health schemes in the country in which I happen to be living at the time)?

Oh well. I guess I’ll have to take this antiviral drug (or benefit from the herd immunity of everyone else taking theirs), and wait for my gene therapy.

*I think an alternative could be to insert additional genes that produce Irf7 – the regulatory protein that has its synthesis repressed by 4E-BP1 and 4E-BP2. Or even add a gene that represses (transcriptionally silences) 4E-BP1 and 4E-BP2.