Some Ideas for Human Cognitive Enhancement via Genetic Modification

Genetic modification has been all the rage in mice for some time. There are plenty of studies with mice with specific genes knocked out, genes edited to exhibit various phenotypes and genes augmented to enhance existing activity. The advent of CRISPR technology and lentiviral and adeno-associated viral vectors has created the prospect of being able to modify DNA of adult mammals including humans. The first daring self-experiments with this technology have already begun. Elizabeth Parrish, CEO of Bioviva, recently modified her DNA to increase her lifespan by increasing telomere length. She also raised her body’s levels of muscle tissue by inhibiting myostatin. These changes were at the genetic level and thus presumably permanent. Since her experiment over one year ago, she’s been doing well, and lab tests suggest that the changes have taken effect.

Given that we are now entering the age of genetic modification, the prospect for intrepid self-experimenters to explore this field is beginning and not just with the modifications pioneered by Bioviva. It would be fun to give ourselves glow in the dark hair via the addition of bioluminescent jellyfish genes to our hair follicle producing DNA. These bioluminescent jellyfish genes have already been used in several glow-in-the-dark rabbit projects and by the inventor of the ODIN DIY CRISPR kit who made glow-in-the-dark beer. However, the more sci-fi minded of us might be keen to gain inspiration from mouse studies that have augmented intelligence.

In the 1999 study “Genetic Enhancement of Learning and Memory in Mice” published in Nature, Joe Z Tsien and colleagues were able to create transgenic mice that overexpressed the NR2B gene. This gene codes for the NMDA receptor 2b which is a receptor involved in early-form long-term potentiation (E-LTP). This receptor complex is also present in humans. E-LTP is critical in generating memories that last up to 3 hours. The NMDA receptor acts as a coincidence detector that signals the cell to strengthen its electrical connections to other cells to form memories via AMPA receptor recruitment to the synaptic cleft. The mice who had this transgenic modification were able to learn spatial memory tasks at double the speed of control mice. The mice with the mutation also had normal growth, body weight, and mated normally. They had no evidence of seizures or convulsions. This lack of seizures is a significant finding because excitotoxicity via overstimulation of NMDA receptors by glutamate can often cause seizures. In the novel object recognition test, which is a test of memory for a previously seen object, the best performance in transgenic mice was seen 1 to 3 days after the test but returned to baseline after seven days.

We know that memories that last up to a lifetime encode themselves via late long-term potentiation (L-LTP) which is a process downstream of and that depends on E-LTP. While E-LTP is dependent on NMDA receptor activation and subsequent AMPA receptor recruitment, L-LTP is dependent on CREB activation and subsequent transcriptional activation of genes in the nucleus of the cell.  There have been several noteworthy findings with regards to enhancing L-LTP by creating transgenic mice with their PDE4 genes silenced. PDE4 is a well studied target for cognition enhancement. It’s such an active area of research that pre-made CRISPR kits are available to knock out PDE4B genes in mice. An experiment in 2011, “Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling“, tested the function of mice who had their PDE4D genes knocked out. This caused their levels of CREB to remain elevated after stimulation, thus prolonging and increasing CREB activation and subsequent L-LTP related gene transcription. The knockdown of PDE4D genes produced a highly significant increase in memory similar to that obtained by Rolipram, a standard PDE4 inhibitor used in rodents.

Doing a Elizabeth Parrish type experiment to increase cognitive capabilities would require a very brave self-experimenter indeed. I wouldn’t really consider doing this one myself until several had done it already or there was some well tested way to easily reverse the procedure if things didn’t go well. Still, as our understanding of CRISPR technology and genetic modification in general improves, I’m sure that we’ll eventually get to a point where these kinds of modifications and their risks will become so well understood enough that some courageous individual will volunteer to be the first person to test these or other potentially cognitive enhancing genetic modifications.




Blinking Lights Used To Treat Alzheimer’s Disease In MIT Study. How Does This Even Work?

The Study

Recently, MIT released a study showing evidence that mice bred to have Alzheimer’s disease, when exposed to blinking LEDs at 40hz, had their amount of illness causing amyloid-beta protein reduced. The effect even worked in “Wild Type” mice that were not specifically bred to exhibit Alzheimer’s symptoms.  The effect prevented amyloid-beta build up in mice in the early stages of the disease, but it also reduced amyloid-beta protein in mice that had already accumulated significant amounts of the protein and were thus at a later stage of the disease.  This result seems hard to make sense of because flashing lights aren’t something that seems capable of having disease curing effects. How could this possibly work given the difficulty in treating neurodegenerative diseases?

Looking more closely at the study, specifically at the mechanism of action proposed by the researchers, we find increased microglial activity. The microglial cells are the primary immune system cells in the brain. Some theorize that infections cause Alzheimer’s in the brain, so according to that theory, increasing the activity of microglia could help fight a possible Alzheimer’s disease causing infection.  In the study, the specific observed activity of the microglia was an increase in engulfing of amyloid beta proteins.  The end products of degraded amyloid protein were also reduced.  This suggests that there was an alteration in endosomal processing.

When researchers blocked GABA receptors, the amyloid clearing effect no longer worked. Contradicting GABA receptor activation being the sole source of the amyloid-beta reducing effect is that in the past GABA agonists failed to improve Alzheimer’s patient’s outcomes.


GABA receptors connect to microglia via astrocytes. Astrocytes modulate microglial activity, and their behavior is affected via GABA signaling. GABA acts as an anti-inflammatory via these cells. Strengthening the anti-inflammatory hypothesis is there is evidence that anti-inflammatories such as aspirin protect against Alzheimer’s pathology.

Astrocytes are related to circadian rhythm brain entrainment and Gamma oscillations. Flicking lights on and off increases glutamate signaling which is countered by GABA signaling from astrocytes. If GABA signaling doesn’t modulate glutamate signaling, that leads to the well known human photoparoxysmal response in people with epilepsy, in which blinking lights can cause seizures, perhaps because of sclerotic astrocytes that can’t function properly to slow down the elevated glutamate driven excitation.

So can we spin together a theory about how this all works? How do blinking lights reduce disease causing amyloid plaques?

My Speculation: Blinking lights cause astrocytes to get activated and release GABA to control photoparoxysmal driven glutamate signaling. This release, along with other signals from astrocytes, triggers anti-neuroinflammation and engulfing activity in microglia which helps clean up Alzheimer’s damage. Lack of effectiveness of GABA agonists alone in the treatment of Alzheimer’s disease provides evidence against the idea that GABA alone was solely responsible for the effect. Perhaps there is some other necessary signal that is released by astrocytes along with GABA to influence microglial anti-inflammatory behavior.

Researchers have linked neuroinflammation to other neurodegenerative diseases, so the applicability of this mechanism of action could be widespread.

The Most Time Efficient HIIT Cardio Treadmill Workout: 19 Minutes 3 Times A Week

The Goal: A Time Efficient Workout of Adequate Intensity

I recently decided I wanted to start a cardio program to get better at running. There is unfortunately a mountain of advice on how to structure a cardio program. Should I run? Do burpees? Swim? Join an endurance race? Run at low speed for 40 minutes every day? Join a soccer team?

I am not a fan of spending a lot of time doing cardio. It just isn’t that interesting to me. Sure, I can make it less annoying with audio books or podcasts, but in the end I just don’t like it. So how can I get the most out of a cardio workout without spending a significant amount of time doing it?

I looked into the 7-minute workout, and did it for a while, but the problem is is that it is not really well tailored to one’s fitness level. I’d like something that I can precisely measure out the dose of exercise I’m getting and tailor it to my current physical condition.

Instead, I decided to look through the research literature to find the most time efficient treadmill workout. I want to use a treadmill because I already have one and running is something I can do anywhere without equipment. I also wanted a workout that was tied to heart rate. That way, it wouldn’t be too hard or too easy, but would match my current condition.

The Norway Studies

A recent study from Norway shows that improvement in cardiovascular function can occur in only 19 minutes 3 times a week.

The protocol is as follows:

10 minutes at 70% Maximum Heart Rate
4 Minutes at 90% Maximum Heart Rate
5 Minutes Cool Down

Performed 3 times a week. According to the study, the maximum heart rate was the peak value achieved during the exercise period, so I view it as an upper limit. One can calculate maximum heart rate using many free heart rate calculators online. The researchers also tested another workout that consisted of a longer training period of 40 minutes of HIIT training interspersed with 3 minutes breaks.

The results after 10 weeks showed that VO2 max, the measure of the maximum amount of volume of oxygen an athlete can use, increased by 10% in the 19 minute group and 13% in the 40 minute group. Stroke volume, the amount of blood ejected by the heart’s left ventricle in one contraction, increased by 14% and 15% respectively. Work economy, defined as the oxygen cost of a 5-min walk at a 4 km/h on a leveled treadmill, improved by 14% and 13% respectively.

The 40 minute workout was more effective at reducing blood cholesterol and body fat (3.2% v 5.2%).

In doing this workout it’s important to precisely measure one’s heart rate. I use a chest strap heart rate monitor. Two models that work well for me are:

JARV – Works with Smart Phones and Low Energy Bluetooth Compatible Treadmills

POLAR-H1 – Works with Life Fitness Treadmills

The best app I’ve found for keeping track of heart rate, if one doesn’t have a treadmill that can talk to the heart rate sensor is iCardio.

New Research Into The Link Between Metals and Neurodegenerative Diseases

Peres, T. V., Parmalee, N. L., Martinez-Finley, E. J., and Aschner, M. (2016). Untangling the Manganese-α-Synuclein Web. Front. Neurosci. Frontiers in Neuroscience 10. doi:10.3389/fnins.2016.00364.

In this article the authors review manganese’s interaction with alpha-synuclein protein as a possible cause of dopaminergic related neurodegenerative diseases such as Parkinson’s. The hallmark of Parkinson’s is alpha-synuclein aggregation in which groups of the protein forms into tangles that cause cell death.  They note that disease of excess manganese (manganism),  and Parkinson’s both involve the dopaminergic systems, but in different areas of the brain.

After reviewing several studies, the authors suggest that manganese is likely only a contributing factor to alpha-synuclein aggregation. It is suggested that it interacts with other metals in the brain in a complex web to cause disease.  The observation of this interaction, in various experiments cited, leads the authors to ultimately conclude that alpha-synuclein may be neuroprotective by helping to scavenge excess metals in the brain, but the protein ultimately gets overwhelmed and begins to form tangles as levels of metals rise and are unable to be cleared from the brain.

The metals that cause alpha-synuclein to tangle up and cause disease are aluminum, copper, cadmium, iron, manganese, and zinc (Paik et al., 1999). Cadmium is a well known toxic metal and should be avoided. Aluminum is present in a wide variety of products and even in food additives and serves no nutritional purpose. Thus, limiting exposure to aluminum might be a practical way to protect against neurodegenerative disease.

My Latest Quantified Self Project

Feel free to use this image, just link to www.SeniorLiving.Org This microstock required lots of post processing to get the blue tint. I also needed a bounce card to get more detail in the glasses.

I think I am in Quantified Self heaven now. I’ve got HabitBull (Misc Habits and Scores on Brain and Braverman Tests), FitBit (Activity + Weight + Food + Sleep tracking) , Timesheet (Work Project Time Tracking), Rescue Time (Computer Use Time Tracking), Fit Notes (Weight Training Tracking) all hooked into advanced machine learning analysis via a bunch of python scripts utilizing numpy and sklearn.

I can ask “what kinds of things that I did/ate/took/spent time doing yesterday are highly correlated with me losing weight and/or body fat?” and get a linear regression on that and a p-value. Currently, the most highly correlated with losing weight right now is calories eaten the previous day, but there are other significantly correlated stats (p-value < 0.05) that are more interesting. For example, the more time I spend doing sedentary activity, like software development, the less weight I lose.

I can find out which supplements influenced various brain test scores on the same day. I can blind myself with randomly numbered containers and then go back in and fill in what supplements I took retroactively.  I can try all kinds of totally random things and see what they do and it’s all automatically tracked and analyzed.

My analysis takes conditional independence as assumed as do all naive bayes techniques. It also takes linearity as an assumption too, which is a weakness. To get around that, I could build a neural net and then use a genetic algorithm against it to generate ideas for non-conditionally independent relationships among things I’m doing.

More on this in the near future…

Image Credit

Adiponectin – A Very Interesting Weight Loss / Diabetes / Metabolic Syndrome target

Adiponectin is a hormone that is secreted by fat cells. It is different than most other hormones in that the production of the hormone falls as the number of fat cells increases. Levels of the hormone are inversely correlated with body fat percentage. So, the higher the adiponectin levels, the lower the body fat percentage.

Adiponectin increases insulin sensitivity by increasing tissue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and muscle. This protein also suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis.

Wow! That’s a pretty cool hormone for weight loss. Yes, people are working on synthetic small molecule agonists for it. There will likely be a huge market for it as the side effects seem tolerable, especially since it extends life span in mice that are genetically predisposed to be obese.

Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

I always wonder: Is there anything herbal that does anything with adiponectin? Ginseng has some benefits:

Ginsenoside Rb1 stimulates adiponectin signaling in C2C12 muscle cells through up-regulation of AdipoR1 and AdipoR2 proteins.

These results suggest that ginsenoside Rb1 promote translocations of GLUT4 by activating the adiponectin signaling pathway. The results can be helpful in understanding the novel antidiabetic mechanism of Rb1 ginsenoside and gain further support for its use as an antidiabetic drug.

Curcumin too:

The compound contains anti-inflammatory activity, which is mediated through an up-regulation of adiponectin and reduction of leptin.

Anyway, this is certainly an interesting area for exploration as far as weight loss is concerned.

Astragalus and Telomeres

For a long time there have been claims that taking astragalus root lengthens telomeres. I have read some studies that profiled the ability of high-priced purportedly life-extending supplements such as purified cycloastrogenol, which is derived from astragalus, to produce significant effects.


Of note, TA-65 did not altered significantly the levels of targets of the Wnt (CD44, CyclinD1) or TGFβ (Fibronectin, Klf4 or p16) pathways (Sup Fig 4), further supporting that TA-65-dependent telomerase activation occurs through transcription factors regulated by the MAPK pathway, which may directly or indirectly regulate the mTERT promoter (hypothetical mechanism in Fig. 2h, based in our current findings and previous results (Wang et al. 1998; Greenberg et al. 1999; Chang & Karin 2001; Inui et al. 2001; Takakura et al. 2005; Pericuesta et al. 2006)).

Unfortunately MAPK is kind of a difficult pathway to activate. According to Wikipedia:

As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase. In contrast to the relatively simple, phosphorylation-dependent activation mechanism of MAPKs and MAP2Ks, MAP3Ks have stunningly complex regulation. Many of the better-known MAP3Ks, such as c-Raf, MEKK4 or MLK3 require multiple steps for their activation. These are typically allosterically-controlled enzymes, tighly locked into an inactive state by multiple mechanisms.

I can’t imagine a simple herbal compound would be able to push all the right molecular biological buttons to activate this pathway so instead I took a look at other means of activation.

As is typical, the cancer researchers , with their brute force investigation of every possible way to kill a cancer cell through every conceivable pathway, have stumbled onto a possible mechanism of action for astragalus, though they don’t realize it, since their objective is to try to find ways to kill cancer cells that want to live forever and not make people and their healthy cells live forever.

AKT inhibits MAD1-mediated target genes (hTERT and ODC) transcription repression and promotes cell cycle and cell growth. However, mutated S145A MAD1 abrogates the inhibition by AKT. Thus, our results suggest that phosphorylation of MAD1 by AKT inhibits MAD1-mediated transcription suppression and subsequently activates the transcription of MAD1 target genes.

And then the cardiology people looking for ways to improve heart health have stumbled upon astragalus’s impact on heart health in the presence of toxins and how it regulates AKT:

. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment. These results demonstrate that [astragalus polysaccharide] APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways

So.. The idea here is that astragalus activates Akt which then inhibits MAD1 which then promotes hTERT which lengthens telomeres.