Categories
Pharmacology Sciences

[Sciences/Pharmacokinetics] Do nano-particles of the Pfizer COVID-19 vaccine cross the blood-brain barrier and infect your brain with mRNA (or will fritz your gonads)?

1. Introduction
[EDIT: Updated the article on 07/05/2021 to reflect some updates on my analysis]

I have recently seen some claims I considered moot resurfacing on social media: first that COVID-19 vaccines render women infertile; second that mRNA vaccines cross the blood-brain barrier and therefore lead to neurological diseases.
These claims have been rebutted by various science communicators including Edward from Deplatform Disease and myself on Skeptical Raptor few months ago, as the Pfizer and Moderna vaccines were rolling out in the US.

Thing is, with anti-vaxxers, claims are never completely dead and keep rising up like some zombies straight out of a Walking Dead episode.

This time, it seems to be materialized through this screenshot, that appear to spread virally on social media over the weekend, especially in various iterations of that screenshot, with a yellow highlight in a table with the following tissue: “ovaries” and total lipid concentrations as only information.

Screenshot depicting estimated aminolipid contents in rats following injection of the Pfizer COVID-19 nanoparticle formulation (source: Facebook).

2. What is the screenshot coming from?

As always, getting back to the source of a document is essential to put this information back into the context. This screenshot appeared to be coming from a leaked document (if I have to judge on the “Pfizer – Confidential” footers) that I was able to find the source. Unfortunately the document is in Japanese but I can speculate this document likely came from an application packet submitted to the Japanese equivalent of the FDA to seek authorization of sale of the vaccine on the Japanese market. 3. What is the document about?
It seems the document provides us with some pharmacokinetics data on the mRNA vaccine done in rats (Wistar Han strain, both males and females) to assess the pharmacokinetics of the nanoparticles inside these rodents to assess the pharmacokinetics of both the lipid nanoparticles and the mRNA (using the luciferase as reporter of mRNA transcription, I will explain it later).
For the majority of the experiments, we have the following situation been used (according to Table 1):

Nanoparticles were used using two aminolipids (ALC-0315 and ALC-1059) at concentrations of 15.3 and 1.96mg/kg respectively. mRNA was encapsulated in these nanoparticles at 1mg/kg (to give you an idea, the actual dose of mRNA in a Pfizer shot is 30ug or 0.03mg from patients ranging of 12 years and older)

Table 1 provides us with some pertinent PK parameters including the half-life (time to eliminate 50% of a drug), the AUC (to compare the relative bioavailability, distribution and calculate the clearance of a drug) and finally the Kanji translated by Google Translate (sorry but that poor Gaijin is illiterate to Japanese despite decades of anime) as “Distribution ratio to the liver“, with 60% of ALC-0315 found in the liver, 20% of ALC-0159 respectively. The number of animals also appear to be N=3/group (male, female as groups).

We have therefore extensive data on the aminolipids metabolism and the metabolites obtained both in vivo (plasma samples mostly), in vitro (using liver microsomes homogenates, a classic in PK/PD studies); distribution of LNPs in tissues and organs using a non-metabolized radio-tracer ([3H]-08-A01-C0 which I quote the document “[3H]-08-A01-C0 = An aqueous dispersion of LNPs, including ALC-0315, ALC-0159,distearoylphosphatidylcholine, cholesterol, mRNA encoding luciferase and trace amounts of radiolabeled [Cholesteryl-1,2-3H(N)]-Cholesteryl Hexadecyl Ether, a non-exchangeable, non-metabolizable lipid marker used to monitor the disposition of the LNPs“, which was given at a dose of 50ug in animals) and finally bio-luminescence assays in which it consisted of injecting 2ug of RNA encapsulated in the LNP formulation in the hind-limbs of rats (we can assume these were adult rats, therefore a weight of 200-250g is not unheard of), followed by live imaging of the animals to track the luciferase activity (following injection of coelenterazine, the conversion of this substrate by luciferase results in bio-luminescence at close proximity which can be detected through a special camera, as Figure 2).

4. What the data is telling us?


The first thing I would tell is that the person behind the yellow highlight not only have absolutely no idea of what to look for in Table 3 but also went into a cherry-picking expedition to use numbers in scaring people with numbers. That person is providing us with amount of the radiolabeled tracer detected in the tissue (e.g. ug/g tissue), with the approximation of total lipids amount in tissue. This assumes that the nanoparticles made it through the tissue complete, but we cannot exclude that we are maybe measuring only the 08-A01-C0 compound accumulation.
In practice, we usually focus our attention on the percentage of injected dose (% ID) when it comes to appreciate the distribution and the delivery of a drug into an organ/tissue. In some fields, like the BBB, such value is usually not sufficient, and we further correct these values to sort the amount that diffused across the blood-brain barrier (BBB) against the amount that is retained in the cerebral vasculature by the time of euthanasia.
Therefore, we have to put our attention on the right-half of the table. I have plotted these values into a plotting software (Graphpad Prism 9) to have a graphical representation.

What we can see is that the LNPs reach a Cmax value of 52.9% of the ID by 1 hour following IM injection and see a biphasic phase of distribution and elimination (which I suspect the drug would follow a 2-model compartment). Liver is the organ with the highest uptake (we know that 60% of the LNPs are uptaken by the liver) with a Cmax of about 18% of the injected dose by 8 hours. This is expected as liver has a formidable blood flow compared to other organ (Q=1500mL/min). Spleen (very important lymphoid organs) comes in as a good second with a Cmax~1%ID by 8 hours. Kidneys in the other hand sees a much lower uptake despite being an organ with a decent blood flow (GFR=~120mL/min) with a Cmax`0.2%ID, suggesting these LNPs maybe eliminated mostly via hepatic clearance route (including metabolism).

[EDIT: I have performed an area-under-the curve analysis, just for the fun of it. We are lacking data, so we will use for informational purpose. The use of the AUC trapezoidal method can allow to guesstimate how much of that radiotracer accumulated in the tissue/organs over the 48 hours period.
If we look at the AUC values of these from 0 to 48 hours, about 57% of the injected dose is found in the liver, 3% in the spleen, 0.25% in the kidneys, 0.17-0.18% in the gonads and finally 0.04% of the injected dose is found in the brain). ]

What about ovaries? Well we are in the same ballpark than kidneys and indeed nothing really much about (0.1%ID after 48 hours). Interestingly, the author hyper focused on female gonads and occulted to show that male gonads (testes) were getting the same %ID (0.07%). I don’t think it was an accident from the author, just a sign of a deliberate attempt to manipulate the narrative by spinning the numbers.
And last, brain, my favorite organ. The amount entering the brain is maybe the lowest of our organ of interest as we measured a meager 0.02% ID there. Keep in mind, we have to be careful on this number as we may have an overestimation here. In the field, when you do brain perfusion and you are about to collect your last plasma timepoint before sacrificing the animal, you have to be sure to perform a “flushing” of your cerebral blood vessels with PBS, to remove any residual blood volume that can contain your drug. Unless you can correct for the vascular volume (which is not as simple), you have to perform this procedure as we did in a paper I collaborated on. Failure to do so can can lead to overestimation of your brain uptake. Until I have evidence of such flushing occurred, we can hypothesize that the investigators sacrificed their animals at the time points, extracted and weighted all organs and proceeded with the radioactive counts. Therefore, that 0.02% ID should be considered as a grand maximum, likely overestimating the real concentration.

Taken together, we can see that aside of the liver and spleen, the uptake of the radiolabeled tracer (and by extension nanoparticles) remains very low in gonads and in the brain, with amounts of 0.1% and 0.01% respectively at 48 hours.

The second set of data we have to look at is the bio-luminescence data (see Page 5). The lab injected 1ug of mRNA in each hind leg, totaling 2ug mRNA in each rat. Considering an average weight of 200g per rat, we can approximate a dose of 10ug/kg for the luciferase assay. As a control (to remove the background noise), control animals were injected with saline buffer. The average bio-luminescence signals were given, and I personally added 10% of this average as an estimated standard deviation to have an error margin, which a value commonly accepted in biological sciences (10% variation around average is considered pretty good data variability).
[Added: The bio-luminescence is also set to a mininum of 10E6 AU, which is important for the rest of the analysis.]

We can see that the luciferase activity at the injection site (which we can refer as our reference tissue) is significantly high within hours of injection (2 hours being the first reported timepoint) and decreases over time. [Added: What is important to note is how does the %ID actually compares to the bioluminescence. The common sense would be the more of the lipids are biodistributing in the tissue, the more mRNA (and therefore luciferease activity) we should detect, no? Well it is more complicated than this. Let’s plot the %ID in the tissue versus the bio-luminescence.

As you can see, an increase of lipid tracer in the tissue does not correlate with an increase in mRNA activity (as seen by Luc activity). It can be meaning two different things:
* The accumulation of the radiotracer present in the LNPs does accumulate in the tissue because of its non-metabolization and therefore may overestimate the half-life of the LNPs.
* Lets assume the LNPs found a way in the tissues, does not mean they made it safely with their cargo. They may accumulate as residues, or may come as empty shells with little or no mRNA left.]


We can assume that the luciferase expression at the injection site last for up to 10 days before being no different of background noise (we also have to be careful to not extrapolate as-is for the spike S protein, as the mRNA and protein kinetics of luciferase enzyme may greatly differ from the recombinant spike protein). However, the risk of off-target effect and having the mRNA expressed outside the injection site seems to be quite dim. Luciferase activity in the liver (which apparently uptake 60% of the injected dose) is down to background level by 48 hours post-injection. [Added: If we look at the profile, we can guess there is some metabolism in the liver that makes the clearance of LNPs and/or mRNA faster than the muscle tissue. From the data of the muscle bio-luminescence, we can see the decay of the bio-luminescence follows a first-order kinetics and puts with a half-life of ~0.75 days].
Ovaries luciferase activity was basically in the range of the saline group (and would be barely detected over noise, if we refer to the expected min. The penetration of the dye emission wavelength should be enough to be caught by the camera, even through solid tissue. If we don’t see any luminescence, it is likely because it is below or same intensity than background in saline) and brain luciferase activity in the brain was basically noise from the beginning to start (remember we have no access on the standard deviation but the numbers being that close from saline suggest we are scrapping background noise).
In conclusion, the risk of having the mRNA expression outside the injection is very unlikely and meaningless when it comes to biological activity.

5. The perils of dismissing the dose and the allometric scale in assessing the risk
So, we have evidence that the LNPs are pretty safe by barely accumulating in gonads and in the brain, that the mRNA activity is mostly not being found to have off-target, but what about the dose and how does it correlate to clinical situation?
This is where important concept of doses and allometric scale have to be introduced.
First, the dose used for the PK study. It was 1mg/kg of mRNA given in rats. As a comparison, the regular dose of the Pfizer vaccine is 30 ug (0.03mg) given to any patient of 12 years and older.  An average 12-years old girl would be 40 kgs per the CDC chart (rounded up to the lower value and for the ease of calculation). This would indicate a dose of 0.00075mg/kg. That’s already a difference of 1333-fold between what we gave to these rats and what we gave to humans, but there is more!
We also have to account to the allometric factor, because rats are not small human. [EDIT: For adjusting to the allometric scale, we will use this calculator ]. The allometric scale tells us that 1mg/kg dose in rats results in a human-equivalent dose (HED) of 68mg/kg if your patient is a 70-kgs adult; 45mg/kg if you are a 40-kgs teenager (~12 year old girl falling in the 50th percentile of the CDC growth chart).

Therefore, we have to multiply it by 45 (40-kgs patient) or 68 (70-kgs), which means if we want to transpose the PK findings as done in the rats, we would need to inject about 60’000 doses of the Pfizer vaccine in ONE girl (91’000 doses if you are a 70-kgs adult). That’s about half one-fourth of all doses distributed to Amarillo until now given to only ONE person [EDIT: One 12-year old teenage girl that is in the 50th percentile], ALL AT ONCE! You see where we going? The very extreme implausibility of the claims that COVID19 vaccines affect ovaries and the brain.
To finish it up, we can also look at the actual mRNA and luciferase.
We know that 8microg/kg was sufficient to see some liver activity, but no activity in gonads and brain. How does it translate to humans? First, lets apply the allometric scale (68x). We would need 544microg/kg for the HED, and translated to a 12-years old girl that would be 21760microg of mRNA delivered, which is about 725 doses of Pfizer given in ONE person at once! You can see that since we cannot detect notable activity if I give 725 doses at once, chance are I will not detect any activity when given a single dose or even two doses of Pfizer.

6. Concluding remarks

In conclusion, we can take the following messages:
– This is a document leaked on the PK of nanoparticles as found in the Pfizer vaccine, showing animal studies have been done before or during the clinical trials and we have the documentation.
– It helps clarify an ambiguous statement made by Pfizer in their summary submitted to the European Medicine Agency a couple of weeks ago about the distribution of the mRNA vaccine.
– The studies were done in a very conservative fashion at doses exceptionally high and impossible to reach in humans
– At such doses, it was shown that aside from the liver and spleen, the distribution of LNPs was minimal in gonads and the brain.
– The amount of mRNA required to be present in the tissue to appreciate an off-target effect is ridiculously low and impossible to achieve in real life and was transient in the liver.
– When accounting for the clinical dose and the allometric scale, this study shows that the Pfizer vaccine is very safe with a very low incidence of the off-target effect. To achieve the same result in humans, it would take a ridiculously high amount and a sheer incompetent healthcare practice to have the probability of having any issues of off-target effect occur in humans.

Categories
Neurosciences Sciences Stroke Uncategorized

[Sciences] Restoration of brain circulation and cellular functions hours post-mortem (Vrselja et al., Nature 2019)

You may have heard about that groundbreaking story last on “pig brains being revived” sounding almost like a scenario of a zombie movie. Let’s say science journalism love to use superlatives and sensationalistic headlines to grab few more clicks and views.
As usual, my skepticism was to first look at the paper and see how the claims hold on. The publication behind that “pig zombie paper” is the study from Vrselja and colleagues published in Nature last week and available here: https://www.nature.com/articles/s41586-019-1099-1
So what is about this story? First it is published in Nature, a top-tier peer-review journal. Second it is a huge paper, coming from Yale University. The paper was initially submitted on February 22, 2018 and got accepted March 1st. You can say a bit more than a year and that suggest that this paper likely went at least two rounds of review and probably more than three peer-reviews (three were named as well as other anonymous). One of the peer-reviewer was Pr. Constantino Iadeccola (Cornell University, NY), a “rock star” in the field of cerebral blood flow (which nicely match for the paper).
Overall, it is a very good paper with some reservations on the greater impact that I will explain later.
To understand the paper, you need to understand first that as until now we consider the brain highly dependent on continuous cerebral perfusion with blood flow to survive. The brain is highly dependent on oxygen and glucose (at least 20% of our daily uptake is taken by this tissue that only represent less than 2% of the human body weight).
We assume that if you stop flowing the brain with blood (e.g. cardiac arrest), you will die within minutes from massive and irreversible brain damage. The whole idea of this paper was: “what if we could maintain a blood flow for 24 hours, can we maintain some neurological function?”. In particular, the authors have developed a kind of artificial blood, cell-free, called BEx. It contains a hemoglobin carrier called Hemopure(R), glucose/pyruvate, as well as a cocktail of neuroprotective agents, antibiotics and some echogenic agents (to measure blood flow). The caveat is that as a control the authors used a simple saline solution without glucose and pyruvate (see supplementary tables below). Considering the importance of glucose for the brain tissue, and the absence of glycogen storage in that tissue, I would argue that this is a non-negligible flaw in the experimental design, giving a serious advantage to the BEx and maybe even overestimating the BEx activity.
Screen Shot 2019-04-17 at 2.06.26 PM

Nethertheless, let’s continue the discussion. Pig brains were not obtained from pigs euthanized for the sole purpose of the experiments, but rather obtained as waste from the slaughterhouse. Thats ethically much more acceptable, even 3R-friendly (as it valorize animal tissues considered as waste) and much more easy for obtaining an IACUC approval. About 300 post-mortem brains were used, I guess mostly for the development and optimization of the technique. The sample size (N) appears to be 32 pigs/group, which is very good for statistical power of analysis.
The surgical procedure (to connect these brain to the system) was about 10 minutes of warm anoxia, which would probably represent a severe cardiac arrest in which CPR is not performed immediately. They exposed these brain to either 1 hour or 10 hours post-mortem interval (PMI) without flow, with control perfusate or with BEx. Note that the perfusion to occur happened about 3 hours since the initial brain flush, the surgical preparation appears indeed tidious, but reproduce a pulsate blood flow similar to what would happen in animals. They also cooled down the brain to 25ºC, which is known that cooler temperature improve the chance of reducing brain damage (the common sense is that drowning in an hypothermic environment (frozen lake) increase your chance of resuscitation compared to drawing in a normothermic environment (swimming pool). The experiment lasted 10 hours for all groups, except the 1 hour PMI group.
The first results shown demonstrated the presence of a functional flow inside the brain tissue, and some vascular reactivity, using nimodipine infusion (a Ca channel blocker commonly used to reduce blood flow) and showing changes in blood flows. In other words, there is a proof of principle that it works.
The second result looked at changes in cerebral edema as a crude estimation of the blood-brain barrier (BBB) function. The control perfusate showed an increased water content, which is not surprising as some of our in-house data (and other studies) suggesting that the BBB function has a greater dependence to glucose than to oxygen when it comes to maintaining the barrier integrity. Since the CP is glucose-free, that is not surprising. The BEx group of course fare better (same level than 1 hour PMI group) but wonder how it would have fared if the CP contained the same amount of glucose and pyruvate. My personal thought is why did not the authors performed a gadolinium imaging of these two brains? They provide some T1 scans, which are nice but confirming changes in the BBB leakiness using gadolinium as contrasting agent would have been better.
Figure 3 show us a series of tissue staining of these brain, in particular from the hippocampal region. As expected, the Nissl staining worsened in the PMI, the presence of CP partially improved the situation and the BEx was similar to the 1 hour PMI and has the lowest cell death (as imaged by active caspase-3). When you look between CP and BEx, the difference is not that dramatic and makes me wonder that if we had the right CP formulation (with same glucose/lactate content), we would unlikely have a difference between CP and BEx, suggesting that perfusion with a saline solution oxygenated and with the correct amount of glucose can do as well than a more complex one.
Figure 4 show that the perfusion with BEx help to maintain astrocytes and microglial cells alive and functional (as measured by the secretion of pro-inflammatory cytokines following treatment with LPS).
Figure 5 show that there are some functional neurons present in BEx, capable to show electrophysiological activity. Small activity (not enough to be detected by EEG) but measurable by patch-clamp analysis.
Overall, it is a nice paper, considering it got published in Nature. There are some interesting stuff, but there are also some questionable limitations and caveats that I would have pointed as a reviewer and expected reviewers from Nature to have pointed it before letting it accepted. It shows that no matter what, never blindly trust a paper even if published in Nature.
The idea is very interesting and can help us better understand the post-mortem brain. It also raises the importance of CPR or any procedure aimed to keep a steady flow in the brain after injury or cardiac arrest and maybe worth considering it.

Categories
Junk Sciences Sciences

[Sciences/Junk Sciences] Essential Oils: The good, the bad and the ugly science behind some claims

Essential Oils (EOs for simplicity). These little bottles are almost everywhere. Advertised as “natural”, “pure”. Some even are trying to sell them as the next big fad. as the next “miracle cures all” remedy.

Everybody swears by EOs, giving them some curative properties despite the lack of evidence backing such claims. Their therapeutic activity is far from being demonstrated, but their ability to siphon wallets and fill bank accounts of those selling them is as efficient as  the Bernouilli’s principle.

The problem with EOs is to sort the good, the bad and the ugly science behind them.

@MommyPhD recently pointed this out in a nice chart taken from a company making a living on EO.

What I can tell, as the pharmacologist that I am, I was not only perplexed but mind-blown by this chart. It was not a nice mind-blowing effect. It was more like a trigger that turned into a “ballistic mode”.

Just see by yourself the chart below:

17634361_1898070473737773_8852685320786733500_n

What is wrong? Well, all the claims from the original infographic (left) are wrong! It just simply no sense if you have any basic in pharmacokinetics. Its time for the BBB scientist to deflect such woo with some science deflector shields.

First, in order to understand EOs, you have to understand their origin. To understand their origins, you have to have some basic understanding of pharmacognosy.

Pharmacognosy and EOs:

Pharmacognosy is the science that studies the chemical and biological properties of substances produced by plants and fungi. They are seasoned experts in botany, plant biology and analytical chemistry. Their main interest is to extract chemicals from different part of the plant (stem, sap, roots, leaves, flowers, fruit….), identify the substances present in such extract and identify their possible biological properties (this is often linked with ethnopharmacology, in which scientists are trying to identify the potential of some medicinal plants with their use from healers and shamans).

Plants and fungi synthesize two major classes of molecules: those involved in the primary metabolism and those involved in secondary metabolism.

Primary metabolism mostly aimed to ensure growth plant and reproduction. You can consider it as the core chemical plant. These are chemicals important for the plant function.

The second metabolism is on its own very interesting. At first, these compounds have no role in plant growth and therefore may appear useless. Indeed compounds produced from secondary metabolism are very important for the plant because these are essential for its survival. Plants evolved to have limited mobility and therefore are easy target for predators. But what plants traded out for limited mobility have indeed traded in one of the most sophisticated chemical warfare. Plants have evolutionary developed one of the most advanced and versatile chemical warfare aimed to control and deter any dangerous entities that may compete for limited resources (water, minerals, oxygen, light, CO2…).

Here are some examples of chemicals synthesized by plants secondary metabolism: Caffeine, atropine, cocaine, morphine, tetrahydrocannabinol, strychnine, nicotine, digoxin, ouabain, terpenes, cyanide, colchicine, vinblastine, paclitaxel, acetylsalicylic acid, phalloidin, forskolin, turmeric acid…….these are all products from the secondary metabolism. Many of them sounds like “poisons” and they are rightly called poisons because they can kill you at the right dose. But if you use these compounds at the right dose, these compounds can also be used to treat cancer, heart failure, glaucoma……..considering the dose makes the poison.

EOs are a particular class of chemicals, because they harbor particular chemical features. They are volatile (they belong to the superclass of volatile organic compounds or VOCs), lipophilic (soluble in fat and oils) and are odorant (this is why we can smell them). They are also capable of some biological activity.

These EOs have to be extracted from the plants via the use of organic solvent. One of the most common solvent is ethyl alcohol or ethanol (CH2OH), that is convenient organic solvent. Ethanol can help dissolve both lipophilic and hydrophilic substances. It is also has a low evaporation temperature (78ºC), allowing it to dissipate fast once on skin contact.
Another property of these compounds contained in EOs is their ability to become volatile. We can refer these compounds as volatile organic compounds (VOCs). This is why we use them as fragrance. Because they are volatile, these compounds are spread in the air and can be caught by our olfactory receptor neurons (ORNs), making what we refer a smell a smell. Smells are very powerful stimuli, even for humans. This is why we are all fond of “eau de toilette”, “eau de parfum” and all these molecular cues that can turn our reptilian brain upside-down.

EOs are very diverse by their origin and their composition. For the simplicity of this article, I will focus on the major source of EOs by their production: Citrus sirensis (sweet orange) and Mentha arvensis (mint) EOs. These are the two most prevalent sources of EOs worldwide.

Two studies that I have found listed the EO composition from these two plants.  C. sirens is  has about 50 different compounds identified, mostly classified as terpenes. M. arvensis  have about 30-40 compounds including terpenes and other organic compounds (http://www.ifrj.upm.edu.my/18%20(04)%202011/(10)IFRJ-2011-062.pdf and http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.927.8806&rep=rep1&type=pdf)

EO composition vary between cultivars, between crops, between extraction procedures. …..It means that EO by nature are anything but “pure”. EOs are therefore impure because you have a mixture of different compounds at different concentrations. It also means  that such EOs are setting the perfect storm for some drug interactions and some toxicity due to photo activation (some terpenes like limonene are know to become phototoxic following exposure to light)  or induction of an allergic reaction.

Pharmacokinetics and EOs:

In this second part, we will refute the claim brought about the penetration and tissue targeting mentioned in the infographic. The infographic have it wrong at so many different levels but two are striking: firstly, the sequence of events followed the extent of these events.

In order to understand the rebuttal, we have to understand some basic aspect of pharmacokinetics (PK). PK is the science that will tell you the fate of a chemical in your body. It will tell you how it is absorbed, how much reach the bloodstream and the tissue, how it gets detoxified and finally how it gets eliminated.
PK focuses on the fate of drugs inside our body, whereas toxicokinetics (TK) focuses on the fate of poisons and toxins inside our body.

Both follow the ADME acronym: Absorption (tegumentary/skin, intestinal/gut….), Distribution (bloodstream, tissues and brain), Metabolism (“detoxification” via chemical transformation and inactivation by the liver) and Elimination (via the liver and kidneys).

This is where the infographic has it completely wrong. It makesthe assumption that the EOs enter the brain, then the bloodstream and finally cells is just what I call “bullshit” and simply a reflection of a sheer ignorance of human anatomy and physiology. I dragged a small sketch to described the EOs ADME profile.

EssentialOilFirst, EOs have to pass the skin (or gut) barrier and diffuse all the way through the bloodstream. This operate through a passive gradient that result in the progressive loss of EOs compounds during the diffusion (depicted by the yellow arrow) into the bloodstream. This phenomenon is called “bioavailability” and investigate how much of a compound can reach the bloodstream following an administration route that is not obtained via direct injection into the bloodstream (intravenous or intra-arterial).

At the end of the day, this is the appropriate order of sequence: skin->bloodstream->brain (if you are lucky enough).

The amount of compounds contained in the EOs reaching the blood circulation remains unclear and poorly understood. But we can use some analogies with known chemicals. We will discuss the case of hydrocortisone (a topical steroid) and nicotine (a known compound capable to cross the BBB and act on the central nervous system).

Hydrocortisone is commonly used by practitioners to treat skin rashes and other irritations with a cream. The good thing about it is that such cream act topically. A thesis has documented previous studies that estimate about less than 5% of the amount of hydrocortisone applied to the skin was able to get a full ride into the kidneys (https://www.unispital-basel.ch/fileadmin/unispitalbaselch/Bereiche/Querschnittsfunktionen/Spital-Pharmazie/Diss_Pellanda.pdf). It is also telling you that a topical administration is probably not the best option for administration of a drug.

Now, there are other cases of topical administration that result in brain delivery. This is the case for nicotine and nicotine patches. These delivery systems are good in giving a good bioavailability, but yet these compounds will take some time to reach the brain. Considering the tmax (time by which a compound reaches a maximum plasma concentration), such delivery systems can only deliver nicotine with a tmax of 5-6 hours following patch application (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364642/?page=4). You can understand that the probability of compounds contained in EOs to reach the brain within 30 seconds is impossible, unless you perforate the skull and perform an “intraventricular injection”. This is a very invasive procedure requiring a brain perforation and the insertion of a canule deep inside the brain.

Now we can argue that some drugs can reach the brain within minutes following injection. This is true for anesthetics like propofol. However propofol administration route and chemical properties are very different from EOs: they are injected via IV infusion and propofol penetration across the blood-brain barrier (BBB) is known and documented. Yet, it still takes about 4 mins for a IV infusion of propofol to achieve tmax , making the alleged claims of 22 seconds in the infographic completely bogus (https://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4354b1-01-FDA.pdf).

Even if your compounds can diffuse the skin barrier at the speed of light (100% absorption and bioavailibity) and have no metabolism (0% loss in EO compounds), you still have to demonstrate that such compounds can cross the blood-brain barrier (BBB). The BBB  blocks about 95% of chemical compounds known by humans. Therefore it is very unlikely that all these EO compounds magically fall within the 5% range.

In addition, analyzing the fate of every single chemical compound present in one EO can be an analytical nightmare even for the most seasoned analytical chemist. @SciBabe can explain you that in more details.

In conclusion, the ability of EOs to exert their biological activity beyond their skin application is simply “dead in water” and subsequently the claims posted in the infographic.

EOs and their “therapeutic claims”: the FDA warning letters
EOs may smell good but they have no scientific basis to support their claims of therapeutic use as depicted on their website. This is why the FDA has decided to enforce its authority via warning letters to two companies.

In 2014, the Food and Drug Administration (FDA) sent two warning letters to Young Living (https://www.fda.gov/iceci/enforcementactions/warningletters/2014/ucm416023.htm) and DoTerra (https://www.fda.gov/iceci/enforcementactions/warningletters/2014/ucm415809.htm) noticing them of the violation of the Food, Drug and Cosmetic Act by advertising therapeutic claims that have not been asserted. Unless you file an application in which you document with a great care the safety and the efficacy of a therapeutic agent, you have no rights to make a claim that compound X will prevent or cure cancer or other illnesses. What was true for these two companies also applies for any companies selling EOs.

Do not use EOs to treat or cure any illnesses because their therapeutic activity have not been proven by scientific methods. Worse, if misused these EOs can become dangerous poisons if swallowed  (http://www.poison.org/articles/2014-jun/essential-oils). You have been warned.

In conclusion,  EOs make great scents and fragrances to make your house smell nicely. But that should be their only application. Use them as personal fragrances with extreme precautions and avoid their swallowing and use as medicines.

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Sciences Stem Cells Uncategorized

[Science/Stem Cells] Stem Cell Therapy and Age-related Macular Degeneration – A Tale of Two Cases Reports

Yesterday, a breaking news in the stem cell field came from a case report published in the New England Journal of Medicine (a respected journal in medical research) (http://www.nejm.org/doi/full/10.1056/NEJMoa1609583?query=featured_home).
What is probably the most intriguing about this case report from a stem cell clinic, that had a clinical trial submitted to the FDA and subsequently withdrawn in 2015 (https://clinicaltrials.gov/ct2/show/NCT02024269?term=NCT02024269&rank=1).
This case report focuses on three patients, elderly patients (70+) and all three suffering from age-related macular degeneration (AMD).
They all three being injected with mesenchymal stem cells. For those not familiar with stem cells, stem cells comes into different flavors depending on their origin and potency abilities. The most pluripotent type of stem cells are the embryonic stem cells (hESCs) that are derived from embryos. Following in their pluripotency comes in the induced pluripotent stem cells (iPSCs). Unlike hESCs, iPSCs are reprogrammed somatic cells (usually skin fibroblasts). Then we have bone marrow stem cells (from bone marrow) that have a narrower pluripotency but proven efficacious for treating patients with leukemia. Finally we have the mesenchymal stem cells (MSCs) obtained from the stream fraction of adipose tissue. Usually these cells are obtained by liposuction and isolated from the fat tissue via defined protocols.
Now this last type of cells has a certain classification that allows to use a loophole. In order to conduct a clinical trial, you have to submit an investigative new drug (IND) application to the Food & Drug Administration to show evidence of safety and efficacy from pre-clinical studies. These are safeguards that ensure patients and medical researchers enrolled in such trials.
Now, when you are dealing with MSCs, these stem cell “clinics” can exploit some loopholes and apply for a non-IND application if your trial follows two criteria: it is an autologous procedure (you are injecting cells from yourself back into your body) and there is no procedures that modify the material used (in that case, the purification steps are not altering the MSCs identity and function).  In addition, these trials have to be done without any financial link. In academic institutions, you neither ask the patient to pay for the clinical trial nor  provide the patient with a financial compensation (only a possible therapeutic outcome, if the treatment work). In this case reports, all patients paid $5000 to that clinic. it is also important to note a certain level of deception from the stem cell clinic as this registration at the ClinicalTrials.gov website appeared to these patients as a clinical trial were it was not. It is even mentioned by the authors of this case report that none of the consent form signed by these patients displayed “clinical trial”.
There is also report in the consent form that the patient were informed of the risk of blindness and were requesting to have the procedure done in both eyes.
These patients rapidly developed post-operative complication including retinal detachment, increased ocular pressure and hemorrhagic events, such complications were not taken care by the clinic involved in the stem cell procedure and were done in eye clinics in patients domicile.

By coincidence, NEJM also published another case report of the use of stem cells in AMD in a clinical trial in Japan (http://www.nejm.org/doi/full/10.1056/NEJMoa1608368?query=featured_home). This procedure was done using iPSCs from patients and derived into retinal pigmented epithelial cells (RPEs). These cells are lining the outer side of the retina and serve as a barrier for protecting the retinal neurons involved in vision. This is the famous “iPSC clinical trial” from Takahashi and colleagues that had to be halted due to some safety issues that were corrected (https://ipscell.com/2016/06/good-stem-cell-news-as-takahashi-ips-cell-trial-to-resume/).
So far, the encouraging part is the absence of post-operative complication and graft rejection and the patient showed an improvement in her vision.Yet, this is a single report and the authors were also very cautious about to make overstating conclusion.

These two cases report should inform into two things: we are making little steps but confident steps in stem cell based therapies but it is also important to raise awareness and vigilance about the methods of some stem cell clinics making unrealistic claims of stem cell therapies or posing as clinical trial center.

My recommendation is if you decide to jump into a clinical trial is to verify the affiliation of the center (avoid any private firms and check the credentials of any institution supporting this trial), ask your doctor to help you read through the consent form and never ever be asked to pay for the procedure. The trial is funded by research grants, if it is requested that you cover the expenses of such procedures run away!

 

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[Sciences] First clinical trial using the CRISPR/Cas9 in China.

You may have heard about the news on the first clinical trial in China that was consisted of inoculating cells modified by the CRISPR/Cas9 technique. In this post, I relaying the original article published in Nature online about the trial (source: http://www.nature.com/news/crispr-gene-editing-tested-in-a-person-for-the-first-time-1.20988?WT.mc_id=SFB_NNEWS_1508_RHBox)

For many of you, CRISPR may not be much explanative except the word that sounds like something being “crispy”. Indeed the technique is.
But let’s understand the technique to better understand why it is a breakthrough. There is a nice video made by iBiology and featuring Dr. Jennifer Doudna (the co-discoverer of CRISPR/Cas9) explaining very nicely exhaustively in lay terms the CRISPR/Cas9 technique that I will quickly resume to keep that post short

 

CRISPR/Cas9 acts as a little genetic scissors, that permit us to cut and paste genetic data into cells. Stricto sensu it is not new and we have doing it in bacteria, yeasts, plants, fruitflies, zebrafish and mice for a while now. But one thing we have been facing is editing genomes in bigger animals like rats, primates and humans. It is extremely difficult and very poorly efficient.

With CRISPR/Cas9, we suddenly have a magic wand that now makes the impossible-possible by making the gene edition in higher mammals much more easier. Also CRISPR/Cas9 allows us a more targeted editing, precisely.
However the technique has known some possible off-target gene editing, such caveat is enough to raise concerns for patients safety. However, as science goes, there is a rapid interest in the technique and improvements are coming in the fast pace.

In this trial, the investigators have taken immune cells from a patient suffering from a lung cancer and removed a gene called PD-1. PD-1 is a receptor for a molecule called PD-1 ligand, a protein secreted by cancer cells. Upon interactions with PD-1L, PD-1 results in a immune suppression and shutdown of the immune system. By removing PD-1, the immune system is no more silenced and now can target and strike cancer cells. This is a new concept in fighting cancer cells called immunotherapy.

This trial will tell us two things. First if the technique is safe and second if it is efficacious. The treatment appears safe (because the cells have been engineering outside the body and reprogrammed in a dish before being reinserted) but we cannot exclude any severe if not fatal side effects.
The second is the efficacy. There are evidence of PD-1 targeting being a novel treatment that showed promising results in Phase II and III clinical trials. But that will work with lung cancer? We will have to wait and see….

If it works, that would be fantastic and open the possibility to revive the gene therapy that has been mostly stuck in limbo by our lack to insert and correct defective genes in patients.

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Sciences

[Science] What if cancer was just a series of bad luck?

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Source: C. TOMASETTI, B. VOGELSTEIN AND ILLUSTRATOR ELIZABETH COOK, JOHNS HOPKINS UNIVERSITY, The Scientist magazine.

Since the “war on cancer” decorated by Richard Nixon in the 1970s, where are we after 40 years of research on cancer and why do not we have a cure for cancer?
We have learned a lot about cancer:

* We referred to cancer as a single disease, but it is indeed  an umbrella for many different types of diseases. A brain cancer is different from a lung cancer.

* We have been classifying cancer based on the tissue of origin (carcinoma, sarcoma…),

* We have identified many genes that once mutated result in cancer, we have identified many environmental factors capable to increase your risk of cancer (tobacco, smoke, obesity, polyaromatic compounds, ionizing radiations….). http://www.ncbi.nlm.nih.gov/pubmed/24816517.

* We learned that cancer is a disruption of a physiological balance, for instance we thought that an excess in oxidative stress and free radicals were promoting cancer. http://www.ncbi.nlm.nih.gov/pubmed/25496272.

* We have highly improved the way we detect cancer, remove surgically cancer and found new chemotherapy that really improved survival rate in many cancer. Yet, malignant brain tumors (glioblastoma multiform and brain metastasis) remain the most deadly form of cancer, in partly because we fail to deliver therapeutics across the blood-brain barrier. The tragic case of Brittany Maynard as well as children with aggressive form of medulloblastoma makes me feel helpless because I know how powerful the blood-brain barrier is in blocking the delivery of these agents. It will be hard to untangle a evolutionary trait to protect our brain from neurotoxic and poisons to deliver it.

* Stem cells and malignant cancer cells seems to share a dark common origin. If you inject stem cells in an animal, they become wild and form teratomas, just as cancer cells would do. But they also share similarity and I like to refer that stem cells keep “the primitive cell phenotype” in a evolutionary standpoint. I like to think that cancer are cells that “accidentally” turn on the time machine and reverse their biological and evolutionary clock back to the time were LUCA (the Last Unicellular Common Ancestor) were swimming in the “Primeval soup”.

So now, we now that “one size fits all” approach to treat cancer and we really need to think about treating it as a personalized approach, using modern technology (genomics, epigenomics, proteomics….) to dress an identity card of the cancer for each patient to find which approach is the best.

Cristian Tomasetti1,*, Bert Vogelstein2,* Science 2 January 2015:  Vol. 347 no. 6217 pp. 78-81  DOI: 10.1126/science.1260825

Source: Cristian Tomasetti, Bert Vogelstein. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2 January 2015: Vol. 347 no. 6217 pp. 78-81. DOI: 10.1126/science.1260825.

The recent study from Tomasetti and Vogelstein indeed show that incidence of cancer is “bad luck”. We know that each time our cells divide, the duplication of our genome is not “fool-proof” and introduce a mutation (1 base pair mutation for every million replicated). This is a handicap (because you loose your information over time) but it is also a blessing because this is how evolution works and what we are. Just a bunch of lucky mutations spanning over a billion of years of zillions of cell divisions. Under normal circumstances, we have “safe-fail mechanisms” (tumor suppressors) that are here to send defective cells into apoptosis (a sort of auto-destruction mode or if you like the cellular version of “hara-kiri”). But sometimes these defective cells do not follow that path and keep proliferating. This is all about. More you have cells within a tissue that keeps dividing, more you increase your risk to increase your pool of potentially tumorous cells. At the end, it is just a long equation of probability in which risk factors just increase the probability to success of the event.

My recommendations? Stay healthy (exercise often, follow the nutritionist recommendation for calories intake), stay safe (especially if you are working in a risky environment, follow your safety and OSHA guidelines), keep a regular check on your health and if you feel something weird do not hesitate to further investigate. And please, follow your physician recommendations.

Happy new year y’all.

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Sciences Society

[Sciences] My Top 10 Sciences Discoveries of 2014

Here I am, a couple of hours before the end of 2014 and lots of excitement in science this year. Here are my top 10 discoveries that marked me this year. It is surely biased (stem cells, blood-brain barrier) but hey I am a scientist after all. There is no particular ranking, so do not use the numbers as a rank.

Note: I will update this blog post by adding additional contents.

1.STAP Cells

The latest blog post from Dr. Knoepfler on the STAP cells debacle

STAP cells: stimulus-triggered acquisition of pluripotency. This was certainly the buzzword of January. Imagine that. Cell reprogramming (following the Yamanaka protocol) of somatic cells into iPSCs is a daunting experience. It is long, expensive and low yield (0.1%). When the technique came, it brought 30% yield and sounded as easy as prepping kosher-dilled pickles. Yep, just that, plunge the tissue into some acidic bath (that is a scientific iteration of the pickling process) and you get 30% of iPSC-like cells (or STAP cells). Sound as easy as ABC, no? Well indeed it was not. And it turned sour very fast indeed with over 10 labs trying without success. First came some statement similar to “it’s complicated”, then inquiry from RIKEN university in Japan followed by obvious scientific misconduct and paper retraction as the first author failed to reproduce the original data. In addition, the senior author committed suicide. A tragic ending for a flawed study, a “too simple to be true”.

2. The first stem cell clinical trials for retinal macular degeneration

This year have seen the first stem cell clinical trials using hESCs and iPSCs in patients suffering from macular degeneration. Preliminary results are showing a relative safety of the technique (no tumor observed so far) and some reports of improvements in certain patients. It is still not known if such improvement is a “placebo effect” or real effects. Similar studies are ongoing for other cardiovascular diseases and for neurological disorders such as Lou Gehrig’s disease or Huntington’s disease at the Mayo Clinic. However, I would like to remind people that there is yet no stem cell cures or proven stem cell therapies. Please, please, please do not listen to those claiming “stem cell therapies” that are working. There is not such thing and there is not yet any FDA-approved guidelines for such. A lot of labs are working to bring stem cells from the bench top to the patient’s bedside but still a lot of way to go.

3. The gut-brain interactions: the blood-brain barrier as the middleman

Diffusion of an IR-dye across the blood-brain barrier in a “sterile” mouse compared to “pathogen-specific free” mice. Note the fluorescence intensity showing a leaky BBB. Courtesy Karolinska Institute.

This was the most interesting and the fast-pacing rise. Until a few years ago, we mostly believed that the gut microbiota would only affect the GI tract without any incidence on the rest of the organism. I was stunned by two studies: one study showing the impact of microbiota composition in the gut flora on autism-like symptoms (http://www.ncbi.nlm.nih.gov/pubmed/23307560) that shows how the alteration of the flora composition resulted in the display of autism-like phenotype. The mechanisms are unknown but it seems the presence of a leaky intestinal tract may trigger neurobehavioral changes. The second comes from http://www.ncbi.nlm.nih.gov/pubmed/25411471, in which they show that the absence of a gut microbiota results in an increase leakiness of the blood-brain barrier. It took 60 years for neuroscientists to admit the presence of a blood-brain barrier. Hopefully, by 2020, neuroscientists will finally understand how crucial the BBB is for the brain well-being and the salute of treating neurological diseases will only come when they will understand that we BBB scientists are as important as them.

4. Human induced pluripotent stem cells as disease modeling and drug toxicity screening

If one biomedical research field that quickly emerged in the last decade, it is certainly the field of induced pluripotent stem cells (iPSCs). For those who are not aware about iPSCs, this is an important discovery of this century. Once the egg is fertilized, it quickly divide into 2, 4, 8, 16 cells up to reaching a stage called a “morula” stage that ultimately evolve into a blastocyst. This blastocyst will eventually become…YOU! Interestingly, all these cells are called totipotent as they can form any type of cells. These are the classical “embryonic stem cells” that have raised hope and fears among the public.
All of our cells have the same genetic information but what makes a neuron from a muscle cell is the number and types of genes that are ON and OFF. This is what we call the epigenome. By reverse-engineering it, we can bring reverse the clock on these cells to bring them into a pluripotent stem cell stage. Once pluripotent, we can reprogram these cells into any type of cells. This dedifferentiation stage was developed by Yamanaka in 2006 (Nobel Prize 2013) and applied to human cells by Jamie Thomson in 2007. Since then, a lot of effort have been done to differentiate these cells into various cell types including neurons. This open a new perspective as we can now try to understand human diseases in a dish by directly having access to patients cells. And this have been successfully applied in these last five years for different types of neurological diseases. If we have to show a poster-child for personalized-medicine, that would be its first iteration. There are numerous studies showing the ability to differentiate neurons from patients suffering from Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, frontotemporal degeneration, Dravet Syndrome, Fragile X Syndrome, schizophrenia….
As we are just starting to understand the mechanism of diseases, we can now foresee the possible usage of these cells to identify novel compounds capable to slow or even relapse the disease.

5. The Edna Krabappel and Lisa Simpson peer-reviewed study

http://www.sciencealert.com/two-scientific-journals-have-accepted-a-study-by-maggie-simpson-and-edna-krabappel

This was one of the big bust, especially when you are in the academic field and know the calvary of publishing your manuscript. Getting your study is a long and patient process in which you have to deal with peer-review process, in which other scientists (anonymously) review your study and give their decision to the editor-in-chief about if your study is good for publishing or not.

In the classical model, the journal charges the authors of the study for publishing the study and the readers to access to the full journal. And having access to journals can be very expensive especially if you are in a small university or if you are located in a developing country. Still even with the best peer-review system, there are still flawed study that made it to publication and get retracted (http://retractionwatch.com). Since these last few years, an important step have been done to provide open-access to scientific papers. The authors pay a publication fee (usually higher than the traditional journal) but the paper is freely accessible to read it.

This new model has of course brought some interest for some people seeing “easy money” to be done, by accepting ANY studies, even from fictional characters. The fact that a paper authored by Edna Krabappel and Lisa Simpson filled of non-sense text fillings raise concerns and make a call to establish some guidelines and ways to select the “good open-access journals” from the bad ones. Also this year, the NIH Library of Medicine, the Pubmed portal (a well known scientific articles search engine for biomedical scientists) has launched the Pubmed Commons to provide an open, post-publication review mechanism in which anyone can comment on any paper presented in Pubmed.

I believe this is the first case of many uncovered and we are expecting to see more. It is a time we have to decide if we keep our science straight and well-sounded or if we let hijacked by flawed and manipulated studies.

6. Rosetta Stone and Philea probe

This was the biggest achievement of the European Space Agency (ESA). Can you imagine sending a remote probe, have it land on an asteroid. You have to imagine piloting a RC buggy car through a screen with 10 minutes delay between the time you see the obstacle and the time the command is executed. Imagine you drive your RC buggy see a tree in front of you, send the command to turn right and have to wait 10 minutes to get it done.

If I have one rant to make, it certainly on some trolls that pointed on Dr. Mark Taylor’s shirt and ignored the scientific achievement accomplished. Yes, having this shirt on live broadcasting was a terrible PR move, but putting on that shirt to blame the problem of women in science is wrong. The problem is much bigger than a shirt and those that are putting bars in the wheels of women in scientific careers are not wearing such shirts. We need to re-think about the whole system to better retain women in sciences, set maternity leaves and adapted schedule to have them the possibility to adapt their work to their schedule, tailor the tenure process to take in consideration that women have to deal with two important choices in their life in the same time and should not be forced to choose one  for the other.

Although Philea landed in a wrong place and rapidly died from low battery, it gave us some information. For a moment, I fell in love with Philea, like a real-life WALL-E. I am looking forward to have it back on track and running up soon.

The also interesting projects are the Mars Curiosity roving over the red planet and found some bursting methane (that could be some microbial life) and of course the Pluto mission coming in early this year.

7. Prosthetic arms and cyborgs

As a kid, I always got fascinated by robots, cyborgs and giant mechas. I grew up watching “UFO Grendizer”, “Star Wars”, “Transformers”, “The Terminator”, “The Million Dollar Man”, “Robocop” but also got frightened by “Galaxy Express 999” in which in a distant Earth future, humans have most of all acquired immortality by replacing their biological parts into robotical parts. Those who failed to afford or refused to become cyborgs are considered as sub-humans and hunted as preys.
Human-mechanical interfaces sounded like science fiction 20 years ago. As we have been progressing in neurosciences, we also have considerably improved in mechanical engineering and electronic. We are just assisting in the first trials in which prosthetic limbs are directly connected to the brain surface or capable to transduce electrical impulse from nearby muscles to execute movements. Two trials especially caught my attention: the one depicted in the picture and currently run at John Hopkins University in the Department of Applied Physics. The two robotic arms can sense muscle activity from the chest and transduce into complicated movements. Watch the video it is really impressive to see this man capable to regain functional from lost limbs.

http://bcove.me/vst8dnvp

The second one from the University of Pittsburgh allowed a quadriplegic woman to gain control of a robotic arm through a brain-connected interface. Look at the fluidity of the arm, the dexterity. Remember this is a robotic arm connected to the patients brain, it is just  awesome to see the improvement of such discipline over the years.

8. The lady with no “Little Brain” (Cerebellar agenesis)

Source: Cerebellar agenesis Luigi Titomanlio, Alfonso Romano and Ennio Del Giudice Neurology 2005;64;E21 DOI 10.1212/WNL.64.6.E21
Source: Cerebellar agenesis
Luigi Titomanlio, Alfonso Romano and Ennio Del Giudice Neurology 2005;64;E21
DOI 10.1212/WNL.64.6.E21

The cerebellum (or little brain in Latin), is an important piece of the central nervous system. Its function is essential in the locomotion and in the coordination of movements. This is also the primary target of ethanol, the active component of alcoholic beverages (or booze if you like it). Thats why when you are drunk you loose your reflexes and have the typical walking pattern of a drunk person.

We may think that the absence or severe malformation of this organ may significantly impact the locomotor function. Seems not according to a recent study from Fu and colleagues (http://brain.oxfordjournals.org/content/early/2014/08/22/brain.awu239.long). Apart from having trouble to keep an equilibrated statute and some episodes of nausea, the patient appears to have a normal life as she is reportedly married and has one daughter. It shows one thing: the brain appears very plastic and can rewire some of its functions if needed. The most interesting aspect now is how the cerebellar function is re-wired and compensated by the other brain area and which areas?

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Sciences Society

World Stem Cell Summit 2014, wrapup and impressions

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Just coming out the #WSCS14 conference that was held in San Antonio this year. Oh boy, three days of intense scientific contents and networking, three days of running from one conference room to another and looking at the program to be sure to pick the most relevant one. Time to metabolize and put some thoughts on a blog.

This was a great meeting, especially for one that I just got introduced. Lots of good speakers, interactions with the exhibitors and with other presenters. It was a truly unique experience to get to know the San Antonio biomedical research area and strengths. It clearly seems to me that UTHSC San Antonio branch really try to built a strong research on stem cells research, including non-human primate based research. It was for me a particular chance to identify possible collaboration within the state of Texas.

The second aspect that i appreciate was the eclecticism of attendees at this meeting. Typically, you have conferences designed by scientists for scientists. Here I had the chance to discuss with scientists (sure it is a scientific meeting) but also with fundraising agencies, core facilities managers, patients and patients advocacy groups. And that is unique to have such patients advocacy groups that brings us back to what is our research is about: finding cures for patients because patients outside are suffering from their conditions and the medical advances are not reaching them. This is where as an outreach enthusiast I can grasp the need to scientists to reach out to the community and understand why their tax dollars means and how it get used.

Another session that i particularly appreciated was the “Ethics and Scientific Misconducts in Stem Cell Research” hosted by various speakers including “Retraction Watch” Ivan Oranovsky and Graham Parker, Stem Cell Development Chief-Editor. The stem research is a promising research field, a fantastic boat to sail on but because it has enormous potential and impact on medical research that can be easily hijacked by snake oil sellers (those claiming to have working stem cell therapies beyond the stage of clinical trials) and the forgery (remember the embryonic stem cell cloning fraud from South Korea in 2004)?

Here I am, waiting for my flight back to the Panhandle, now boosted more than ever to push on my research interests, developing new avenues of collaborations and hopefully developping the stemming stem cell research community in Texas.

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History: Great myths die hard

http://www.nature.com/news/history-great-myths-die-hard-1.13839?WT.mc_id=FBK_NatureNews

Joseph Lister bringing the concept of anesthesia and aseptic conditions, Alexander Fleming miraculous finding of Penicillin, Pasteur discovery of the anti-rabies vaccine…..Science is full of these unexpected findings and discoveries that brought us these heroic moments. But are these stories really true?

Read the latest scientific history article co-authored by Dr. Heloise Dufour, a remarkable colleague here at UW-Madison, also a talented HHMI teaching fellow and proven science out-reacher. A must-read.

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Supreme Court: Natural DNA is not patentable (but cDNA is)

Supreme Court: Natural DNA is not patentable (but cDNA is)

The recent decision of the Supreme Court is a big relief for scientists like me, following the battle engaged between Myriad (the company behind the BRCA test and Angelina Jolie’s story). It clearly stipulates that natural DNA cannot be patented, but artificial (cDNA) can.
What are the differences and how it would impact us? Lets take the BRCA gene as an example.

Mutations in the BRCA genes (BRCA1 and BRCA2) are linked to increased risk in breast and ovarian cancer (thus explaining Angelina’s decision for the double mastectomy that I would argue against but this not the topic of this blog). Before the decision, Myriad had the exclusivity of the BRCA gene including the gene product (protein), thus making the development of detection kit and assays exclusive to Myriad (at least in the US). The problems of this test? Very expensive ($3000-6000 per screening) and not 100% reliable. On the other side of the Atalantic Sea, French have also a BRCA kit that is slightly cheaper than the US one but also more reliable. Thus, we can clearly understand that having the open access to the genome would help the development of new technologies and at the end decrease the cost of this kit, good for your health and your wallet.

The proof of my reasoning? Look at the cost of DNA sequencing. You even have a company called “23 and Me” that sequence your genome for $100 (but also opens another genie contained in the bottle).

In the other hand, artificial DNA is still under patent. What does it mean? For the general public not much but for scientist, that means now virtually everyone can patent any cDNA or recombinant DNA (for example someone that created a hybrid of the BRCA gene fused with a green-fluorescent protein contained in a plasmid could apply a patent on it). That can be a no-problem for scientists (as patents most of the time protect the intellectual property by the scientist that formulated that cDNA and you have to acknowledge them in your publications at minimum) but may become a hassle for all these companies like Affymetrix, Illumina or Agilent that heavily rely on cDNA for the DNA microarray analysis (the next BIG THING is personnalized medicine). So let’s how things are going in that direction….