[Sciences] Today’s awareness day is Rare Diseases Day

Today is February 28th, it is Rare Disease Awareness day. Rare disease (or orphan disease) are diseases that have a small incidence among the population. We talking about patients fewer than 200’000 (Source: raredisease.org). That’s paradoxically a lot of patients suffering from diseases most of the time misunderstood or as I like to call a scientific “black box” although 80% of them are genetic and 50% affect children.

They are challenging for two reasons: parents and patients have to visit many doctors to find a cause of their disease condition and once identified they often end up with the same answer: no known cures. No cures because the number of individuals affected are small and making a drug costs a lot of money.

Don’t blame Big Pharma, Big Pharma is a business and like another business he has to make benefits out of its products to live. Unlike other markets in which return on investment are fairly good (e.g. hi-tech companies), pharmaceutical companies gamble high on R&D with a high risk on dead-end with a big negative value (important money loss). To give you an idea, only 1 out of 10’000 compounds that have shown promising hit in a screening platform will end up FDA-approved, in other means starting to bring cash in.

I am a scientist and you may know from my blogs that my research focus on the blood-brain barrier. Its play an important role as a gatekeeper, a cellular custom border patrol allowing the entrance of documented aliens necessary for the proper brain functions and to block the entrance of undocumented or suspicious aliens that may have harmful activities inside the brain.

We know that the blood-brain barrier breaches during several neurological diseases, but yet we poorly know how genetic disorders may affect the blood-brain barrier integrity. There are indeed some rare diseases that have a dysfunctional BBB but because it affects neurons, it mostly go unnoticed and are classified as neurological disorders. To raise awareness about rare diseases, I wanted to present two of them that have been linked to some of my research:

– Allan-Herndon-Dudley Syndrome (AHDS):

The Clive Svendsen’s lab (Cedars-Sinai) focuses on understanding neurological diseases using induced pluripotent stem cells (iPSCs) from patients. I have worked with Pr. Svendsen, Dr. Gad Vatine and Pr. Eric Shusta (University of Wisconsin-Madison, not pictured) to try to better understand the contribution of the blood-brain barrier in the disease.

AHDS is what I call a fairly rare disease (<100 cases) but we may just have tipped an iceberg. It is what we call an X-linked mental retardation. It mostly affect boys and rarely girls. Why? If you remember your high-school biology class, mens have a XY pair and women have a XX pair. The X always come from the Mom, the Dad in the other hand gives either a X (thus XX) or a Y (thus XY). The mom carries the mutation, thus the son display the disease.
The disease is very dramatic has its sign appears during the first year of life. Infants start to show problems in their psychomotor growth and cognitive development. According to Dr. Vatine, these kids brain somehow stop growing around 8-12 months, whereas their body keep developing normally. They barely babble words, have severe impairment (require constant care) and have no cures.
These patients suffer from a mutation in MCT8 (monocarboxylate transporter 8), a nutrient transporter involved in the uptake of bioactive thyroid hormone (T3). Patients show a high plasma level of T3, yet some studies suggest a low T3 level in the cerebrospinal fluid. Although mouse models of the disease (MCT8-knockout mice) have been developed, they failed to fully represent the signs of the disease. A problem observed with rodents is the interspecies differences, rodents are not humans and sometimes they do not reflect human diseases. It has been that indeed OATP1C1 (a nutrient transporter expressed only in rodent BBB) can transport T4 (the precursor of T3) into the BBB. Humans do not have any identified T4 transporter.

If you want to know more about the AHDS syndrome, feel free to consult the SMILE/Sherman foundation: http://mct8.info

– GLUT1 deficiency syndrome (GLUT1-DS)

The brain surely not run on Dunkin Donuts, but run on something highly enriched in their donuts: sugar. Glucose in particular. The brain is a high glucose consumer. Compared to its size (1% of the total body mass), the brain take over 20% of glucose of your total intake. However, if you fast or starve on an Atkins diet, the brain can bypass the glucose as source of energy and can use fatty acids degradation byproducts, in particular ketone bodies as a alternative source of energy. Yet there is this disease called GLUT1-DS or De Vivo Syndrome.

In this disease, the patients have in the mutation in GLUT1 transporter, a nutrient transporter that uptake glucose from the blood to the brain. These kids are doing fine during their first year and then start to develop epilepsy type of seizures in the same age, that is very unusual for children (usually toddlers and kids have absence seizures or “petit mal”). These kids fail to respond to their anti-epileptic drugs and their only positive outcome is the diagnosis and the change in supplementation into a ketogenic (Atkins) diet.
I am wondering if such condition may be more spread than expected, as nearly 30% of patients have refractory response to common anti-epileptic drugs
Hopefully, there is some good news ahead from these patients, as some clinical trials with trihepatonin have shown some positive outcome as a dietary supplement in lieu of the ketogenic (Atkins) diet.
If you want to know more about the GLUT1 deficiency syndrome, feel free to consult the GLUT1 foundation: http://www.g1dfoundation.org

[Metal] Adrana – Frozen Path

Facebook is fairly often full of trolls about considering what is metal or not, but sometimes you can find some interesting bands that you would have never heard of. For instance, French symphonic metal bands. Maybe in Europe I may have a chance to heard some of them. In the US? No way!

2015 has been so far a discovery of French or French-speaking symphonic/progressive metal bands. I never much adhered to the French music scene, that I personally found too mainstream and lacking of publicized and quality metal bands. But these couple of years have seen some firebrand coming out of nowhere.
Check out Whyzdom’s latest album “Symphony of a Hopeless God”, it has been a long time that I did not hear a great album that can rivals with Epica. There is also a couple of hopefuls like Ethernity (progressive metal) or Unseelie (gothic metal).

My latest discovery is Adrana. They have been fairly silent since their 2011 album “The Ancient Realms” but maybe for a good reason. They have an album in the making. Their latest album is fairly good, by convention I do not review albums that have been already published. You can find it on iTunes (it is the only one listed on iTunes by the way).
But what really impressed are the vocals from Anae.  Holy Goodness, that vocals! Opera-quality vocals, a soprano-mezzo range, slightly under in terms of tone compared to Tarja or Floor, much lower than alto such as Sharon or Simone. It is really impressive especially for a “little league” metal band.

Here is one of their track of their previous album, to let you judge of gifted Anae vocal range:

Slowly but surely, 2015 will be the year in which Gallia will take its share of symphonic metal along the Batavian divas and the Valkyries of Asgard.

[Metal] Ethernity – Entities

This year seems to be fairly interesting in the metal scene, especially in terms of French-speaking metal bands. I have reviewed the latest album of Whyzdom in one of my previous post.
This time, there is a new video from a Belgian band called “Ethernity” with their first single called “Entities”. I believe this is their first album to come. It sounds pretty good for a newcomer in the progressive metal scene and tease me enough to put a pre-order of their album on iTunes (I believe the album will be out in stores by end of March).

Definitively a progressive metal band to watch….

[Junk Science] The Food Babe: “There is just no acceptable level of any chemical to ingest, ever”

The Food Babe: “There is just no acceptable level of any chemical to ingest, ever”.

Based on her comments, she is good to die within days. Water? Chemical (dihydrogen oxide). Bread? a-D-glucopyrannosyl-1,4-glucopyrannose polymer. Chemical. Coffee? 1-methylxanthine. Chemical.

Fallacy and junk science? “There is no acceptable to level of any junk science to accept, ever”

Skin Test May Shed New Light on Alzheimer’s and Parkinson’s Diseases

Today have been an interesting day so far for sciences News. Apparently, there is a Neurology conference coming in DC this April, the American Academy of Neurology 67th Annual meeting. And it seems they have some breaking news to announce in this conference.

What is interesting is this press release from the society citing a study currently presented in the meeting.

In this study, the authors have hypothesized that neurodegenerative diseases may have some phenotype outside the brain, especially involving protein misfiling or wasting accumulation like Alzheimer’s or Parkinson’s. The authors hypothesized that if these proteins accumulate in the brain, why about the skin?

If you ever had Embryology 101, you know that from the single fertilized egg, you end up generating over 300+ different cell types with distinct structure and function. We also know that the nervous system and skin system share the same origin. After all, the nervous system derives from the neural crest, that derive from the ectoderm (thus the term of neurectoderm classically used to refer to these types of cells). Therefore, if you face a problem with the generation of toxic byproducts in the brain, you should see the same phenomenon happening in your skin cells.

Seems so, or at least for a very small number of patients (n=20), so you really have to take it with a big grain of salt, but it is fairly exciting. They observed an increased (7-8 fold increase) in tau protein, alpha-synuclein in skin biopsies from Alzheimer’s and Parkinson’s diseases respectively compared to control groups.

Thats sounds very exciting and promising, as the current medical intervention is based on diagnosis of the disease with a confirmation only by post-mortem analysis. Maybe detecting AD or PD early on may help to tame or reduce the dramatic impact of the disease.

Link to the press release:

Skin Test May Shed New Light on Alzheimer’s and Parkinson’s Diseases.

The Supreme Court rules out iPSCs cell patent

If you are in the stem cell field, you know that one of the problem actually mining the field like a minefield is the intellectual properties and patents. Especially here in the US, in which both human embryonic (hESCs) and induced pluripotent stem cells (iPSCs) are subject to patents and IP through the Wisconsin Alumni Research Foundation (WARF).

That have created some stirs with a series of court decisions to define if WARF have the rights to patent these stem cells and hold exclusive aspect of it. This of course ended up at the Supreme Court to get the final word on it.

Well it seems the Supreme Court get its final word to end up its imbroglio, according to U-T San Diego and reported by the Genetics Policy Institute:http://www.utsandiego.com/news/2015/feb/24/supreme-court-rejects-warf-patent-case/

And the final word was a “Yeah!” for the embryonic stem cells (in other words WARF keep their exclusive patents and licensing on them) but a “Nay!” for the iPSCs, in other means anyone could derive the iPSCs without having to request a license to do so from WARF.

Now let’s see how things deconvolute and how the fallout of this news will shake the stem cell field but I think an old post from Pr. Paul Knoepfler worth to be updated in the light of the newest development, here is the original link to the article: Putting the IP in iPS cells: patent war looming? | Knoepfler Lab Stem Cell Blog.

Did HARE5 blew the WNT of change in Adam’s brain?

Okay, it is surely a lousy wording from me but it’s all about these “brainiac” mice that have shown an enlarged brain, in particular in their neocortex (a brain region associated with high cognitive and social task processing).
In the study by Boyd and colleagues published in Current Biology entitled “Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex: Current Biology“, the authors have inserted a particular DNA region called HARE5 into mice and observed the expression of this genomic sequence during development using the classical LacZ reporter. For those who do not know about LacZ, it is an enzyme that is expressed in bacteria such as E.coli that breakdown lactose into glucose and galactose (a close cousin of the same enzyme that make you lactose-tolerant or intolerant). The good thing about this tool for biologist is that it can act as a great tracer to screen when and where a gene is turned ON. Once ON, this gene is transcript into messenger RNA and then translated into proteins (central dogma, Biology 101 anyone?). Then you can track the enzyme activity with a chromogenic substrate, in this case X-gal. X-gal gets cleaved by LacZ (because LacZ may think it is a lactose) and release the X from the gal, giving a nice indigo blue color like the picture below:

If you place a DNA sequence that you think acts as a promoter for a gene, just stick it next to the LacZ gene, insert into your embryos and track it down during different developmental stage (a mouse have about 22 days of gestation).
Now what it is interesting is that the authors pinned HARE5 as an interesting candidate, as it enlarged mouse brain in HARE5 transgenic mice compared to wild type. But this enlargement was only present in transgenic mice containing the human HARE5 sequence not the chimp one, bringing the speculation very high about this sequence on the evolution of Adam’s brain from our chimp far-distant cousins. It would be interesting to track back in time how the “lucky winner” individual diverged the road from our common ancestor and how that sequence among the human and non-human primates.
The second thing that was really exciting was the possible candidate driven by HARE5: FZD8. FZD8 denotes “Frizzled 8”, a important receptor of the WNT/beta-catenin pathway that appears to share important role in both neuronal cell differentiation AND the blood-brain barrier differentiation. I am very excited to see how this HARE5 may impact the blood-brain barrier function of these animals. Do these animals have a better BBB tightness, a higher vascular density, a different in nutrient uptake (there is a lot of speculation about the DHA transporter and DHA (aka Omega-3 fatty acid) in our brain homeostasis.
Lets see now how these puppies perform in behavioral tests….