[Videogames] Bioshock: The Collection (Remastered) coming this september on XB1, PS4 and PC.

2K games just announced a very good surprise that was a long speculation: a remastered edition of Bioshock series (including the original Bioshock, Bioshock 2 and Infinite) for current generation consoles and PC.
It will be a pleasure to dive again into the Rapture and rediscover a game with a groundbreaking story, critical decision-making and a remarkable gameplay experience.
“A man chooses……..a slave obeys”. “Would you kindly?”

Source: Remastered BioShock: The Collection Coming September 13, 2016 for PlayStation 4, Xbox One and PC

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[BBB] A thank you note for G1D foundation

Few days ago, I experienced as a scientist one of the greatest gratitude moment you can experience: being awarded a research grant for funding my research.
This was not an ordinary grant for me, as it came directly from the GLUT1 Deficiency (G1D) Foundation. This is a grant getting funded by money fundraised by patients suffering from G1D and their families, the sum of tireless effort and time of baking sales, fundraising walks and other activities to raise funds to promote basic and clinical research in order to find a cure of G1D patients.

  1. What is GLUT1 and what it is function in the brain?

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Glucose is the main source of energy in the brain.  We estimate that almost 25% of daily glucose is exclusively reserved for the brain tissue. Given that the brain average weight is only 2% of the total body weight, we can easily understand how the brain is overwhelmingly dependent on glucose.
Glucose is a small molecule, but yet glucose is a highly polar molecule. It dissolves very well in water but it dissolves very badly in fat. Because cell membranes are made of fat (phospholipid bilayers), glucose cannot freely diffuse across the BBB and needs a carrier that will shuttle glucose from the blood to the brain.
GLUT1 is a member of the glucose transporter superfamily. We estimate over 14 different GLUTs expressed in mammalian cells lithesome specificity in where such transporters are expressed. At the BBB, GLUT1 is considered as the predominant isoform expressed, although some studies suggested the presence of GLUT3 and GLUT4 at mRNA levels but no one demonstrated their presence at protein levels and their presence as functional transporters. GLUTs function as facilitated carriers, they do not need energy to function and only rely on gradients (more concentrated to less concentrated to function).

2. GLUT1 deficiency syndrome (G1D)

Glucose transporter 1 deficiency syndrome (G1D or GLUT1DS) is a genetic disease firstly coined by Pr. Daryl De Vivo (University of Columbia Medical College) in 1991 in the seminal paper published in the New England Journal of Medicine.
G1D may have been already a existing disease but by its nature may have been largely undergo misdiagnosed as an type of epilepsy.
The major clinical feature of the disease is the onset of epileptic seizures during early infancy, usually by the age lesser than 1 year old. The diagnosis is usually reinforced by a spinal tap that usually note a low glucose level in the cerebrospinal fluid compared to normal range. The final diagnosis is usually obtain by measuring glucose uptake in patients red blood cells, however this procedure remains cumbersome and not systematically performed.
Patients respond in general poorly to their epileptic seizures and until now the major intervention with these children is the  use of ketogenic diet (KD), a variation of the Atkin’s diet (no-carbs diet).
Under fasting condition, the body can break down fatty acids from the fat storage compartment into ketone bodies (acetoacetate, beta-hydroxybutyrate). These ketone bodies can used as alternative fuel for the brain and allow to function quasi normally.
The disease is triggered by mutations in GLUT1 transporter, yet the relationship between sites of mutations and severity of the clinical symptoms are not yet established.
The average number of G1D cases worldwide is relatively small (~250 patients) but it may be a more prevalent condition, as it is often misdiagnosed as an idiopathic type of epilepsy.
The KD is not the panacea and has its challenges and limitations, in particular in terms of dyslipidemia and also in following the dietary requirements and personalization.
Recently, the development of anaploretic diet using triheptanoin (short odd-chain fatty acid) supplementation may help improve the quality of life for G1D patients.

3. Why do we need fundraising and why researchers need grants?

Scientific research is a long and expensive intellectual endeavor with no guarantee of success to translate findings into patients.
In academic research, most of the money comes from public agencies such as the National Institute of Health (NIH). This money is originated by every citizens through taxes, thus we can say that research funds are made of “taxpayers money”
Because money is not an infinite ressource and you cannot ask taxpayers to pay ludicrous amount of taxes,  funding agencies have to set funding priorities for diseases that have the highest priorities. Most of the time, this priority is determined by the prevalence of the condition. This is where we are facing challenges when you have a “rare disease”. Because “rare diseases” are by essence rare (less than 1 patient out of 100’000), funding agencies are reluctant to invest into this disease and pharmaceutical industries are reluctant to invest into a drug discovery program that will be costly and with little return to cover the cost.
This is why foundations are essential for us scientists. They provide us with funds that allow us to generate experimental data that are robust enough to be considered by special funding agencies (that support research on rare diseases) to take us seriously and provide us with a higher fund to further investigate such disease.
Funding agencies and foundations rarely if not never fund any projects without having it evaluated by a scientific broad that assess the validity of the science behind and the robustness of the investment to be made.
This is why I am very thankful to the G1D foundation to give me their trust in my research proposal and fund my work. If you want to help the G1D, you can donate them money through their donation page.
If you have another disease you want to contribute, please look up for a foundation held by patients or families, in particular support foundations that have a low fundraising maintenance cost (15% or less) and that have defined programs and goals including research grants and patient care.
Again, I would like to thank G1D and really looking forward to attend their 2017 meeting, with data as fruits of the scientific harvest made possible by this seed grant.

 

 

[BBB] Gordon Research Conferences “Barriers of the CNS’

This week I am attending the Gordon Research Conference “Barriers of the CNS”. This is now my fifth GRC I am attending. If you wanted to have an idea of what is a GRC, it is like a summer camp for scientists. It is maybe the smallest form of scientific meeting (usually less than 200 attendees) but it is also the most exciting type of meeting because you can sit next to the most seasoned scientist in the field at breakfast and engage into communication. There is also a lot of science that is straight out of the bench and still work in progress. To avoid any conflicts, filming and picture taking are forbidden.
However, I decided to snap one picture following an evening session last night (see picture below).
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After the end of the session, we had a special session for Dr. David S. Miller (former researcher at the NIEHS in Research Triangle Park, NC), one of our scientist fellow that abruptly ended his research career due to a severe medical condition.
David was initially a trained kidney researcher, specialized in transporters in kidneys.
Transporters are a special class of membrane proteins that helps to bring molecules inside the cells and other molecules outside the cells. Some are essential in allowing the transport of glucose, amino acids, lipids and nucleic acid inside the cells, providing the cells with the rudimentary bricks and fuel it needs to fully function. In the other hand, we have other transporters that plays an important role in getting rid of cellular waste and harmful chemical compounds produced by the surrounding environment. For instance, we have powerful pumps that keeps us away from being poisoned by tar residues, poisons produced by plants.
After spending a couple of decades in studying transporters in the kidney, David decided that the study of such transporters in the brain would be an exciting endeavor to initiate. And it was. It was to such a point that that David became a leading expert in transporters at the BBB. He was the expert if you have any question about transporters and their regulation at the BBB.
When I was an undergraduate and obtained my master thesis on the transport of flavonoids quercetin and naringenin across the intestinal and endothelial barrier, I swore I will never touch anything related to transporters. Indeed I did not touch them for during my whole PhD training and early postdoctoral career.
Then I attended the first Gordon Research Seminar “Barrier of the CNS” in 2010, a 1-day event preceding the GRC meeting. The goal of the GRS is to provide an less intimidating atmosphere to  graduate students and postdocs and allow to meddle with seasoned scientists from the field. Among the few senior scientists in the field present in this inaugural GRS, David was one of them.
You can identify an amazing mentor by his/her charisma to engage with young scientists and feeling being part of their circle by the time you share the first handshake. David was one of them.
David brought the enjoyable and good spirit into the research and discussion, describing his work and the challenge of such transporters in drug delivery across the BBB, using the metaphor of the “800 pound gorilla”.

800poundgorilla

To give you an idea on how engaging his scientific presentation was, David convinced me that the field of transporters at the BBB is an important field that is essential for both drug delivery perspective and also to understand crucial neurological disorders. By that time, I slowly but surely worked my way back to bring these transporters interest into my research interest.
Hearing all the good words and stories shared by several David former trainees and fellows was such an emotional time and realize that we have now an empty chair, a absent voice that was asking relevant questions and providing comments and feedback that was valuable not only to the speaker, but to the whole community as well.
Science is more than just working on the next big idea and tremendous hours on the bench to demonstrate that your idea is great. It takes a village to build an accomplished scientist and it takes several wise elders to craft and raise the next generation of scientists.
David was one of them and if David read this post one day, I wanted to personally thank him for inspiring a whole new generation of scientists in our field to excel and enjoy their research in the field.

[Metal] Exalt The Throne – The Tempest

Exalt the Throne, a melodic death metal band from Texas Dallas-Fort Worth area just released a lyric video for “The Tempest” from their upcoming album “Long Live The King”.
The album release date is scheduled on June 24th and will be accompanied by a promoting gig the same evening at Tomcats in Fort Worth.

 

[Junk Sciences] About that scientific paper retracted from Scientific Reports yesterday and the limits of peer-review

A tenet of becoming a scientist and earning a doctoral degree (Ph.D) in hard sciences is to be able to develop a critical thinking and skepticism over scientific findings. We learn how to not accept scientific claims as facts “just because someone said it” and learn to fact-check such claims by analyzing the data and see if the data are robust enough to support the claims or if they are simply inaccurate, non-conclusive or worse…..simply fabricated.
Data fabrication, adulteration, plagiarism and manipulation is unfortunately present in science. This is why peer-review is playing an important role in filtering out studies that are robust enough from studies that are murky or questionable enough. That latter is usually what I refer as “junk science”, scientific studies that are not standing to scientific rigor and should not have been reaching the publication stage. The peer-review process is not the most optimal one. If you want an analogy, consider peer-review as the wooden fence lining your backyard: it will not stop a burglar to climb over it but it will stop trespassers and marauders to come too close from your home.
Yesterday, I woke up straight in a middle of a Twitter firestorm about the retraction of a paper. Seeing papers retracted is not uncommon, there is even a website for that called “Retraction Watch” that track studies retracted by scientific journals. But yesterday it was such a bad paper that yesterday’s Dr. Derek Lowe that hold a PhD in Chemistry from Duke University had a fiery blog post about it (the access was denied soon after I read it but seems to be online again this morning) named “Crap, courtesy of a major scientific publisher“.
The problem was not facing a junk scientific paper, there are plenty around nowadays since Open-Access journals started to kick inside the world of scientific publishing and thanks to predatory publishers (I will talk about it later). The problem was the journal that has such junk paper published: Scientific Reports (SciRep, from Nature Publishing Group) (Disclosure: I have co-authored a paper published in Scientific Reports). Scientific Reports is the response of NPG to open-access (OA) journals such as Public Library of Sciences (PLoS). Because it is coming from NPG, everyone is expecting to attain a certain rigor for peer-review (Nature is one of the hardest journal to get your scientific study published). I always joke around that it is so demanding that we are facing “icebergs” papers, studies with five main figures and 50 supplemental figures that are only accessed online.
Using this debacle, I thought it would serve well as a poster child to expose some scientific fraud and provide some tips to distinguish good papers from bad papers.

1. Scientific Publishing 101: Peer-review, open-access, predatory journals and publication fees.

Publications in peer-reviewed journals is the bread and butter of academic researchers. It is as vital for a researcher as a credit report is for anyone living in the US. Two criteria matters in big time decisions such as finding a job or earning tenure in an University: how many papers you have your name affiliated to and which journals. These metrics are very important, especially with the latter driven by the impact factor (IF). The IF is the equivalent of a BBB rating: the higher, the better. Two giants dominates the field: Nature (from NPG, IF ~42) and Sciences (From the American Association of Advancement of Sciences or AAAS, IF~32).
It is so important that the number of papers coming from these two journals conditions the odd of a researcher to get a job in prestigious institutions such as Harvard, MIT, Stanford or UC Berkeley.
Papers are part of a particular cycle that I don’t know if we should call it vicious or virtuous.
1. To publish papers you need data.
2. To obtain data you need research funds.
3. To obtain funds, you need to write winning grants.
4. To have a grant having a chance to get funded you need papers
5. Repeat step 1.
All peer-reviewed journals follow the same procedure: I submit my draft manuscript that I consider solid enough for peer-review to a journal. The editor-in-chief (usually a well seasoned scientist) decides using both an objective and subjective point-of-view what to do with it: the objective one is if the paper fits into the editorial policy (for instance publishing my work on BBB into a plant biology journal is fairly no-sense) and the subjective one is if the paper is “attractive” enough for the editor-in-chief or not. If not, it will toss it fast. If it is, it will proceed and pick 2 reviewers that have more-or-less the adequate expertise. Such reviewers are kept anonymous for most journals with very few exceptions. Reviewers have a moral obligation to keep their review objective and fair. Sometimes they do, sometimes they don’t. You can easily imagine that if reviewer X is a scientist working on the same topic than me, that reviewer feels the risk of being scooped and therefore will work hard to find flaws to get my paper rejected and work hard to scoop me.
At the end, 2 or 3 reviewers will provide their comments and feedback giving the editor-in-chief the decision to accept or reject your paper. Once rejected, you have no other choice to move on to another journal and restart the same game.
The competition is fierce, with only less than 1% of papers submitted to the top 2 journals will end up being published. This also raised a race-arms to publish only papers that are groundbreaking science in big way and usually can shake up an entire field and a fierce competition for getting published. This is what I call the “wow factor”. But thats only a small problem that raised to OA journals and sometimes it can backfire due to scientific misconducts (examples: Two stem cells papers retracted because of data fabrications such as the Hwang paper about the cloning of hESCs from human oocytes published in Science in 2005 and the STAP “pickled stem cells” published in Nature in 2014)
The main problem is that once accepted, this study will suffer from a double-jeopardy in terms of publication fees: the authors have to pay publication fees to get the accepted paper published (usually goes from ~$1000-3000 per study). Once published,  you secede the copyrights to the publisher, this publisher will ask anyone wanting to read the paper to pay for its accession (~$50 per study). This second fee hinders how many scientists can read your study, limit access of scientists from developing countries to these studies and also limit the number of studies that will cite your study. Certain public health agencies like the National Institute of Health (NIH) responded to such issue by asking any studies funded with $$$ from NIH grant to be available free 12 months after publication through their “Pubmed Central” portal.

OA journals were born from these concerns. The OA publication follows the same protocol than regular published journals except for two aspect: they will accept any papers based on the robustness of the data rather than the novelty or “wow factor”. If your paper is not as exciting and breaking ground as higher journals but it solid and can provide the field with small but solid information, it will get accepted.
once published such studies are made open-access. Anyone can read them freely. This is because once accepted, the journal recover the costs by asking higher publication fees (~$2500-$3500) from the author of the study.
This is an interesting alternative publication method, however it also opened a new wild wild West in academic publishing. Like any good Western movies, you have wandering snake oil sellers and in academic publishing these snake oil sellers are represented by predatory journals and publishers. These publishers found some easy preys to feed on: academic scientists with studies that are so poorly designed or just simply fraud and could not pass the peer-review filters. As long as you give them money in form of publishing fees, they will publish your paper through an expedited review. This lead in recent years in the appearance of “junk papers” that are little or no scientific merit and yet get the right to get cited. This lead to a hall of shame through the Beall’s list of predatory publishers providing a database of journals and publishers with suspicious or demonstrated predatory practices. There is even one publisher found with a mailing address pointing….to a suburban house. How serious this can be? This is what feed most of the pseudoscience outside. Anti-GMO, anti-vaccines, chiropractic, naturopaths and homeopaths are all relying heavily on such “junk science” to provide a scientific rationale to their claims.

2. What was about this paper that made such firestorm and retraction by Scientific Reports?
The paper in question is titled “Novel piperazine core compound induces death in human liver cancer cells: possible pharmacological properties” by Samie and colleagues from the University of Malaya, Kuala Lumpur, Malaysia and published in SciRep last April. As today, the paper was not available through SciRep yesterday and seems back online today. I guess the academic firestorm put the server into severe stress.
I will go step by step and explained in comments what is wrong with this paper (see figures below).

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3. Conclusions

After reviewing the paper, you can notice how many flaws and blatant data manipulation was mined inside this paper. Peer-review cannot be a fool-proof system, as some very elaborated data fabrication may go unnoticed even by the most seasoned reviewer. I am not surprised either to see such junk study to made it through publication, if it was coming from a predatory journal. But seeing such paper coming from Scientific Reports being unnoticed although a fairly reasonable turnover (it was received in October 1 2015, accepted March 23 2016 suggesting at least one round of review and the submission of a revised form) is disturbing. Scientific Reports editorial has to consider what went wrong and investigate the review history of this paper but also whether reviewers assigned to review this study displayed the expertise needed and the objectivity to do it.
At that time, I would not be reviewer 1 or 2 (even 3) that reviewed this junk paper. Garbage in, garbage out.

[Neurosciences/Stroke/Stem Cells] A cautionary tale in selling overhyped stroke stem cell therapy

Waking up this morning with a “stunning” finding about the recent publication of a study by Stanford researchers that noted the improved outcome in stroke patients following injection of stem cells have been positively headlined in the fairly serious “Washington Post” journal.
As a neuroscientist and stroke researcher, this sounds like a very good news because there are not much good news when we discuss stroke clinical trials that show something better than placebos. But also me and others like Pr. Paul Knoepfler as he rightly wrote in his blog post to not fail into overhyping and overselling a pilot study and by the way promising the moon to patients and come back to them with a disappointing news.

I thought it would be a great idea to discuss a bit more about this paper, its observations and  outcomes and current limitations.

1. What is the study that was has been cited in the Washington Post and how does it stand in terms of scientific publication?

According to the Washington Post, this study has been published in Stroke journal and authored  by Gary Steinberg, MD-PhD (Stanford University) listed as leading author. Based on the information, we are likely referring to the following article. I have attached a screenshot of the abstract page from the journal website:
Stroke
First thing, is to classify the authorship ranking. Dr. Gary Steinberg is what we refer as the primary author, usually the person that has performed most of the experiments and analyzed the data. On the other hand, we have Dr. Neil E. Schwartz as a senior author. It is usually the one that has the first thought process, planned the experimental design, wrote and finalized the manuscript and usually the one that have put the money on the table (the funding awardee) to run this study. Here, I would argue that we have a difference in what we consider as the lead author of the paper. I would consider Dr.Schwartz as the lead author due to the ranking, but thats some science bickering.
The paper got published in Stroke, that is the flagship journal of the American Stroke Association (a subdivision of the American Heart Association). Being published in a society journal is a good step but in case not enough to justify the overhyping. Why? Impact factor. Impact factor matters. Stroke, according to the American Heart Association, has an impact factor of 5.76. Thats good but a clinical paper can get better rating. For instance, Circulation (the highest-ranked AHA journal) is listed with an IF~15, whereas Nature Medicine (a mastodon for high-impact translational studies) has an IF of 27.
The paper is surely good, but does it qualify for the “stunning” adjective? Certainly not and the overselling of it is not justified by the publication metric.
Also note the title, this is a Phase I, IIa. So it means it is very a early stage of the clinical trial. Phase I in the first stage of clinical trial in which we test the safety of a novel treatment, Phase IIa is to try if there is any efficacy in a very small subset of patients (less than 50). Again, at this stage, it is a dangerous step to oversell something that yet to show efficacy with hundreds of patients.

2. What does the paper says?
The paper is behind paywall so I cannot publish any figures and text. The paper got one round of revision, as it was received in February 9, revised in April 1 and accepted in April 26. If we consider a 4-6 weeks turnover between the time you submit your draft and the editor respond to you with reviewer comments, we can speculate that the revision was minimal and quickly addressed by the author.
This study rely on using mesenchymal stem cells (MSCs) in a small cohortof patient. The study uses a particular type of MSC, the SB623 bone marrow MSC cell line.
MSCs are a particular type of stem cells. They have the least pluripotency because they have already been engaged inside a differentiation (to make it simple, they are programmed to give rise to blood cells such as white blood cells, red blood cells or platelets) and therefore have little opportunity to be re-wired to form neurons or cardiac cells. However, because they are already into a certain differentiation stage, these cells are considered as the safest for implantation. Other stem cells (such as embryonic or induced pluripotent stem cells) are nefariously known to wreck havoc if injected as undifferentiated (they cause what we call teratomas), safety of differentiated precursor cells (such as neural precursor cells) remains to be addressed. Thats also alleviate the issue encountered with previous stem cell therapy based studies that consisted as injecting a mixture of bone-marrow stem cells without knowing exactly which sub-population is carrying the protective effect. Interestingly, these MSCs carry a plasmid allowing the overexertion of a protein called Notch-1 intracellular domain (ICD). Notch-1 ICD is a fragment of the full Notch-1, that is cleaved by certain enzymes. Such ICD can therefore act as a messenger inside the cell and exert some biological activity.
The study used three doses of cells and were directly injected around the site of infarct (peri-infarct area). In stroke injury, we have the core or infarct area that is considered as the ground zero. We consider it as the necrotic area or the wasteland zone. Everything inside is dead and highly hostile for repopulation. However, the peri-infarct surrounding this zone is battling for days and weeks, torn between signals telling neurons to survive the injury from signals telling neurons to die. This fine balance is one target for therapies as we consider finding factors that can title neurons in favor of survival can help them recover and minimize the loss done by the stroke injury.
What is interesting is that these MSCs have been shown to only survive for one month. Thats a good point for the safety issue.  In this cohort of patients (18 in total), very few side effects were noted suggesting a fairly safe method for up to 12 months. However, one caveat of this study is the lack of proper control or placebo.

3. Why this study has been overhyped and oversold by the WaPo?

All patients improved over the 12 months period compared to their initial timepoint (the day after stroke injury). Furthermore, all three doses have been pooled together, so we cannot tell if there is a better recovery with a higher number of cells. This is a serious concern that has to be mentioned: we cannot tell if these patient recovered by their own or due to the treatment.
If we had a placebo group, we could have been able to compare and contrast the gain due to the stem cell treatment. We also cannot see how each individual and each group have been recovering. It would be interesting to see how age and sex (male/female) played a role in the recovery.
This is the sin of mainstream news media: they have again sinned in overselling a study that is interesting but still lacking solid evidence to sell that case. The study and approach is interesting but the version sold in the news is a  far-stretched version of where the study actual said. Selling it as “stunning” is not only wrong and inappropriate, it is also a dangerous move that will serve some for-profit stem cell clinics to make profits on patients that have been experiencing stroke and despairingly looking for a “miracle cure”.

[Junk Sciences] Remember that viral video about the virtue of organic produces on your urine pesticide levels? There a lawsuit for that. Coop Sued For Misleading “The Organic Effect” Marketing Campaign

A year ago, Coop Sweden published a viral video that was shockingly claiming that consumption of conventional grocery produces was leading to high levels of pesticides in urine samples from a family of four. However, once the family switched to organic grocery, it miraculously cleaned their pesticide levels down to zero.
For a non-scientist, it was a shocking video. But for a scientist, it was another example of how a pool designed study was tortured to feed a marketing ploy.
I have been discussing and debunking that study a year ago:
https://scientistabe.wordpress.com/2015/05/10/junk-sciences-organic-diet-will-clean-you-from-pesticidesfrom-conventional-food-not-from-the-ones-contained-in-organic-foods/

A couple of days ago, Debunking Denialism posted an article that is bringing a follow-up on that viral video and study.

Coop, the company behind the pro-organic marketing campaign “The Organic Effect”, is now being sued for misleading and false marketing by Swedish Crop Protection Association.

You can read more on Debunked Denialism article below (free-access): Coop Sued For Misleading “The Organic Effect” Marketing Campaign