[Metal/Heavy] Iron Maiden – Number of the Beast 35th Anniversary

Today marks the 35th anniversary of Iron Maiden’s “Number of the Beast” release. 35 years and this beast has not any inch of its stamina and elegance. A damn good album it was, certainly one of my favorite from Iron Maiden by its consistency and its engaging lyrics. It was an 40 minutes beautiful album spanned over 8 tracks.
It starts with “Invaders” telling the story of Viking invaders ready to raid, loot and set ablaze. A sort of setting the path to what we refers as “Viking Metal” nowadays. It is followed by “Children of The Damned”, playing on one of the melodics that give the Iron Maiden sound, with engaging lyrics and remarkable Bruce storytelling. The third track, “The Prisoner” is directly inspired by a 60’s British TV series called “The Prisoner” in which people are trapped in a prison island, strapped from their name and referred as Numbers, with Number 6 being the main character.
The fourth track “22 Acacia Avenue” gives on the energy of Bruce and Iron Maiden, a very pleasurable experience.
Then comes one of the masterpiece of the album “The Number of The Beast”, the fifth track of the album. Introduced by Vincent Price (a master writer in science-fiction and horror), it starts into a grandiose shredding going up crescendo until Bruce starts with his mythical “Yeaaaaaaaaaahhhhhhhh!”. The archetypical Iron Maiden song, if you never heard about Iron Maiden before, this should be your first song to listen!

We continue in the apotheosis with the legendary “Run To The Hills” marking the sixth track. Damn if there is a top 10 Iron Maiden songs, this one should be in the top 5. You get into an exalting drumbeats and guitar melodics, with the story of Native Americans told by Bruce, witnessing the arrival of the European explorers and other conquistadors. Oh yeah, thats Iron Maiden baby!

“Gangland”, the seventh track is in my opinion one of the weakest track of the album, if not the weakest one. Its good but not much arousing to my ears. But this is not enough to eclipse the last track of the album “Hallowed by Thy Name”. This has to be in your top 5 Iron Maiden songs. If I have to pick one song from this all album this is the one I pick!
Great lyrics, great melodics, great everything!

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[Sciences/Stroke] PCSK9-FOURIER trial and why newer drug is not always better

You may have heard about the FOURIER trial making the news…..or maybe not. What you have maybe heard was this new published clinical trial that has created a divide in the news: In one hand it sounds evolocumab (a PCSK9 inhibitor) is the next cholesterol lowering blockbuster that would put statins into the category of “old drugs”, in the other hand it was raised how this new treatment provide little benefits for a hefty added price ($14’100/year price tag according to this article) compared to statins ($1’409/year price tag for a branded form).

So what is about this study, how does it fare and does it really have such a beneficial value that worth paying the extra $$$? Lets go through together. For this post, I will base my comments on two articles: the FOURIER clinical trial  (Ray, Landmesser et al. 2017) and a recent meta-analysis on the benefits of statins on cardiovascular events (Chou, Dana et al. 2016) .

How does statins and PCSK9 work?

You have heard about statins as a cholesterol-lowering drug, heard about the LDL/HDL ratio with one being “bad” (LDL) and the other being “good” (HDL). Cholesterol is part of our normal functioning. We need cholesterol for our cells and our tissues. Cholesterol is an important component of our cell membrane allowing it to have a certain “fluidity”. Cholesterol is also the precursor of any steroid hormones and it is the source for essential groups of steroid hormones such as glucocorticoids (anti-inflammatory), mineralocorticoids (blood pressure), androgens (male sexual hormones) or estrogens (female sexual hormones).

Cholesterol can come from two sources: diet (by consuming animal products) and by de novo synthesis by the liver from acetyl-coenzyme A (acetyl-coA, through a very long and complex biochemical pathway).

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Our liver can produce the amount of cholesterol we need daily, therefore the cholesterol obtained from the diet is an extra amount that is pooled with our endogenous cholesterol. Cholesterol is a fatty acid, it is a lipophilic compound (like fat) that is poorly dissolving in water. One biological adaptation in our evolution was to combine these cholesterol on some proteins called “lipoproteins”, allowing cholesterol to piggy-back and therefore be “soluble” in blood and in interstitial fluids. You have different flavors of these “lipoproteins” based on their physico-chemical properties as observed by ultra-centrifugation. We have the light form called “low-density lipoproteins” (LDL) and the heavier form called “high-density lipoproteins” (HDL).

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LDLs are taken up by cells through a particular receptor called “LDL receptors” (LDLR). These receptors are expressed on the cell surface, in particular by liver cells and endothelial cells (cell lining the inner side of blood vessels). LDLs are the one found mostly in atherosclerotic plaques that are responsible for myocardial infarction (MI or heart attack) and cerebral ischemia (ischemic stroke).

Therefore, it is important to keep these LDL levels within normal range. You have two possible actions: either you reduce your dietary intake and/or use medication aimed to block the endogenous cholesterol production.

This is where statins and PCSK9 inhibitors come into action.
Statins target the enzyme called HMG-coA reductase that is involved in the early step of cholesterol biosynthesis.

Proprotein convertase substilisin/kexin 9 (PSCK9) inhibitors in the other hand block the interaction of PSCK9 with LDLRs. PSCK9 is produced by most of our cells and have an affinity to LDLRs. Therefore PCSK9 can compete with LDL for binding to LDLRs and therefore increase the amount of circulating LDL. Worse, once bound to its receptor, PCSK9 forces the internalization of LDLR and block its recycling, further accentuating the amount of circulating LDLs. By blocking PCSK9 ability to bind to LDLR, you can free more LDLR to bind circulating LDLs and therefore decrease your LDL levels.


What is evolocumab?

One compound have been approved by the FDA in this matter, its name is evolocumab (Repatha®, Amgen). It is a biologic, an antibody that will bind to PCSK9 and impeach its binding to LDLR. Because it is a biologic, it is very expensive to produce because it is a high molecular weight protein that cannot be synthesized by chemistry. We have genetically-modified yeasts or mammalian cells that know how to synthesize it if you give them the right gene. Yet, synthesis is only one problem solved, the other problem is protein folding.
It is like an origami folding, a very tortuous and complicated series of step to achieve a desired shape. Like an origami, fail to properly fold and you will have a far cry of a desired finished product.
Yeast and mammalian cells may not fully be efficient at this task and therefore you have to deal with small amount of biologically active product at the end of the manufacturing process. Evolocumab has been approved by the FDA in 2015 for the use in people that cannot use statins and that failed to control their cholesterol levels by dietary intervention. Because it showed interesting outcomes, it was tempting to consider the added benefit of this biologic over statins. We have a good idea on statins risks and benefits and one major advantage of statins are their price. We have generic forms that are very cheap, much more cheaper than evolocumab (at least 10 times cheaper, considering the full price before coupons and insurance plans).

The FOURIER trial
This is the clinical trial that is at the epicenter of the news. In this trial, they assess how evolocumab (EVO) stood against statins and possibility outperformed statins. Statins have been shown their added benefits for patients with high cholesterol compared to placebo treated.

Because it is unethical to assess EVO versus non-treated individuals, you have to compare groups taking their statins with EVO versus groups taking their statins without (refered here as placebo). This is also a method to show that EVO outperforms statins.

We have two groups of reasonable sample sizes: EVO (N=13’784) and placebo (N=13’780) with matched parameters (age, sex, ethnicity, condition, medication……) to ensure the effect you observe are mostly due to EVO and nothing else.
The striking data here is the lowering of the LDL. In placebo, this level is about 90 mg/dL. In EVO group, we are going down to 30mg/L. That’s fairly impressive. But at the end, you want to see the outcome right?

In our case, our outcomes are how many cases of heart attack and stroke we are dealing with.

This is were the results are becoming more contrasted and less exciting.
If we look at secondary endpoint (death by cardiovascular event, heart attack or stroke), EVO fared a bit better than placebo (5.9% versus 7.4%).

For 2000 persons suffering, EVO saved the life of one person death by cardiovascular death. For 200 patients, it saved one person from an heart attack and one person to stroke injury compared to placebo (statins) group.

Considering the possible side effects reported to the medication, the lack of pharmacovigilance and foremost the price of the drug, you have to weight the benefits over risk and costs. This is where things are less shiny. This study fails to show us how EVO will replace statins.

Statins are the devil we know, they are doing their job well, we know their risks and associated side effects fairly well and they are very affordable. EVO is certainly great for patients that cannot rely on statins to control their cholesterol. But the benefit of EVO over statin is marginal and not worth the risk and costs.

References:
Chou, R., T. Dana, I. Blazina, M. Daeges and T. L. Jeanne (2016). “Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.” JAMA 316(19): 2008-2024.

Ray, K. K., U. Landmesser, L. A. Leiter, D. Kallend, R. Dufour, M. Karakas, T. Hall, R. P. Troquay, T. Turner, F. L. Visseren, P. Wijngaard, R. S. Wright and J. J. Kastelein (2017). “Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.” N Engl J Med.

 

[Sciences] March for Science – Why I will march on April 22nd?

There has been some interesting discussion this weekend amongst the scientific community and weighing the pros and cons of marching for science.

Among fellows scientists that decided not to march, my colleague the Mad Virologist decided on his blog not to march (http://themadvirologist.blogspot.ch/2017/03/why-i-wont-be-participating-in-march.html) because of the infiltration of the March by some groups (including pseudosciences enthusiasts) posing as science groups but fail to uphold on the tenet of scientific thinking via their cherry-picking in science topics such as climate science (supporting the consensus of global warming) and biotechnology (refuting the consensus that genetically-modified organisms are safe for consumption).

As the Mad Virologist elegantly metaphorized in this article “Science is not a buffet where people can pick and choose the parts that they like and disregard the rest.”  I completely agree with his point of view but I also disagree with his outcome.

Let me be clear, I like the Mad Virologist. We are in very different research fields (he is in plant virology and work to develop techniques to counter crop loss through viral infection, I am a neuroscientist and stem cell researcher) but if we were not separated by 500 miles, he would be my best drinking buddy.

I loathed plant sciences during my undergraduate classes (Botany 101? Ugh!), but there is something special about plant virologists. These are some special kind of plant scientists. These are plant virologists. They are smart. Very smart. I had a virology class during my senior year (as I was navigating in my post-graduate research direction) and most of the class was taught by plant virologists. However, these guys made a remarkable job to teach us human virology that you would not know these instructors were no human virologists at all. Same with the Mad Scientist, he is doing a heck of a job in science communication and knows very well about anything related to pathogen-hosts interactions and infectious diseases.

But this is where I have a divergence with the Mad Virologist. I feel if we don’t “stand our ground” during these Marches, we will let the same people we are trying to shoo away from science outreach take the upper hand and do the outreach for us…..at our own demise.

If we don’t march to these Marches, we will be sending a signal to our legislative bodies that the proposed deep budget cuts and deregulations of key governmental offices and programs will have no impact on our lives and our societies. We will de facto accept that the protection of our society health and environment is not in need of budget maintenance or regulations.

There is no surprise that science is attacked by different sides. From celebrities making fallacious scientific claims that seems to be coming straight from the middle-age (Flat-Earth theory, denial of the germ theory of diseases…..), from “sanctimommies blog” using their fear and lack of understanding of basic sciences to appeal to authorities (because Youtube videos and Google outweigh your 10+ years college training from any doctor and scientists), from “quacks” making a living from selling bogus therapies through their Youtube videos, books and premium monthly subscriptions, from politicians that deny facts going against their beliefs and moral standings.

In all these cases, such fear and anger is fueled by lack of critical thinking, resulting into demonizing the authority refuting fallacious claims.  This is where we, as scientists, have to stand our ground because this is our duty to equip the community with a remarkable tool: critical thinking.

There is unfortunately nowhere seen in any K-12 curriculum a sizable chunk dedicated to scientific reasoning and critical thinking. We are pushing on our teacher to squeeze imperatives to fulfill learning objectives within a timeframe, to assess them with performance metrics through student achievements, asking them to do “more with less”. We are living in an age that was 50 years ago unthinkable. 50 years ago, we were trained to retain information and facts because access to literature was limited by space and time (you had to block a time to seek the information in a library, if you could find it there).
We have now almost access to all human knowledge within the touch of our thumb on a touchscreen making this need secondary. Yet we are failing to teach our students to process at higher level: to analyze the information, contrast and assess the reliability of the sources used to get this information and make a decision based on the pros and cons. This should be no surprise and at the age of “fake news” and “post-truth” it just blew on our face.

We academic scientists have been very good to talk to our peers, yet we fail to reach out to the community despite having the luxury of a notion called “academic freedom”. There are several reasons that can explain our failure to reach out: not enough time (working to fit a 24-hour workload into a 12-hour day is no easy), fear (I am a tenure-track faculty and walking into it is like walking in a minefield, feeling that any wrong move can blow my P&T and my sense of job security away), self-censorship (afraid that a personal tweet may be taken as a political stance from the academic institution with severe financial fallouts).

Yet, we cannot keep on living with fear. If we don’t talk and express our concern we will see our science tortured by quacks to push their agenda and their vacation budget into some luxurious Caribbean island, see our science funding cut by politicians as they fail to understand the relevance of our research and conclude it is “wasted tax payer money” and let the distrust of the community towards up built up, fueling the fallacious picture of “The Mad Scientist”.

Next month,
I will not march with any label, union or any organization.
I will not march to push any political agenda.
I will not march quietly amongst wolves in sheep clothes and I will denounce their presence loudly if needed.
I will march as a way to connect with the public and explain to them why I march.
I will march to explain why science is a long and tortuous process that is not measured by immediate and short-term gains.
I will march to explain that not all science is equal and there are standard in science that help us sort the “junk science” from the genuine scientific discovery.
I will march to explain that we scientist change our minds based on scientific evidence that surpasses the consensus by its quality and number.
I will march to show that anyone with a spark of curiosity, a feel to plunge in the unknown and willing to persevere can be a scientist.
I will march to show thats science is not only reserved for the middle and upper-class students, that a blue-collar student can become a scientist too.
I will march to help tear down the walls between academic scientists and the community and build bridges for a mutual dialog.
I will march with the hope that my local representative at the State and Federal House and Senate understands how the tax money spent on my research is helping in finding cures to stroke and Alzheimers but also that no one can predict how what may labelled as “wasted tax money” may have significant impact on the society in 5, 10, or 50 years after its discovery.

[Metal/Gig] Sweet Iris/Red Beard Wall/The Ditch & The Delta/ Rozamov – Zombiez Bar @ Yellow City (03/19/2017)

Having metal gigs in Yellow City is not common, having a doom metal band performing is even rarer than a blue moon. However, that does not mean it will not happen. It is all about probability and last night it happened.
Yes, the date was awkward (Sunday for a gig is maybe not the best night to play a concert) but it was indeed a very kind gesture from the bands to stop by and play at the Zombiez Bar (the local spot for any metal gig in YC).
The gig started with Sweet Iris (?), playing some good old psychedelic rock as a warmup, giving the vibes of the early 70s scene, including early keyboard arrangements. I could not find more about the band, so if they recognize themselves please let me know.

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The second band playing was Red Beard Wall (Plainview, TX), a a skeleton crew metal band raising the potentiometer into heavier stuff and bringing on the heavy riffs as the night was settling.

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The third band to perform was the Ditch and The Delta (Salt Lake City, UT) bringing on the heavy stuff (https://theditchandthedelta.bandcamp.com/releases). The sound was becoming heavier and slower, just in time, bringing the doom metal atmosphere as the night became darker and colder.  These guys are touring around Utah and it was a pleasure to have them come in town. If you are living around Utah watch out for their gig, some good stuff. Also a kudos to the drummer, a headbanger and Trekkie fellow :).

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Finally, the “plat de resistance” was Rozamov (Boston, MA; https://rozamov.bandcamp.com). I did not realize these guys were from Boston and one of the guitarist was fairly surprised to see me harboring a “Armageddon Records” tee. It was pure coincidence when I was picking my tee prior attending the concert. I bought it when I was touring Boston last summer before attending a scientific meeting (I take a couple of hours during my scientific meetings to visit local metal records store as we have no more record shop in town, leaving Best Buy the only store selling physical copies). Finally, listening to some doom played live was worth the waiting. I have to salute the band decision to stop by YC on their way to Albuquerque (playing there this evening) and playing in town. It was heavy, slow and depressing, as you expect from any doom. Really some good stuff to try if you have been running over your Candlemass, Ahab, My Dying Bride and looking for some fresh tunes to listen, you should give them a try.

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If I had an only wish, I wished they were playing in town during a weekend evening. Starting a Monday sleep-deprived is not the best idea but honestly for the evening I had it was worth.

[Metal/Metalcore] In This Moment – Beautiful Tragedy 10th Anniversary

Today marks the 10th anniversary of the release of In This Moment freshman album “Beautiful Tragedy”, that same album that introduced us to Maria Brink and the use of the dual clean/growls from the front singer. Retrospectively, it is an enjoying moment to listen back to the original style of the band as I found the first three albums (“The Dream” and “A Star-Crossed Wasteland”) were damn solid rock and somehow got lost with “Blood” and “Black Widow”.
But let’s go back to the album, bringing us some very good metalcore through their 11-tracks  album, totaling 42 minutes.
We starts through the sound of rain with “Whispers of October” giving us a nice and zen introduction. We quickly follow to “Prayers” giving us the first encounter with Maria’s dual singing style: a mix of clean voices and growls and the very musical arrangements that takes us into it.
https://youtu.be/Oppxl1F2fNo

Then came “Beautiful Tragedy”, one of the highlighted tracks and one of the few official videos from the album. I found it very refreshing and innovative compared to the common stream of metal style played in the US, giving us some fresh air.
https://youtu.be/khairmZadHg

“Ashes” follows the step of “Prayers” and “Beautiful Tragedy”, nicely blending the brutal style of the US metal (predominantly death and similar) with Maria’s voice. “Daddy’s Falling Angel” nicely continues this dynamic making the album very solid and consistent. “The Legacy of Odio” breaks on into something more intimate and softer, allowing us to appreciate the languishing voice of Maria’s voice. One of my favorite track. “This Moment” brings us back to the metal core and put back in the continuation, whereas “Next Life” brings on the heavy, making the song of the heaviest of the whole album with Maria growling for a good 30 seconds! Thats some ass-kicking growls!
“He Said Eternity”  brings us back to “Prayers” and “Beautiful Tragedy” and continues so with “Circles” and concludes with “When The Storm Subsides”, an acoustic track following the path of “The Legacy of Odio”.

Looking back into it, I really wish In This Moment reconsiders getting back to their roots, as I felt their artistic performance were best in their first half and slowly drifted into an “empty shell” syndrome prioritizing a sort of  Maria becoming a “Lady Gaga” on Xanax and sacrificed the artistic punch on their way.

If you want to get into “In This Moment” big way, start with this album, a very solid first album that after 10 years is still an enjoyable musical experience as it was on day 1.

[Sciences/Policy] What does the proposed NIH budget cut will mean for the US biomedical researchers?

This morning, President Trump administration published its blueprint for the 2018 Federal Budget proposal. Among the different news outlets that have been publishing on this news, the Washington Post has provided a clear and concise details on the highlights on this budget (https://www.washingtonpost.com/graphics/politics/trump-presidential-budget-2018-proposal/?utm_term=.e9dadd623102#dept-7).

An important aspect of this proposed budget are the cuts to compensate in the addition of some programs including increased military expenses ($54B) and the first phase of Mexico-US border wall ($1.6B).

Now there were some expected cuts based on the campaign promises but what was certainly the most surprising and unexpected was the whooping 18% cut in the Department of Health and Human Services (DHHS), this include 18% cut in the National Institute of Health (NIH) budget.

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Why does it matter? It is matter because this cut will affect much more than the NIH, it will hurt the whole US biomedical research and ultimately affect how the US stands as a pioneer in finding new cures and treatment.

As a science communicator, I have experienced by interaction with non-scientists how misunderstand how research is done and funded. A common misconception amongst the population is that universities fund research directly from their tuition fees and from states and federal funds, with a virtual unlimited financial supply. Indeed, this is a wrong assumption.

How does biomedical research funding works?
Firstly, universities provide only a limited funding to its researchers. It will fund newly hired faculty appointment via startup funds, propose some intra-mural grants that are modest in size ($10K-$50K) but enough to prime preliminary studies to increase chances to get fundings. Thats what universities commonly propose to their academic researchers.

Then you have foundations, public-private collaborations that can provide small to medium-size grants ($10K-$200K range) rarely exceeding 2 to 3 years of funding. But the lion’s share comes from federal funding agencies. For biomedical researchers, such funds are mostly requested via the NIH, through its different branches. In my cases, most of my research I seek to get funding is through the National Institutes Neurological Diseases & Stroke (NINDS) that funds anything related to brain and brain diseases.

There are different funding mechanisms but the most common sought by principal investigators (PIs, what we usually refers as the faculty-scientist) are the R21 (high risk, small reward grants that are rarely exceeding $275K for 2 years) and the R01 (low risk, high reward grants that have a modular budget of $250K/year for 5 years).

The NIH gets its money from the federal budget, that gets it mostly from taxes and from borrowing from the Federal Reserve. It means your federal income tax withdrawn (as well as the Social Security and Medicare) falls into a big potluck that will fund many programs and departments.

If you judge by the publication records (how many papers the US publish), the US is doing well and the NIH has been doing pretty well indeed if you look by the chart below (source: NIH):

figure-1-nih_papers_per_year

Now we have to put this graph into perspective by taking into consideration the NIH budget and the number of funded research for a similar time interval. Vox  has put a very nice infographic (http://www.vox.com/2017/3/16/14943816/trumps-budget-health-winners-losers) that accounts for these two items and shown below:

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As you can see, the NIH budget has been strongly increasing up to the early 2000s and since has been maintaining a steady-state. We may conclude that the injection has resulted in more publications. The true is it is not. It is the increased number of PIs in the academic research workforce. As you can see, the spike in NIH publication occurred only after the pre-2000’s bump. The increase in NIH funding has by retroactive effect encouraged more scientists into research and therefore increased the publication.

But…..the NIH increased budget means more funds for scientists no?

In fact no. To prove this fact, look at the proposal success rate: we fell from 30.5% to 18.3%. We have indeed the same dilemma than having one pie and guests: how many guests can you feed on a pie. You can reduce the slice to an extent but you reach a point you can go below a certain size. Also the NIH funding mechanism is designed such that only the best and most innovative grants get funded. It is like deciding with of your guest deserve a slice of a pie.

For 100 grants submitted, the NIH will first recruit peer-reviewers considered experts in the field (mostly academics) for a nominal sum (usually just to cover the travel expenses and a small tip for their time spent reading these grants). Please note here you have no distinction between junior and senior PIs, you are competing as a little leaguer against some MLB seasoned World Series champion.

The first phase is what we call “triage”. Out of 100 grants, 50 will get back to their PIs even before sitting on the discussion table because three reviewers concluded that it was not enough. The other 50 are brought into discussion and scored. Based on their final score and ranked. In the NINDS, the average success rate is about 14%. This means only 14 of these grants will get a chance to get funded.

If you are a young PI like me and that your grant ended at 18th or up to the 22nd position because you apply for your first R01, so you have the “early investigator” perk. Considering that the R01 is the bread-and-butter for running a lab and the average time between submission and notification is about 6 months, you can easily understand how stressful it can be. Wait it is even more.

In order to increase your odds of funding, you need to show a research productivity by publishing papers. To publish papers, you need to produce data. To produce data, you need to invest in workforce and consumables. To invest into these, you need funding……So you can see how research can become a Sisyphus quest.

Well, a $250K research grant is not bad, no?

To be honest, it is better than other countries but still it can be still stressful. Now you have got funding from the NIH, you think you are rich, huh? Well you are not. First you have to recoup some of your salary. There are some universities, especially high-ranked universities consider that having you on their payroll at a rate of only 50% will give you an incentive to seek funding to run your lab.  Therefore you have to remove a chunk of this salary and benefits (health insurance, retirement…..) from this budget.

Then you need the workforce to run the lab. You need a reliable lab technician ($30K/year with benefits), a postdoc ($60-70K/year with benefits) to have the horsepower to produce data. Then you have to cover costs for consumables, reagents, core facilities use and purchase equipment…..

Over the last 40 years, the average cost of research has doubled, we went from $100’000/publication to over $200’000/publication (using inflation-adjusted grade) according to a recent study by the National Center of Science & Engineering Statistics (https://www.nsf.gov/statistics/2016/ncses16200/ncses16200.pdf).

So you see the situation: You have less funding success per capita (remember the pie?), the cost for research are steadily increasing. And as a scientist, you start to feel like Luke Skywalker inside the trash compactor, waiting for C3PO and R2D2 to stop this march to your death.

But wait, you can do without research in academics and keep your job….

In fact, thats another fallacy around people. When you are hired as a faculty, you are put on probation for 5-6 years. We call it the “tenure-track”. You have to comply in three major areas: teaching, research and (administrative) services. In most Tier 1 and 2 universities, research takes 60% of your appointment, teaching 30% and then service about 10%. But usually, all expect you spend more time so you are ending up working on a 200% pace fit into a 100% allocated time.

You have to show you publish good papers and get good funding, you have good student evaluations and teaching and you can ensure a good service to the university. After 5-6 years, you are set for a Promotion & Tenure packet, that get a recommendation from your Department Chair (yeah or nay), your Dean (yeah or nay), your University (yeah or nay) and finally the Board of Regents (a board composed by members appointed by the state Governor) that will decide if you are a good investment or a dead horse.

Getting tenure gives you a small sense of job security but does not give you research fund to run the lab, your tenure is also evaluated on a regular basis. If you are refused tenure you are out for a job and currently the job market for academic is tough, very tough.

But its only a 20% proposed budget cut, it will be dissolved into the whole NIH

No it will not. The NIH like any administration is acting like a perfect gas: it is incompressible. Well it is, but it will cut where it can: the extra-mural funding (80%). By cutting the extramural funding, it will give less to each branches, these branches will give less to grants and therefore the number of funded grants will decrease.
By estimation, we can realistically think that the NINDS playpen will reach only 10%, that means you will have a higher chance to have your grant graded as excellent but because you are facing fiercer competition, you don’t get funded and have to resubmit it again in 6 months to have a chance to get it funded. A spiral of hell in sort of.
One thing we should learn from this post is that cutting budget in sciences, humanities  and arts never “make a country great again”. It simply make the country worse and may have long-lasting damage.
NIH-funded biomedical research is at the basis of any biomedical innovation. Pharmaceutical companies have no envy or interest to fund basic sciences as they have to make priorities and their budget too. However, the innovation in pharmaceutical companies is driven by discoveries funded by public funds. Cut it from the bottom and I can guarantee the ability to provide new therapies will sink down fast, very fast.

[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!