When it comes to antibiotics, resistance is anything but futile!

If there's one constant that we can rely on in the never-ending hunt for better, safer drugs it is that a drug that lowers cholesterol or blood sugar today, will still do so decades from now. Thus, the massive investment that was required to develop that drug pays off not just in staggering short-term rewards for the investor (typically big pharma), but also in considerable long-term rewards for future generations who can benefit from discoveries made perhaps before they were even born. 

However, there is one class of drugs that we cannot say that about, the efficacy (or lack thereof) of which is becoming a bigger and bigger problem - antibiotics. We are in somewhat of an evolving crisis with this class of drugs, and "evolving" is the appropriate word because this class of drug, unlike one for say dyslipidemia, diabetes or depression, is working against a living organism; the drug-target interaction in this case is far from a static one, and just like many bacteria have learnt to evolve and live with us over eons of evolution, so can/do they learn to live with us in the presence of antibiotics. 

Antibiotic resistance is often discussed in terms of being a contemporary issue, but you know, we have known of resistance as far back as the early 1940s, when penicillin resistance was first identified. Ditto tetracycline, from which a resistant strain of Shigella evolved on the cusp of the sixties, and it only took two years after the launch of methicillin in 1960 for a resistant strain of Staphylococcus aureus (MRSA) to evolve. Millions of people have had their lives saved by antibiotics since their introduction, but ironically today those bacteria are back and threatening lives due to inappropriate use (as well as abuse) of those antibiotics.

Experts have been banging the table for years about the problem, and how rampant prescribing and overuse of antibiotics is going to come back to haunt us, as well as pointing out that modern agriculture is also at fault in terms of farmers putting antibiotic-fueled growth of livestock (and profits) above the nation's health.  Today it seems that at least one prominent personality has had enough, and that person is President Barack Obama, who tabled an executive order last Thursday demanding that his administration do something about it. 

"This is an urgent health threat, and a threat to our economic stability as well," stated Dr. Thomas Frieden, director of the U.S. Centers for Disease Control and Prevention.

Obama's executive order bypasses Congress completely, and immediately requires the setting up of a joint task force led by the Secretaries of Health & Human Services, Defense and Agriculture, whose role is to prepare a report and outline a five-year action plan by no later than next February. The task force also has to pore through a report produced by Obama's own Council of Advisors on Science and Technology, and recommend which action items to execute in the near term. 

The take-home message is clear - doctors need a go-to test that confirms that a patient has a bacterial (and not viral) infection, so that inappropriate (and useless) prescription of antibiotics is eliminated, as well as a test that can determine that a patient has an antibiotic-resistant infection. The executive order puts $20M on the table as a prize for anyone who invents such a test(s) that will have far-reaching impact on the careful, correct and conscientious use of antibiotics, as well as newly improving incentives for big pharma to return to the barren battlefields of the (seemingly forgotten) war against superbugs.

Additionally, current federal spending on that war is to be doubled - from its current investment of $450M a year - to $900M, and it is expected that antibiotic discovery research in government-funded labs will see significant improvements as a result. Of course, Obama wants the biggest weapons brought back out onto the battlefield to help, and that means persuading big pharma to unlock their doors - something which is estimated to require another $800M to persuade and facilitate big pharma to discover just one new antibiotic. 

It's an aggressive move, but one totally justified by the developing crisis and the future health and economic costs of widespread antibiotic resistance; not least because antibiotic resistance just hasn't seemed a "sexy" challenge of late, and we need to change that fact - and fast. The burgeoning gram-negative bacteria are the masters of such resistance, capable of invoking it in mere days when conditions threaten them, and turning a patient from recovery back into illness again during the same course of antibiotics. But you know, their very existence has centered on their capacity to survive disadvantageous environments, and that's been going on for millions and probably billions of years, so of course they are damn good at their job!

While big pharma as a collective abandoned antibiotic discovery due to a combination of extremely challenging science, unfavourable economics and a brutal regulatory environment, there was one pharma that proudly retained its interest in the segment - Pfizer. They were no newcomer to the field either, having been extremely successful in producing and marketing penicillin as far back as the forties, and Pfizer was widely believed to have had one of the top antibacterial pipelines and divisions in the world. But these days it's less about competition from other pharma (who have exited the space) and more about R&D competition from within - do we develop a novel antibiotic or a PCSK9 inhibitor?

The economics of classical big pharma force the choice of the latter. The very nature of antibiotics makes them less attractive as drugs - we only take them for 7-10 days (or less, and that is also part of the problem) and we may never have to take them again, whereas a cholesterol-lowering drug or a blood sugar-reducing drug may be taken for life. Rather ironically, we also tend to regard the latter two as life-saving drugs yet take antibiotics somewhat for granted. Even if it is truly the antibiotic class that has had the biggest impact on saving lives and extending lifespan, historically and currently, in various crisis situations.

But seemingly, a problem that gets eradicated in a week with some cheap antibiotic seems to garner a lot less respect than seeing one's cholesterol numbers go down with an extremely expensive regimen. It might be truly some kind of inverse financials that's at the root of the problem, and only if antibiotics are significantly raised in price will any form of sustainable economics arise for the discovery of new ones. We expect to swallow penicillin for the price of some salt and sugar, but are okay with companies charging tens of thousands per year for a cancer drug?!

What's the difference? They are both life-saving treatments. Flesh-eating bacteria are not that much different from a metastatic cancer, in that both develop resistance to drugs designed to kill them, and both of them are hell-bent on killing you via the resistance they develop. But one major difference is that cancer is not an infectious disease while bacteria are all around us and in us, and bacterial resistance is a community issue, a population issue, a global issue. Antibiotics (and resistance to them) must not be taken for granted. 

We have got to introduce a new model that includes economic opportunity for big pharma to return to antibiotic R&D because resistance is on the rise, and the overuse of antibiotics continues recklessly. Education of the public, doctors and healthcare professionals, and even of the government itself (by scientists) is needed in order to raise awareness and reverse the trend ongoing due to the widespread misuse of antibiotics. Barack Obama is clearly intending to get this issue firmly onto the evening news and dinner table while simultaneously pushing too readily-prescribed pills off our bedside tables, and I think that can only be a very good thing. 

Whether illicit drugs or antibiotics - the more you use, the more you lose!

Nature - no longer the only Editor-in-Chief?!

Science, medicine and technology race ahead relentlessly, changing our world in both wonderful and drastic fashion, depending on your viewpoint, but it is true that sometimes science seems to surge ahead of society's willingness to accept it or even our own (as scientists) readiness to regulate it responsibly.

Major game-changing advances always get announced in a whirlwind of enthusiasm and excitement, but it is the job of medical ethics experts to dampen that furore by pointing out the downside of the upside. And you know, whether it's the internet and wireless technology, smartphones and social media, or our increasing capacity to mainpulate and actually alter the human genome - there always is a downside to the upside. 

Historically and currently, one of the most contentious areas of biology has derived from our exponentially increased understanding of our genetic material, how to manipulate it, and how to potentially select for or change particular traits that are undesirable. Now of course this can only be a very good thing when it comes to disease or clear susceptibility to it, but quite obviously it also opens up the possibility of altering other aspects of individual phenotype that have nothing to do with disease, and more to do with vanity. The creep of cosmetic enhancement and plastic surgery from their previous old people's home all the way back to young thirty-somethings says it all in that regard.

In vitro fertilization, gene therapy, stem cell therapy and now gene editing are all areas that have caused contention and considerable debate among scientists and ethicists, and occasionally outright hysteria in the public forum. Somehow we manage to race ahead in spite of the concerns, and this was exemplified recently by the British Parliament approving a form of genetic manipulation that will create children from the DNA of three individuals. 

The central concern for many has less to do with what happens when we edit nature itself, particularly if we edit it in an inheritable fashion by playing with the germline, allowing those changes to be handed on to future generations. As much as we predict that there won't be any shocking surprises if we get it right, it is impossible to know how altering a genome that has exquisitely evolved over even millions of years will ultimately impact the human organism.

Of course, what is at the heart of the matter, is specificity. It's one thing to show that a given technique can chop out a small defective piece of DNA from a target gene, and insert a corrective sequence which restores normal function to that gene, in cells in a laboratory or in an intact laboratory animal. The problem arises out of the million dollar question - how can we be sure that we do not alter any other non-target genes in the process? Currently, we have no way of knowing that with certainty and it remains a black box.

While such concerns have been around for some time with respect to gene therapy and to the more contemporary promise of gene editing via either zinc finger or TALEN technologies, the latest evolution in genetic engineering has motivated some big name scientists to take a stand as the process becomes ever more streamlined, sophisticated yet seemingly simple. Simpler means more people are going to have a go at it, and this is where the blood pressure begins to rise. 

Nobel laureate David Baltimore made the news this week with a paper in Science calling for a moratorium on the use of the hottest new gene editing technique, known as the CRISPR-Cas9 system: "A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed". It can appear weird that a scientific pioneer who was known as a trailblazer in his prime now comes across all conservative regarding a major new advance, but the stakes are high. 

As controversial as Baltimore has been on occasion, no one questions his intellect and he is accompanied on the paper by some esteemed company such as Keith Yamamoto and Paul Berg (among others), as well as Jennifer Doudna (one of the discoverers of CRISPR) and George Church (a proponent of the technique) who are co-founders of biotech company Editas. The main point of contention is that while CRISPR will almost undoubtedly be clinically useful in human disease, it is a much scarier prospect if unscrupulous use of its power is applied to the germline for inheritable traits, and allows us to play God not only in terms of disease but also with looks and intelligence. 

“We worry about people making changes without the knowledge of what those changes mean in terms of the overall genome. I personally think we are just not smart enough - and won’t be for a very long time - to feel comfortable about the consequences of changing heredity, even in a single individual.”

While no one in the USA or Europe is likely to go rogue and attempt unsanctioned use of this new technology, the authors are concerned that in countries with much less stringent regulations there could be attempts to profit from offering would-be parents the genetic traits they want to see in their child, for example. It's one thing to have corrective plastic surgery for a genetically inherited "defect" that is affecting a young person's confidence, and entirely another to attempt to select height, hair and eye colour and brain power from some shopping list that makes up the "ideal" child.  

It is my personal opinion that we would be in for some severe shocks when playing with apparently benign traits involving our appearance, when they are altered in the context of the mixed genome we inherit from our parents. Years ago we would never have associated bacteria with stomach ulcers or gingivitis with cardiovascular disease, yet today we know they are linked. Our phenotype is an extremely elegant one, and the days of thinking of it all in separate compartments and separate chemistries are over - we truly are the sum of all our parts and the output is an integrated one involving enormous complexity. 

So how do we know or how can we be sure that unnaturally changing aspects of our appearance will have no consequences? Does anyone know what effect turning a black-haired genome into a blond one has, or how producing a green-eyed child from a brown-eyed genome may impact more than just eye colour? The short answer is - no. God only kmows what would happen when we try to mess with the brain and intelligence! 

It may be ironic to read a Nobel laureate saying that even in 2015, we are simply not smart enough - but he is right. The key is understanding the message, and not sensationalising it. Like all pioneering advances, CRISPR has opened a world of possibility. So has Google's driverless car. In both cases, until much research is done and we comprehend how to use the technology properly, we need to keep a lid on it, and stop the technology from falling into the wrong hands and being abused. 

A driverless car is one thing, with unmanned vehicles patrolling our highways and towns representing a level of progress the dangers of which are readily apparent, but genetically altering a human at even one (in principle) precise segment of DNA is a much more in-the-dark prospect. Perhaps a bit more like the manned car, though with the driver blindfolded - we know where we want to go, but we can't see a thing - so we are driving in the dark, today. Just as we all don't want an umanned car having a brainstorm and speeding off in any direction causing complete havoc, so do we not want a supposed sequence-specific DNA-altering tool to go off the trail and target even one more gene than desired, never mind a few. 

The potential of such technology to impact human diseases that have a genetic defect at their root is breathtaking, and we must push forward. As for all groundbreaking discoveries, scientists simply need to take a deep breath, pull back a little, and crank through the meticulous research and clinical development that is at the core of our drug discovery process. This is what Baltimore et al. are asking for, and that no one gets carried away until the techniques are refined and all safety concerns have been addressed. 

Indeed, only once we get a crisper grip on all of the safety and ethical issues involved therein, will we be in a better position to realise the full potential of CRISPR! Until then, beginning an international debate on the pertinent questions surrounding this exciting new technology can only be a good thing, and a move that should be encouraged and welcomed by us all. 

When peer review seemingly goes down the pub, there's PubPeer!

More than ever before, the term "publish or perish" pervades the corridors of life science institutions everywhere; it's so ingrained into the architecture and infrastructure of science that it's effectively become a subliminal message whispering (howling?!) out of the very walls themselves. And you can be sure that anyone holding a very prominent position in the halls of power in academic life science understands the value of publishing in prominent places. 

That value, of course, ideally translates into cold, hard cash in the form of prestigious research chairs and heavy duty research funds for the laboratory, which ultimately facilitates the creation of a laboratory empire with one big research star at the helm. Competition for research funds in tough economic times means that the stakes are higher, and it can literally be a fight for survival for those further down the ladder. 

The system is feeling the pressure, creaking on it's suspension springs, and the current scenario perhaps unsurprisingly favours the seasoned, established research stars with both the reputation and empire that have thrived and who appear to be most capable of delivering on their promise. The younger scientists still striving to make their first big breakthrough (which means first big paper in a big journal) are feeling the squeeze and feeling left out. 

In terms of the (real) value being created by scientific publication, there is a building argument that scientific publishing is in the midst of a crisis, that the peer review process is itself broken, and that the "value" of publication has been driven down by the fact that a shocking amount of published science appears to be difficult or even impossible to reproduce - this is something that goes totally against one of the supposed benefits of publishing in the first place - i.e. that other scientists can build upon the foundations laid down in the published piece of work. 

It seems that the problems inherent to a "publish or perish" mindset in life science have come home to roost. If publishing is critical to a laboratory's existence and survival then publication must and will happen, more or less at any cost. Ironically, this may have lowered the value created in the process, by forcing individuals to cut corners and maybe lower their scientific standards to get a paper sent out in time for that institutional review or maybe the next big grant application. Further, the battle for precious research funds has become so bloody that I am pretty certain many don't want other scientist competitors trying to reproduce their work, and ensure it isn't possible by omitting small but vital details in their papers. 

Thus, the very mantra of the ivory tower might be the fundamental problem behind its current woes, and recent stories about serious problems in the peer review process only further underline that thinking. The Journal of Irreproducible Results or Retraction Watch can both testify to the prevalence of such problems in the scientific literature. I came across an article recently that discussed the fact that a fake cancer study sent out by a Harvard researcher as a test of the system got accepted in half of the some 300 journals it was sent out to - even though it was quite clearly flawed - now that's scary! Even scarier was the fact that some journals agreed to accept it for a price, which goes completely against the entire process of scientific research.

The system now does have a new watchdog that is gaining traction, if not popularity, in the form of PubPeer, an online platform where scientists can comment on or critique published work anonymously. That anonymity is in line with the peer review process itself, but it is much less popular when it comes to post-publication commentary. Peer review by esteemed colleagues is one thing, but a public forum where anyone can pick apart your work and expose the flaws is quite another. It quite obviously has potential to facilitate scientific harassment (if not outright abuse) via one laboratory repeatedly attacking the work of a top competitor, in order to discredit it. 

One of the other aspects that causes much apprehension is that it even allows insiders in one laboratory to have a go at say, the bosses favourite, and reveal details about Figure 7 that only an insider could know; details which at worst could lead to a paper's retraction. Anyone who has ever been a doctoral student or postdoc has seen that level of jealousy and frustration many times, in more than one lab probably. Now it's one thing if such spying/reporting leads to a bad paper's retraction, but quite clearly it has the power to effectively cause a mutiny in a given laboratory. 

Some believe post-publication review represents the future of the peer review process, and the numbers are beginning to back that up. Since 2012, some 25,000 comments have made it onto PubPeer, in certain cases leading to identification of scientific fraud, and social media has allowed the word to spread very rapidly; in one case expanding a single comment thread on PubPeer into something seen by as many as 250,000 Twitter users. Such post-publication databases do have the potential power to make or break a career, so there is a lot at stake. 

As much as allowing anonymity by unregistered users facilitates open critique of published works, there remains the possibility of abuse, and the fact that a US cancer researcher has sued PubPeer over the treatment of his papers on the site sort of says it all. That researcher has also issued a subpoena to have the names of his detractors exposed, and that might open up a real can of worms if it goes that far. 

That PubPeer is itself anonymous displays the delicacy of this situation and the impact such matters can have on the career of even young scientists, and the founders of PubPeer currently remain anonymous. All three are at the beginning of their careers, and while they have aspirations to open up and make their identity public, well, they are not quite there yet. Whistleblowers are not always beloved, and even if in this case the three founders are merely facilitating the whistleblowing, they are clearly concerned with not blowing themselves into a corner they cannot work themselves out of - unless they can convert PubPeer into their day jobs, at least. 

Only time will tell how all this works out, and whether they will prevail against the suit by a prominent cancer researcher who lost an incredibly lucrative job offer from the University of Mississippi due to PubPeer. Unquestionably, post-publication review has been pretty much restricted to sanctioned put-downs inside private lab meetings, or maybe the occasional heated exchange at international conferences between two big shots, but rarely does science wash its dirty laundry publicly - PubPeer may change of all that. 

Whether it is PubPeer or some enhanced and improved version of it that prevails, exposing the flaws in peer review and spotlighting research misconduct can only lead to an improved scientific process, which will save us all some blood, sweat and tears, as well as time and money, in the long run. As long as the founders focus heavily on preventing abuse, I think PubPeer may have a bright future and could play an important part in forcing researchers to not use the "publish or perish" mantra as an excuse for what is at best misconduct or is at worst  classifiable as scientific fraud. 

Just because it's rare doesn't mean we shouldn't care!

This last weekend marked an annual day that passed by with as little fuss as implied by its name, even if for those afflicted it is anything but a triviality - Rare Disease Day. It is one thing to have a "mainstream" disease with modern medicine and local infrastructure all geared up to deal with you, and quite another to be faced with something sufficiently esoteric that you might even have trouble finding someone to talk to about it, never mind actually treat it. 

Hence Rare Disease Day (2015), an advocate movement trying to shine a spotlight on those unfortunate enough to be living with a rare disease, often feeling neglected by both the medical community and the pharmaceutical industry, in favour of the "big hitters". However, there has been a shift in recent years, and rare (orphan) diseases have become viable targets for pharma, even if they are nowhere near as commercially interesting as cancer or diabetes, for example. 

Although it is common and somewhat natural to think of this segment as minor in terms of human disease in general, it can be somewhat shocking to realise that some 6,000+ rare diseases have been identified to date, and it is estimated that as many as 350 million people globally are living with one. Collectively that seems a lot less "rare" than the name implies, and we should be doing more about it, given the burden that such disease clearly must place on family, friends and caregivers of the patient. If there's no treatment and no known mechanistic cause of the disease, essentially all they have to turn to is family, friends and caregivers. 

Even here in Canada, the Canadian Organization for Rare Diseases (CORD) estimates that a rather chilling 1 in 12 of us have a rare disorder, with many others susceptible to or unknowingly having some type of rare disease. CORD's mandate is to provide a network for other organizations dealing with rare disorders and to advocate on health policy and development of a healthcare system better aligned with the needs of this growing segment of the patient population.  

One question I hear a lot is - how rare does a disease have to be, to be called a rare disease? It's an excellent question and one whose answer varies with geography, which might explain the confusion. In America, a disease is considered rare or orphan if it affects less than 200,000 people, while in the UK that number shrinks to 50,000. Of course, extremely rare diseases affect significantly fewer people than these numbers, and those patients are often left feeling like they are out there struggling in the crashing waves on their own. 

The problem is of course, primarily a commercial one. When the giants of (pharmaceutical) industry do not see a viable return on their massive potential investment into a particular product, then their business end tells them to run a mile. Who would build a car that market research has estimated will sell only a few thousand in any particular country? Developing a medicine for a very rare disease is not often considered to be the best investment, at least not unless you are going to charge an-arm-and-a-leg for it, almost literally - and even then, there will be howls of derision from profiting so egregiously from individual patients. 

However, if we look at it from a more human standpoint, and disregard the commercial take; why would we treat anyone with any less compassion or desire to intervene therapeutically if they have Acromegaly or ALS versus having cardiovascular disease or cancer? In many ways, those suffering from a rare disease need greater levels of support because even the medical experts themselves are often educated about a rare disease by those suffering from them - because so little is known about their causes and such patients and their symptoms are seen so infrequently by a typical clinician. 

The obvious answer is the humane one - to redirect some of the substantial profits deriving from drugs treating "mainstream" diseases into hardcore R&D on rare disease, facilitating new treatments for the unfortunate few. This has to be backed up by healthcare policy at the governmental level, providing incentive (both in terms of hard cash for new research as well as for advocate groups) and advantages to big pharma digging into the rare disease segment, and commit to making a difference in the lives of patients living with a rare disease. 

It's heartwarming to know that things are already moving in that direction, with Novartis, GSK and Genentech all having been quite vocal last weekend about #RareDiseaseDay, and Pfizer's recent bolstering of it's rare disease pipeline. Even as a very early stage fund, we at AmorChem take rare diseases seriously and we have recently invested in an opportunity for Friedreich's Ataxia, a debilitating, inherited rare disease that manifests itself as a life-shortening neuromuscular disorder. Additionally, we previously invested in disovery of novel therapeutics for another orphan disease, Type 1 Myotonic Dystrophy - a program which we have since partnered with Roche. 

We have to start somewhere and given the length of time from R&D to clinical trials to the bedside, it's best we begin immediately and invest heavily. Such diseases may indeed be rare, but that does not mean that they don't have a huge impact and often devastating consequences, for the individuals concerned. When it comes to human disease, we should all be equal, irrespective of geography and equally irrespective of which disease is diagnosed.