From Quora: What is it like to work in a biotech venture firm?

The intellectual skills needed in startups are very different than those needed in academia or big pharma.  Academics usually succeed by learning more and more about less and less.  They become the world's leading expert in a very narrowly defined field.  Top-notch scientists, of course, manage to relate this focused domain knowledge to big-picture science as well.  But first you have to truly master a topic, and that means narrowing your focus.

Biotech startups don't have the luxury of focusing on one problem, because there are hundreds that have to be solved in order to demonstrate the feasibility of your technology and bring it to the market.  The company usually has been founded on the basis of one or two academic publications which show some promising result, and has been sold to the investors as a nearly-solved problem requiring just a few million of investment to smooth off a few rough edges and get to the clinic.  As a result, most startups are undercapitalized and the scientists are under tremendous pressure to make the promises of the founders not look like bald-faced lies.

So rather than become experts in one narrow specialty, biotech scientists typically have to acquire many skills, at least to a "good enough" level, because there is simply no one else around to do the job.  In my career, I've had to learn nucleotide and protein modification chemistry, conjugation chemistry, DNA and RNA sequencing and analysis, analytical and preparative HPLC, immunoassay development, in vitro protein synthesis, in vitro transcription, flow cytometry, macromolecular modeling, in vivo imaging, biodistribution and pharmacokinetics, microarray assay development, photochemistry, liposome formulation and a bunch of other things that I have forgotten about.  This is not too unusual.

The other notable aspect of startup life is constant disruption.  Programs are initiated, staffed and then cancelled in short order as priorities change.  You will never be (nor should you be) left alone to work out all the problems that are your responsibility to solve. If you are fortunate enough to work in a company environment that fosters communication and teamwork you will need to bring problems to the attention of your team as soon as possible, so that you can get help in solving them.  If you are working in a company that runs on the star system, bringing up these problems will be seen as an admission of failure, so you need to be prepared to solve them on your own.

From Quora: Why is there no simple diagnostic test to determine if a URI is bacterial or viral?

You ask a great question.  The market for such a test is huge, and the clinical impact would be enormous.

The technical challenge in developing a bacterial/viral test is substantial.  Trying to detect the bacteria or the viruses directly is probably not a good approach - there are hundreds of them, and the presence of a certain bacterium or virus does not necessarily mean that it is the culprit causing the infection.

An alternative approach would be to detect not the bacteria or viruses, but the body's response to the infection.  Different parts of the immune system are activated for viral vs bacterial infections.  Unfortunately, there is no single biomarker that reliably distinguishes the two responses.  But there have been publications that report suites of genes that discriminate viral and bacterial infection responses.  Unfortunately, the technological platforms that can generate this information and return it in a reasonable amount of time - probably less than an hour - and for a reasonable cost (<$50) - don't yet exist.

From Quora: When should one post negative results in powerpoint presentations of scientific research?

It depends on your audience.  If they are a general audience wanting to be entertained, then your negative results can be presented as obstacles on the road to enlightenment.  They are part of the hero's journey, illustrating the difficulties you had to overcome.  Depicting these setbacks as frustrating and seemingly insuperable makes your final triumph all the more compelling and validates your character and intelligence to the audience.  This of course assumes you have some positive results to share, thus making a good story.

If on the other hand, you are presenting to a group of colleagues trying to collectively solve a problem, you first have to assess the dynamics of your team.  Most biotechs and pharmas, and all academic departments operate on the star system.  That is, rewards are handed out to those who appear to unfailingly successful.  If this is the case, you need to tell the hero's story, as per above.

If your team is actually focused on solving problems, rather than establishing a hierarchy of perceived merit, then presenting negative results is one of the most important and valuable things you can do.  Most ideas are flawed, and fail; only a few are genuinely good.  High-functioning teams try many ideas, and eliminate the failures as quickly as possible, so that they can focus on the ideas that really have a chance to succeed.  Presentation of negative results is absolutely critical for this fail-fast model to function.  This in turn requires group leaders who can distinguish process from results - that is, who can distinguish a negative result that proceeds from poor effort from a negative result that proceeds from a flawed underlying hypothesis.  Since the group leaders usually determine which hypotheses to test, it is difficult for them to admit that the effort was good but that the premise was flawed.  Count yourself lucky if you have such a leader, and try to become one yourself.

From Quora: Have we already lost the fight against bacterial resistance to antibiotics?

Yes, we have lost the fight, if by "lost" you mean that doctors are no longer able to prescribe antibiotics effectively based on signs and symptoms alone.  This was the case for the first few decades of the antibiotic era, and we came to accept it as normal.

But the vast majority of bacteria are still susceptible to at least one antibiotic, so in that sense we haven't lost.  We just have to change tactics.  Rather than prescribing from a formulary or antibiogram, doctors should order - and pay attention to - lab tests that determine which antibiotics a given infection will respond to.

We have picked all the low-hanging fruit in discovering new antibiotics based on natural compounds, and squandered this bounty with imprudent and wasteful antibiotic prescribing practices.  Those days are over, although far too many doctors do not realize it yet.  However, prudent use of antibiotics combined with good infection control practices will allow us to manage bacterial infectious diseases in the future, despite high levels of antibiotic resistance.

From Quora: How can the global community (specifically the UN) deal with antibiotic resistance?

The useful lifespan of antibiotics is usually much less than 40 years, and the development of resistant strains is inevitable.  Most medically useful antibiotics are based on natural compounds that have been in the biosphere for many millions of years.  As a result, bacterial resistance genes have had plenty of time to develop, and so have also been in the biosphere for many millions of years.  When an antibiotic enters widespread use, it is only a matter of time until resistance genes in the biosphere find their way into pathogenic strains.

This time can be extended by the prudent use of antibiotics.  This means administering antibiotics only when there is a bacterial infection (90% of upper respiratory infections are viral and will not respond to antibiotics), only for as long as necessary, and to only prescribe antibiotics to which the infecting bacterial strain is likely to be susceptible.

Unfortunately, antibiotics are misused worldwide - for growth promotion in livestock feed, as a "just in case" treatment by ER and primary physicians (egged on by patient demand), and as a panacea in many countries where they are available over the counter.

Antibiotics - more specifically, antibiotic susceptibility - should be seen as a common resource that can be depleted by overexploitation, just like fisheries or forests.  Because antibiotics have few side effects and are inexpensive, it can benefit individuals to take them "just in case" they have a bacterial infection.  But the collective benefit to individuals turns into a net loss to society, as the next person who gets an infection is ever slightly more likely to be infected by a resistant strain generated by antibiotic overuse.

Ideally, we would have treaties that limit antibiotic overuse.  But the same can be said for many threats to common resources - forest and fishery depletion, CO2 dumping in to the atmosphere, etc.  The prospects for collective action to preserve antibiotic usefulness are not good.

Why is phage science so weak?

 

My last post discussed the disappointing results of a study of the effectiveness of phage therapy in animal models of diabetic ulcers. Although the authors reported improvement over sham treatment, the effects were only marginally significant - there was some reduction in bacterial load, but little or no effect on wound healing.

Well, that happens. Drug development is hard, and there are always going to be results that are less than stellar. The question is what has been learned, and can it be put to good use in improving the technology. Unfortunately the authors of the study did not ask this question, at least in print, so it is hard to tell if the study is a tiny step forward on the path to therapeutic development, or if it is just another random result that goes nowhere.

I'm sorry to say that this is where the vast majority of phage therapy studies go - absolutely nowhere. And given that phage therapy could have a real role to play in infectious disease therapy, it's tiresome and unacceptable. We really should be moving beyond the stage of reporting phage therapy results as mere phenomena. After all, there is more than a century of clinical and preclinical behind us, and you would think that phage therapy development efforts would be pretty sophisticated by now. But you would be wrong.

The thing that I find so appalling about this study is that the authors simply collected phage for the study from a convenient sewer. I'm sure they tested them for reactivity against a panel of clinically relevant strains grown in pure cultures in rich media to log phase and plated on agar plates in the lab. But these phage didn't do so well in the complex environment of a diabetic wound, causing only a slight decrease in the bacterial load. This shouldn't have been a surprise, but apparently it was.

Most bacteriophage genes are dispensable in the laboratory environment. That is, they can be mutated or deleted, and the phage are able to propagate just fine. The functions of these genes remain largely unknown, even to the present day. But we can guess, intelligently. My guess is that a large fraction help the phage adapt to less-favorable environmental conditions. They allow the phage to productively infect potential hosts by defeating a variety of host defenses, and to maximize their output of progeny in a host that is constantly warding off immunological, bacteriological, nutritional and environmental challenges.

If this is true - and it has to be true to some degree - then the notion of taking a phage that has adapted to sewer life or life in the gut, and expecting it to thrive in the environment of a wound is somewhere between naive and downright stupid. It doesn't advance the development of phage therapy, it discredits it. It is fundamentally unserious.

There are serious scientists who are interested in developing phage therapy. Steven Abedon's work is an outstanding example. But they are still a minority. I don't know how many times I have sat through presentations at a phage meeting that were just embarrassing, thinking "why did the organizers of this session pick this clown to speak?". But then the session leaders would get up to give their talk, and it would be just as bad, and I would have my answer.

So the question arises as to why phage science is so bad. There are a number of contributing factors of course. It is no longer the 8th day of creation. Molecular biology has "moved on" to more complex organisms, and funding has largely dried up. This has been true not just of phage biology, but microbiology in general.

Funding is surely a factor, but isn't the whole explanation. RNA science was a backwater in the 70's, but this didn't prevent brilliant science from being done by the likes of Noller, Woese, Spiegelman and others. Instead, I think it is the lack of funding combined with a low barrier to entry that makes phage science such a refuge of mediocrity. RNA science in the 70s and 80s was really hard - there was no way to synthesize RNA either enzymatically or chemically (except for very small fragments in very small quantities), and so getting enough material to do a study often required heroic efforts. But that didn't stop Woese from fundamentally reorganizing the Tree of Life, or Noller from showing that it is ribosomal RNA which directs protein synthesis.

That phage science hasn't made any paradigm-shifting discoveries since the 60s is hardly shameful - phage long ago secured their place in the Pantheon of model organisms. But it is scarcely credible that so little progress has been made in converting these model citizens of science into useful therapeutics.

Phage are everywhere and can be isolated, propagated and analyzed by very simple methods. That's what led professional physicists/amateur biologists like Delbruck and Crick to adopt phage as models of living systems. But it also means that just about anyone can find a new phage or alter an old one, stick it into some diagnostic or therapeutic model system, and show an effect that is statistically significant but functionally meaningless. This has been happening over and over since antibiotic resistance began to emerge as a significant medical problem, leading to an endless succession of review articles touting phage therapy as a new and emerging therapeutic alternative to antibiotics. That phage therapy keeps not emerging does not seem to make it any less new and promising to the writers of these reviews, nor does it abate the flow of such articles.

For translational phage science to improve, the first step is to call out the purveyors of mediocrity - to acknowledge that there is a problem, and that a higher standard is required. There is a real clinical need that phage therapy can fill, and enabling second-rate science benefits no one.

 

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A swing and a miss for team phage

The rise of diabetes in the developed world has brought along with it a rise in persistent ulcers and abscesses. These infections don't respond particularly well to either systemic or topical antibiotics and as a result, an unfortunately high proportion have to be resolved by amputation. This is nobody's notion of an acceptable medical outcome.

Phage therapy has been used in wound and burn treatment for decades in some countries, and should have several potential advantages over antibiotics in treating diabetic ulcers. Unlike antibiotics, phage tend to be highly specific in their action, allowing them to be targeted toward pathogens (S. aureus, Pseudomonas, Streptococcus, Acinetobacter) while leaving commensal bacteria alone. Antibiotics are much more indiscriminate, killing the good bacteria along with the bad. As some commensals, such as S. epidermidis, have been reported to secrete immune-stimulating compounds, it would seem that a treatment which spares them might confer a significant clinical advantage.

Phage have also been reported to be able to penetrate biofilms, which antibiotics fail to do. Biofilms are characteristic of persistent infections, making their resident bacteria much more resistant to eradication.

Phage also have the power of replication: one phage-infected bacterial cell will give rise to tens or hundreds of phage progeny. These progeny can then go on to infect other bacterial cells, potentially creating a chain-reaction that could wipe out the pathogen bacterial community at a wound site.

Phage treatment of diabetic ulcers would thus seem to have great potential to improve the care of these stubborn infections. That's why the recent paper from Mendes et al is such a disappointment. The authors did indeed see a positive response to phage treatment of diabetic ulcers in two animal models (mice and pigs), and the responses sometimes were strong enough to probably not be random. But that's about all you can say - the differences between treated and untreated wounds just wasn't all that great. Given the fact that most preclinical results, even very strong and powerful results, usually fade significantly when translated to clinical settings, it is hard to get excited by marginally observable effects in animal models.

Why such weak results? Phage therapy really should work for this indication, and I think that it can be made to work. But my brows were lifted in disbelief when I read this description in Methods: "S. aureus ... P . aeruginosa ... and A. baumannii lytic bacteriophages were isolated from sewage water from the Lisbon area." What!!?? Bacteriophages are highly diverse creatures that have evolved under intense selective pressure to thrive and survive in specific environments. There is no reason to expect that a sewage phage - which probably had been living and competing in the environment of the lower intestine - would prosper in the entirely different environment of a diabetic ulcer.

That the phage fared poorly in wounds is implied by the doses used in the experimental treatment: 10 - 100 times the number of bacteria in the wounds. At this concentration, bacteria do not have to even successfully infect a host in order to kill it. The degradative enzymes they use to gain entry to the cell are sufficient to do the job. The authors probably found in preliminary experiments that low doses of phage had no effect, and rather than find better phage, simply upped the dose.

Phage therapy is a promising approach for treating diabetic ulcers and deserves to be pursued. But it is unlikely that a random phage picked up in the environment is going to be an effective medicine. Screening and selecting phages that work in the environment of a diabetic ulcer will require a lot of hard and frustrating work. That's just how drug development is. Random chemicals rarely turn out to have the efficacy, tox profile and PK/PD required of useful drugs. It is naive, and ultimately harmful, to expect development of phage therapeutics to be any less difficult.

 

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