Friday, 30 August 2013

Post-industrial antibiotic production?

This week's post on the Archdruid Report blog has inspired me to begin publishing this blog, which I have been considering for a while. John Michael Greer, the blog's author, uses the rise of antibiotic resistance as an example of the futility of ideas of 'conquering Nature'. This is a subject close to my heart because following the completion of my PhD in 2010, which included a study of genes for antibiotic production, I have been wondering about the possibilities for production of antibiotics in the age beyond globalisation. 

After the fall of the Roman Empire, the availability of many commercial products declined in quality, described beautifully in a previous post on the Archdruid Report blog.  I think it is likely that unless a strong program of innovation arises based on the reality of resource limitation and the post-oil age, that many of the fruits of technological developments in the previous centuries may be lost to people in the next few centuries, and thus of course the availability of these advantages to ordinary people may vanish entirely over time. The global empire that is collapsing in our times is the one built by the availability of oil: an energy source dwarfing all of those whose production is sustainable. There are several examples in the comments following JMG's post this week illustrating the way antibiotic production has already declined, in line with the economic contraction, for example this story about Wyeth's production of injectable Penicillin G. It may be that the antibiotic resistance crisis is a product of the economics of the pharmaceutical industry colliding with natural selection carrying on as usual.

It has occurred to me that since production of early antibiotics was achieved in the middle of the twentieth century, and hence before many of the energy-guzzling habits of today's big science had become routine, that it might be possible for a group of amateurs to do garage-scale, or at least some kind of low-tech production. I can see possibilities which may echo those of radio communication networks which have been discussed in the comments of the Archdruid Report blog at least since this post in 2008.

I think it would be possible to set up a microbiology lab for ongoing discovery: microscope, incubators, broth-making, gels, and tests for isolating producer organisms (soil organisms being the source of the original clinical antibiotics, which are thought to function in the soil community as communication and resource-defence innovations); and a pharmacy lab for production. Careful adaption of innovations in chemical engineering that allowed upscaling of production in the 1950s would be essential, such as Margaret Hutchinson Rousseau's. The technicalities of quality control are also important, of course. I can see that careful investigation into the history of antibiotic production, for example by interviewing researchers whose work contributed to the so-called Golden Age of antibiotic discovery, may allow the recovery of techniques that would allow this kind of technology transfer.

The commenter 'Shining Hector' appears to be dismissive of the crisis of antibiotic resistance, having not yet seen its impact in his practice. Some of the points he makes are correct according to my understanding. Hector's assertion in the comments on this week's post by JMG that "when we ease up the selection pressure towards [antibiotic resistance], it will fall off" may be true in relation to some biochemical mechanisms of resistance. This is one of the views I have encountered in the discovery research community. Evolution of organisms includes the ongoing selection pressures on resistant forms, which in some cases are being maintained via inappropriate antibiotic use. I have heard of this approach being used by at least one physician treating stubborn infections in cystic fibrosis patients. I need to do some more reading to refresh my understanding of the biochemical mechanisms involved in resistance to the various classes of antibiotic drugs and their likely survival. It should be possible for example to do fermentation experiments in which a culture medium is innoculated with a mixture of phenotypes, to assess the survival rates of resistance traits in a non-selective environment. Those had not been done prior to 2010 as far as I am aware, and would usefully illuminate the viability of ongoing antibiotic discovery approaches.

I think Hector is also correct as I understand it in pointing to the economic dimensions of the difficulties in anti-microbial drug availability, also alluded to in at least one of the papers JMG linked to in his response to Hector in the comments, describing the problem: " ... the problem is exacerbated by a dry pipeline for new antimicrobials with bactericidal activity against gram-negative bacteria and enterococci", (from here).This supports JMG's points in previous posts about about the economic viability of scientific enterprises, for example: 
". . . the archipelago of university departments, institutes, and specialized facilities for research that provide the economic and practical framework for science as it’s practiced today—[face] massive challenges as we move forward into the deindustrial world. "
From here.

I think if we are willing to be good students of the organisms who produce these amazing compounds in the natural world, then for instance in two or three hundred years a monastic insitution or craft guild might be able to achieve production of a small range of oral antibiotic treatments. Such products are perhaps only a little more technically difficult than for example the Chartreuse liqueurs that economically maintain Carthusian monasticism. Some antibiotic production might be both possible and economically viable in the future if enough people work now to secure that possibility. Of course the problems of antibiotic resistance will persist, as these are the kinds of response we can expect to selection pressure on organisms which may reproduce a dozen times a day. Antibiotic resistance is the essential limitation on the power of antibiotic therapy. However I think that in the post-industrial future, there is a possibility that some useful antibiotics may re-emerge because of the way natural selection operates on these communities of organisms.

The present crisis of antibiotic resistance certainly is real, and the world before antibiotics was a very different place. Although many infections are still controllable, and the message about antibiotic resistance is being acted on in some places in the world, situations on the global stage are also producing uncontrollable infections. These are especially horrifying to progressive minds who have been trained to believe in the power of drugs and the inevitability of progressive triumph. The predicament of antibiotic resistance however is being engaged with by at least some interest groups: for example the call to action published in BMJ in 1998 was one of the factors that resulted in a complete EU ban on growth-promoting veterinary antibiotic use from 2006 onwards. Scientists in this area, like all others, are fighting for a share of shrinking research funding and must make the case that their apocalypse-defence programme is the most urgent. As the death toll from antibiotic resistance rises, it may be that this crisis acquires the power to command a continuing share of the resources available -- or it might be that this technology like many others may disappear into history.

At present I am still working on factors that I see as pre-requisites for the project -- researching and acquiring basic pre-digital laboratory equipment, gathering a community of interested people and so on. I see plenty of work to be done in studying the scope of the enterprise and developing a strategic approach. I have so far only been able to interest one other researcher in the sustainable antibiotic production enterprise (who is supporting my efforts with technical conversations and access to literature and textbooks). I have wondered whether I might be able at some stage to try offering a poster presentation at a professional society meeting. I have also heard of some institutions which address the challenges of fostering public health on an appropriate technology platform, for instance the Sustainable Sciences Institute which looks to me the right kind of thinking: science for a world of limitations.

9 comments:

  1. very interesting, id love to hear your thoughts on zero oil production of antibiotics, do you think this is possible, or would it be simpler to use herbs?, in a preventative sense..

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  2. This is fantastic! I have a more ambitious project for which researching craft production of antibiotics is one component:http://culturalspeciation.blogspot.com/2012/04/luddite-manhattan-project-first-stage.html, but I think my project is too ambitious at this point and yours might be just right for the current time. Please let me know how to support you on this. I have worked as a physicist, engineer and molecular biologist (the latter only for about 4 years), so I have some relevant experience.
    Iuval

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  3. Hi talus wood. I think non-fossil fuelled production is possible -- that's what I am thinking with this post. It's not going to be easy, there is a steep hill of infrastructure and knowledge to be built and maintained. There's a reason I'm talking about Carthusians and other monastic institutions -- religious dedication is the kind of thing that could get this done.

    Herbs are great. I use herbs, and they can teach us a lot. As you say simpler. Herbs are genuinely sustainable and accessible medicine, and I'd certainly like to see more people using nourishing herbs to maintain and build health, as well as knowing how to use them to treat illnesses. I want to have antibiotics available as well if at all possible, as what they do is also important and valuable, and that's what I'm basing this project on. It may be that the age of antibiotics has already passed, but I am hoping not. It may be that resistance mutations become fixed in wild populations of bacteria, in which case herbs and so on will be all we have. That's already the case for people who don't have access to industrial medicine for reasons of poverty or location.

    At present the public health crisis of antibiotic resistance is a rising tide -- as I understand it, inappropriate antibiotic use breeds resistant organisms which cycle into the human community and accumulate in hospitals and intensive livestock farming systems so on. It's likely that at least some of these mutations will persist in the wild, but it's possible that some antibiotics will either remain useful or become useful again in the future as and when the availability of antibiotics declines further.

    Hello Iuval Clejan! I recognise your name from the Archdruid Report comments. Thanks for the encouragement, it's great to find another person who has some relevant skills and is interested in exploring this option. I had a look at your blog: you're talking about simulating a whole raft of such projects? I did a bit of simulation programming as part of ecology courses in my undergraduate degree and I've not remined convinced of its value for the kind of things I'm interested in. As I see it, a combination of intellectual work in published papers that attract intelligent comments, and real life implementation is what is required. Resources are already crunching down, and I have found so far that implementation is 90 % of the difficulty: sims can only include what you already know about, but real life shows you all the things you hadn't realised.

    Commenting is a much-appreciated means of support at this time, and I hope you might continue to read along and chime in where you have expertise to offer. Perhaps in the next post I will sketch out some of the pre-requisite skills for this project, and you can fill in gaps from your knowledge?

    I think a review of the molecular mechanisms and the likelihood of their maintenance in the absence of selection is a key determinant for the viability of the project, and for selection of likely production organisms and compounds. I've been encouraged by what I have heard about the example of Norway for instance, where the public health policy has been to keep antibiotic use very low, and they've seen a corresponding decline in resistance in hospital infections. That would seem to indicate that antibiotic use is related to the level of resistance in community populations. This is a problem at the level of hospital practice because as has been mentioned in the Archdruid Report comments this week, basic hygiene practices have been neglected because of reliance on the magic of antibiotics -- but without these hygienic procedures, complete destruction of resistance strains does not happen and thereby there's emergence of unit-specific resistant strains.

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    1. Dear Alice,
      I am familiar with the limitations of simulation, having worked as a process simulation engineer at Motorola, simulating VLSI fabrication. The simulation was only supposed to be the first stage of the project, and as you say it was only supposed to simulate things we know about, but not how they interact. For example, we might know that a farmer needs metal and wooden tools and that a blacksmith can produce some of them, but we don't know how a non-industrial network of blacksmiths, farmers, etc. (hundreds of specialties) would function. The simulation/game would show missing links and compute basic needs of people both for consumption and for producing needs of other people/producers/consumers in the network. (e.g. calories of food, other nutritional needs, soil requirements, btus of energy, weights of materials for production of various things).

      The simulation would not show how to do something that we don't know yet. If purifying anti-biotics (which I suspect would be the hardest part of your project) is something we can do with craft technology, then the simulation/onlne game could help. But if it involves new techniques, of course there is no substitute for real life experimentation and theory. Both the Luddite Manhattan Project (a terrible name that must change soon) and your project require these. Here is a link to the LMP proposal:
      http://culturalspeciation.blogspot.com/2012/02/proposal-for-funding-blueprint-of.html. I would love your opinion on it, but it's OK if you are busy and just want to focus on the anti-biotics project.

      As far as producing anti-biotics, I wonder how big pharma does it now. Do they have libraries of fungi that they subject to the specific bacteria they want to kill and just select those on which no colonies grow?

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    2. It may be that coming up with new anti-biotics would be harder than just making known ones and hoping that resistant strains don't happen very often.

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    3. Hi Iuval. I'm not convinced by your argument for simulation so far but that doesn't necessarily mean I'm right. I hope we can carry on the conversation and if you see a way to simulate something that would help move the project forward, go for it.

      Current antibiotic discovery: yes there are organisations that pursue new products based on activity. De-replication is a major challenge, as it's hard to know whether the compound you have just found is the same one as has been known about for decades. Gene-based discovery is also a thing. New sequencing technologies allow studies of genomes, and it's possible to spot complexes of genes that are likely to be involved in antibiotic production by their similarity to previously discovered genetic systems. Those can be cloned into organisms in which production can easily be controlled to over-produce the candidate bioactive compound, and that compound can be studied by analytical chemists who may be able to work out what it is from mass-spec fragmentation patterns and so on.

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  4. Alice
    Some bloggers can set up an email contact list when they put up a new post - I would appreciate being on such a list for your blog.
    spam protecteded philsharris2zerozero2 y'hoo co united k'dom

    I am getting a bit long in the tooth and am not specifically experienced in microbiology but I helped set up multipurpose agri crop-related diagnostic labs in the Balkans. One trouble with those projects was that they wanted all the latest most expensive kit. My understanding though with most pharma-related upgrades in ex Soviet etc is that most was achieved by focussing on quality control. A lot of nightmare generics are produced in 3rd World but some are pukka. It would be good to find researchers with experience in those difficult and cost constrained environments. I know of an 'alternative technology' spin-off in Wales still with contracts for off-grid cold storage and transport - mostly related to vaccines, but useful in any sustainable lab technology.

    My main 'health hope' is obtaining 'behavioural environments' that maintain low rates of (expensive) cancer and chronic disease, (these environments exist if we look round the world, and at least these days we begin to understand the 'how' and 'why'), but it is good that you envisage dedicated communities that can focus on supplying materials and training for key interventions - childbirth and infant weaning being two examples. These are an obvious priority where on occasion selected prophylactic antibiotic use can be key to survival rates.

    Of the papers quoted by JMG, I found this 2009 one to be the most useful http://www.nejm.org/doi/full/10.1056/NEJMp0804651
    Like JMG I would like to know the prevalence of these MRSA conditions - by patient type and world location if possible.

    Will stay in touch
    best
    Phil H

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    1. Hello Phil H., thanks for your comment.

      I completely agree about the importance of behavioural environments that promote health. I think the discovery of the microbe completely obscured all the previous studies about what helped people avoid and recovery from illness. I am interested in the local food movement because it's a way of building a culture of preparing and enjoying fresh food, which I see as a key determinant of health.

      It's interesting that you identify birth and weaning as key intervention point for use of antibiotics, if I understand your comment correctly? As I understand it is best to entirely avoid antibiotic use around pregnancy, birth and until the gut microbial flora 'set' around two to five years of age. As I understand it this 'set' may co-incide with the age at which children tend to stop having mother's milk. After this age, the microbial flora which will occupy an individual's gut is more or less determined, and will be restocked faster or slower depending on environmental availability in case of upset.

      Avoiding antibiotics around birth and during infancy is a good tactic for avoiding colonisation with resistant organisms. I would recommend never using antibiotics prophylactically; otherwise they will very shortly be no use at all. I know this is in opposition to current practices for women found to carry Group B Streptococcus in their gut flora. I think it would be interesting to know whether such women were exclusively breastfed during their infancy and whether they were exposed to antibiotics during their infancy.

      I would recommend good hygiene around birth, and use of antibiotics could be used where there is life-threatening infection -- given the difficulties of infections in abdominal wounds from C-sections for example. Also, low rates of breast-feeding in industrial countries are a huge threat to public health: without maternal antibodies provided in breast milk, infant guts lack vital information about how to select for the most useful gut flora.

      You might want to look at search terms such as "Staphylococcus aureus genotyping". Here's one fairly recent publication. Techniques such as MLST (multi-locus sequence typing) are used to build up 'family trees' of how the strains isolated are related to each other, though thesis may be confounded by mobile genetic elements. It may be possible to find out more about the emergence of the strains mentioned in the Xie et al. 2011 paper -- how long did it take to collect those 108 isolates? You may be able to work out if this comparable with other locations around the globe from finding other studies of S. aureus genomes, and find out for example if it correlates more closely with population or with antibiotic use.

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    2. Hi Alice
      I agree with all your points regarding the sparing use of antibiotics - and especially your point about building up 'good' populations of protective bacteria.

      My concern with childbirth and early years is for surgical intervention in childbirth (we would have lost a daughter when her attempt at natural home birth proved impossible), and for the occasional but critical interventions for infants to stop a 'bacterial accident'. Early years are an especially vulnerable period.

      I am away from home just now but value your pointer to the Staph paper. Will follow it up later.

      I hope that diagnostics, like antibiotics, can survive as continuing disciplines and useful for practical intervention, alongside anti-septics and hygeine and various preventive and avoidance strategies (diet etc)to both cut down infection and parasite burden and to strengthen healthy bodies with fewer burdens in middle age.

      very best
      Phil H

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