Jack Heinemann Interview

His research interests include genetics and evolution, including the effects of stress (particularly induced by antibiotics and agrochemicals), risk assessment and the influence of language on science and eugenics.

Jack published a paper in November 2017 about the link between the use of herbicides (and other chemicals) and antibiotic resistance in bacteria. (B. Kurenbach, P. S. Gibson, A. M. Hill, A. S. Bitzer, M. W. Silby, W. Godsoe, J. A. Heinemann, "Herbicide ingredients change Salmonella enterica sv. Typhimurium and Escherichia coli antibiotic responses", Microbiology 163: 1791-1801) It received a large amount of press. (See http://www.scoop.co.nz/stories/SC1711/S00045/new-research-finds-herbicides-cause-antibiotic-resistance.htm) Link to the paper:

https://static.politico.com/53/55/a826dbcd41a9877f32685eda3708/heinemann-microbiology-ms-final.pdf

See the Scoop article for a link to the 2015 paper.

Summary of the Study

Two bacteria were studied (E. Coli ; S. Enterica). For each bacteria the following experimental method was conducted: Bacteria were grown (cultured) and then plated out. The plates had been prepared to have a growth medium supplemented with a herbicide (or other nasty ingredient) and an antibiotic. In other words, the bacteria would find themselves in an environment with both herbicide and antibiotic, and then their growth (or death) would be monitored over 4 days. The graphical depiction of the results are visually fairly striking (big orange bars standing when the blue bars have faded away).

More subtle is how this can be understood as "adaptive antibiotic resistance". In other words, that the effect can be attributed to efflux pumps rather than just the fact that the antibiotic is in a soup with the herbicide and therefore being less effective due to chemical effects. This is explained in the paper by considering some variants of the bacteria that have certain efflux pump genes deleted. They repeated the experiment to "determine whether the effects of the herbicides on antibiotic response could still be observed when the gene was deleted". Their conclusion is that "Antibiotics and herbicide ingredients on their own explain the majority of variability in the dataset."

Jack Heinemann is a Professor of Biological Sciences at the University of Canterbury. He is Director of the Centre for Integrated Research in Biosafety, that is engaged in assessing whether and how various products of biotechnology may pose risks to humans and the wider environment.

Interview with the Author

The interview was conducted over email in December and January.

Q: How did your work on antibiotic resistance from herbicides begin? What led you to consider the question of antibiotic resistance? What is the relationship between the 2015 and 2017 papers (and any other relevant literature by you or other groups)?

Can you please explain a little about how antibiotics work to kill microbes (i.e., what mechanisms). Also it would be helpful to set the scene by mentioning the specificity of various antibiotics to certain microbes, and the most common ways that microbes can become “resistant" to an antibiotic.

I suppose somewhere or other you'll need to give the reader an idea of what an "efflux pump" is.

• Can you briefly sketch the specific findings in your 2015 and 2017 papers?
• What was the methodology or scientific basis behind selecting the: (a) species of bacteria, (b) type of antibiotic, (c) chemical/surfactant/ingredient?

I've been interested in antibiotic resistance since my days at the US National Institutes of Health, in the early 1990s. My work has always had an aspect of this theme though it hasn't always been the primary focus.

Antibiotics describe many different chemicals that kill or inhibit bacteria. There isn't one way that they kill. There are many different targets for these drugs with some inhibiting essential enzymes in DNA replication or gene expression, and others attacking enzymes that maintain cell integrity, and so forth. We usually restrict the term antibiotic to the much smaller number of chemicals that are or might be used as medicine. Many other chemicals can also be toxic to bacteria but are not suited for medical or veterinary use.

Moreover, not all antibiotics are equally effective against all bacteria. Because of this, we say that some bacteria are 'innately' resistant. At some concentration of a drug, even these bacteria may be killed. However, that concentration may be too high to be useful, or safe, in a patient.

Susceptible bacteria may become resistant to a particular drug through a mutation or by horizontal gene transfer, where a resistance gene is transferred from a resistant bacterium to a susceptible one. These forms of resistance are called 'acquired'. When we talk about the resistance crisis, we mainly refer to acquired resistance because it is this that causes an effective drug for relevant pathogens to become a useless one.

Amongst the ways that bacteria can become innately resistant is an inducible response. It is called inducible because the genes, while present in all the bacteria, are not routinely expressed. They are ‘turned on' when the bacteria sense a toxin. Antibiotics that are still effective against this form of resistance are able to kill the bacteria before the genes are expressed. But if the genes are expressed before the antibiotic stops them, inducible resistance can protect the bacteria. One inducible response is the production of efflux pumps. These proteins move toxins from inside the cell to outside, maintaining a sub-lethal intracellular concentration. This mechanism turned out to be centre stage for our work on herbicides.

This work naturally evolved from a question that I had after examining the chemical structure of the herbicidal molecule dicamba, when I was reviewing a few years ago the risk assessment of a (then proposed) GM crop plant genetically engineered to resist dicamba. The molecule reminded me of other chemicals that had been shown in the 1980s to induce a multiple antibiotic resistance response in Escherichia coli.

Initially, my group and I formed the hypothesis that there was something special about a small number of related chemical structures that caused this effect. 2,4-D is chemically similar to dicamba, so we included it too. Glyphosate isn't. As the world's #1 herbicide it is easy to access and made sense to use as a ‘negative' control. In the work we published in 2015 we reported that commercial formulations with any of these herbicidal active ingredients caused exposed bacteria to become resistant to several very different antibiotics all at once: a classic multiple drug resistance. An interesting difference was that 2,4-D and dicamba made the bacteria more resistant to a different group of antibiotics than did the glyphosate herbicide. Thus, the kind of molecules related to dicamba do cause multiple drug resistance, but a larger number of kinds of small chemicals cause multiple drug resistance and to different drugs.

We found that the herbicides turn on the genes for efflux pumps, thus in a sense ‘vaccinating' the bacteria from the more toxic antibiotic. Interestingly, though, the herbicide could act more quickly than the antibiotic. No pre-exposure to the herbicide was necessary for the full protective effect. In the work we published in 2017, we further confirmed the genes being regulated by the herbicides and looked at individual actual or potential herbicide formulation ingredients. The overall effect of the commercial formulations followed the label active ingredient. We also found that chemicals used as surfactants caused the effect too, but not always to the same group of antibiotics as did the formulation or active ingredient. What is concerning about this is that surfactants are also used in processed foods, as emulsifiers.

We chose to look at E. coli and Salmonella enterica for several reasons. First, they are my main research organisms dating back from my first days as an independent researcher at the US NIH. Second, they are very important human and animal pathogens; as species, they straddle the environment and human being. Thus, they were logical to use for an experiment in which agro-chemicals and antibiotics were the test variables. The limitations of these are that they are both of the category Gram negative, and they are gastrointestinal. Hence, they at best represent about 1/2 of bacteria and mainly ingestion exposures. Future work uses Gram positive bacteria and bacteria that represent dermal or contact exposure.

Many researchers are linking different commonly used chemicals with induction of antibiotic resistance. These chemicals are used in food packaging, processed food manufacture, household cleaners and so on. They are part of the large mass of products that have components never tested for sub-lethal effects on microbes, but are used so widely and regularly that if they are important for causing antibiotic resistance then they could be a significant barrier to retaining useful medicinal antibiotics. For example, the scientific community has now come out strongly against the use of certain antibacterial chemicals incorporated into direct-to-consumer cleaning products, both because there is no valid evidence that they provide a benefit to consumers and because there is growing evidence that they undermine antibiotics or use of the chemicals in, eg, hospitals. It is becoming obvious that this problem is not limited to particular soaps but may be far more general. It can be hard to find soaps without added ‘antibacterial' ingredients; it is common to find antibacterials added to house paint, clothing, even the materials of mobile phones and laptops. Yet we have no idea what such mass scale, sub-lethal, exposures do to the bacteria that cause disease.

Q: Tell us how you got involved with the GMO issue.

Readers should be aware that I am a genetic engineer, make many GMOs on a routine basis, but I personally have no interest in commercialisation of these products. I find the technology exciting and some commercial applications very interesting, particularly in the medical field. Until recently, most crop applications have been technical achievements but scientifically, to me anyway, rather boring. So what is it about this topic that has caused me to become involved? There are too many reasons for here, but the main reason for this example is that I see the role of public scientists to be inseparable from a university's legislative obligation to serve as critic and conscience of society. Among other demonstrations of this, it is to bring forth unpopular and controversial opinions. Why me and not leave it to NGOs or others? Because I believe my position is part of what the public invests in to protect itself from a monoculture of thought and a loss of opportunity. I know that my work has been made more difficult, and my career probably will be less bright, as a result of crossing those in the science and commercial sectors that want to see more of this technology faster. But if there were no risk to academics, and no actual cost to taking on the risk, then there would not need to be university academics and no institutions required to serve as critic and conscience of society. After all, there are plenty of public and private institutions of either learning or research, but no other institution in New Zealand is required to be critic and conscience. It should be what we do most, instead of what we neglect the most.

Truly serious scholarship about the science of safety of GMOs (meaning both environmental and human health, but also potentially economic and social justice) already takes a back seat in the curriculum to promotion of what the technology can (or sometimes does) do, and practicing the skills of genetic engineering. When other issues are even discussed, they are usually further marginalised in the science curriculum as issues of ‘ethics', not technical science. When competence in these issues is tested at all, it is usually in an essay form of he said/she said rather than requiring the same technical rigor in answers on the chosen technical issues.

Overwhelmingly, the research funding system is focussed on the potential applications of science rather than the potential for a mix of approaches to serving society's needs. Genetic engineering is a practical tool that slots well into applied research funding, especially when the only road to public good for technology is distribution through private wealth generation instruments (i.e., intellectual property). Again, at the research and career level, there is comparatively little space for deep scholarship on whether this technology or other means would produce the same or even better outcomes for society. I think it is likely that both public and private institutions, and their derivative professional societies, thus become weighted toward those who, for practical, entrepreneurial or philosophical reasons, are less critical of technological solutions to problems, and more inclined to describe problems in a way that frames a technology as a potential solution.

For such reasons I stepped into this controversial space because, though I too have a natural tendency to appreciate technology for the sake of it, I believe my professional obligation is to bring forth other legitimate points of view, even argue them quite separately from my point of view (which has no more standing than anyone else's). This is because the critic and conscience of society does not exist to bring forth only personally held unpopular and controversial opinions, or to bring forth the fruits of one's own research (for which much of SciComm seems to exist) or even to bring forth controversial and unpopular opinions as a means to balance what is heard. When the unpopular or controversial opinion is held by those with substantially more power, I don't see it within my responsible use of public resources to make their argument for them. Thus, when I see academics making arguments that are in essence the same as those that can be made by large corporations or often even by government, regardless of how independent those arguments may be, I wonder why they thought it necessary to use public resources, particularly their privileged academic freedom, in that way instead of on a topic that was an orphan of academic champions.

Q: I was surprised by your comments about bringing forth "legitimate points of view...quite separately from my point of view".

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I doubt that very many academics think this way. It was a shock to me to hear the view expressed.

I've heard some shocking things that academics have said about academic freedom and the critic and conscience role too. That is why I believe that we need to reintroduce scholarship on these things into the curriculum and staff inductions.

I think that the essence of academic freedom is the obligation to take a personal and/or professional risk, including the risk of being wrong, because to not do so would be a greater harm to society. By confining academics to speak out only on issues with which they hold a strong (likely personal) conviction, or are themselves ultimate authorities, is to reduce the critic and conscience role to the level of quackery or irrelevance.

Few problems facing society will ever be exactly what someone is researching. Thus, relevance always means uncertainty. Academics are regularly asked by Parliament to construct and reconstruct views that may conflict, so that the uncertainty may be exposed. Doing this regularly and professionally likely means that no academic will ever personally subscribe to all views they are responsible to present. That is what makes an academic scientist different from another scientist in a different sector.

Regardless of where you are on the spectrum of confidence about something, uncertainty exists. It is possible, for example, to generally support vaccines but also recognise that there can be unsafe ones, ones unsafe for some, safe ones that have for the wrong reasons displaced better ones. All these things can be true. Thus, to proclaim that all vaccines yet to be invented or sold will be safe based on the experience of those already in the marketplace, would be without foundation. However, to proclaim that all vaccines yet to come will be safe provided that they are developed and tested to at least the same standards that have delivered all our safe vaccines, would have the benefit of some evidence.

We must be able to be wrong. If the penalty for being wrong is too high, then there will never be challenge to what will prove later to be incorrect views. While it would be great to just say it's okay to be wrong from time to time, we know that in reality there is a tremendous professional and often personal cost to it. The cost is too large for most commercial activities because of brand damage. So what do you expect them to do when backed into a corner, rightly or wrongly? Unfortunately, too many academics also perceive the cost as too high.

Let's give all this theory some test. I'm no discipline expert on climate change science. So what is my role as an academic? How do I personally choose what to say on this issue?

1. I may not say anything. This is okay provided that I'm not doing this on EVERYTHING. I have an obligation to the public to serve as critic and conscience. But I have only so much personal capacity. Thus, I may not speak on climate change provided that I'm not just avoiding my obligations altogether.
2. I might see the arguments against human causes of climate change as unpopular and controversial. Should I take them up? Yes: I might decide that some arguments reveal uncertainties that should be heard. I may do this regardless of whether I personally agree or disagree with the overall argument. For example, these uncertainties may not be sufficient to prove no link between human activity and climate change, but they may be important for when society is deciding on options about what to do about it. No: if the balance of financial or political power rests with those who hold such views then I may decide that this is not an argument that needs me. At best I would be a redundant voice next to the PR agencies and other resources at their disposal. At worst, I'd be a tool regardless of whether I was on the right or wrong side of history.

Nothing that I've said above constrains my options for my personal point of view, or my personal right of expression.

Q: Was it easy to set up the Centre for Integrated Research in Biosafety?

No, it wasn't easy to set up the Centre. For starters, the Centre does not generally promise to deliver most of the things that the university business plans (at least of the day) expected. And mainly we haven't delivered those things. But we have delivered good work on the backs of a small number of people dedicated to our founding mission. I am very grateful that UC maintains the Centre on its books but I also hope that it does so because it recognises the Centre for making critic and conscience activities core business, rather than one of the occasional outcomes of research.

Q: Do you think most NZ academics are doing a good job as critics and conscience (C&C)? Do NZ universities encourage or incentivise this?

Our academic community is second to none in serving as critic and conscience. But we are far from doing a good job. It is a difficult thing to do and is often misunderstood both by those with academic freedom and those who manage and lead universities, leading to conflict or actual or unintended suppression. The academic community must take responsibility for this. After all, we are among those at universities that can use academic freedom to defend academic freedom!

First, despite the critic and conscience role being a defining characteristic of a university there are few examples of any curricula that teach about it and provide explicit skill building opportunities. Where are the courses in our science curricula called ‘Critic and Conscience' in science? Even a lecture? There are some, undoubtedly (and I know that there are now modules for this at UC (University of Canterbury)), but they are really rare. How many academics had such courses in their schooling? I had none.

Second, academics must see C&C as core work. Ask an academic what they do, and >90% of the time, unless they are alerted to the nature of your question, they will say ‘teaching and research'. Then they'll complain about admin. Most don't get to C&C ever. Ask a manager what an academic workload is, and they will say “x% teaching, y% research and q% admin (or service)”. Where is the C&C? Fill out a form for promotion and I defy you to find a category called C&C with the status of teaching and research. If it exists somewhere in the form at all, it is buried in the mire of all things service. When your colleagues are more likely to discuss your silence on an issue than they are the expression of your opinion, then we are on the road to a culture where C&C is normal.

Third, academic freedom and C&C must stop being post hoc defences when institutions turn on academics. We must professionalise the role and make it an a priori consideration. Know when our actions are really those of the critic & conscience and when they serve mainly ourselves.

Fourth, advocate for explicit responsibilities and funding streams for those fulfilling C&C responsibilities. In the short term, perhaps make C&C a PBRF outcome.

[Editorial comment: PBRF is a periodic government audit of research at universities and research centres that is used to determine institutional funding levels.]

After all, we allow commercial activities to be considered, why not purely public good activities that could otherwise conflict with the entrepreneurial aspirations of even the universities? Universities will have no excuses to avoid promoting and enhancing C&C, and the funding stream will help them to manage the risk to reputation that they seem to fear.

Q: Is the majority of the NZ public listening anyway?

I don't think that the public, in the main, is listening. But that isn't their fault; it is ours. Then Cabinet Minister Lianne Dalziel made this point to me during a strike we were having at UC around 2006. When we said something about academic freedom and C&C she rightly asked, in essence:

Why should I care about this? Show me what it has done for government, or anyone else in the public. The long tradition of the Tertiary Education Union's Academic Freedom Award is an important space for this, but it isn't very visible. The recent initiative by the Vice-Chancellors to set up a national award is a promising step on the journey to make C&C visible to politicians and the public. While somewhat more visible, it also isn't enough. Moreover, it shouldn't be left to VCs alone to pick the best examples of c&c, because they will have trouble rewarding critics of their own institutions, and of themselves, and despite good intentions may also seal into the award a particular framing of what C&C covers.

Q: Your work on antibiotics was picked up by a number of what I would call "crank" or "quack" websites (such as natural news and davidicke.com). This is possibly because one of the herbicides studied in your work (Glysophate) is associated with Monsanto and is widely loathed. How do you feel about this sort of coverage?

There are also lots of journalists, medical blogs and fellow researchers quoting my work. My work has also been used by industry (sometimes incorrectly in my view), supported by professional societies and other scholars, attacked by industry groups, and attacked by pro-industry groups sometimes under the banner of the `public'. Sometimes these are for the right reasons -- all research has a uncertainty and all methodology has limitations. But oftentimes the lauding or the criticism misses this point and is more about other agendas, or because of double/conflicted (possibly subconscious) standards. The research I do is public, and that is what the public does. I'm not saying that I subscribe to the views you highlight. But if I did, that would be about me personally not what my role is as a researcher and, importantly, an academic.

I'm not sure what you mean by quack. If it is any person or group that promotes for financial or ideological reasons a particular belief, then all of us are quacks, at least about some things. If it includes those who accept particular beliefs, even weakly, but have not done their homework, then all of us are quacks, at least about most things. It is reasonable to support the use of herbicides, eg Roundup. However, it is another matter when scientific authority figures offer to drink it, especially in front of audiences that might include children. That in my view could be called antiscientific quackery too, from scientists.

Q: Anything else you'd like to add, or to say to the NZ skeptics audience?

I suppose I would say this. Too often it is authority and not the scientific method to which we subscribe. The formal role of a scientist is to present as accurately as possible the results of her research; the formal role of the academic scientist is that plus to bring forth unpopular or controversial opinions. It is the role of decision makers, not scientists, to take account of all of this and because of uncertainty, other things too. By this I don't mean that scientists shouldn't vote (they should!), or that they shouldn't express personal viewpoints (they should!). But I think that there is a growing tendency to use science and scientists as the equivalent of soothsayers and wizards: because of their privileged access to things we personally don't understand (and are thus often indistinguishable from magic) we can defer to their rightness. Indeed they have deep knowledge, but not always wisdom.