Wolbachia vs. malaria – we may be the real winners

It is estimated that there are 220 million cases of malaria each year and a total of 3.3billion, half the world's population, at risk of the disease. The number at risk is continuing to rise as climate change extends the regions in which the vector for the malarial parasite, Anopheline mosquitoes, can live; making malaria one of the most pressing issues of current infectious disease control. Fortunately there are some preventative measures that can be taken to avoid Anopheles mosquitoes as they are night biting - it's fairly easy to sleep under a net in an area of risk. However, getting these nets to those in most need is a different issue entirely. Fortunately, pathogens such as Plasmodium species (the parasites that cause malaria) have a life cycle that involves stages in two different organisms, opening a whole new avenue for preventative strategies. If we can directly control the vector of disease, mosquitos, then this could theoretically block human infection since the malarial parasite cannot pass directly from human to human. Attempts have been made with the large-scale use of insecticides or oil in the lakes where eggs are laid by mosquitoes, but these approaches are costly and unsustainable. However, recent work has hinted at a new method of control that may well be able to make an unprecedented contribution to our fight against malaria, and moreover our fight against another mosquito borne disease, dengue fever.

Similarly to malaria, dengue fever is carried by mosquitoes, and over 2.5 billion people arethought to be at risk. There are two major, and important, differences between the two diseases. Firstly, malaria is caused by a parasite while a virus is responsible for dengue fever. Along with the different causative agents, the two diseases are transmitted by two different species of mosquito, with malaria being carried by Anopheles and dengue being carried by Aedes species. This has important implications for control of disease. Aedes mosquitoes are day biting, meaning that avoidance of the two species poses different challenges. While sleeping under mosquito nets may work for malaria, this will have little impact on control of dengue. However, the two diseases do have the important commonality that they are both completely reliant on mosquitoes for spread, and as such, cannot spread within a human population without their respective vectors.

In 2011 results were published from a study looking at the possibility of directly controlling the Aedes mosquito in an attempt to prevent human cases of dengue fever. A team in Australia led by Scott O'Neill showed that it is possible to substantially reduce the spread of dengue virus with the simple intervention of infecting Aedes mosquitoes with bacteria and releasing them into the wild. The bacterial infection responsible for this potentially remarkable breakthrough is from a species known as Wolbachia, which naturally infects many arthropods. 

Wolbachia have evolved to spread between arthropods and invade the population. The main way the bacteria are able to spread and become established is through an effect known as cytoplasmic incompatibility (CI). If you imagine a cell like a balloon filled with water, then cytoplasm is the water. Once inside the mosquitoes, Wolbachia are capable of infecting germ line cells, these are the sperm and eggs, and residing in the cytoplasm of these cells. Upon fertilization of an egg by a sperm there is fusion between the two cells causing mixing of the cytoplasm of each cell. If an infected male mates with a healthy female then the fused cell is destroyed by the presence of incoming bacteria; meaning there is no fertilization. However, if an infected male mates with an infected female there is no issue, the sperm and egg, each with bacteria in their cytoplasm, will fuse and there will be fertilization to give new offspring. Similarly, if a healthy male mates with an infected female there will be successful fertilization. This gives the bacteria a maternal inheritance pattern, as the female always needs to be infected. The newly produced offspring will all carry Wolbachia in their cells allowing invasion of the population by the bacteria. In essence the Wolbachia bacteria have developed a way to kill off any uninfected mosquitoes by making the adults sterile (for all intents and purposes). Only infected mosquitoes are ever born once CI has taken true effect within a population.

What makes Wolbachia infection even more interesting (other than simply as an evolutionary fascination) comes from the fact that infected Aedes mosquitoes are unable to carry enough dengue virus to effectively transmit it to humans. It isn't fully understood why yet, but it seems that this may be down to the mosquito mounting an immune response against the bacteria that causes collateral damage against the other microbe.

The effect of Wolbachia on dengue transmission is beginning to look like a truly viable option for control. However, dengue is just one of a whole host of mosquito borne disease; sitting at the top of the list for those most desired to be tackled is malaria. Much interest therefore stemmed from the dengue studies into how this approach could be used for the control of malaria. However, for a long time this proved elusive, that was until the last couple of weeks. A new study in China led by Zhiyong Xi has managed to find a species of Wolbachia capable of invading an Anopheles mosquito species, and suppressing the level of malaria within the mosquito.

A malaria causing plasmodium

This is a major breakthrough. Until this paper was published no Wolbachia species had been found that was capable of becoming established within any Anopheles species. What's more, the study showed that Plasmodium falciparum, which causes the most dangerous form of malaria, was affected by the presence of Wolbachia. The next stage will be to release infected mosquitoes into the wild and see if the bacteria can become established outside of the laboratory setting. If these Wolbachia infected mosquitoes can become established in the wild then we may well have a way to significantly reduce the spread of a disease that so many people are at risk from. Probably the best way to truly protect people from malaria will be to develop a vaccine, but until we manage that we need other strategies to tackle the infection. Our best strategy, at present, is the use of insecticides and nets. However, getting nets to the poorest areas of the world, which are often those most at risk, is not always an easy task. An easier goal may be to find a way to block mosquitoes from carrying malaria, making their taking of a blood meal essentially harmless. The discovery of a Wolbachia species able to establish within Anopheles population brings us on giant step closer to achieving this goal.

Mixed viruses with a mixed message

A little over a week ago I stumbled across a story in the journal Science describing work investigatingthe transmissibility of the influenza virus H5N1, commonly known as bird flu. Bird flu has sporadically made headlines ever since it was first detected in humans over fears that it could cause a serious pandemic. The fears are justified; pandemics are, for the most part, caused when the human population has no prior immunity to a virus. Traditionally, only H1-3 viruses have infected humans meaning there is no immunity to a H5 carrying virus, as we have never encountered it. However this fear has at times become somewhat out of hand; take for instance the hoopla over the two transmission studies on H5N1 at the start of last year, which I have previously covered on this blog (a two post article so here is link 1 and link 2). Those studies caused to a worldwide moratorium on influenza research, which has only recently been lifted. This most recent study is cut from a similar cloth and true to form, has been blown way out of proportion in the press (as an example). So, after a fairly long absence from writing my blog, I’m back to deconstruct what this headline making research actually did and explain why we don’t need to be as scared as it may seem.

An illustration of an
influenza viral particle

I’ll start with some background so that everyone is up to speed and can hopefully follow the discussion of the work in question. Everyone knows influenza as a virus that infects humans and causes seasonal outbreaks of the disease flu. However, influenza isn’t actually a human virus per se, it is more a virus of birds. On the surface of an influenza viral particle there are two proteins known as hemagglutinin (HA or H) and neuraminidase (NA or N) that we use to classify the virus. There are currently 17 known forms of HA and 9 forms of NA, however, only viruses with combinations of H1-3 and N1-2 are known to productively infect humans. All of the other HA and NA molecules combine in different ways to produce viruses that infect birds. The situation is changing slightly with the gradual emergence of H5N1 and, more recently, H7N9 viruses in human populations. However, to date, these viruses have shown very poor (if any) ability to spread between humans. While there have been many cases (particularly of H5N1) these have all be contracted directly from sick birds.

To add further detail about the influenza virus, it is a RNA virus with a segmented genome. In essence, a virus is simply a structure made of proteins and fats that encase genetic material. You can think of a virus as a vehicle ‘designed’ in the simplest possible way to carry its passengers (genetic material) into a cell. In the case of influenza, the passengers within the vehicle are 8 distinct RNA strands (RNA being the genetic material). These strands carry the instructions (genes) to make proteins that are used to produce new viruses, allowing infection to spread. Every new virus produced must contain a single copy of each of the distinct 8 strands of RNA so to produce a replica of the original infecting virus. Most viruses are not segmented in the way influenza is and just have one long strand of genetic material. There is a consequence to this segmentation, if more than one distinct influenza virus infects a cell at the same time, strands from one virus can be exchanged with strands from the other. This is a process known as reassortment and means a completely new virus is formed that is genetically different from either of the two original infecting viruses. This process of reassortment is the major cause for pandemic spread of influenza and is thus the topic of much research.

A basic diagram of reassortment

Currently H5N1 cannot transmit in an airborne form between humans, however H1N1 influenza viruses can (this was the virus responsible for the most recent pandemic in 2009 – Swine flu). If an H1N1 virus and an H5N1 virus infect the same cell at the same time there is a possibility that reassortment could occur. It is therefore possible that the H1N1 virus could swap some genes with H5N1 that confer the ability of airborne, human-to-human transmission. The reassortment produces a new virus, but as long as the HA gene does not exchange; it will still be an H5N1 virus. This is a very realistic possibility as pigs have been identified that have been infected with both H5N1 and H1N1 viruses.

This leads me nicely into the paper I wish to discuss which is investigating this very event. The work was conducted in China’s Harbin Veterinary Research Institute by a group of scientists lead by Chen Hualan. The group systematically produced every possible combination of H1N1 virus mixing with H5N1 virus. They started with an H5N1 virus with all its 8 strands of RNA, then artificially (not through infection of a cell) exchanged strand 1 of the H5N1 with that of an H1N1, giving a hybrid of H1N1 and H5N1. They did the same for every individual strand, and then moved on to produce combinations (eg. strand 1 and 2 of H1N1 with the rest being from H5N1, and so on). In total, they produced 127 H1N1/H5N1 hybrid viruses (no small task). Those proficient at maths may notice that 127 isn’t the total number of possibilities that could occur from the exchange of 8 gene segments between 2 viruses. However, since the team wanted to look at the spread of an H5N1 virus they needed to keep the segment that codes for the H5 gene meaning the maths becomes 2⁷ (minus the original H5N1 parental genome).

Having produced all of these hybrid viruses the team tested their pathogenicity in mice and subsequently looked at the transmissibility of the most dangerous ones. Obviously they cannot test them on humans, so instead animal models need to be used. The two most commonly used animal models for studying influenza transmission are ferrets and guinea pigs. The Chinese team opted for guinea pigs. Now just in case there was any doubt in your mind, guinea pigs are not the same as humans (the same is true for ferrets - which are also not the same as guinea pigs, just to clarify). These animals are MODELS, they allows us to get an idea of what may occur in humans and are the best we can do for the obvious reasons of not wanting to deliberately infect humans. The knowledge that is gained from the study of these models must always come with the caveat that humans are very different to guinea pigs and ferrets.

The genome segments of influenza

The team found that their parental H5N1 virus could transmit between guinea pigs by contact, but not through the air, where as the H1N1 parental virus was able to spread through the air (similar to the human scenario). Upon testing their selected viruses they made some interesting discoveries. Firstly, only 5 of their hybrid viruses had “highly efficient” transmission (comparable to that of the parental H1N1) with one addition hybrid capable of “efficient” transmission (not as good as H1N1 but higher than H5N1). Not only is it interesting that so few viruses were able to transmit, but an interesting theme emerged when assessing which viruses could transmit and which couldn’t. It was found that H5N1 viruses that receive the PA or the NS genes from H1N1 become transmissible. The hybrid viruses with PA or NS can receive other H1N1 genes and maintain their transmissibility, but if they receive either the NA or M genes the transmissibility is reduced. The PA and NS genes are therefore key determinants of transmission. The PA gene forms part of a protein complex that replicates the virus genome while the NS gene has two roles, firstly it plays a large role in evasion of the host immune response, and also plays a role in getting influenza genetic material out of the nucleus (where it is replicated) so that it can be packaged into new viruses. It is interesting that the NA gene of H1N1 causes a reduction in transmissibility of hybrid H5N1 viruses since both are considered to be N1. Clearly there are intrinsic differences between these two genes even though, in a broad sense, they are very similar.

I find this research very interesting from a scientific point of view, but the real motivation behind my desire to write this blog and explain the research was the response the work received in the press. Headlines proclaiming “killer flu” being produced in China or calling the work “appallingly irresponsible” are hyperbolic to say the least! There is certainly an element of playing with fire in terms of making H5N1 viruses transmissible, but the authors took the highest necessary precautions and made a point of explaining these in their published work. They used the second highest level of biological containment making it very hard for any of the virus to escape. There are only a handful of facilities equip from the highest level of containment and if all transmission studies were forced to use these nothing would ever get done. I direct you to a Wikipedia page should you be interested in the definition of these biosecurity levels.

Aside from the biosecurity aspects, the statements that these scientists were making “killer flu” really angered me. The press articles I have read seem to have conveniently missed a very important sentence written in the paper (twice) regarding the guinea pigs that became infected with the transmissible hybrid viruses, “NONE OF THE GUINEA PIGS DIED.”  Now as I have already mentioned, guinea pigs are models for humans and what is true for guinea pigs may not be true for humans. You could therefore throw that back at me and say these viruses could kill humans, which I cannot dispute (because we simply don’t know). But as far as the guinea pig model goes, these viruses are far from “killer.” The real point is that this study has given us some very interesting and useful insights into the necessary changes that may need to occur to allow H5N1 to become transmissible, and has hinted that with the ability of airborne transmission, some of the pathogenicity of the virus may be lost. With the knowledge gained from this paper we will be able have improved surveillance over cases of human H5N1 to look specifically for these changes allowing us to be properly prepared should H5N1 begin to spread amongst humans. Any prior warning, no matter how small, of a potential pandemic will allow us to stockpile the necessary drugs and formulate vaccines allowing us to have a rapid and effective response to stop the spread as soon as possible and potentially save countless lives. This paper has truly added useful knowledge to the influenza field, regardless of much that has been written about it maligning that fact.

Are we on the road to curing leukaemia? With HIV!?

Imagine having leukaemia. A cancer of white blood cells, the same white blood cells that usually fight off invading organisms and help keep you alive, but cells that are now slowly killing you. After numerous rounds of chemotherapy nothing has helped and you’re knocking on death’s door. At this point would you allow doctors to remove close to a billion of your cells and infect them with HIV in an attempt to cure you? Sounds strange and counter-intuitive, but this is exactly what is going on in Philadelphia, and even more strangely it is saving lives.

A white blood cell amongst red blood cells

So far results have been released for a dozen patients that have received this very treatment for advanced chronic leukaemia. Out of these twelve, three adults and a child have gone into complete remission and four additional adults have significantly improved, although have not entered remission (the rest showed no effect). So what is this magic HIV that is helping ‘cure’ people of leukaemia?

HIV is a retrovirus that integrates its genome into our own; tricking our cells into producing the viral proteins needed to spread HIV (the virus cannot produce these itself). Since HIV can add DNA to cells and cause new proteins to be expressed it has always been hoped that we may be able subvert this system and use it to our advantage. What is to stop us using HIV to deliver genes into cells to produce helpful and useful proteins? Imagine a patient has a disease because they are missing a specific protein, why can we not use HIV to infect the cells and produce the protein, and thus cure the disease? The answer is that we can do this. However, the issue is safety and actually getting it to work in a human being, not just cells in a lab, many trials for genetic engineering have caused cancers or simply not worked. Excitingly, these two hurdles have, for the most part, been cleared for leukaemia treatment.

Leukaemia cells

In the trials being conducted in Philadelphia HIV is being used to carry a gene into T cells (a subset of the white blood cells that make up our immune system) that allows them to detect and kill leukaemia cells. I have been saying that they use HIV, however this is not strictly true as the virus has been “gutted,” it is just the bare bones of a HIV virus (like stripping a car down to the chassis). All of the genes that would normally allow the virus to spread from a cell it infects have been removed, meaning the virus is only able to enter cells, produce DNA for the gene and then insert it into the genome (it is a dead-end infection since cannot spread from integration). The gene carried by this specially modified HIV allows the T cells to recognise a protein known as CD19. Whenever a T cell binds to this molecule on another cell’s surface it will kill this cell, the CD19 is a big bull’s-eye for the modified T cells (like a hunter tracking a deer, only when he sees the deer will he shoot and kill it). CD19 is a protein expressed exclusively on B cells, another subset of our immune system cells. These B cells are the very cells that mutate and become cancerous in leukaemia patients. By using HIV to genetically engineer T cells we are able to produce an army of leukaemia killing cells.

So how does this all work in reality? So far the trial has been conducted on patients who are at the worst stage of their disease, they have had multiple rounds of chemotherapy and still the cancer persists. The only remaining option would be a bone marrow transplant, a risky and costly procedure. Instead, the patients in the trial have their blood filtered to remove as many T cells as possible. This allows the scientists to collect roughly one billion T cells from the patient. These cells are then treated with the specially modified virus described above making them able to target and kill cells that carry the CD19 marker. The genetically modified T cells are then frozen and stored while the patient receives another round of chemotherapy. This chemotherapy kills all of the T cells in the patient’s body that escaped the filtration process so that they won’t interfere with the genetically engineered cells. Once this has been done, the genetically modified T cells are thawed and infused back to the patient’s blood from where they set out on their mission to kill all the cancerous cells they can find.

It’s tempting to jump to the conclusion that we have cured leukaemia, but lets not speak too soon. So far, only a very limited number of patients have received this treatment, many more will need to be tested before we can begin to talk about a cure, however, it is a very promising step in the right direction.

There is a big but to this tale, in that there are severe side effects. When a patient first receives the infusion of their cancer fighting army they enter a state medics nickname ‘shake and bake’ due to patients entering a horrible period of fever and chills (chills causing shivering/shaking). The more technical description for this is a cytokine storm. Cytokines are proteins released by immune cells when they are fighting and killing something, such as cancer cells, or more commonly invaders such as bacteria or viruses. It is these cytokines that are responsible for fever and other general symptoms you get when you are ill (‘shake and bake’ is just an exacerbation of this normal response). The storm can be so strong that drugs may be needed that mop up some of the cytokines in order to save the patient’s life, as was the case with a 6 year old child who receive the treatment (she went into full remission though so it ended well).

A second side affect is known as tumour lysis syndrome. When cancerous cells are killed they release a lot of chemicals, when a lot of cells are killed, a lot of chemicals are released. All of these chemicals need to be filtered out of the blood in the kidneys. When there are excessive levels of these chemicals the kidneys can become clogged up and damaged. So kidney damage is a potential side effect of the treatment, indeed one patient had to take drugs to prevent this from happening.

Injectable antibodies

The final side effect to consider is that the cells don’t discriminate between cancerous B cells carrying the CD19 protein and normal, useful B cells that also carry it. Therefore these engineered T cells don’t just target cancer, they go on a murderous rampage and kill all B cells in the blood, cancerous or otherwise. Unfortunately, B cells are pretty damn useful because they produce antibodies that help protect use from invading organisms such as bacteria and viruses. Fortunately there is a way around this through the intravenous administration of antibodies (a fancy way to say we can inject antibodies into a patient to protect them) once every couple of months. Unfortunately, in a sense, these antibody injections need to be taken for the rest of a patients life because the T cells persist in the body as memory cells (just like normal T cells) However, while this persistence means life long injections it does mean that should any cancerous cells start to emerge they will be killed straight away, so it’s probably worth it.

There are side affects and risks associated with this treatment, but would you rather go through a short period of fever, chills and the risk of kidney damage followed by life-long injections of antibodies or die of leukaemia? A bit of a no brainer really.

As I’ve said it’s still early days for this treatment, however that hasn’t stopped Novartis, a major global drug company, noticing the promising work and committing $20 million to a new research centre at the University of Pennsylvania in order to bring the treatment to market. As things stand the treatment costs in the region of $20,000 per patient, which isn’t exactly cheap (albeit cheaper than a bone marrow transplant). However with the funding from Novartis, and continued work in the field this figure is likely to drop. It may not be long before we start winning our war against leukaemia by turning our usual adversary HIV into a friend. Even more exciting is the fact that this approach could potentially be modified to target other forms of cancer, could HIV be our cure to cancer?!

We need some CRE-ative solutions

“Superbug” is an expression we hear far too often. Due to our excessive use of antibiotics over the past 65 or so years we have excelled this term from a potentially comical image of a flying inset that fights crime, to something we genuinely need to fear in a medical context. Admittedly, I am not a fan of the term “superbug,” but it is certainly catchier than the more accurate description of drug resistant or multi-drug resistant bacteria. The bacteria that will most likely spring to mind as being “superbugs” are MRSA and C. difficile. Both of these bacteria are well known to plague hospitals worldwide and cause potentially life-threatening disease in those people at their most vulnerable (in hospital for some other aliment). While MRSA and C. diff. are well established as health care-associated resistant bacteria, a new player is starting to come to the attention of healthcare officials and its emergence is being greeted with genuine fear.

Before discussing these new resistant bacteria I’d first like to talk about why we have resistant bacteria at all. In one sense, we can blame evolution. Bacteria are always looking to survive and will evolve to deal with anything that threatens this. The emergence of resistance is a wonderful example of the process of natural selection that drives Darwinian evolution. Let us consider a situation in which a patient has a bacterial infection. If this patient takes antibiotics these will kill the bacteria and aid the patient’s recovery. However, not all bacteria are created equally and when they multiply the progeny can carry mutations that set them slightly apart from their parent. It is possible that these mutations confer the bacteria with a slightly increased chance of survival against the antibiotics. If this occurs then this, potentially lone, bacteria will survive at the expense of all the others and will continue to grow (‘survival of the fittest’). All the competition for space and recourses has been removed due to the death of all other bacteria so this resistant bacterium will thrive. In the face of continued antibiotic treatment any new mutations that confers even greater protection will cause the same affect, continually selecting the bacterium that has the best protection from the affects of the antibiotic. The logical end point for all of this is that a bacterium will emerge that is completely protected from an antibiotic and it will thrive and spread.

MRSA - probably the best known "superbug"

While it is easy to blame evolution for the emergence of resistant bacteria, that is not the full story; we as humans need to take a fair share of the blame. Since the discovery of a process for the mass production of penicillin shortly after the Second World War, we have overused antibiotics. Antibiotics have been overused in the context of bacterial infections and most likely have been used to treat bacteria that are not susceptible to that drug (only certain antibiotics are effective against certain bacteria). However, more worryingly there are many cases of antibiotics being used to treat infections not caused by bacteria, such as the common cold, which is ridiculous since the drugs only work on bacteria (like using a cough sweet to treat a heart problem). The reason that overuse, and incorrect use, causes an issue is that we have billions of bacteria inside us; put these in an antibiotic context and you promote the emergence of resistance. Consider the fact that MRSA is a strain of the bacteria Staphylococcus aureus, a bacterial species that the vast majority of us have naturally in our lungs and on our skin, the only difference is MRSA has evolved resistance to the antibiotic methicillin.

MRSA and other resistant strains of bacteria are dangerous, however we do still have some “last line of defence” antibiotics that can be pulled out at the last minute to save the day like a cheesy action film. However, more and more cases of a new type of resistance are being seen, particularly in the USA, known as CRE. CRE stands for carbapenem resistant Enterobacteriaceae, with carbapenem being one of our few remaining “last line” antibiotics. Enterobacteriaceae are a bacterial family that include many well-known bacteria such as E. coli, Salmonella, Shigella and Y. pestis (which caused the Plague).  These are the well-known species in the Enterobacteriaceae family; however so far, most cases of CRE have been seen in Klebsiella and Enterobacter species that cause lung, intestinal and urinary tract diseases.

CRE bacteria have been spreading through the USA since their first detection about 5 years ago. Studies have suggested that these bacteria are endemic in major population centres such as New York, LA and Chicago (a report suggests that 3% of patients in intensive care units in Chicago carry CRE bacteria). There are also small pockets of CRE throughout other areas of the USA. So far CRE cases have been confined to health care facilities such as hospitals and care homes, as is the case with other “superbugs” such as MRSA. However, as with anything there is always the potential for spread outside of these facilities. The thought of spread is a worrying one when you consider the fact that CRE infections currently carry a reported 40% mortality rate, much higher than that of MRSA. If I was writing this blog for a newspaper this is where I would leave that statistic, 40% of people who get CRE die, everyone be scared and fearful! However, mortality rates are a pretty useless statistic as they rely on the ability to detect every single case of CRE to be accurate, yet chances are, only the most serious (and therefore life-threatening) cases are likely to be detected, skewing the data in favour of a higher death rate. When you also consider that until recently CRE has not garnered much attention, meaning no-one has really been looking for it, you get a further skewing of the data (only the most serious will be taken notice of). There is also difficulty in detecting CRE bacteria since carbapenems are not readily used, in the hope of preventing the emergence of resistance. This is not to say we shouldn’t consider these bacteria as inconsequential and we should (as we are) be treating them with a well-deserved level of respect.

The bottom line is that CRE bacteria are resistant to our last remaining antibiotic against this family of bacteria. All that we can do at this stage is prevent, the age-old techniques of rigorous hand washing, protective clothing and isolation are the main ways to protect from CRE infection. If someone becomes infected there is no effective treatment, with the exception of some old antibiotics that have been shelved for years due to their high toxicity (not necessarily something you’d want to take).

CRE bacteria are something we should be rightly fearful of, however they also bring to the forefront a gapping hole in our medical research. While we have some new and improved antibiotics in the pipeline, very few of these are though to be of any use against CRE, and there is very little incentive for the major drug companies to look for ways to tackle CRE. The problem lies in the fact that antibiotics just don’t make enough money. Why would a major drug company want to spend a fortunate making a drug that is used for maybe a couple of weeks, until the patient recovers, when they could spend their money making drugs to target chronic diseases that will need to be taken for the rest of a patients life. Not only is the treatment time short, but also resistance emerges so quickly that any drug produced could rapidly become obsolete, making the money spent useless. It sounds wrong to neglect people who could die from an infection on the basis of economics, but unfortunately, that is how it is, in the bluntest (and a slightly cynical) way.

I titled this blog post as the fact that we need some creative solutions, both for the play on the CRE bacteria naming and because, simply put, we do. There are ideas out there, such as the use of phage to kill bacteria. Phage are viruses that only infect bacteria so if we can find a way to use these then it may provided a good alternative to antibiotics. There is also work being conducted to look for new and untapped sources of antibiotics with the discovery of new fungi and bacteria (which produce antibiotics) in obscure locations such as caves and oceans, however, as I’ve alluded to, there is a shortage of funding in these area.

Process of conjugation, one of the main ways resistance spreads

One potentially promising area of research may lie in targeting the mechanism used by bacteria to spread resistance. Resistance is controlled by the production of protective proteins from genes. It is very common that these genes are located on mobile genetic element known as a plasmid (stick with it as I will clarify what that means). Like us, bacteria have a genome that contains all the instructions needed to produce a functional bacterial cell. However, in addition to the genome many bacteria can have addition chunks of DNA (plasmids). These extra units of DNA float around the cell, separate from the rest of the genome, and can be passed from one bacterium to another. Think of this like books, if the genome is a full instruction book for producing the bacteria then a plasmid, is like a page taken from another book. These plasmids (extra pages) can move between bacteria through a structure known as a pilus, in a process often termed bacterial sex (due to some obvious similarities – Google it). If we can find ways to block this process, correctly known as conjugation, then we may be able to stop the spread of genes that confer resistance and maintain the efficacy of our current stock of antibiotics. However, as it stands, this is just a hypothesis.

CRE bacteria are worrisome, they are resistant to pretty much all of our current stock of antibiotics and the number of cases are on the up. There is a reported death rate of around 40% for CRE infection, and while this may be slightly skewed, it is still clearly a dangerous situation we find ourselves in. We need new and innovative ways to tackle these bacteria as simply stopping the spread with preventative measures can only go so far. However, whether the funding will reach the research into these areas is yet to be seen.