Five answers to the question ‘why microbes?’

Last month, Amelia gave us five great reasons to love plants. But plants aren’t the only species worked on at the John Innes Centre that lack the respect they deserve.

 

As a microbiologist I thought it was only fair to come up with my own ‘five answers’ – and show that microorganisms aren’t just here to cause us harm. In fact, they are essential for many processes, and have great potential for many more.

 

1. Antibiotics

The world is facing a crisis: antibiotic resistance. The best way to fight this is to treat antibiotics with a bit more respect – stop prescribing them when unnecessary, and follow treatment schedules properly. Until we solve this problem, however, we need to go out and find more to battle the strains that are multi-drug resistant.

 

Antibiotics are produced in nature as a defence against bacteria in the environment – such as streptomycin produced by Streptomyces, found in the soil. We are in a ‘drought’ of antibiotic discovery, with few breakthroughs in the past few decades. Scientists are now searching far and wide for new bacterial strains that can produce novel antibiotics to compete in the ‘arms race’ between humans and their pathogens.

 

We have barely scratched the surface with microbe discovery – and there may be more hiding away that we are unable to culture, or in environments we barely know. Examples of these are in deep sea trenches or the guts of insects. Some people even think there may be bacteria on Mars – and I’m sure if we do find them, people will be looking for antibiotics there too.

 

2. Genetic engineering

Microbes can be easily manipulated, and so have huge potential for genetic engineering. The best example of this is for the production of human insulin for treatment of diabetes.

 

Initially, diabetics were treated with insulin derived from animals – which often came with side-effects. As biology progressed the structure of insulin could be characterized (earning Fred Sanger a Nobel Prize), and entirely synthetic human insulin could be produced. Further developments meant that yeast could be engineered to produce human insulin – and this is how medical insulin is now produced.

 

Another example of a medicine produced by microbes is human growth hormone. Before we engineered microbes to make this, it would come from human cadavers!

 

Other potential uses for bacteria include developing them to clean up pollution (‘bioremediation’), fight tumours or detect arsenic in drinking water.

 

3. Food

If you say the words ‘microbes’ and ‘food’ to most people, they would probably think of food poisoning. However, some of our favourite foods wouldn’t exist without microbes.

 

Many industries rely on ‘fermentation’ – the ability of microorganisms to break down chemicals. Both brewing and baking require yeast fermentation (specifically Saccharomyces cerivisiae) to produce the gas bubbles that we need for beer and bread. Another example of fermentation is in the production of yoghurt, which uses a bacteria that converts lactose sugar in milk to lactic acid, giving yoghurt its sharp taste.

 

Bacteria aren’t the only microbes that are used in the food industry. Quorn, the popular meat alternative is produced from mycoprotein – produced from the fungus Fusarium venenatum.

 

Another use for fungi in food production is in cheese-making. Blue cheeses are treated with moulds which grow within, creating veins full of flavour. Soft cheeses such as brie have a bacteria growing on their outsides, allowing them to age from the outside in and allowing the interior to become runny.

 

4. Fuel

Our fossil fuel reserves are running out, and the race is on to find alternative sources of energy to sustain us.

 

Scientists are looking to bacteria for help. Like all organisms, bacteria are able to convert chemical energy (such as glucose) to other forms of energy (such as movement). In 1911 a scientist was able to produce an (albeit very small) electric current from E. coli. So the concept of microbial fuel cells was born.

 

Humans respire using oxygen, converting fuel (sugars) to energy, producing carbon dioxide and water. Many bacteria are able to respire without oxygen, and so instead of producing water in this reaction, produce protons and electrons. If we can harvest these electrons, then we have bacteria that produce electricity – a microbial fuel cell.

 

It is hoped that these fuel cells can be developed to be more efficient, and to use waste products such as those from industry as their fuel. If this can be achieved, it could have a huge impact on electricity production, as well as waste processing.

 

5. Symbiosis

The soil is a world full of microbes of all shapes and sizes – from bacteria to fungi to oomycetes. Although some aren’t friendly and can cause plant disease, many of them play quite the opposite role. Plants and specialised fungi can live together in harmony, and even help each other out. These beneficial relationships are known as symbioses.

 

There are two cases of soil symbioses that are particularly well-studied. The first of these (and the field in which my PhD falls) is the rhizobia-legume symbiosis – where bacteria convert nitrogen from the air into a form that plants can use in return for plant sugars.

 

The second is the case of mycorrhizal fungi, which associate with plant roots to get direct access to sugars. In return, the fungi scavenge through the soil for important nutrients and minerals such as phosphates.

 

There are many other cases of symbiosis that shape the world we live in – see this post from last year if you want to read more about rhizobia and some of our other favourite mutualistic relationships.

 

Interactions with plants aren’t the only case of bacteria living in harmony with other species. Our guts are full of bacteria with a wide range of benefits. They help us digest our food, stimulate cell growth, protect us from harmful microbes and help train our immune system to protect itself.

So, next time you think of microbes, don’t tarnish them all with the same brush. There is huge diversity across the microbe world – and huge potential for their use in many different areas of science.

To see Amelia’s answers to the question ‘why plants?’, click here

Izzy is a John Innes Centre PhD student. She’s on Twitter as @isabelwebb.

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Norwich leading the fight against antibiotic resistance

It’s mid-November, it’s cold, it’s dark and as I make my way to the Conference Centre I see a crowd of people gathered inside. They are here for the Friends of the John Innes Centre’s Fight Against Antibiotic Resistance event – an evening of talks by Norwich Research Park scientists. It’s busy, and some 250 people – a mix of students and members of the public – have turned up to hear what the night’s speakers have to say.

Setting the stage for the evening is the John Innes Centre’s Mervyn Bibb. As the audience settles in, he begins to explain the current crisis of antibiotic resistance and problems associated with discovering new drugs to treat resistant pathogens.

Very few new antibiotics have been discovered since the so-called golden age of the 1950s and 60s, and the current pool of available antibiotics has been poorly stewarded. In many countries, antibiotics can be readily bought without a prescription. Even where prescriptions are required for antibiotics, there is an apparent cultural trend to overprescribe them. The use of antibiotics for nonmedicinal purposes further complicates matters. Around 30% of antibiotics produced in the US, for example, are used for promoting growth in livestock.

The frequent exposure of bacterial populations, coupled with their incredible ability to develop drug resistance through multiple pathways, has resulted in a rapid increase in the number of multi-drug-resistant (MDR) organisms. Methicillin-resistant Staphylococcus aureus (MRSA), perhaps the most well-known MDR pathogen, is sadly just one member of an ever-growing list.

To make matters worse, the pharmaceutical industry has almost completely lost interest in developing new antibacterial compounds due to their low market value and short term usage. In Europe, around 25,000 people die each year from antibiotic-resistant infections and members of both houses of parliament have stressed the dangers of leaving this problem unchecked.

Thankfully, there are researchers trying to solve the problem. Tonight we get to hear from three of them.

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Solving the problem of antibiotic resistance

If you’ve been paying attention to the news for the past week, you may have noticed more than a few mentions of antibiotic resistance. Firstly, solving the problem of antibiotic resistance won the Longitude Prize, confirming its importance in the eyes of the public. Then, a few days later, David Cameron has been all over our screens warning that the problem could lead to our world being ‘cast back into the dark ages of medicine’.  He has announced investigation into why so few new antibiotics have been introduced, and plans to encourage development of new antimicrobials. However, despite being mentioned hugely this week, however, this is far from a new problem.

Antibiotics are chemicals that are able to either kill a microorganism, often a bacteria, or inhibit its growth. Antibiotic resistance is the ability of a microorganism to resist the action of the drugs. This resistance arises naturally as a result of bacterial evolution. Just as with all other organisms, mutations can occur. If a mutation is beneficial to the organism due to ‘selection pressures’ in its environment, then the mutation is likely to stick. In the case of bacteria, the selection pressure is the presence of an antibiotic, and so a mutation that allows the bacteria to survive will be carried forward into the next generation. Since bacteria can share genes with neighbouring bacteria (horizontal gene transfer), the resistance can often spread rapidly through a population. Often bacteria become ‘multidrug resistant’, or as they are more commonly known, superbugs. In these cases we need to find new antibiotics to fight the bacteria, and this is where our problem lies.

As mentioned earlier, mutations will stick if there is a selection pressure, such as antibiotic presence. It makes sense, therefore, to only prescribe antibiotics when they are needed. Unfortunately, this is not what is happening. It is widely agreed that antibiotics have been inappropriately prescribed in the past, and probably still are. Patients have been known to insist on getting antibiotics when they are not necessary – for example, a third of people believe that they can take antibiotics to treat the common cold1 (which is a virus, and so completely unaffected by antibiotics). Another way to reduce the chance of resistance occurring is to ensure that patients complete a course of antibiotics. Just because you feel better, doesn’t meant that your infection is gone. Reducing or stopping a course of antibiotics can lead to reduced levels of the chemicals in your body, giving the organisms a lower level to fight against (and win). GPs and their patients need to be more aware of these issues in order to try and reduce the occurrence of resistance.

Inappropriate treatment of humans isn’t the only issue contributing to the rise of resistance. Nearly 50% of all antibiotics are used in farming – mostly in intensive livestock farms2. These intensive farms have crowded conditions which could lead to a fast spread of disease. A large proportion of livestock receives regular antibiotics, whether they are showing signs of illness or not. Paying for these antibiotics may seem like a large cost to farmers, but it can mean a huge saving if it prevents them losing their entire year’s income due to a disease outbreak. This issue has already been identified, and there are many campaigns trying to make changes to these antibiotic regimes on farms.

Solving the problem of antibiotic resistance isn’t a simple case of producing new antibiotics, however. If we are to stop this problem spreading, we need to learn how to treat our infections properly and treat the correct infection with the correct antibiotic. This is a case of improving diagnostics and hospital procedures, and this is where it is most likely that the Longitude Prize money will end up going – because it is a long-term solution and not a short-term one.

New antibiotics can be found from a huge variety of places (All images from Wikipedia)

New antibiotics can be found from a huge variety of places

The issue highlighted by David Cameron this week is that there are no new antimicrobial drugs reaching the market. The case is that the pharmaceutical companies are not investing in sending these drugs to the market, and not because the research is not going on. It costs tens of millions of pounds to get a drug to the market – and in the world where resistance is occurring so easily, it is unpredictable whether developing a new antibiotic would be profitable. To imply that we are not discovering the antibiotics is certainly incorrect. I work in a molecular microbiology department who has a large group of scientists working with Streptomyces, soil bacteria whose antimicrobial products were discovered back in 1943. Many of these scientists are investigating whether we can use these bacteria to find even more microbial compounds. Elsewhere on site, researchers are investigating bacteria from insect guts for the same cause3. Elsewhere in the UK, research is being done to hunt for antibiotics from bacteria from deep ocean trenches.

Both the Longitude Prize and the following press coverage from David Cameron have highlighted a key issue in the world today. But we should not be investing all our money into finding new antibiotics, because this is not the solution we need. If we are to prevent even more superbugs emerging, we need to be focusing our efforts into understanding the bacteria, and understanding how we can fight them best. We need to be educating the public into the risks of treating antibiotics with less than the respect that they deserve, and we need to be making farmers do the same. Evolution will never stop happening, and so bacteria will never stop trying to become resistant. Maybe, however, we can slow the process enough to stop it from  ‘casting us into the dark ages’.

The latest offering from the John Innes Centre YouTube page:

  1. McNulty et al. (2007). “The public’s attitudes to and compliance with antibiotics”. J. Antimicrob. Chemother.60 Suppl 1: i63–8..
  2. http://www.soilassociation.org/antibiotics
  3. http://www.bbc.co.uk/news/uk-england-norfolk-23903861

All images from Wikipedia By Isabel Webb, a 2nd year PhD student in the lab of Prof Phil Poole

Searching for a needle in a genetic haystack

In the last year, a brand new technique for genome editing has appeared with the potential to revolutionise the way in which scientists engineer genomes. It provides the ability to make cuts in the genome at precisely controlled locations, resulting in the silencing of that particular region. This technique is known as CRISPR. To make such a precise cut, however, requires the active protein to find a unique 20 base pair region within the vast sequence space of the entire genome.

“Seek and Destroy” – Nature issue 7490 (image from Nature.com)

The CRISPR system originates from the bacterial immune system in which a segment of the bacteria’s genome contains short elements of viral DNA (protospacers), which act as guides to attack invading viruses by disrupting their genetic code [1]. This segment (known as the CRISPR array) contains so-called ‘Cas’ proteins capable of cleaving segments of DNA, that are guided into place by the protospacers stored in the array. The bacteria are able to add new stretches of foreign DNA to this array to develop immunity in future encounters with the invader.

The genome editing technology [2,3] takes this CRISPR array structure and replaces the viral DNA sections with lengths of the target genome that are intended to be silenced. This can then be inserted into the target genome by standard methods and, when transcribed, the Cas protein finds its way to the point in the genome with precise sequence complementarity to its guide. However, despite this technique’s success, the mechanism enabling the Cas-RNA complex to find its target was unknown, until now.

In this week’s nature cover article [4], Sternberg et al. show that a particular Cas protein, Cas9, can only bind to regions containing a three-nucleotide motif region, known as a PAM, that is found adjacent to protospacers. When searching for a needle in a haystack, you would not pick up every piece of hay, compare it to a picture of a needle, and then replace it when it didn’t match. Similarly, Cas9 does not try every point on the genome and compare the local sequence to its guide. It first limits the number of places to search by only binding to PAMs. This could be likened to the first step in searching for a matching phone number; you only compare the numbers with the same area code.

Of course, there are still a large number of PAM sequences in a given genome (or else the technique would be somewhat limited), but it vastly simplifies the problem. Furthermore, the PAM acts as the start point for the guide/genome sequence comparison, which proceeds one nucleotide at a time in sequence. The process is such that if the first 2-3 nucleotides do not match, then the complex rapidly disengages from that region and can move on to try a different location.  These factors combined ensure that the complex spends as little time as possible at incorrect locations.

This work is an impressive demonstration of how biological systems are able to solve difficult problems. An invading virus needs to be dealt with quickly if a bacterium is to survive. The CRISPR system therefore needed to find a rapid way of finding a target within a large search space. It achieved this by utilising a regular motif present within the target genome, choosing to only incorporate stretches of DNA adjacent to these motifs. It seems the trick to finding a needle in a haystack is to choose a smaller haystack to lose it in.

References

  1. Wiedenheft, B., Sternberg, S. H. & Doudna, J. A. RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331-338 (2012).
  2.  Mali, P. et al. RNA-guided human genome editing via Cas9. Science 339, 823-826 (2013).
  3.  Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823 (2013).
  4.  Sternberg, S. H., Redding, S., Jinek, M., Greene, E. C. & Doudna, J. A. DNA interrogation by the CRISPR RNA-guided endonuclease Cas9. Nature 507, 62-67 (2014).

By Matthew Evans- a second year PhD student in the lab of Dr Richard Morris

No microscope? A smart solution

I recently saw a bit of a buzz on twitter about being able to turn your smartphone into a microscope using just a drop of water on the camera. Since water refracts light differently to air, the drop of water magnifies the image that is travelling to the camera lens. Last week I accumulated some microscope slides to look at – but my lab has no microscope! It seemed the perfect time to try out this smartphone trick. It worked beautifully, and so I was quick to tell anyone who would listen to have a go. Microscopy can be essential in many projects that are going on here at the John Innes Centre – so a few of us on the blog team thought we’d share with you our smartphone microscopy photos – with a bit of a background so you know what you’re looking at of course!

lovegrass

Eragostis tef aka teff or lovegrass

Eragrostis tef (aka teff or lovegrass) is one of the smallest cereal grains in the world, with a similar size to poppy seeds. In this image the top grain has been stained with iodine; the blue/back colour shows that the grain is full of starch. This grain is used to make an Ethiopian beer called tella. It has similarities to the barley grains that are used in the malting process for the production of beer, whisky and malt products like maltesers. Because of its small size Teff is useful for high throughput screening of chemicals capable of interfering with the malting (grain germination) process. Once these chemicals are identified they can be used as tools to better understand the malting process.

nodule

Bacteroids inside a pea root nodule

Plants in the legume family, such as peas and beans, have a symbiotic relationship with rhizobia bacteria. These bacteria live as a differentiated form inside ‘nodules’ on the roots of these plants. The differentiated bacteria – known as bacteroids – carry out a reaction to convert nitrogen from the air into ammonia which the plants can use to make nitrogen compounds such as amino acids. In return, the plant provides sugar to the bacteroids to provide them with the energy that they need for the nitrogen reaction. Understanding this biological nitrogen fixation has a lot of potential for improving future yields of crop plants or reducing our dependence on artificial fertiliser production.

Fallen pollen on the hairs inside the snapdragon flower

Fallen pollen on the hairs inside the snapdragon flower

a

Bee’s eye view of the Snapdragon mouth

Antirrhinum majus (or the Snapdragon) is a common garden plant in the UK.

The flower has a special closed mouth which can only be opened by bees landing on the lip of the flower. The bee climbs into the flower to reach the nectar at the bottom and whilst inside pollen rubs on to the bee’s back which it then transfers to the next flower it visits pollinating it.

e

There are lots of different colours and patterns in Snapdragon flowers. For example the flower on the left has pink only over the veins in the petals. We use these obvious differences to investigate the gene networks involved in controlling colour. We also use populations of different coloured Snapdragons to investigate inheritance. Many of the principles discovered for gene control networks and inheritance can be applicable to other systems too, even human genetics!

d

The complex shape of the Snapdragon flower makes it a fantastic tool to investigate how shape forms. One way we look at how shape forms during flower growth is through clone patterns. Clones are the pink spots in this picture; they form when a single cell turns on the pink colour gene, then all of this cell’s daughters are pink forming the clone spot. By looking at the sizes and shapes of clones we can tell where more growth happens in the flower and in which orientation. The principles learnt from studying the Snapdragon shape can be applied to other plant species (including Grasses!) and even animals. We can also investigate evolution of shape because close relatives of the Snapdragon, like Foxglove don’t have this complex flower shape. 

By Mike Rugen (Teff), Izzy Webb (nodule) and Annis Richardson (Snapdragon)

Young Microbiologists Symposium 2013

On Monday 18th November my department at the John Innes Centre, Molecular Microbiology, hosted a day of talks from ten up-and-coming scientists in the field. The majority of these were in the middle of a post-doctoral grant, others starting their post-doctoral training while a few were coming to the end of their PhD projects. The speakers travelled from the USA, mainland Europe and the UK to present their work to the audience.

The wonderful world of microbiology (all images from Wikipedia)

It was obviously lovely to see some familiar faces giving talks and seeing what they are up to now. And at the same time, it was great to get an insight into what is happening in the research community outside of my area. A range of bacteria was spoken about from cell cycle models such as Caulobacter crescentus to previously uncultivated microbes in sea sponges. Some talks were mainly bioinformatics, which to be honest is not my strong point, and I have to admit, I did not completely understand… Others were on natural products and how to mine them from genomes – a field which is becoming increasing important. All in all, it was a good day with lots of new information learnt, as you always get from conferences!

Maybe we will see some of these scientists as project leaders one day – who knows? Or, maybe they will be joining the JIC soon possibly in more senior fellowship or group leader positions. It would be exciting to have some of their fantastic brains (and more nice people too) in our department! Or, on a more positive note, it is always nice to know that any one of the many PhD students in the JIC could be giving a talk at a symposium or at a conference, and maybe their future boss will be in that room!

By Rowena Fung, a 3rd year PhD in Jake Malone’s Group