Bacteria rule the planet - and we need to understand them, says MRC LMB director Dr Jan Löwe
‘What we try to find out is rather simple,” says Dr Jan Löwe, director of the MRC Laboratory of Molecular Biology in Cambridge, discussing his own group’s research.
“It’s about how you get two bacteria out of one. Bacteria proliferate differently to us. They don’t normally have sex. They don’t have offspring as we do. They have a simpler process where a bacterium grows to a certain size and a decision is made that it’s too big, so it splits in the middle and you get two out of one. If you do that many times, you get many more.
“That process has been known since bacteria were discovered by Antonie van Leeuwenhoek.”
The father of microbiology, as van Leeuwenhoek is often known, discovered bacteria in water in 1676 when using single-lensed microscopes of his own design.
An extraordinary, self-taught individual who also observed protozoa, he never wrote any formal scientific papers, but shared his discoveries of what he called “animalcules” in letters to the Royal Society.
In the three and half centuries since, the mystery of how bacteria divide has taxed microbiologists. Cracking it could help us prevent the rapid reproduction of harmful bacteria.
“It is not known at a molecular level how that works. The goal of my work is to find out how it happens.” says Dr Löwe, a fellow of the Royal Society who took over as LMB director in April.
“It turns out that at the heart of the process is a molecule that forms chains of molecules, or filaments.
“One of my early contributions here was to show that this molecule is related to a molecule that is in our bodies that does something different but looks very similar.”
Dr Löwe discovered that bacterial proteins FtsZ and MreB resemble tubulin and actin – two filamentous proteins that are key components in the cytoskeleton of our cells.
The cytoskeleton helps give our cells shape and structure, plays a role in the transport of material within cells, and in and out of them, and is important in the process of cell division.
Until the mid-1990s and Dr Löwe’s work on the subject, it had been thought that only eukaryotes – organisms that have cells with a membrane-enclosed nucleus such as human beings, animals, plants and fungi – had an organised cytoskeleton.
But it emerged that bacterial proteins had similar folds and formed similar filamentous structures to tubulin and actin.
“The function of chain or filament formation has been conserved for three billion years during evolution, so it does something very useful,” notes Dr Löwe. “The discovery of that prompted the search for other molecules that form filaments in bacteria because it was not known that they did that. That’s now termed the cytoskeleton and it’s what my group has done for the last 20 years.”
FtsZ is now known to play a key role in the proliferation of bacteria, being the first protein to move to the site of division and helping to recruit other proteins to form a new cell wall.
It is known as a “homologue” of tubulin because of an intriguing evolutionary connection.
“The idea is that both of these come from something even older,” said Dr Löwe.
Bacteria were among the first life forms on Earth and can be found almost everywhere – from our own guts, to radioactive waste.
A 1998 study by William Whitman, David Coleman and William J Wiebe estimated that there are 5x1030 bacteria on the planet. Astonishingly, there are about 40 million bacterial cells in a gramme of soil and a million in a millilitre of fresh water
“As human beings we tend to see the world through our own species’ eyes,” says Dr Löwe. “We look at things at a certain scale, speed, temperature, pressure. But it turns out that the planet is actually mostly populated by bacteria. The biomass of all the bacteria on the planet is greater than any other class of organisms.
“The fact there is oxygen in the atmosphere for us to breathe came about because there was a certain class of bacteria – cyanobacteria in the oceans – that learned how to use the rays of the sun to make energy.
“The toxic byproduct was oxygen, which is actually very dangerous because it makes everything go up in flames! It was a sort of environmental catastrophe, if one can call it that, very early on in evolution.”
This Great Oxidation Event took place some 2.45 billion years ago, although it took another billion years or so for oxygen level to rise sufficiently for animals to evolve. Our presence, then, is only possible thanks to bacteria.
Dr Löwe says: “Bacteria rule the planet and because they have been around so much longer, their diversity is much greater. The gene pool is enormous.
“The variety of different proteins or genes in prokaryotes [organisms without membrane-bound nucleii] vastly outnumbers that in all the other organisms that we know like plants, animals and yeasts.
“Because of that, we need to have a very good look.”
Indeed, a 2016 study by Ron Sender, Shai Fuchs and Ron Milo estimated that the body of an average man contains about 39 trillion bacterial cells – compared to 30 trillion other cells – and the study of our micobiota is a burgeoning field in science.
And while we owe our lives to bacteria, they are also responsible for many of humankind’s most potent enemies, such as tuberculosis, cholera, diphtheria, bacterial meningitis, tetanus, Lyme disease and syphilis.
“The reason why one wants to work on cell division at the Medical Research Council is very easy to explain. Cell division is one of the most basic processes needed for bacteria to proliferate.
“It’s clear that some bacteria can cause disease and if you find new ways to stop them growing then you are not far from new antibiotics,” says Dr Löwe, who has previously collaborated with others hoping to develop such medicines.
Antibiotic resistance – which occurs when bacteria evolve to evade the effects of a medicine – is a critical global challenge. The World Health Organisation puts it bluntly: “Without urgent action, we are heading for a post-antibiotic era, in which common infections and minor injuries can once again kill.”
And it warns: “A growing list of infections – such as pneumonia, tuberculosis, blood poisoning, gonorrhoea and foodborne diseases – are becoming harder, and sometimes impossible, to treat as antibiotics become less effective.”
Despite the recognition of the problem, Dr Löwe believes much more needs to be done.
“I’ve become more outspoken about the lack of investment in this area,” he says. “I’ve just learned that the Medical Research Council has made anti-microbial resistance (AMR) as one of its priority areas because pharma is not investing enough money in this area.
“It’s not because they don’t want to. It’s because they find it difficult to make money out of it. So other ways have to be found to develop new anti-microbials. There are many different ways to do that but one way is to learn more about the biology before you develop new drugs. It’s called target validation. You want to find molecules inside or on bacteria to target with new drugs.”
He adds: “Resistance against anti-microbials is something that happens eventually. It is an arms race that we can never win. We can only keep up with it. So it is required to constantly work on better compounds and more controlled, targeted use of them in order to slow down the development of resistance and make resistance less dangerous.”
The LMB’s work to understand how bacteria divide and conquer could prove vital to meeting this challenge.
Opportunity to develop a genuine campus feel
The MRC Laboratory of Molecular Biology was one of the first to take up residence at the now flourishing Cambridge Biomedical Campus.
“I still remember when this was just windswept fields,” says Dr Jan Löwe, looking out the window of his office. “It’s still windswept….”
The campus, with Addenbrooke’s and the Rosie hospitals at its heart, is home to Cancer Research UK Cambridge Institute and numerous University of Cambridge institutes, and will soon be home to life science giants Abcam and AstraZeneca, while the Royal Papworth Hospital will open its doors next year.
“We really love being here. It’s grown into something really big,” observes Dr Löwe. “It’s fantastic. There are thousands of people with different ideas, skills and aims, and yet you can see how it all belongs together: the medics, the pharma companies, the biotechs, the research institutes and the charities.
“It’s all here and it’s fantastic. There is a lot of contacts and collaborations and shared interests.
“For example, we have AstraZeneca across the road and we have an AZ-LMB Blue Sky Fund that funds 30 post-docs in this institute where we do projects together.
“It’s very successful and there is very interesting science. It fosters these personal connections that are so important to do something amazing.
“We also have contacts with the clinical school, which is fantastic.”
But Dr Löwe is also clear that the site is a work in progress – and there is room for improvement.
“I’m not sure I would call it a campus yet,” he says. “There is an opportunity to grow this into a real campus where people meet randomly while they are getting their lunch, or when they go somewhere, and it’s a proper site where we all feel we are there together.
“I’d be inclined to say that hasn’t happened yet. But everybody knows that – our neighbours say the same thing. It’s important to recognise that and see the opportunity as something that everybody wants.
“It has grown extremely rapidly and there are reasons why it has been difficult to have an overall vision that can be put in place.
“But I think it’s a unique opportunity in Europe. It is a unique constellation in terms of the sheer number of people, but also the breadth of expertise and interests.”
Dealing with the data demand
The next advances in molecular biology could be driven as much by developments in computer science as anything else.
“It’s a very important insight and should inform decision-making on where investment needs to be made in science,” says Dr Jan Löwe.
“It’s very important that students are taught computing and programming, because everybody needs that, and that we invest in IT infrastucture so that the tools are available. Both of those are happening but one could argue maybe not enough.”
Since completing his doctorate in Munich in 1995, Dr Löwe has witnessed an explosion in the sheer volume of data created by modern research techniques.
“It’s several orders of magnitude worse. It poses technical problems in terms of storage and processing and analysis but it’s also a huge opportunity,” he says.
“When DNA sequencing was invented here by Fred Sanger it took months to read 1,000 bases of DNA. Now you can buy a machine that sits on a desk that can do a few billion in one day. That’s just one part of biology. There are many other areas where data generation is just exploding.
“Electron microscopy is another example. One of those machines generates more than a terabyte of data a day. We can deal with that - computer science is progressing as well.
“But at the heart of it there is a problem. We cannot use our own brains anymore to analyse all of this data in sensible ways.
“It’s becoming clear that hypothesis generation – which we think of as our last domain of dominance – may not be left entirely to humans in the future as machine learning steps in.
“There is huge excitement all over the world about it, both in academia and on the industrial side. It’s very, very powerful.
“I still remember in the 1970s and 1980s the ideas of using computational neural networks to mimic how brains learn. We realised it was powerful but not how powerful because we didn’t have the computers to scale this up. Now we do, it’s a game-changing transition. Computers can see objects or images much more precisely than we can.”
From number plate recognition to finding a red pen in a million images, the ability of computers to sort through data is already well-established.
“There are more serious applications in science, where it is about finding pieces of patterns in huge amounts of very noisy, unstructured, complicated data sets which a human being would not be able to do. Humans are very bad at that. But machines can extract surprising detail out of this data,” says Dr Löwe.
“It goes even beyond that. It it now possible to do abstractions. It turns out these networks produce outcomes that enable us to find patterns that we didn’t even know were there. It’s hugely exciting and it’s an area in which we, and everybody else, are really trying to make progress.”
Today, in common with other research institutes, the MRC Laboratory of Molecular Biology employs not just molecular biologists. Data science and bioinformatics can now be as key to discoveries as peering down a microscope.
“It’s a classic example where a single discipline is not sufficient to make progress,” says Dr Löwe.
“For example, in cryo-electron microscopy, machine learning is very important and Sjors Scheres here collaborates with people in the University of Cambridge Department of Mathematics and has for several years, trying to adapt algorithms to exactly what he needs. Most people here don’t have training in machine learning – we are the users who find applications. We hire physicists and mathematicians with the understanding that it is really at the interfaces of all these ways of thinking that progress will be made.”
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