Dr Jan Löwe on the next frontier for MRC Laboratory of Molecular Biology in Cambridge
As we walk through the vast atrium of the £212million home of the world-renowned MRC Laboratory of Molecular Biology in Cambridge, director Dr Jan Löwe pauses at the display detailing the 12 Nobel Prizes awarded to its scientists over the years.
It has just been updated, following the award of the 2018 Nobel Prize in Chemistry to Prof Sir Gregory Winter, master of Trinity College, for his work that led to the development of antibody drugs. He collected the prize on Monday (December 11).
Next to him on the display is Richard Henderson, a former LMB director who shared the 2017 Nobel Prize in Chemistry for developing cryo-electron microscopy, which transforms our ability to determine the structure of biomolecules.
Prof Winter and Dr Henderson’s awards begin a second row on the display.
I point out that there now appears space alongside them for many more. No pressure, Dr Löwe.
“We may redesign it,” he laughs.
Cambridge’s Nobel Prize factory, as it is often known, has been leading the way in molecular biology since the inception in 1947 of a Unit for Research on the Molecular Structure of Biological Systems by the Medical Research Council.
It was in 1962 that a new building – the LMB – was opened for the unit, and in 2013 it moved to its current home on Cambridge Biomedical Campus, an imposing 27,000 square metre hulk designed to resemble a paired chromosome with two long laboratory areas joined by the cavernous atrium.
“I came to the LMB in 1996 as a post-doc, straight after my PhD in Munich. Looking back, I would never have dreamt to have become director here. This is a really fantastic opportunity for me,” he says, as we settle in his office.
Dr Löwe was joint head of the laboratory’s structural studies division, and became deputy director before taking over in April from the retiring Prof Sir Hugh Pelham in April.
“It’s an interesting job because what the LMB does is bottom-up science. There are about 55 groups here and we hire the best scientists we can find from anywhere in the world.
“They get resources, space and time and then they do the best work they can do.”
One of the secrets of the LMB’s success is the trust it places in its brilliant scientists.
“As a director, there is no directing in the sense that we don’t tell people what to do,” explains Dr Löwe. “Yet it is rewarding because my job is to enable people to do their best. I think the LMB is very good at that.
“I will do my best to keep the LMB where it is now. With its inception in the 1940s it was the first institute in molecular biology. It has had a fantastic run in that it has remained at the forefront of its field for a very long time now.
“The recent prizes, awards and recognitions, and especially the Nobel Prizes in 2017 and 2018, have been an indication that the lab is still going very, very strongly.”
Dr Löwe has a core budget of £190million to deploy over five years, and 700 research and support staff.
But with no firm top-down direction, how do the LMB’s scientists determine what to study?
“That is driven by what we want to know about our world,” says Dr Löwe. “Our job is to create knowledge about biology in the wider sense, always with a focus on how that eventually can be used to improve human health.
LMB scientists position themselves at the boundaries of biological knowledge.
“It’s a fine line,” Dr Löwe acknowledges. “Either you can be behind the curve and be in a big sea of competition where the rest of the world is doing the same, and that’s not very interesting, or you can be ahead of the curve and you find yourself working on something that never delivers.
“That’s where I think leadership and guidance is sometimes necessary.
“But the subject matter people choose themselves and they are free to change if they feel that’s needed.
“Our main aim is to understand the processes of life in sufficient detail in order to do something with it.”
The translation of that knowledge is often passed to industry, a spin-out company or achieved in collaboration.
Indeed, the lab’s intellectual property has generated more than £700million in income for the MRC through technology transfer.
But it is its impact on human knowledge for which it is justly renowned.
“The most significant development recently has been the development of cryo-electron microscopy, for which Richard Henderson was awarded the Nobel Prize in 2017,” notes Dr Löwe.
It is an example of the long-term approach and vision of the LMB, which has played a leading role for decades in the development of the technology.
The first prototype electron microscope was built in Germany in 1931, and the LMB began using the technique on biological material in the 1960s and 1970s.
Aaron Klug, the former Nobel Prize-winning LMB director who died last month, helped to develop methods of determining three-dimensional structures from two-dimensional images.
“That became very important for CT scanners and all sorts of three-dimensional imaging technologies.
“But the actual method of using electrons to image biological molecules and resolve atoms didn’t work for many, many years and it wasn’t entirely clear why,” says Dr Löwe.
“Richard kept working at it with people from other places and only a few years ago it started working properly.
“There was a detector development that he led, and another in the United States. We have Sjors Scheres here, who developed the most successful software in this area. We bought many expensive new microscopes. Taking all this together, eventually it worked.”
Cryogenic electron microscopy, or cryo-EM, begins with the preparation in water of a pure sample of the target molecules, which is rapidly frozen in liquid ethane. This holds the atoms in their natural structure within a very thin sheet of ice.
Electrons are fired at the sample, detected by a camera and thousands of images are then sorted and pieced together using software to create a high-resolution 3D structure that can give insights useful in, for example, designing new drugs to fit precisely into a molecule.
“We’ve always been interested in this idea that once you understand biology at the atomic level then it becomes more like chemistry and physics,” says Dr Löwe. “And that becomes very powerful because we know many laws and principles that we can apply about how things work at the atomic level. That’s the very basic idea of molecular biology.”
Before the development of cryo-EM, scientists relied on X-ray crystallography to determine structure – technology again indelibly linked to Cambridge.
Father and son William Henry and William Lawrence Bragg, at the University of Leeds and University of Cambridge, invented crystallography, winning the 1915 Nobel Prize in Physics.
The LMB’s Max Perutz and John Kendrew then shared the 1962 Nobel Prize for Chemistry after using X-ray crystallography to determined the structures of haemoglobin and myoglobin.
The technique relies on creating crystalline structures of a sample, which cause X-rays to diffract in different directions, from which three-dimensional pictures can be built up.
“That was very powerful and still is, but it’s difficult because you need to take purified molecules and crystallise them. That’s not something that nature does and many things don’t crystallise.
“Electron microscopy does away with the crystals, so it’s a liberation of the entire field. We can now solve the most amazing structures.”
Another of the LMB’s stellar scientists, Venkatraman Ramakrishnan, spent years determining the structure of the ribosome, the large molecular machines that make proteins, using X-ray crystallography. He shared the 2009 Nobel Prize in Chemistry for the achievement.
“You can now solve ribosome structures in a day if you need to!” says Dr Löwe. “It illustrates how electron microscopy has really moved structural biology forward.”
Now bigger, more complex and less well-defined structures can be resolved, including those which do not crystallise.
“They can be a bit floppy, there can be bits hanging off and it doesn’t matter so much,” explains Dr Löwe.
Each of the LMB’s four divisions – cell biology, neurobiology, protein and nucleic acid chemistry (PNAC) and structural studies – now make use of the LMB’s three huge cryo-EM microscopes, which cost £4million-£5million each, and many other smaller microscopes.
Electron microscopy will also be critical in advancing what Dr Löwe sees as the next major area of discovery for the LMB.
“Molecular biology has had fantastic successes. We have learned about genetic inheritance and how to use that knowledge to cure diseases,” he says.
“What molecular biology has not really delivered so far is a good understanding of the brain. Even until 10 years ago, this used to be completely intractable.
“Nobody really had a good angle on how to investigate it. I would argue that this has just changed.”
The LMB’s 2002 Nobel Prize winner, Sydney Brenner, once said: “Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.”
Dr Löwe agrees. For it is technology that has given us new hope of mapping the human brain.
“We can now image the entire brains of small animals, like flies for example, and map all the connections between the neurons,” he says.
“Together with methods to interpret the system or image its dynamic function, it’s possible to find out how certain behaviours are encoded in the brain.
“I find that very exciting. I think it’s a very important extension of molecular biology to find molecular explanations for some of these questions.
“What is memory? How do we remember things? What is the physical basis of information storage? How is decision-making done in our brains?
“I think that’s a very natural progression for the LMB. We have done some of that but I would argue we haven’t done enough.
“One of my jobs, I think, is to try to go into that area and expand that significantly.”
In doing so, Dr Löwe will be picking up the baton from the late Sir John Sulston, who shared the 2002 Nobel Prize with Dr Brenner and Bob Horvitz for their discoveries on the genetic regulation of organ development and programmed cell death, which they studied in the life cycle of the adult nematode worm.
“John is best known for his work on human genome sequencing at the Sanger Institute but with John White he also looked at the first complete nervous system of an animal – this small worm.
“This was the first lab where that was done and I think we missed a bit of a trick by not continuing that properly. I would like to go back to that in quite a big way.”
Mapping the brain uses another form of electron microscopy.
“You take the entire brain and take images of slices of it. If the slices are thin enough and the imaging has enough resolution, you can essentially reconstruct a complete three-dimensional image of the entire brain,” explains Dr Löwe.
“Then you can use computers and machine learning, or crowd-sourcing, in order to trace all the connections between neurons.
“To give you an idea of the scale of the problem, the worm has a few hundred neurons and you can do that in a few days. The fly has about 250,000 neurons and with all the connections between neurons that is a task of years for many people.
“The human brain has tens of billions of neurons. That, at the moment, is currently not possible.
“But once it is automated and machines can do the tracing, it will be done.”
The end result of the first human brain map is not yet known, but it could help us understand some diseases better.
“The brain might seem special but the basic unit is still a cell as it is for the rest of our body. It’s just that they are very specialised cells with very specialised functions.
“I would argue it is a very natural transition to apply the thoroughness of molecular biology to the investigation of the brain.
If the LMB’s scientists succeed in this emerging area, under Dr Löwe’s leadership, it will write another chapter in the extraordinary laboratory’s history.
And it might just fill another slot on the Nobel Prize display.
Look out for part two of our interview, in which we discuss Jan Löwe’s own research, his thoughts on machine learning and his verdict on the Cambridge Biomedical Campus.