NOT a lot of people know this, but babies are made with a handshake. True, that isn’t all that is involved. Often it starts with two people falling in love. But at some point biology takes over and a sperm must burrow its way into an egg. There is, however, more to the story.
On reaching the egg, the sperm meets the zona pellucida, a thick jacket of sugars that only sperm cells have the right biochemical tools to grab hold of. That “molecular handshake”, as at the University of California, San Diego, puts it, is the most crucial step in the process that gets human life started.
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Sugary handshakes aren’t just involved in baby-making. It turns out that every type of cell in our bodies has a unique sugar coating. And whenever anything interacts with a cell, it must recognise that sugar code and use the appropriate secret handshake. It happens when bacteria and viruses infect us, when a growing brain cell feels its way past its neighbours, and when our stem cells receive the marching orders that will define what type of tissue they will develop into.
Learn to read and write this sugary language, then, and we would have a powerful new way of intervening in cells’ activities to control disease and plenty besides. It won’t be easy. Unlike DNA, this code is fiendishly complex. But we are finally beginning to master the language of our cells.
To see why the sugar code is so important, try imagining you are a bacterium, says , a chemist at the University of Leeds, UK. You are approaching a host cell, parachuting down over a forest of biomolecules on its surface. The first things you will meet are the branches of sugars, which are connected to the cell membrane by protein trunks. “This is like the canopy of your forest,” says Turnbull. Anything wanting to get inside must have a grip shape that matches the branches to use them as handholds.
That is a tall order, because the branches are complex in shape. The genetic code has just four biochemical letters strung together in lines. But the sugar code, known as the glycome, contains tens of different sugars that fit together in branched strings called glycans (see Diagram). Reading the sugar code isn’t just a case of decoding it letter by letter, but recognising the shape of each sugar and understanding what it means. That is hard. “It was so much easier to build on the DNA code, to develop tools for genomics,” says Godula.
The things that latch on to cell surface sugars in nature – the hands that do the grabbing – are proteins called lectins, which have internal cavities that fit snugly around specific sugars. We have known lectins existed for well over 100 years and recently began to make artificial versions of them (see “Beating diabetes“). But simply cataloguing the different lectins didn’t in itself advance our understanding of the sugar code much.
We learned more as chemists isolated particular sugars and worked out their structures. As they are so bewilderingly large and complex, the best way to do that is to run them through a machine called a mass spectrometer. This breaks them into small fragments, giving a series of pieces from which we can reconstruct the parent molecule with the help of algorithms.
By the early 2000s we had identified a few of the sugars decorating some types of cell. Things got more interesting as we began to map out which lectins they paired with. In 2002, at Imperial College London and her colleagues came up with the idea of fixing hundreds of individual sugars to a plate, then washing all sorts of lectins and other molecules over them to see which would bind. These microarrays marked the start of an automated approach to understanding the glycome. Before long, people were using them to find out which sugars on the surfaces of human cells the and the swine flu viruses grab hold of during infection.
We still don’t have all the answers though. It is thought that more than half of the proteins in our bodies have sugary appendages, but we don’t know exactly what they look like. That is why the was launched in late 2018. Founded by biochemists at Harvard Medical School and at the University of Zagreb in Croatia, it is an umbrella organisation for many individually funded projects and will attempt to sequence all human sugars.
That is a truly colossal task. There is one human genome, but the glycome differs from one organ to the next. You can think of it like a sugar atlas of the body, says Cummings. “You’d flip through the chapters of this atlas and one would be on the human brain, another would be on the human spleen, and so on.”
Total rewrite
A few chapters are already near complete. For example, we know most of the sugars in human breast milk – the fact that they are free-floating makes them easier to analyse – and this is already influencing the recipe for baby formula. Cummings is hoping better algorithms for sorting through mass spectrometry data could speed things up, and these . “We could keep saying the technology’s not quite ready,” says Cummings. But he insists that sugar mapping is a job we have to get on with.
Reading the glycome is all well and good, but how about writing it, or rewriting it? That means stitching together individual sugar building blocks into glycans, a job that is carried out by enzymes in the body. We have been aping this in the lab for years, but it was painstaking work that involved laboriously priming each and every sugar to chemically react in the correct way.
In 2001, Peter Seeberger, now director of the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, came up with a better way, which involved sticking a growing glycan chain to a solid surface and sequentially washing solutions of sugar over it to extend the chain. , but only a small number of sugars were commercially available then. Now GlycoUniverse, a firm co-founded by Seeberger, is providing 80 ready-to-use sugar building blocks and has invented that fits them together as the user desires. Making a six-sugar glycan by hand in the lab takes several weeks, but with the machine “you program it and start it, you go home – and the next morning it’s done”, says GlycoUniverse CEO Mario Salwiczek.
“Each organ has its own set of sugars. Mapping these differences is a huge task, like making a sugar atlas of the human body”
Eventually, anyone with one of these machines could write their own sugar codes. One reason that could be useful is to make vaccines. The glycans on the coats of disease-causing microbes are “good starting points for developing vaccines”, says Turnbull. Such vaccines prime the immune system to spot these glycans and kill the microbes. Some vaccines for flu and meningitis already contain sugar components and, if the sugars can be made easily enough, there are hopes the approach could be effective for other diseases, including malaria.
At the same time, we are beginning to bring all this knowledge together to show how understanding and manipulating the sugar code can be medically useful in other ways.
Take cancer. We have known for decades that sugars on cancer cells change and this can make the cells less recognisable, for example to medicines. This might explain why some people with breast cancer who should respond to the drug trastuzumab, sold as Herceptin, see no benefits, says at the University of Westminster in London.
Dwek’s team has dosed cancer cells with a chemical that impedes the growth of the sugar forest and then introduced Herceptin. In test tubes, it was effective: . The chemical they used in these proof-of-concept studies was pretty toxic, so Dwek is looking for alternatives to test in people. She says that if she can get it working in breast cancer “then hopefully it should be applicable to all sorts of other tumour types”. The team is partnering with Phytoquest, a company running a trial to test similar approaches in dogs with tumours that don’t respond to treatment.
Cancer could be just the start. Winfried Römer at the University of Freiburg in Germany studies the molecular handshakes that occur between human cells and the microbes that invade them. Previously, it was thought that the sugar-binding lectins of viruses and bacteria were just the glue sticking them to our cells. But by incorporating natural glycans and lectins into synthetic membranes that can be easily studied, Römer’s group showed that the handshakes actually trigger a physical reaction in the cell membrane, causing it to bend and wrap around the invader, swallowing it.
Römer realised that if he could find ways to , and stop microbes clawing their way into our cells, he could have powerful alternatives to antibiotics on his hands. He and his team looked for lectin blockers for Pseudomonas aeruginosa, a hospital infection that is resistant to multiple antibiotics. To jam up the bacterium’s lectin and stop it binding to human cells, they had to find something that it would mistake for its natural glycan target. So they took some of the important molecular components of that glycan, built them into 625 different glycans in various permutations, then tested them. One glycan bound the bacterial lectin really well, and when the team added it into a mix of human cells and P. aeruginosa, it blocked entry by the bacterium 90 per cent of the time. “You can’t imagine: there were physicians all over the world who asked for this compound,” says Römer. Clinical trials are the next step.
Shake on it
The most exciting work involving the sugar code has to do with stem-cell therapies. Stem cells are blank canvases that can become any type of cell, giving them huge potential in regenerative medicine. But getting them to develop in a particular direction is tricky. Scientists have often simply plied stem cells with proteins called growth factors that direct their development along a certain route. But in the body, sugars on cells’ surfaces have to shake hands with these growth factors in order for them to have an effect. So now Godula is trying to copy that.
His approach is inspired by the work of at Stanford University in California, who in the 1990s fed cells unnatural sugars and found that they incorporated them on their surfaces.
Godula does the same, but bathes his cells in sugars designed to shake hands with specific growth factors. It only takes an hour for the sugars to stick to the cells’ surface and they soon wash off. “But we do see long-term effects,” says Godula. In mouse stem cells, his team recently showed that even after a short programming bath, the cells towards the tissues that make up muscles and red blood cells 10 days later. Tailoring stem cells’ sugary canopies to greet specific growth factors should give scientists greater control over how they develop. The dream is to get this working inside a living person, where the stem cells could be instructed to regenerate muscles, organs or in principle almost anything else.
We have known for years that sugars are as fundamental a part of our biology as DNA and proteins. But only recently has the sugary language of cells been getting the attention it deserves. “There’s a lot of interest now in bringing sugars back into the mainstream of science, where they’ve been missing for a long time,” says Godula. Small wonder, when medicine has so much to gain.
Beating diabetes
For the 422 million people worldwide who have diabetes, sugar is dangerous. Too much glucose in the blood and the risks of long-term health problems are heightened. Too little, and you could pass out.
To guard against that, scientists have long dreamed of creating a replacement for insulin, the natural enzyme that regulates sugar metabolism. One of the most crucial parts of the challenge is to design a receptor molecule with an internal cavity that can recognise glucose. That is devilishly tricky, partly because there are other sugars that look like glucose, and partly because clusters of water molecules do too.
Nevertheless, a couple of decades ago, chemist Anthony Davis at the University of Bristol, UK, set himself the challenge of making a glucose receptor. In 2012, after years of toil, his team finally built one that . But when they tested it in blood, it also bound to fragments of DNA, rendering it useless.
Davis soon came up with a better design using computer modelling. “As soon as I saw this thing on the computer, I thought, ‘this is going to work’,” he says. He was right. When his team tested the new design, the snug fit of glucose into the receptor .
They rushed to patent it and in August 2018 struck a £620 million deal with the healthcare company Novo Nordisk, which specialises in diabetes. The company hopes to use it to make glucose-responsive insulin that would help avoid dangerous dips in blood sugar.
The chemical details are yet to be worked out, but the idea is that Davis’s receptor would switch insulin on and off, depending on the concentration of glucose in the blood. For many people living with diabetes, it could be life-changing.
Article amended on 29 March 2019
We corrected who is running the trial to test the approach in dogs
