The Sugar Code
Perhaps one of the best kept secrets in popular science is that cells identify and interact with one another through a sugar code. This enigmatic code if cracked will pave the way for scientists to better marshal stem cells into specific fates and also create new antibiotics (for which there is a critical need).
But what is this code? And why do so few people know about it?
The Sugary Coat
Every cell in the human body is coated in sugar, not the type of sugar that glazes donuts, but a unique sugar coating that you need a secret password, or indeed biochemical “handshake”, to get past and into the inner workings of the cell. Bypassing this sugar code is vital from the very outset of our lives, conception. It has often been joked that babies are actually created from a molecular “handshake”. Specifically when a sperm meets an egg, they are stopped by a sugary jacket called the zona pellucida. Only sperm have the biochemical tools to attach to this layer and enter, and so it is that all our lives began.
However, like all great codes there are those whom want to break in and bypass these secret handshakes. In the natural world the best hackers of our sugar code are bacteria and viruses. The are able to mimic secret passwords and guess the handshakes that are meant to keep them out, thus ultimately causing havoc within our bodies that we know as “disease”.
The genome is made up of four bases, or biochemical letters, the “glycome” contains tens of different sugars that join to form chains called “glycans”. It is these chains that anything wanting to enter a cell must grab hold of and match with the correct grip in order to be able to be granted access.
As with most things in nature the job of attaching to these glycan chains is performed by proteins, namely “lectins”. Lectins have cavities that fit snuggly around specific sugars. Despite knowing about lectins for over 100 years, and cataloguing them, this has done little to advance the understanding of the glycome.
We learned more as chemists sugars and figured out their structures. As there are so many different potential options, and they are thus such large and complex molecules, 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, Ten Feizi 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 HIV and the H1N1 swine flu viruses grab hold of during infection.
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 Human Glycome Project was launched in late 2018. It will attempt to sequence all human sugars, a 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.
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.
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.
GlycoUniverse, a firm co-founded by Seeberger, is providing 80 ready-to-use sugar building blocks and has invented a machine called the Glyconeer 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.
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.
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 Carolyn Bertozzi 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 were still on their intended track 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.