Cracking the sugar code: the secret language cells use.

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When it comes to communicating the fundamentals of life, DNA gets all the credit. Almost everyone is familiar with the distinctive double helix, an iconic structure that has been familiar ever since 1953 when Watson and Crick published the now-legendary article announcing its discovery.

But what about life’s other language? The code which has been all-too-often overlooked next to its older, more famous sibling? You may not have heard of it, but it is called “the sugar code”, and it has the potential to be used as a powerful, potentially life-saving, tool.

We know that cells use the sugar code (or “glycome”, in more formal terms) to convey all kinds of vital information to each other, and also that these cryptic communications play a role in countless diseases ranging from food allergies to cancer. If we could only learn to understand the code, or perhaps even use it to “write” to cells, the possibilities are endless. We could employ it to harness the regenerative powers of stem cells, for instance, to control disease and to develop new antibiotics. Unfortunately, this has proved to be a gargantuan task, and so far the secrets of this mysterious cellular language have remained frustratingly elusive.

But that could be beginning to change.

How cells communicate using the sweet stuff.

To be clear, Instead of the familiar white substance found in the traditional British “cuppa”, or glazing a ring donut, sugar here refers to simple molecular blocks, which are stacked together to form a long, branched structure known as a glycan. In contrast to DNA, which is stored in the “headquarters”, or “nucleus” of the cell, these glycans protrude from the cell’s surface like trees, and, importantly, can be grabbed hold of, if you happen to have the right tool for the job.

It turns out that all of our cells wear a thick coat of these long, sugary structures. Not only this, but the specific combination of sugar blocks varies according to cell type. In other words, the “jacket” of a skin cell will be decorated with a different selection of branched glycans to that of a kidney cell. This means that a cell type can be identified by its unique sugar coat in much the same way that a member of the Hell’s Angels can be identified by the distinctive red and white winged-skull on the back of his leather biker jacket. This has many biological implications — determining which cells can interact with each other, for instance, or providing an indication of where the cell is likely to be found in the body. (Incidentally, I believe the biker jacket of the Hell’s Angel has a similar effect, albeit on a much larger scale).

To illustrate the importance of this secret cellular language, we can turn to the proverbial miracle of conception. You might think that humans do most of the hard-work involved in baby-making, but a sperm cell would probably be inclined to disagree. After an arduous pilgrimage through the perilously acidic environment of the vagina and up the fallopian tube, the sperm finally reaches the egg. It must now navigate the “zona pellucida”, a thick forest of sugars encasing the egg cell. To do this, it has to be able to grab hold of a glycan on the cell surface, using a specified molecular tool which perfectly compliments the shape of the sugar. Once one pioneering sperm cell has managed to do this, the shape of the other glycans surrounding the cell changes. This is a bit like changing the locks on a house, the “keys” that the rival sperm have will no longer fit the sugary branches, and they are blocked from gaining access to the cell. This nifty mechanism ensures that an egg cannot be fertilised by more than one sperm, a scenario that would cause all manner of troublesome complications.

Another example of the sugar code in action is in the immune system. For cells tasked with protecting the body from malicious invaders, the ability to distinguish between an organism’s own cells and those of a virus or bacterium is critical. For the sake of argument, let’s bring back our cell wearing the leather jacket adorned with the red and white colours of the Hell’s Angels. In our analogy this can be the “self” cell. Now let’s imagine the cell of a parasite, such as malaria, wearing the red-and-gold insignia of a rival Bandidos biker group. The colours on the jacket betray the foreign identity of the malaria pathogen, and immune cells –much like bikers– happen to be highly territorial. In this way, the sugary “jackets” worn by the different cells allow our body to detect threats and launch targeted attacks.

This ID method is not watertight, however, and some sneaky invaders have evolved ways to bypass the system. A group of bacteria called B streptococcus, which can cause infections in babies, have learnt to carry around sugars which look like those on our own cells — like a Bandidos biker travelling with a Hell’s Angels badge sewn onto his jacket. Some viruses, like HIV and Ebola, have even managed to exploit the system for their own nefarious purposes, developing tools the right size and shape to grab the sugars on the surface of the immune cells. Once they have gained access, they hijack the manufacturing machines inside these cells, using them to replicate themselves over and over. The noxious offspring burst from the cell, destroying it in the process, and are free to seek out a new target to infect. Scientists believe that this entire cycle could be prevented if they could find a way to block this virus-glycan interaction, and therapies based on this strategy are currently in research.

Cracking the sugar code.

It’s certainly clear that the sugar code is important, but why is it such a tough nut for scientists to crack? The short answer is that this fiendish code is staggeringly complex.

By way of comparison, we can again consider DNA: The DNA code is made up of four letters. These can be sorted into different orders and combinations, but are always linked up into a straight line.

The sugar code, however, is a whole different ball game. For starters, instead of being comprised of four basic units, it is made up of twenty. And then there is the matter of shape. In order to properly understand this language, you have to be able to identify all of the subtle variations in the branched structures of the different sugars, and then try to interpret what they might mean. Not to mention the fact that while each cell inherits the same set of DNA instructions to work with, when it comes to their “sugar jackets” they are much more particular. Like celebrities on the red carpet, no two cell types would dream of being caught in the same outfit.

So how are scientists taking on this behemoth task? A lot of important work has been done by chemists, isolating individual sugars and breaking them apart in order to better understand how they are structured. Researchers are also trying to figure out which specific molecular tools can grab onto which sugars. To do this, they fix glycans onto a surface and wash them with a solution of molecules. It is then a case of checking which tools have successfully latched onto which sugars.

Using a similar method scientists have also begun to experiment with “writing” in the sugar code. This involves gradually building up the structures one block at a time, a bit like working with tiny, molecular lego. Early in the millennium, Peter Seeberger, the director of the Max Planck Institute in Germany, was working on a technique where, again, glycans were fixed to a plate and bathed in a solution. Only this time they were washed with blocks of different sugars, which attached, one-by-one, onto the fixed strands, slowly extending the structures. Now he has helped to invent a machine called a “Glyconeer” which can build custom-made sugar strands for a user overnight, revolutionising the process completely.

So now that we are slowly becoming sugar-literate, what’s next? Well, the possibilities truly are endless, but there is one particularly fascinating avenue of research: stem cells. Put simply, these are cells which have not yet become specialised to do one job — they are not yet committed being a muscle cell, for example, or a bone cell. Because of this they have the potential to become a range of things, but can be surprisingly stubborn, and must be coaxed one way or another using signals. A scientist called Kamil Godula at the University of California has found that bathing stem cells in specific sugars is an effective way of influencing their development towards becoming different cell types. This technique holds lot of promise for the field of regenerative medicine. If we could manage to control the development of stem cells like this in living organisms, there is massive potential to help people who have suffered damage to various organs through disease or injury.

If one thing’s for sure, it’s that the long-overlooked sugar code is finally getting noticed. “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, speaking to the New Scientist. After all these years of neglect, it turns out that life’s alternative language might be pretty important after all.

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