14 January 2019

Proteins - the Cells' Workhorses

Behind the research

Even though we give diet advice, write training guides and print labels on convenience goods based on our current knowledge of proteins, the field of health and medical sciences has actually uncovered surprisingly little about the small molecules and the puzzling ways in which they keep us alive. Therefore, research into proteins could improve both diagnosing and disease control markedly.

Cells

We often talk about proteins in food and as training supplements, but in reality, proteins are much more than a part of your diet. The small molecules are vital to your survival, because they build and rebuild your body every day.

Today, many scientists believe that protein research will deliver one of the next big quantum leaps within the health and medical sciences and will be able to answer some of the most basic questions about human health and illnesses.

This is because proteins are the most active molecules in the entire human body – in fact in all living organisms. They work hard in each and every cell to keep you and your body healthy and alive. And they are really good at it:

When you breathe air into your lungs, the protein haemoglobin transports oxygen via the blood to all cells in the body – including your muscles, enabling you to move, and your heart, enabling it to beat.

Some hormones such as insulin, which controls the blood sugar, and oxytocin, which can make pregnant women go into labor, are proteins.

The immune system’s antibodies that defend your body against bacteria and attacks from without are also proteins.

Research into proteins has already given us some groundbreaking answers. Today, it is possible to predict, at an earlier stage than previously, a person’s risk of developing prostate cancer or blood clots in the heart by measuring the level of protein in a blood sample.

However, we still have extremely little knowledge of the proteins in the human body. There is therefore a need for researchers to study them in places like the Novo Nordisk Foundation Center for Protein Research (CPR) at the University of Copenhagen.

Four Billion Proteins in One Cell
One of the basic things we still do not know about proteins is how many there are.

They are so difficult to map that we actually do not know for sure how many there are.

Professor Jesper Velgaard

Proteins consist of a chain of amino acids, in most cases 20 different kinds of amino acids. You would therefore think that mapping all proteins was a manageable task. This is far from the case, though.

The simpler proteins contain a couple of hundred amino acids, but the more complex ones can hold thousands. Therefore, in principle, the relatively few amino acids found in the human body can be combined in an endless number of ways.

"We know for sure that we have at least 20,000 different proteins, because we have 20,000 genes producing proteins. But one gene can produce several proteins, and one protein can take on so many different forms that it almost does not make sense to talk about it as one protein. So depending on how you define a protein, it would also be fair to say that there are hundreds of thousands of them. They are so difficult to map that we actually do not know for sure how many there are", says Professor Jesper Velgaard Olsen, Deputy Centre Director of the Novo Nordisk Foundation Center for Protein Research.

Before being investigated, proteins often have to go through the process chromatography.

However, we are not just talking about many different kinds of proteins, but also about the fact that there are so many of them. Illustrations of human cells often look like large vacuums, like an aquarium, where molecules like proteins swim around unaccompanied.

In reality, the human cell is a very busy and densely packed space, where proteins dash about tirelessly solving different tasks. Research conducted at the Novo Nordisk Foundation Center for Protein Research indicates that a medium-sized human cell contains four billion proteins – all of which have important jobs to do.

Molecular Handyman
There is a reason why we have so many proteins. They are probably the busiest part of the human body – they are the cells’ and thus the body’s workhorses.

They keep us alive in so many different ways that it is difficult to provide an overview. In fact, they can do more or less anything. Among other things, they can act as:

A lightning quick workman building large molecules of smaller building blocks or dissembling larger molecules – sometimes several thousand times a second.

A freight company transporting different things around the body. E.g. haemoglobin transporting oxygen to the muscles.

A skeleton or scaffold keeping cells and tissue together.

A doorman or security man who makes sure that only the right molecules enter and exit the cells.

And these four categories only apply to the proteins that we actually understand, which is far from all of them.

Previous research has shown that we basically do not understand around 35 per cent of the 20,000 proteins that we know for sure exist, because no one has studied them yet.

Studying this large, underexposed part of the human protein pool thus holds great potential – both with regard to disease control and drug design.

Sometimes the researchers count cell colonies in order to assess the effect of an intervention.

Static Genes and Dynamic Proteins
To make matters even more complex, the same protein can do various kinds of jobs, as they change depending on whom they are communicating with.

Following a short chat with substances like sugar or phosphate they can suddenly be performing a completely different function in the body. In modern scientific lingo this is referred to as posttranslational modifications, which constantly change what the individual protein is doing.

So many vital tasks require some form of control. Each cell and each protein inside the cell follow a recipe that we know as DNA. The genes that we have inherited from our parents do not just determine whether we will be red-haired or brunettes. They contain the entire recipe for being human.

The full recipe – all our genes put together – is called the human genome. But the genome or recipe is not enough. We also need someone to follow the recipe. And this is where proteins enter the picture; they do everything.

Where the genes are just as dead as the cookbook lying on the kitchen table, the proteins are just as alive as the person running around the kitchen preparing a meal. Whereas the genes do not change from the moment we are conceived and until we die, the proteins constantly change and do different jobs. 

From Genome to Proteome
Before we learned about the many important functions performed by proteins, science focused rather one-sidedly on the genome for many years. This was useful in many ways, but if it would be left like this, the one-sided approach would stall the progress in biomedicine. This is because the genome and the proteome – which is the term for the total amount of proteins in the human cell – are inextricably linked.

Nevertheless, scientists have only recently begun to focus their attention on the proteome. In fact, one of the pioneers in this area works at the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen. Professor Matthias Mann was researching the proteome even before someone came up with the term.

Proteins are too small to be seen with the naked eye. Therefore, they have to be visualised in other ways.

His early influential research has made him one of the leading players in the world of protein and proteome research. His scientific articles have been cited repeatedly by other researchers. More than 200,000 scientific citations have thus been recorded, which is more than world-famous researchers like the sociologist Robert Merton and the economist Milton Friedmann.

"Relatively few researchers have contributed to establishing this research field. Therefore, a lot of researchers refer to our previous research. The good thing is that it shows that protein research is growing and developing fast", says Matthias Mann.

.. A lot of researchers refer to our previous research. The good thing is that it shows that protein research is growing and developing fast.

Professor Matthias Mann

When so much attention is directed at proteins today, it is also because researchers arrived at a kind of saturation with regard to genes. We learned to map the human genome in the 1990s, and today we are so good at it that anyone with a bit of money can have their genome mapped.

But the human proteome still has not been mapped completely. And the proteins follow the genes’ orders. Therefore, the space between the genes’ instructions and the proteins’ activities holds the key to understanding many of the world’s hereditary diseases.

Improved Diagnosing with Protein Mapping
The methods researchers use to map the unknown parts of the proteome are so advanced that they can seem like science fiction. They study them from a number of different angles, which together can offer a 360-degree understanding of proteins.

Proteins are seperated with chromatography before being led to the next machine, the mass spectrometer.

Using so-called mass spectrometers, they study the great protein differences between sick and healthy cells. Part of the process involves heating the proteins to the gas state and then shooting them at high speed into a gas chamber.

When proteins collide with the gas particles, they break, and digital readings of the small protein pieces appear on a screen.

This enables the researchers to map proteins and determine which proteins seem suspiciously active or inactive in sick cells.

The great hope is that this technology will, in the near future, result in greatly improved prediction and diagnosing of diseases, because it enables us to look for the proteins that we know are linked to specific diseases – for example in a simple blood sample. 

Facebook Proteins
Modern protein research can do more than that, though. Researchers can study how cells react when the suspicious proteins are sidelined or forced to be more active. This may, for example, exacerbate the disease and cause the cell to die.

Often, however, it does not make sense to look at the individual proteins, as a lot of the activity going on in the cells cannot be explained by looking at individual proteins.

Sometimes the proteins communicate in a network, comparable to how humans behave in social media networks. They affect each other’s behaviour and tune each other in different ways.

Therefore, researchers are also doing holistic network studies of groups of proteins and how they communicate.

Mass spectrometers are highly advanced equipment and researchers are using them almost around the clock to get as many results as possible.

By thus studying the signals in the cells – both individually and in larger networks – the researchers learn how diseases unfold in the body right down to the molecular level.

Once the researchers have boiled down this information about the behaviour of proteins inside the cells, they use computers with extreme processing power to crosscheck them against big data from large population surveys.

Among other things, they can study the general distribution of genetic mutations that lead to suspiciously active proteins, whether people with this mutation suffer from certain, characteristic diseases and whether the pathological pictures can confirm what the researchers have observed at cell level.

Satellite Images at Molecular Level
If the researchers after this long process still believe that specific proteins are interesting in connection with specific diseases, they can choose to use one of the most advanced tools available to them, namely the cryo-electron microscope.

Using this technology, they can produce 3D models of the surface of the cells – almost like satellite images of the surface of a planet. The researchers are especially interested in finding the parts of the surface containing the large craters or holes.

This enables them to perform simulations showing which molecules are able to attach to the holes on the cell surface, almost like a key sliding into a lock. Using this method, they can – depending on the objective – weaken or intensify cell signals.

In other words, they can show how the cell can be manipulated to reach the desired health effect.

It is not yet all research that has moved into advanced technological machines.

Once the researchers learn which proteins are over- or under-represented in different diseases, they will be able to measure and diagnose them at a far earlier stage than is the case today.

And if they also learn how to directly manipulate the proteins to act in the ’right, health-promoting way’, the potential is in principle endless. It will make it possible to solve disease-related mysteries that scientists have been pondering for hundreds of years.

We know that we cannot survive without our proteins. Therefore, we need to learn more about them and their influence on the body.

They are being investigated because they can do so much more than boost your muscles.

Watch this video if you want to know more about proteins and the Novo Nordisk Foundation Center for Protein Research

Contact:
Press Officer Mathias Traczyk
93 56 58 35
mathias.traczyk@sund.ku.dk