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Lude Franke wants to know what causes disease

Fighting cancer with big data

Illnesses like cancer don’t usually emerge because of a single cell abnormality. More often than not, cancer is caused by dozens of abnormalities that, taken individually, are fairly innocuous. Lude Franke spends his days digging through big data to figure out where it all goes wrong.
By Christien Boomsma / Translation by Sarah van Steenderen

The device is approximately as long as an iPhone, but only half as wide, and thinner. It isn’t very pretty but its processing power is stunning – to put it mildly.

Insert a little bit of DNA into the machine and connect it to your computer: within a few minutes, the screen will reveal whether you have a predisposition to cancer, diabetes, or cardiovascular disease.

It was only twenty years ago that scientists found a way to map the entire human genome – after more than a decade of trying. And until recently, sequencing DNA required giant machines in complicated labs. But now, RUG geneticist Lude Franke carries this little device that does it all in his backpack. Nifty.

Common diseases

‘This’, he says, ‘is the height of technical innovation. Using ICT and nano technology, we have extremely fast access to information – not just about DNA, but also RNA, methylation, and cell proteins.’ In the field of systems genetics, this information is indispensable.

Systems genetics investigates the machinery of all the different genes in a human cell, how small abnormalities affect things on a cellular level, and why seemingly harmless abnormalities causes cancer in some cases but not in others.

This is the height of technical innovation

The field relies on big data. When Franke starts his DNA calculations, he’s not looking at how gene abnormalities cause things like cystic fibrosis, or muscular dystrophy. These serious diseases are rare but easy enough to find. He focuses on more common diseases like cancer, which are often caused by hundreds of different abnormalities.

In addition to being the head of research at the genetics department of the UMCG, Franke recently joined the prestigious ONCODE institute, where dozens of scientists come together to try and crack the ‘cancer code’.

Three billion letters

Franke’s research looks at the DNA and RNA of thousands of people – a unique approach that just might be the key to figuring out how cancer develops. Like cardiovascular disease or coeliac disease, a multitude of factors have to come together first.

‘You have to see it like this’, he says: ‘Our DNA consists of three billion letters. There can be up to a one-percent difference between people. That means there are about a million possibilities where something can go wrong.’

But someone with diabetes, for example, doesn’t differ from a healthy person in just one of those million letters. There will be lots of abnormalities, he says – ‘hundreds of locations where the patient’s DNA is ever so slightly different than that of a healthy control person.’ And on top of all that, there is also ‘the environmental influence.’

Daft name

DNA sequencing allowed researchers to map these abnormalities. But they still didn’t understand how an abnormality in a specific chromosome could make someone sick. ‘So then we thought: could we use this technique on RNA, and look at the proteins that do the work in the cells themselves?’ Franke says.

We know that there’s a lot we don’t know

He started with a test group of one hundred people, collecting their genotype and gene expression data. When that started to look promising, he also started collecting information on methylation, protein levels, metabolites, and lipids; the so-called multiomics approach. ‘It’s a daft name’, he apologizes, grinning. ‘It’s a combination of genetics, genomics, metabolomics, proteomics. A bit of a hodgepodge.’

By combining the information from all these different people and slowly stripping it down, he hopes to understand how complex common diseases such as diabetes or cancer work. But the amount of data he needs is flabbergasting.

Giant data sets

Say you find hundreds of abnormalities in a million genes, and each of those abnormalities have another hundred variations on the RNA level, and each of those variations has another hundred possibilities at the protein level, and you have 30,000 samples: the number of different combinations is practically incomprehensible. ‘We’ve discovered so much already’, says Franke. ‘But we also know there’s a lot we don’t know. That’s what makes it so exciting.’

He’s convinced he’s on the right track – that’s not a problem. The biggest problem with his approach right now lies with the computers that analyse the giant data sets, and the researchers who need to combine their scientific knowledge with the right technical skills in order to ask the right questions. Fortunately, technology is developing at a rapid pace, as evidenced by Franke’s mini sequencer. And as the field is growing, which means more researchers.

‘We have to sift through this colossal database’, he says, ‘to figure out how gene expression, proteins, methylation, or metabolites end up messing with the cell, to find out how the snowball effect of all these together lead to a disease.’

Healthy people

Franek focuses mostly on the cells of healthy people, such as the 16,700 participants in the LifeLines project who made their DNA available for research. He also works with data sets from international research that has been made freely available. This gives him insight into thousands of gene profiles belonging to people who are at risk of disease but not sick yet – which means the abnormalities in their genes aren’t big enough.

So what is the cause of disease?

We know we can help people

They key, Franke suspects, is in the key driver genes. These are genes that are under the influence of ten or more other genes. When all those genes come together and cause disorder in the key driver gene, things go awry.

Influencing the behaviour of ten different genes is almost impossible, and probably not even that effective. But the best discovery to come out of this research, he says, is that it might be possible to influence the behaviour of a single key driver gene with medication. He has already identified several of these genes, and his search isn’t over yet.

Modest

Pharmaceutical companies are chomping at the bit to collaborate with Franke. He has taken research into minimal changes in gene expression on a cellular level and made it into something that could be used in medical practice. Who knows what will happen when we tweak the cell a little? It could just lead to a new medication to treat cancer.

Franke’s success inspired him to sign up with the ONCODE institute and add what his expertise is to that of all the other researches who are trying to solve the puzzle of cancer.

Will he be the one to come up with the solution?

But he shakes his head – he’s modest. ‘There is no guarantee that what we’re doing will make a difference.’

Still, there is no question that he will make an important contribution. He and his people have the tools necessary. ‘It’s led to a really positive vibe at the lab’, Franke says. ‘We know that we can help people.’

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