Diagnostics
Most scientists agree that there are about 20,000 proteins in the body, but some studies suggest the number is much higher.
related to disease, says Ferrucci. For instance, a protein may be associated with stress but have a useful function, like showing how your body is reacting to it. So, you wouldn’t want to inhibit that protein. “That won’t be a target, but something causally related to the disease will become a target,” he explains. “At this stage it’s very difficult to understand: what is a biomarker? And what is a causal signal?” To get there, we need more insight into which proteins and their interactions are linked with disease. “You need to study the function of the protein,” says Borchers. “Then you can interfere.”
“We can create drugs that affect the splicing variants generated. This is a formidable pharmacological target for the future.” Dr Luigi Ferrucci
Managing disease To make matters more complicated, instructions from our DNA can be amended before they’re delivered to proteins, which can generate what’s known as splicing variants. These proteins can influence how a disease develops. Splicing variants happen when a molecule called RNA, which copies and passes on DNA’s instructions, doesn’t copy them perfectly: RNA may add, delete or replace certain bits. A protein is then formed to carry out these altered instructions, but it’s a variation of what would have been made had the instructions been copied correctly. If we can identify splicing variants, we may be able to predict how a disease will affect the body and take steps to manage
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this, says Ferrucci. “We can create drugs that affect the splicing variants generated. This is a formidable pharmacological target for the future,” he adds. Ferrucci gives an example: in people with peripheral artery disease, two splicing variants have been identified for VEGF, a protein that promotes the growth of blood vessels. But each variant has an opposite effect: one can improve symptoms by helping blood vessels to form, and the other works against this, making the disease more severe. Targeting the latter variant with a drug could improve the quality of life for millions living with the condition. To find splicing variants, you need to have technology that can read long strands of RNA and figure out where the DNA’s instructions have been altered. “By doing this, people are finding many more splicing variants, but this research is not in the realm of clinical application,” says Ferrucci. While amended RNA indicates that splicing variants are present, it can’t tell us how many modified proteins are actually generated. One strand of RNA can create tens or even hundreds of proteins. Identifying the number of mutated proteins can help us decide whether to use certain drugs, says Borchers. He shares an example where he and his team investigated the suitability of metastatic colorectal cancer patients for anti-epidermal growth factor receptor drugs – a key strategy in the treatment of the cancer subtype. Having a modification in the KRAS protein disqualified them, and one of the patients had this mutation, but in only 10% of their K-ras proteins – meaning that the remaining 90% could still be targeted by the drug. Had the team looked at genetic data alone, they’d have identified the RNA instructions for creating the modified KRAS protein but not known how many were made from them. They’d simply recognise that this mutation was present, and that patient wouldn’t have qualified for the drug at all. Borchers hopes that soon, it will be standard for proteomics data to inform doctor’s decisions about cancer treatment.
The future of precision medicine While it may take decades to realise the potential of proteomics, the future looks bright. We already know the biological function of proteins, but we’re onto a winner if we can use them as biological markers of disease. “If we do that, that is the next frontier. In order to do this, people need to work together. Nobody has enough data to make a step forward,” says Ferrucci. Borchers predicts that a person’s protein data will one day be seen as their “blood passport” – a profile of proteins unique to them, like their fingerprint. Doctors could check for any changes to it as part of a regular check-up. In the meantime, we’ll see proteomics technology used by leading labs gradually trickle down to the clinic, he adds. “In the end, science will always win.”
Practical Patient Care /
www.practical-patient-care.com
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