Genomics has come a long way, but it can only take you so far. A genome sequence tells you a great deal about a patient’s potential for future disease, but it is of limited use on its own in understanding the markers of disease progression in the here and now. Proteins are the true indicators of the interaction between genes and environment, and recent advances in the throughput and reliability of proteomics tools are beginning to transform both our understanding of human health and the drug discovery process.
A consortium of biopharmaceutical companies has recently teamed up with the UK Biobank to complement genomics profiling of 500,000 people with proteomics studies that will initially cover a subset of more than 50,000. The project involves Olink Proteomics as its technology provider. Evan Mills is Director of Strategic Accounts at Olink Proteomics and has spent the past eight years looking to work with forward-thinking pharma and biotechnology companies who are seeking to incorporate high-multiplex immunoassay solutions for protein biomarker discovery to better inform their drug development efforts. The marriage of proteomic and genomic profiling is set to become a ‘game changer’ in human health.
Genomics, transcriptomics and proteomics profiling are not new techniques, but the way in which industry is using them to gain a more complete picture of diseases of interest is being facilitated by technological advances. As Mills points out: “The big trend I’ve noticed is the big data approach. Essentially companies see the value in adding broad screens, or -omics, to better understand drugs and disease versus the more traditional, narrower approach focusing on a handful of biological nodes."
Whilst large-scale genetics studies on population cohorts have undoubtedly improved our understanding of disease, it is at the protein level where things get really interesting. Mills shares an analogy: “If you had a leak in your roof, looking at the blueprint of your home will not help you protect your house from water damage. It’s obvious that you would get up on the roof, find the source of the leak, and fix it. Genetics are the blueprint, and perhaps a faulty design in the roof increased the risk of a leak, but to diagnose the current problem and come up with a solution, looking at the roof, or the proteins, is much more impactful. Proteomics is much more actionable and provides a view of the ‘right now’ to understand disease and treatment options," he says.
Mills indicates that the real historical challenge has been the lack of proteomics tools that are up to the required job. “It has been extremely low throughput and the tools available have been both prohibitively expensive and slow, or they just simply couldn’t adequately cover enough of what people really wanted to measure,” he says. Furthermore, simultaneously providing highly multiplexed proteomics and maintaining the high-quality standards that scientists demand has been extremely challenging.
Mills adds that mass spectrometry has been a very powerful tool but is severely limited for the kinds of broad interrogations of proteins that researchers are now looking for to complement genomics and transcriptomics. The new project that Olink is now a part of is looking to do just that. “There is a desire to get a more phenotypic level of information, to add data that’s a bit more real-time,” says Mills, “and to add some more actionable insights to what they have already seen with the genetic associations.”
Enabling technology has been the key to all this, and Olink released a version of its multiplex immunoassay platform, Olink® Explore 1536, earlier this year that runs on the Illumina NovaSeq next-generation sequencing (NGS) platform – the very system that has been used for the consortium’s previous whole-exome sequencing and which is used by many large-scale genomics projects. Olink technology employs matched pairs of DNA-coupled antibodies that generate a small DNA amplicon upon binding to the correct protein. Readout of this signal was previously achieved using qPCR, but with Olink Explore, the readout is on NGS. Mills notes: “That was the real game changer in terms of throughput and breadth of coverage. Now we can measure 1,500 proteins from < 3 microliters of blood, and by putting it on the NovaSeq, we’re able to realize throughput that would have been unthinkable a year or two ago.”
That is the kind of technology that opens up a wide range of large population cohort studies. Starting in 2021, the UK Biobank project will analyze 56,000 samples in the space of four to five months using Olink’s proteomics immunoassay platform.
The potential benefits of harnessing proteomics profiling can hardly be overstated. With drug development widely known to be an inefficient and at times frustrating enterprise, Mills asserts that “the biggest potential long-term benefit is that these companies will understand which protein targets for new therapeutics are actually linked to genetics. If you are pursuing a therapeutic program that has genetic evidence, studies have demonstrated at least a twofold increase in the chances of success in the clinic.”
Mills suggests that the main reason many potential therapies fail is because they are not targeting the right proteins. Proteomics technologies present a means of providing evidence early in a drug discovery program that a target is not worthwhile, yielding significant cost savings to pharma companies whilst also ultimately helping patients and the healthcare systems supporting them. “If you can reprioritize towards targets that have more evidence behind them, that’s a huge benefit for the whole system, patients included. There could be rare or even common diseases where novel approaches can be uncovered by combining genomics and proteomics that you simply wouldn’t have come up with if you hadn’t taken this multi-omic approach,” Mills concludes.
Furthermore, intelligently selecting the proteins to be measured is critical for delivering impactful data for drug discovery. Olink has partnered with world-recognized leaders, Mathias Uhlen, from the Human Protein Atlas, and Dr. Leroy Hood, from the Institute of Systems Biology, to carefully select the most relevant protein targets to measure in an effort to cover critical biological pathways to drive our understanding of disease biology and optimize drug development.
Mills indicates that Olink is certainly not resting on its technology laurels. “As of right now,” he says, “we can measure 1,500 proteins. We’re committed to doubling that within the next year to get even more insights, and tripling it in two years.”
He adds that Olink is trying to build the best tools, and that will probably be to everyone’s benefit.