At the cancer symposium in Ireland, there were many companies promoting their products, from new drug therapies to improved imaging technologies. The only company that I thought was truly revolutionary was SomaLogic, and they are actually based in our very own
Boulder, Colorado.
Traditionally, physicians and scientists use antibodies to identify proteins of interest, these antibodies
run into issues of specificity, they are expensive to produce, and most
importantly – it is too expensive for researchers to use more than one antibody at a time, and way too time consuming to do a complete proteomic analysis of a
tumor sample. Imagine a cost-effective way to have a complete proteomic profile
of a tumor sample in just one procedure. That’s what SomaLogic has done. By
combining a CGH array and modified DNA aptamers to sample a tumor tissues’
proteomic profile.
Aptamers are peptide or nucleotide sequences that bind to specific molecules. SomaLogic has taken DNA and modified their bases to increase their binding affinity. These Slow Off-rate Modified Aptamers, or simply SOMAmers, bind to proteins like antibodies. They are very specific and very tiny, easily able to bind both intracellular and extracellular proteins. The advantage of this is that unlike antibodies, you can easily sequence DNA. After SOMAmers bind to their specific proteins, they are washed off and put into an array. From here it is like array CGH, except it is now for protein expression. If tumor samples overexpress a certain protein, it will more likely bind to the oligomers in the array plate, where their copy numbers will be detected. Each plate will have hundreds of wells, each containing a specific sequence for a SOMAmer. This way, in one array, you can get a complete proteomic read on a tumor tissue to understand what proteins are over- or under-expressed, and thus, much easier to identify where the problem is in a patient’s cellular pathway. If the thought of DNA binding to protein hasn't blown you away yet, there is more good news. Since it’s just modified DNA, SOMAmers can be produced very quickly and cheaply by PCR. On top of all this, we now know that there are free-floating tumor cells in the blood stream of cancer patients, but antibodies are often not specific enough to be used diagnostically in those samples. SOMAmers however, are able to identify the proteomics of those cells. Although more verification needs to be done, and more research is needed to identify what the complete proteomic profile actually means for personalized treatment, this technology is potentially a huge step towards early cancer screening, diagnosis, and drug targeting.
Citations:
Gold L, Ayers D, Bertino J, Bock C, Bock A, et al. (2010) Aptamer-Based Multiplexed Proteomic Technology for Biomarker Discovery. PLoS ONE 5(12): e15004. doi:10.1371/journal.pone.0015004
Kraemer S, Vaught JD, Bock C, Gold L, Katilius E, et al. (2011) From SOMAmer-Based Biomarker Discovery to Diagnostic and Clinical Applications: A SOMAmer-Based, Streamlined Multiplex Proteomic Assay. PLoS ONE 6(10): e26332. doi:10.1371/journal.pone.0026332
This is some truly groundbreaking technology! I sure hope there will be applications for this technology outside of proteomics. Anschutz houses one of very few metabolomics cores in the world, which looks at metabolite products of different cells giving you a picture of how active these cells are and what type of fuel they are using to run. In the hierarchy of upstream to downstream, I believe the different investigatory techniques would be genomics, proteomics, and then metabolomics.
ReplyDeleteI know how expensive and painstakingly time intensive this metabolomics procedure can be as my lab was using it to determine differences of metabolism between glioblastomas and meningiomas and normal cells from brain samples taken during surgery. First, the cells would have to be incubated, grown, and radiolabeled with Carbon 13. Then the cells would need to be painstakingly lysed and separated based on lipid-solubility or water-solubility, all the while never leaving ice for more than 20 seconds maximum. After neutralizing the various components (and trust me, you don't want to be the lab tech that forgets to neutralize his sample and destroyed some very expensive equipment, stories of that poor (and stupid) tech are still told years later), the samples would finally be ready to go on the lyophilizer for dehydration. Days later, the samples will need to be transported from the lyophilizer glasses to tubes that can be used in NMR, but the delicate crystal structure created by lyophilization means that any small amount of static electricity can permanently ruin a sample, so scraping it from one glass to another is not an option... Finally my work would then be done and it would be out of my hands, but the procedure that remained was to run the samples in NMR and then interpret the data, which only one person at Anschutz was capable of doing. All in all, the preparation process lasts about 2 weeks, but there is so much data to analyze, my boss had been waiting a couple months to finally get his results back.
Whew! that was long, but it was meant to iterate how intense metabolomics can be! I hope SomaLogic will find a way to use modified DNA to bind to and analyze levels of glucose, choline, and citrate - the molecules examined in metabolomics - so that I never have to go through that process again!
Merz, A. L., Serkova, N. J. 2009. Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer. Biomarkers in Medicine, 3 (3).
Yes! I understand how technically challenging it is to do some of these experiments, there is absolutely no room for mistakes. If one step is out of order, your samples is ruined, if you didn't label something correctly, your samples is ruined, if you didn't time things right, your samples are ruined. Samples are precious and very time-sensitive, that's why technology is sorely needed to make things easier. I see a lot of potential for this type of new technology, I have no doubt this can also be applied to diagnostic imaging to guide surgery or any other purpose for that matter, because this stuff will clear out of your body within half and hour to an hour, it is not radioactive, and I don't see your immune system attacking DNA. I guess we will have to see where this goes in the future.
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ReplyDeleteLike Nate said, this is amazing technology, and as you both eluded to there is a huge range of application for aptamers. And speaking of using PCR, I had chance to witness a wacky Kerry Mollis lecture in 2008 where he talked extensive about the use of aptamers in immune response for different infections. Similar to Somalogic technology, he discussed using a hybrid aptamers specific to a target infections disease linked to a alpha-gal epitope, which are found in non-primate tissue. All humans produce Alpha-gal anti-body, hence a high B-memory cell population to this protein. One of potential uses of these aptamers highlighted in his lecture, was if a new epidemic infection broke out, like bird flu/swine flu, the CDC could provide a hybrid aptamer cocktail to launch a naturally strong memory immune response on highly resistant and dangerous bugs. Scary thing is specificity and preventing an over active immune response with such by using aptamers this way. We will have to see how the research comes along. It will be interesting to see where aptamer technology goes in medicine.
ReplyDeleteOn a sidenote, when I looked up Kerry Mullis to for background I noticed he has started a company called, Alterume using this linked aptamers. Also, Kerry Mullis's did a TED talk on aptamers. Check out the biotechniques.com link below.
http://www.karymullis.com/altermune.shtml
http://www.biotechniques.com/news/Kary-Mullis-outmaneuvers-drug-resistant-bacteria/biotechniques-174085.html
Galili, U. (2005). The alpha-gal epitope and the anti-Gal antibody in xenotransplantation and in cancer immunotherapy. Immunology and Cell Biology, 83(6), 674–686. doi:10.1111/j.1440-1711.2005.01366.x