Researchers from Intel and Stanford University are collaborating on silicon-based peptide arrays that could prove useful as a platform for applications including clinical research and point-of-care diagnostics.
In a paper published this week in Nature Medicine, the scientists detailed a proof-of-concept study in which they constructed a silicon peptide array containing peptides covering the N-terminal tail of human histone H2B. They used it to map minimal binding epitopes for several commercial antibodies and identify H2B epitopes recognized by autoantibodies linked to systemic lupus erythematosus.
The project is part of ongoing biological research at Intel, which in the past has published on 'omics work including efforts to use chelator-modified field-effect transistors for DNA sequencing (In Sequence 2/28/2012).
According to Madoo Varma, head of research and development at Intel's Integrated Biosytems group and an author on the paper, the company saw that "there was perhaps an unmet need" in the peptide array field, which has struggled with various technical challenges including low throughput, cost issues, and reproducibility (PM 6/27/2012).
The opportunity "is maybe not as big as with sequencing, and peptide array may not address conformational studies but there is certainly huge unmet need in whole proteome studies for example," Varma told ProteoMonitor. "So we were interested in demonstrating a proof of concept and seeing where it takes us."
The key advantage to using silicon as opposed to glass for the array surface is the potential for building integrated circuits into the chip that would allow for real-time, non-fluorescence-based sensing of peptide binding, said Paul Utz, leader of the Stanford team that collaborated with Intel on the paper.
Such a system, he said, could eliminate a number of the washing and scanning steps currently required by conventional peptide arrays, reducing their variability and making them more suitable to use in point-of-care diagnostics.
"With fluorescence-based detection, each of your slides has to first be blocked, then probed, washed, probed again with a secondary antibody, and then scanned," Utz told ProteoMonitor. "So with each of those steps the variability from chip to chip is quite high."
Sensing via integrated circuits built into the silicon, on the other hand, "allows you to apply the sample directly on the array, then add the secondary antibody, and you can immediately start sensing," he said. "You can do real-time sensing and have a computer integrate the data so you're doing the analysis in real time, as well. That, I think, is the transformative aspect of this."
Intel, Varma said, is pursuing such a system in collaboration with Utz and other Stanford researchers. However, she noted, the silicon-based devices currently use conventional optical detection methods.
Building circuits capable of collecting data from 50,000 to 60,000 protein interactions "is not trivial," Utz said, noting that it will "take a lot of research and development." There is also the question, he suggested, of whether the ultimate payoff will be enough to lure Intel's continued interest and investment.
"If one is going to try to commercialize this and make many millions of peptide arrays for use in biological applications, or, as we're thinking, doing this for real-time sensing in a doctor's office or lab, the fact is that it's not going to generate enormous amounts of income like you would get from chips that go into computers," he said. "I think there is a market, but I don't think it's anywhere as big as what Intel is involved with in the computer industry."
Utz recounted being asked by executives at Intel "how many billions of dollars" such a device could ultimately generate. "Usually my response is that you probably have to put a few hundred million dollars of research to get it to that point, but after that I don't know if it would even be in the billions of dollars," he said.
Then again, Utz noted, an Arizona State University team led by Stephen Johnston recently won a $30 million contract from the Defense Threat Reduction Agency of the US Department of Defense to build a prototype of a peptoid array-based health monitoring chip (PM 4/27/2012) similar to the chips being developed by Intel and Stanford.
"So clearly somebody out there thinks this is an important area and something that could be used in very large numbers of different applications," he said.
Biotech firm Opko Health is similarly pursuing peptoid-based biomarker detection, in April licensing rights to its Alzheimer's diagnostic platform to Laboratory Corporation of America (PM 4/6/2012). According to a report commissioned last year by proteomics firm Proteome Sciences, protein biomarkers for Alzheimer's could represent a cumulative $9 billion market over the next ten years (PM 06/13/2011).
Varma said that at present the project is "a research program" designed to look at the question "from a proof-of-concept perspective." If in the future Intel was interested in developing the technology for commercial and clinical purposes, "we would do it obviously in partnership with others," she said, noting that the chip-maker is "not a life sciences company."
Nonetheless, Intel has "a substantial group" working in the biology space, Varma said, although she declined to say specifically how many employees were devoted to that effort.
While low throughput and poor reproducibility have hindered commercial production of glass slide-based peptide arrays, given its "semiconductor prowess and manufacturing scale," Intel is potentially well-positioned to achieve high-throughput, wafer-scale synthesis of silicon-based devices, Varma added.
Utz noted that when Varma's group first approached him about the collaboration, he was skeptical silicon would work as an array surface.
"Our lab has been developing protein and peptide arrays for over a decade and we've tried many things on glass and nitrocellulose and other different surfaces," he said. "When Intel approached us… we thought, 'Well, it doesn't hurt to work with them and do the experiments,' but we really didn't think it was going to work. Much to our surprise it worked better really than any other surface."
In the Nature Medicine paper, the researchers built silicon-based arrays containing all possible overlapping peptides in a protein sequence covering the N-terminal tail of the human histone H2B.
Using the arrays they identified the minimum binding epitopes for several commercial antibodies, resolving "the reactivity of [these] antibodies to peptides as small as two amino acids," they wrote.
They also used the platform to detect H2B-reactive autoantibodies in patients with systemic lupus erythematosus, replicating previous findings by Utz's group that serum from patients with high interferon SLE is more reactive to H2B peptides than serum from low interferon SLE patients.
SLE and autoimmune diseases more broadly are primary research interests of Utz's group, which collects blood for clinical research from roughly 1,700 autoimmune disease patients enrolled in a registry at Stanford Hospital.
This clinical experience was key to Intel's interest in working with Utz, Varma said. "I was looking for a clinical/applied research group to partner with because I wanted to be able to look at clinical samples," she noted.
The goal, Utz said, is to use devices such as the Intel microarray for applications like predicting disease flare-ups and identifying responders to drugs, particularly biologics like tumor necrosis factor inhibitors.
That work, he said, is progressing on a number of different platforms including traditional protein arrays, flow-based assays, and the silicon-based peptide arrays.