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Ram Group Developing High-Sensitivity Label-Free Sensors for Early Cancer Detection


NEW YORK (GenomeWeb) – Ram Group made its first announcement this week of plans to develop blood-based DNA and protein tests for the early detection of cancer using a novel sensor material and proprietary electric field detection methodology.

According to the firm, the approach eliminates a need for PCR, opening up market potential in point-of-care, or potentially even over-the-counter or home-based testing.

Ram Group is not yet disclosing many details about the materials science that underlies what it says is an ability to outperform existing electrochemical detection methods, and it has yet to publish on the analytical sensitivity and other performance metrics it claims it can achieve, so time will have to tell whether the approach does indeed see a path to the clinic.

CEO Ayal Ram said this week that in pure concept, the company's planned tests will not be much different some other systems, using probes to bind specific targets — either DNA or proteins — in a way that creates a signal that marks the presence of the analyte in question.

Ram Group believes it can develop tests with much higher sensitivity than current technologies allow because its methodology and sensor material signals the binding of these targets differently than others.

According to Ram, many groups are now investigating label-free non-optical detection technologies like field effect transistors and silicon nanowires.

"There is a lot of work being done there [with] systems that are essentially detecting the charge transfer that happens with different molecules. But there are two critical issues there," Ram said.

The first is something called Debye screening length, which limits the ability of sensors to detect targets in straight biological samples like plasma or serum

"All of these electronic sensors are all fantastic but they are useless commercially … for quantitative rapid diagnostics," Ram said.

For example, although some firms, namely QuantumDx, have integrated silicon nanowires into their technology, they still must perform significant preparation to appropriately dilute and amplify samples so that they can be applied to the sensor without Debye screening length being a problem, Ram argued.

Secondly, Ram said, current silicon platforms suffer from signal-to-noise limitations inherent to that material.

Though he said the Ram Group sensor is based on a material called gallium nitride, he declined to describe it in more detail. However, the company claims the technology allows electrons to run freely without the scattering and resistance seen in silicon.

Furthermore, Ram explained, unlike in previously described electrochemical sensors, the binding of targets in the Ram Group system is not detected directly via a change in electric charge. Rather, the material used allows the creation of a phenomena called a "spontelectric field membrane."

"It has to do with being able to elevate the energy state of this field on the surface of the sensor … and by modulating that we can detect changes in concentration and specific analytes [down to] femtomolar concentrations," Ram said.

The company has not published on this, nor have other groups, according to a search of the scientific literature. Papers on spontelectrics are currently limited largely to a single author.

"It goes away from the classical physical charge effect and into the quantum mechanical world, so we are dealing with different types of fields, not just electric fields," Ram said. "There is a process that happens between the solid-liquid interface on the sensor and in that interaction, different analytes expose their electric and dielectric properties and that has an interaction with the field and that is what we are measuring," he explained.

One investigator that has been listed on publications with Ram Group, Sven Ingebrandt of the University of Applied Sciences Kaiserslautern in Germany, published a report in NanoLetters last year describing what he and coauthors called a "Label-Free Ultrasensitive Memristive Aptasensor."

In that publication, Ingebrandt and coauthors wrote that the sensor relies on the "hysteretic properties of memristive silicon nanowires functionalized with DNA aptamers" to provide a label-free and ultrasensitive biodetection technique.

Applying the approach to PSA, the investigators wrote that they could achieve a limit of detection down to a 23-attomolar concentration, which they claimed was the best ever published value for electrochemical biosensors in PSA detection at that time.

According to the authors, the results suggest that "biosensors can be proposed to detect a wide range of cancer markers with unprecedented ultrasensitivities to also address the issue of an early detection of cancer."

Ram Group was not a coauthor on that study, but Ram confirmed that the firm does work with silicon nanowire memresistance on a research basis though it believes that its newer gallium nitride-based material overcomes issues this other sensor type would have with mass projection and commercial viability.

In its work so far, the firm has used a fluidic chip to separate red and white blood cells from plasma, but it plans to move to a lateral-flow strip, much like a glucose test, for planned commercial products.

The company is now at a point where it is beginning a set of blinded clinical studies to demonstrate its detection sensitivity and support commercial test launches, said Ram. As that moves forward, it also expects to publish details of the sensor material and other technical aspects of its platform before the end of the year.

The group already has early results from tests with clinical samples, he added. In one study, Ram Group used its sensors to measure tumor-associated antibodies in samples from patients with breast, prostate, colorectal and lung cancers, and were able to distinguish cancer patients' samples from normal controls with 95 percent sensitivity and specificity.

Then, looking at samples from a longitudinal study of healthy people (some of whom eventually went on to develop cancer) the approach could discriminate the individuals who would develop cancer up to 1.5 years before their clinical diagnosis. None of these results have been published.

The company has since moved from an antibody-based approach to one in which sensors are arrayed with very short peptides that bind specific circulating DNA targets, Ram said. This is based on work with Israeli collaborators who have developed a strategy for creating these molecules to target specific mutations.

Future cancer tests would be developed by creating panels of 10 to 100 of these peptide probes that target a set of mutations relevant to a particular cancer type.

According to Ram, the question of optimizing these biomarker panels is secondary to the firm's ability to detect the markers in question at the great sensitivity it claims, directly from a biological sample, without the need for preparation steps and PCR.

"Looking at current diagnostic platforms, it was just quickly very evident that the issue was not in creating better biomarkers or capture reagents with higher affinity because all of that doesn’t matter if your sensor is the bottleneck or the limiting factor," he argued.

In addition to tests that detect DNA markers, Ram said that the company and its Israeli collaborators have also developed a proteomic test that includes a panel of seven proteins, one of which is MMP9.

Sensitivity alone is not a solution to early cancer detection from blood or other body fluids. Biomarkers of cancer have to actually be present early in the disease in these samples and consistent from individual to individual. In other words, even exponentially higher sensitivity offers no advantage if there is no mutation in a sample to detect.

The clinical field has yet to determine definitively whether tumors shed relevant biomarkers into the blood very early in their development, or only later, or whether certain biomarkers turn up only in some cancer types versus across the landscape of the disease. However, investigators have embarked on studies to attempt to characterize pre-cancerous states and early cancer in order to better understand these basic biological questions.

As a result, it remains to be seen whether the Ram Group's proposed analytical sensitivity advantages translate to an actual clinical detection advantage over other detection methods.