Biochip Breakthrough

Antimicrobial resistance represents an increasingly serious threat to public health around the globe. Molecular diagnostics systems enable rapid identification of pathogens through nucleic acid amplification tests (NAATs) and occasionally facilitate the detection of resistance-causing mutations. But despite the promise of enabling appropriate antibiotic selection, existing systems are restricted by their limited multiplexing (the maximum number of strains and sequences that can be detected) and low accuracy for identifying point mutations, such as single nucleotide polymorphisms (SNPs). Now, a team of researchers has developed a new approach: a miniaturized semiconductor biochip and multiplexed NAAT that is capable of swiftly amplifying, detecting, and quantifying DNA or RNA sequences in their hundreds.

A novel platform

Arjang Hassibi, CEO of InSilixa, the company responsible for the new technique, started his career in a different discipline before turning to biotechnology. “I was trained in Stamford as an electrical engineer, but toward the end of my PhD, I switched from just doing electronics to building analytical instruments and platforms.” It wasn’t until 2012 that Hassibi founded InSilixa and joined the fight against antimicrobial resistance. “The push toward antimicrobial resistance was just starting, and as we moved on, we found that there was a need for an analytical platform that could not only identify the organisms, but also look at the drug susceptibility profile and drug resistance.”

The new platform comes in the shape of a disposable biochip composed of 1,024 independent DNA biosensors that use inverse fluorescence techniques. Although the multiplex capacity of conventional, solution-based qPCR assays is constrained by the availability of dyes with different spectral properties, the new platform can detect hundreds of different sequences. The researchers demonstrated their method’s genotyping accuracy by simultaneously identifying multiple respiratory viruses within a single clinical sample – but, even more impressively, the platform was able to detect mutations that distinguished drug-resistant from drug-sensitive Mycobacterium tuberculosis. Hassibi highlights the potential significance of the technique: “You know exactly what drug to use, and which drugs aren’t going to be effective, so the expectation is that the treatments are going to be much more efficient. I think it would save lives in certain cases; for example, with hospital-acquired infections and times when you’re dealing with patients who are fragile or have supressed immune systems. It would also slow the increase of drug-resistant strains to some degree, because you’re not using antibiotics and antimicrobial agents willy-nilly.”

The biochip can perform microbial scans in under two hours, without the need to culture the microbes in the lab, which often delays the whole process by days or even weeks. Hassibi believes such time-savings could have direct benefits for patients. “After developing a urinary tract infection in the aftermath of surgery, a patient was given antibiotics that didn’t work. Only after a second and third course of antibiotics was a drug susceptibility test carried out, after which the right antibiotic was prescribed to cure the infection. It took two and a half months and the patient was suffering for this long period,” he says. “Now, we have the technology to do it in hours. There are generally three or four different drugs that can be prescribed for urinary tract infections, each conferring resistance to different antibiotics. Why should you go through three months of pain and suffering when the technology is there to check for resistance? The patient has to demand that.”

Pursuing perfection

A limitation of the new platform is its inability to discover new microbes and mutations; it can only detect previously characterized target sequences or mutations that are known to represent a medically important phenotype. And so, Hassibi and colleagues hope to develop a molecular diagnostics system with an open platform, allowing pathologists to create new biochips when new strains of microbes are discovered. “Every year, there might be a new strain that needs to be added. A lot of labs are very competent in doing the critical work and they’re set up to do various diagnostics. If they have access to technology that can produce a new diagnostic test within six months while also putting it through clinical approval and everything else they need, that would be a game-changer. We are opening it up so that our partners and customers, who have their own specific applications, can use the technology to create a product that they can take to market.”

A big challenge during the development of the laptop-sized biochip reader was the lack of funding available for the creation of new diagnostic technologies – which is accompanied or driven by a poor attitude towards the value of diagnostics. “The US is a treatment-driven society, and I think diagnostics are not a big part of it. Specifically, for areas in which the urgency is not out there and where the cost of treatment is not considered high, people think they can afford not to do the proper diagnostic testing and go bouncing off different antibiotics or treatments,” Hassibi says. “Diagnostics in healthcare is the ugly duckling. It’s a stark point of view, but there is some truth in it. The clinicians do care, but they will talk about the large investment required to make these technologies happen, and the industry incentives are lower. The problem is that, alongside an increase in antibiotic resistance, why should our treatment-driven society worry? If you look at it from an investment-motivated point of view, if you’re selling the drugs and they’re buying without testing, why should you worry?”

Hassibi believes that more investment is required in diagnostics, while also directing efforts toward developing complete or so-called actionable diagnostics. “My personal opinion is that you will win if you pay a little bit more for precision diagnostics than you pay for the treatment. There will be an incentive for more effective drugs, so they will not lose out financially – but, rather than having mundane antibiotics, they might have new ones. Doctors would be happy; patients would be happy. I don’t think there would be any losers. The overall cost of healthcare might not go down drastically, but the outcomes would be better.”

What’s next?

After proving the viability of the biochip, Hassibi’s ambition for the next few years is to take the product to market. “We’re getting to the product development and manufacturing stage, which is a very capital-intensive process; we have to be very careful because once you start it, you cannot slow it down.” However, the fact that Hassibi’s company plans to develop a platform technology rather than a clinical assay will dramatically reduce the cost required to take the product to market – the clinical work and applications will come from users of the platform. “Our model is not very common in biotechnology, because most companies adopt a vertical model and use integrated systems that do everything; they have the software, the instruments, the chemistry, and they do the clinical work.” Though Hassibi doesn’t think there is anything inherently wrong with the “old and proven” model, he believes that biotechnology should draw inspiration from other areas, such as the technology industry, where it is common to use parts from different sources in a more horizontal model. 

Despite the challenges ahead, Hassibi is relatively optimistic about microbe profiling platforms. “Low-cost platforms near the point of care for patients will definitely exist in our lifetime. But whether it will take five years or 25 years, I don’t know.” The ultimate aim is to enable the simultaneous profiling of 100 microbes or strains, which would facilitate the detection and identification of multi-drug resistant pathogens. If successfully translated into the clinic, such rapid molecular diagnostics platforms would give healthcare professionals actionable data on the most effective drugs – a big step forward in the ongoing fight against antibiotic resistance.