Posted in: Healthcare, IBM 5 in 5, Systems

New IBM research: Making silicon biochips to stretch single DNA for future disease detection

Just last month, IBM released its “5 in 5” predictions, an exercise to identify five innovations that will have an impact on society in five years. Among the five, it was predicted that, with the help of IBM “lab-on-a-chip” technology, doctors could have a device that isolates tiny bioparticles from bodily fluids to reveal signs of diseases like cancer, before symptoms appear. One of the goals in this project is to shrink down to a few silicon chips many of the components and processes necessary to analyze a disease that would normally be carried out in a full-scale biochemistry lab.

The heart of this innovation is IBM’s nanoDLD technology, which can process a liquid sample through a silicon chip that sorts the biomarker-containing bioparticles – exosomes, proteins or DNA – through an asymmetric pillar array. NanoDLD uses a set of pillars to deflect larger particles along the asymmetry direction, while allowing smaller particles to flow straight through the gaps of the pillar array unabated, effectively separating the particle “traffic” by size while not disrupting flow. The continuous flow nature of this technology circumvents stop-and-go batch processing typical of conventional separation techniques, making screening and diagnosis simpler, faster and cheaper.

We’ve paid special attention to isolating exosomes as we begin to understand their usefulness as biomarkers for the diagnosis and prognosis of malignant tumors. The genetic cargo in these tiny packets has been shown to reveal signs of a developing cancer and other diseases, providing a non-invasive and convenient option for early stage diagnosis and monitoring how well a treatment is working.

nanoDLD: A medical lab “on a chip”

DNA, too, is an incredibly useful indicator of disease – if we can more easily isolate and analyze it. When it comes to using DNA as a biomarker, scientists have discovered that certain alterations (such as fusions of different parts of DNA, or an unusual amplification of the number of copies of certain genes, or a simple change in the DNA sequence) can substantially increase a person’s susceptibility to disease, or be the sign of a developing cancer. The challenge is detecting those telling alterations in DNA with affordable and easy to deploy technology. Today, medical facilities and biological labs have technologies to detect genomic alterations from patients’ DNA samples. But processing these DNA samples from a biopsy or drop of blood still requires lengthy and expensive sample preparation, a lot of specialized equipment, time and experts to run the various processes.

Individual DNA doesn’t look like the perfect double-helix spiral staircase of textbooks. Rather, when we examine individual DNA in the lab it coils around itself into a globular shape. In this shape, picking out a mutation is a bit like finding a particular spot on a clump of spaghetti. Our team at IBM designed a silicon-chip based technology that pre-stretches the DNA molecules from their natural coiled state to a more elongated state, making it easier for the DNA molecules to thread into nanoscale channels, allowing biochemists to more easily detect the presence of genomic alterations in the DNA molecules. In our recent paper “Wafer-Scale Integration of Sacrificial Nanofluidic Chips for Detecting and Manipulating Single DNA Molecules,” published in Nature Communications, we explain the details of this approach.

We can then think of the nanoDLD and the DNA stretching nanochannel technologies as modules of a pipeline. After a subject’s DNA is introduced in a chip, it can be separated based on its size using the nanoDLD chip. The fragments of the intended sizes will then be piped in the nanochannels for closer analysis for the detection of possible DNA alterations.

With this approach, it is possible to find the existence of mutations such as those in the genes BRCA1 and BRCA2 that confer an increased susceptibility to breast and ovarian cancer.


Video: Fluorescent microscopy video of lambda-DNA molecules (~48,000 base pairs in length), as they stretch, before they get linearized when they translocate through nanochannels of a width of tens of nm.

Manufacturing labs on a chip… like a chip

Our goal is to speed up the analysis of DNA samples by generating more automated technology. To that end, we’ve been able to put some of the needed capabilities together – on a standard silicon chip, using standard CMOS wafer fabrication processes – to create our biochip.

A silicon wafer designed to sort particles found in bodily fluids for the purpose of early disease detection.

A silicon wafer designed to sort particles found in bodily fluids for the purpose of early disease detection.

For technologies such as the nanoDLD for exosome-based diagnostics, and nanochanels for DNA alteration detection to have global impact, they need to be compact, cost-effective, and mass producible. Using a standard silicon chip enables this. Our vision is that down the road we will integrate these fluidic chips with electronics making it possible to transmit the data from the chip to datacenters for analysis. You can envisage a handheld device packaged with the biochip to allow DNA testing that then sends the information streaming to the cloud for analysis.

It’s important to note that while this will make it easier for people to monitor their health, medical professionals will always be needed to know which gene mutations to look for and what to do with that information. Having the means to screen for early disease is only half of the equation. The other half is integrating this information with the rest of the patients’ medical information to determine the best course of treatment for individual patients – and may help avoid the problem of over treatment.

In the U.S., most men over 50 undergo a yearly PSA (prostate specific antigen) test to screen for prostate cancer, the most common cancer in men. Many of those men diagnosed with prostate cancer are faced with making hard decisions, with options that go from doing nothing to dealing with a prostatectomy and its associated side effects. Unfortunately, a fraction of those who underwent prostatectomy or other invasive treatments would not have died or even be bothered by prostate cancer¹. The same occurs in breast cancer, where overdiagnosis can be the result of mammography screening programs that recommend all women over 40 years of age have a yearly mammography. Some studies have estimated that overdiagnosis resulting from mammography screening can be as high as 30 percent².

IBM lab-on-a-chip technology could be combined with cognitive tools such as Watson for Genomics or Watson Oncology to help overcome this challenge, interpreting the presence of DNA alterations and proposing treatments tailored to patients with those mutations. As with all Watson technologies, the goal is to augment human intelligence. In this case, helping doctors make more informed decisions.

 

  1. Overdiagnosis and Overtreatment of Prostate Cancer, U.S. National Library of Medicine, National Institutes of Health

  2. Implications of Overdiagnosis: Impact on Screening Mammography Practices, U.S. National Library of Medicine, National Institutes of Health

Comments

  1. Claire says:

    Nice story!

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L-R: Qinguang Lin, Gustavo Stolovitzky

L-R: Qinghuang Lin, Research Staff Member, Project Manager & Master Inventor; Gustavo Stolovitzky, Program Director, IBM Translational Systems Biology and Nanobiotechnology, IBM Research

"Our team at IBM designed a silicon-chip based technology that pre-stretches the DNA molecules from their natural coiled state to a more elongated state, making it easier for the DNA molecules to thread into nanoscale channels."