Popularity of the pocket-sized gene-sequencing device continues to prove that DNA testing away from clinical laboratories in remote clinics and outlying field laboratories is not just possible, but in some cases preferable
Once again, Oxford Nanopore Technologies (ONT) is demonstrating how next-generation gene sequencing technology can make it cheaper, simpler, and faster to sequence without the need for big clinical laboratories. And its successful raising of $180 million to expand development worldwide shows the support it has with capital funding investors.
Dark Daily has repeatedly reported on the development of the UK-based company’s point-of-care DNA sequencer going back to 2011. Called MinION, we predicted in 2015, that once brought to market, the pocket-sized gene sequencing machine “could help achieve the NIH’s goal of $1,000 human genome sequencing and, in remote clinics and outbreak zones, shift testing away from medical laboratories.” (See Dark Daily, “Point-of-Care DNA Sequencer Inching Closer to Widespread Use as Beta-Testers Praise Oxford Technologies’ Pocketsize, Portable Nanopore Device,” November 4, 2015.)
Since then, MinION’s use worldwide “for a number of biological analysis techniques including de novo sequencing, targeted sequencing, metagenomics, epigenetics, and more” has only expanded, according to multiple sources and ONT’s website.
How Does MinION Work as a Gene Sequencer?
The MinION nanopore sequencing device weighs about 100 grams (less than four ounces), is about the size of a standard deck of cards, operates off a laptop USB plug, and can sequence genetic material in a matter of minutes.
To perform the nanopore sequencing, a strand of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) is pushed through small pores in a membrane. An ionic current is then applied to the material and voltage is implemented to measure any disruptions in the current. The resulting measurement represents an electrical signal that is converted to human-readable sequence.
“It’s like the ultimate barcode,” Gordon Sanghera, PhD, Chief Executive Officer at Oxford Nanopore, told BBC News.
Oxford Nanopore Technologies’ diminutive MinION gene-sequencing device has the capacity to directly recognize epigenetic markers that control gene activity and cellular processes involved in the onset and development of disease. Early detection of cancers, testing for birth defects and infectious diseases, and blood screening are possible future clinical laboratory applications for the MinION. Click on this link to watch video on MinION. (Photo copyright: Oxford Nanopore Technologies.)
Why is MinION Important?
One advantage to this technology is that it has the ability to sequence much longer strands of DNA when compared to existing technologies. The MinION can sequence over a million letters or bases, around 2% of a DNA strand or chromosome with 96% or above accuracy. The device can read remarkably long stretches of consecutive DNA letters. Readouts of several thousand letters are common and the record for the MinION is 882,000 consecutive DNA letters, Technology Review noted.
“One of the most important findings of this research was that, even though the human genome reference was completed or thought to have been completed a while ago, it still contains many missing pieces and we were able to close some of those gaps in the sequence by developing a new method for developing these extremely long reads using nanopore sequencing,” Nick Loman, PhD, Professor of Microbial Genomics and Bioinformatics at the School of Biosciences at the University of Birmingham, UK, told Pharmaphorum. Loman worked on research with Oxford Nanopore on nanopore sequencing.
“We’ve gone from a situation where you can only do genome sequencing for a huge amount of money in well-equipped labs to one where we can have genome sequencing literally in your pocket just like a mobile phone,” Loman told BBC News. “That gives us a really exciting opportunity to start having genome sequencing as a routine tool, perhaps something people can do in their own home.”
Using MinION in the Field
According to the Oxford Nanopore website, the MinION:
- Is pocket-sized and portable;
- Has up to 512 nanopore channels;
- Has a simple 10-minute sample preparation time;
- Allows real-time analysis for rapid and efficient results; and,
- Is adaptable to direct DNA or RNA sequencing.
The MinION Starter Pack is available for purchase on the company’s website with prices starting at $1,000. The kit includes:
- The MinION device;
- Flow cells;
- Sequencing kits;
- Wash kits; and,
- MinION community support.
Researchers at The Kinghorn Center for Clinical Genomics at the Garvan Institute of Medical Research in Darlinghurst, Australia, are currently using the MinION for research purposes.
Members of the Zebra Project (above), an international group of scientists, used Oxford Nanopore Technologies’ MinION to sequence genomes during epidemics in Latin America. With just a laptop computer for power, MinION can run complex gene-sequencing and achieve superior results than other similar technologies. It is in use worldwide bringing clinical laboratory testing to patients in remote, outlying locations. (Photo copyright: Ricardo Funari.)
“I think it’s really expanding the arsenal of tools we have to peer into cell biology and the root causes of cancer and various diseases,” Dr. Martin Smith, Head of Genomic Technologies at the center, told Australian Financial Review. “It’s really just starting to open the lid off the jar and peer more deeply into the genomics of the cell.”
Dr. Sanghera hopes the gadget could be utilized in the future to identify common infections at home and help consumers avoid unnecessary trips to doctors, clinics, and hospitals, and avert the misuse and overuse of prescription medications. He also feels MinION has applications outside the healthcare industry, such as detecting the presence of harmful microbes in food and water supplies.
As gadgets like MinION become more popular, the potential to move DNA sequencing closer to the patient (and out of the core lab) has implications for clinical laboratories and anatomic pathology groups. However, core labs would still be a preferred source to collect the raw data, store that data, then do the annotation of the DNA sequences and report the findings to the referring physician.
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Researchers demonstrated it was feasible to encode digital malware onto a strand of synthesized DNA and infect the gene sequencers and computer networks used by medical laboratories
As if anatomic pathology groups and clinical laboratory leaders don’t already have enough to think about, here comes a security vulnerability right out of a sci-fi thriller. Researchers at the University of Washington (UW) have used synthesized DNA to encode digital malware into a physical strand of DNA capable of establishing a remote connection to the computer network on which the sequenced DNA is read!
Stated differently, researchers have now demonstrated that is possible for bad guys to hack into a medical laboratory’s instrument systems and computer network using a physical strand of synthesized DNA that is encoded with digital malware.
Another Threat to Clinical Laboratories, Pathology Groups?
Does this translate into an immediate security issue for medical laboratories? For now, the threat is only theoretical. While researchers did succeed, their study findings should provide some comfort to pathology groups or medical laboratories worried about the implications of DNA-based malware. The UW researchers published their findings at the 2017 USENIX Security Symposium.
Synthetic DNA Malware Exploit is More Proof-of-Concept than Immediate Threat
At its core, computer code (AKA source code) is similar to DNA in that it is composed of a set number of states—with binary, zeroes, and ones. This led UW researchers to question whether they could translate the AGCT elements (adenine, guanine, cytosine, and thymine) of DNA into binary code capable of hacking DNA sequencers and accessing the information they contain.
In an article in The Atlantic, Tadayoshi Kohno, PhD, Short-Dooley Professor in the Department of Computer Science and Engineering at UW, who led the research team, noted that, “The present-day threat is very small, and people don’t need to lose sleep immediately. But we wanted to know what was possible and what the issues are down the line.”
Complexity of Engineering a DNA-Powered Computer Virus
To begin the process, researchers needed to create a specific DNA strand encoded with the exact proteins that would later convert into their exploit. An article in ArsTechnica suggests this would be a challenge due to the physical properties of DNA’s double-helix design.
In the article, John Timmer, PhD, wrote, “DNA with Gs and Cs forms a stronger double-helix. Too many of them, and the strand won’t open up easily for sequencing. Too few, and it’ll pop open when you don’t want it to.”
The study shows it took multiple attempts to find a DNA sequence that would both carry the malware code and withstand the synthesizing and sequencing processes. Even then, researchers needed an exploit for the software used on sequencers in clinical laboratories and other diagnostics providers to prove their theory. Study authors used their own modified version of an open-source sequencing software, adding an exploit they could target, instead of a version of the software already publicly in use.
Lee Organick (above left), Karl Koscher (center), and Peter Ney (right) worked with Luis Ceze and Tadayoshi Kohno, PhD, at the University of Washington to develop the DNA sequence containing the malware code. The researchers determined that it was feasible for the gene instruments used by clinical laboratories to be infected with the malware, which could then move to infect a clinical lab’s computer network. (Photo copyright: University of Washington.)
With their proteins synthesized and customized software in place, researchers still faced challenges getting the code to trigger. “With reads randomly appearing in an FASTQ file,” the researchers noted, “we would expect the modified program to be exploited 37.4% of the time.”
As with genetic code, the binary code of a program is highly sensitive to errors. Any misread bases or splitting of the code resulted in failure. When sequencers only read a few hundred bases at a time, ensuring the code doesn’t hit one of these splits is a challenge.
One unique difference between binary and genetic code also caused trouble—genetic sequences aren’t direction dependent, while binary sequences are. If the code is read in reverse, it won’t execute properly.
Future Concerns for Clinical Laboratories and Genetic Researchers
Today, the threat to medical laboratories and the sensitive data generated by sequencing is minor. However, tomorrow that threat could be more common.
In a WIRED article on the subject, Jason Callahan, Chief Information Security Officer for Illumina stated, “This is interesting research about potential long-term risks. We agree with the premise of the study—that this does not pose an imminent threat and is not a typical cyber security capability.”
Don Rule, founder of Translational Software, agrees. When asked about the threat posed to clinical laboratories, he said, “… if you have to pre-introduce the hack in the analytics program, this is a pretty circuitous way to take over a computer. I can see how it is feasible and right now Norton Antivirus is not looking for viruses encoded in the AGCT code set, but we are right not to lose a lot of sleep over it.”
However, as genetic sequencing becomes a common part of medicine, attackers might have increased reason to disrupt services or intercept data. The UW researchers cite “important domains like forensics, medicine, and agriculture” as potential targets.
While their successful attack was highly engineered, their research into open-source sequencing software revealed a range of common security weaknesses. Many clinical laboratories and anatomic pathology groups also run proprietary analysis software or use hardware with embedded software.
They recommend that medical laboratories work to centralize software updates and create ways to verify data and patches through digital signatures or other secure measures.
Already, genetic researchers take care to avoid synthesizing potentially dangerous sequences, and to contain tests and data. But this study shows that not all threats come from within the research or clinical laboratory environment. Both engineers of sequencing technology and hardware—and the medical laboratories using them—will need to optimize operations and monitor trends closely to see how security issues evolve alongside sequencing capabilities.
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Portable devices have potential to analyze DNA and produce results in the field in minutes to hours, eliminating the need to return to a medical laboratory to analyze samples
Pathologists continue to hear about research efforts to create small devices that can perform DNA analysis. In the past year, four research organizations, including one in the United States, one in New Zealand, and two in the U.K., have unveiled several devices that will analyze DNA in the field.
This line of research is of particular interest in developing countries where resources such as electricity for refrigeration are scarce. Some of the DNA testing devices will produce results in minutes to hours, eliminating the need to return to a clinical laboratory to analyze samples.
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