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Credit: Massachusetts General Hospital

An automated health-care interface aims to streamline preventative screening.

MIT Technology Review, February 26, 2009, by Lauren Gravitz — A computerized kiosk under development at Massachusetts General Hospital (MGH) can take a patient’s medical history, weight, pulse, blood pressure, and other vital signs, and even perform simple blood tests for glucose and cholesterol. Physicians hope that the device, slated to begin field testing in the United Kingdom in June, will one day bring relief to the overburdened healthcare system, and allow doctors to intervene earlier in chronic disease.

Doctors’ appointments in the United States often feel like more of an inconvenience than a help, both for patients, who can spend hours in waiting rooms, and doctors, who spend hours filling in charts and organizing patient information. Ronald Dixon, director of the Virtual Practice Project, imagines that his kiosk–a small, Windows-based desktop computer with just a few peripherals–could one day revolutionize doctors’ visits just as ATMs transformed banking. By removing the tellers from the interactions that could be easily automated, banks saved face-to-face contact for more complex transactions. Dixon, who’s also a primary-care physician at MGH, believes that the same could be done for doctors.

The kiosk consists of a tabletop computer and a number of peripherals–a blood-pressure cuff, a scale, a pulse oximeter to measure blood oxygen levels, and a peak-flow meter to determine whether someone’s airways are constricted–as well as a blood-testing device commonly used in emergency rooms that can measure cholesterol and glucose levels. (The current version requires a trained assistant to do the finger stick for blood collection, although future versions will be automated.)

Ideally, Dixon envisions his kiosks placed in supermarkets and big-box stores: customers could step up, key in their password-protected information, answer questions related to their personal health history, and then get their checkup. “The results would then go to your provider, and that provider sends a message back to you the way you want it–either through e-mail or texting–about what to do with that result,” he says. It could determine whether current medications are doing their job, whether a particular strategy is working or changes need to be made, and whether a more in-depth exam is necessary.

In June, the kiosk will get its first glimpse at prime time. A pilot version will be tested in stores and other public spaces in Britain as part of a newly established vascular screening program to prevent cardiovascular disease, stroke, and heart attack. The United Kingdom is an ideal testing ground because it has a nationalized health-care system: everyone has an assigned primary-care physician and electronic health records, so the infrastructure for sharing and responding to the results is already in place.

“They’re trying to catch people who typically don’t get screened, since a lot of the population doesn’t go to the doctor unless they’re sick,” Dixon says. “But everyone goes to the drugstore or grocery store once in a while.” A 10-minute interaction will include a blood-pressure check, combined with blood glucose and cholesterol screens. The information can then be sent off to a central database. Those residents at highest risk for disease will receive a phone call from their physician.

While some might worry that the kiosk will perform medical care best left in the hands of a doctor, Dixon notes that it’s not geared to diagnosis: the machine is designed to collect and relay test information in a much more streamlined fashion than that used today. And it is targeted, at least in part, to patients who might not otherwise visit a doctor’s office.

The ability to efficiently screen for and monitor chronic diseases, such as diabetes and hypertension, whose rates are predicted to rise over the next 10 to 20 years, will be especially important. “Treatment for these should be very streamlined to make sure that people are on the medicines they need to be,” says Kristian Olson, a pediatrician at MGH involved in global-health initiatives. “And all of that should be routinized as much as possible, or else you’re reinventing the wheel for each patient.”

Other physicians familiar with the project have created their own visions for how the kiosk might be used. “A trip to the doctor’s office is a fairly clunky process,” says David Howes, president, chief medical officer, and CEO of Martin’s Point Health Care, based in Maine and New Hampshire. “It takes a lot of effort, it takes a lot of time, and it doesn’t really use the time of high-paid specialized professionals in the best possible way.”

Howes believes that just placing versions of Dixon’s kiosk in doctors’ offices could streamline the process and completely change primary care for both patients and their physicians. “Think about your process of going to the doctor: you go in, the nurse sits down with you, takes a lot of history, takes vitals, and might even order some lab studies. And then the physician comes in and replicates a lot of that work,” he says.

But a kiosk would allow for much of that to be accomplished before a patient ever sits down in an exam room. “By the time you get in to see the physician, the information has been gathered and organized,” Howes says. A clinician can look at the information and determine what conversations she and the patient need to have. “We’ve daydreamed that a tool like this, in the intake process, would be very useful.”

An automated system like the health kiosk could also be used to extend health-care access to the poorest nations. “It’s clear that there’s a human-resource limitation overseas that’s far larger than what we have in this country,” says MGH’s Olson. The kiosks, in combination with just a single physician or nurse practitioner, “could provide common care to a huge percentage of people,” he says.

In developing nations, Olson views the kiosk as less of a preventative screening tool than one that could be used for vital follow-ups. “I could see it being incredibly useful for routine follow-up for patients with issues such as tuberculosis or HIV,” he says. “It’s a way to follow up with physicians, demonstrate side effects, talk about whether [patients are] taking their meds.”

George Whitesides has created a cheap, easy-to-use diagnostic test out of paper.

MIT Technology Review, March/April 2009, by Kristina Grifantini — Diagnostic tools that are cheap to make, simple to use, and rugged enough for rural areas could save thousands of lives in poor parts of the world. To make such devices, Harvard University professor George Whitesides is coupling advanced microfluidics with one of humankind’s oldest technologies: paper. The result is a versatile, disposable test that can check a tiny amount of urine or blood for evidence of infectious diseases or chronic conditions.

The finished devices are squares of paper roughly the size of postage stamps. The edge of a square is dipped into a urine sample or pressed against a drop of blood, and the liquid moves through channels into testing wells. Depending on the chemicals present, different reactions occur in the wells, turning the paper blue, red, yellow, or green. A reference key is used to interpret the results.

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Color change: Paper tests, such as those shown here, could make it possible to diagnose a range of diseases quickly and cheaply. A small drop of liquid, such as blood or urine, wicks in through the corner or back of the paper and passes through channels to special testing zones. Substances in these zones react with specific chemicals in the sample to indicate different conditions; results show up as varying colors. These tests are small, simple, and inexpensive.

Credit: Bruce Peterson

“Pill ID”

MIT Technology Review, March/April 2009, by TR Editors — To deter the theft and counterfeiting of medication, NanoGuardian has developed a way to apply nanoscale patterns to individual pills and capsules so that they can be authenticated or traced. The company won’t say how the technology works but claims that the mechanism for producing the pattern can be built into a capsule mold. Detection of the nano pattern has to be performed by NanoGuardian itself, using proprietary means. The technology has been approved by the U.S. Food and Drug Administration for use by a NanoGuardian client.

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What is Nanoguardian?

NanoGuardian provides a state-of-the-art, nanotechnology-based defense against pharmaceutical counterfeiting and illegal diversion.

Utilizing a patented NanoEncryption™ process, NanoGuardian delivers true forensic, multilayered authentication and tracing capability on each and every dose.

In the NanoEncryption process, NanoCodes are incorporated directly onto tablets, capsules and vial caps. These codes may be associated with an unlimited amount of manufacturer-determined data, including product information (strength and expiration date), manufacturing information (location, date, batch and lot number) and distribution information (country, distributor, wholesaler and chain).

Where Nanoguardian Works

NanoGuardian was first introduced as a solution for the pharmaceutical supply chain, which is estimated to suffer more than $35 billion1 in lost revenue a year.

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NanoGuardian’s NanoCodes can also be linked to on-package e-pedigree technologies such as radio frequency identification (RFID) and 2-D barcodes, creating a true multilayered protective shield of each individual dose from plant to patient. At the overt level, a simple field inspection can reveal if a dose is authentic. The forensic-level NanoCodes, however, can only be detected with highly specialized, proprietary tools within NanoGuardian’s Product Integrity Centers, enhancing the unrivaled security of the NanoGuardian process.

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But in fact, counterfeiting and illegal diversion plague industries throughout the world, with counterfeit currency, bogus credit cards and fake watches as widely cited examples. Less publicized is the widespread counterfeiting of auto and aircraft parts, medical devices, software, luxury goods, ID cards, passports and more.

Fortunately, the NanoGuardian process provides authentication and traceability of a product, at the unit level, throughout the supply chain. If you’re curious as to whether NanoGuardian could play a role in securing and protecting your brand, please go to the Contact Us section of this site.

1 The Center for Medicines in the Public Interest

Closed-Loop Protection

Once NanoGuardian’s NanoEncryption technology is fully implemented for a particular product or products, you can take advantage of NanoGuardian’s Closed-Loop Protection™ offering.

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Closed-Loop Protection combines the dual-protective benefits of NanoEncryption™ technology with a proactive market-monitoring program, creating an “early warning” system in the fight against counterfeiting and diversion. This results in reduced risk to brands, companies and patients.

Whether global or regional in scope, Closed-Loop Protection allows you to proactively focus brand protection efforts wherever in the world you suspect counterfeiting or diversion. With Closed-Loop Protection, NanoEncrypted doses are authenticated within 24 hours of receipt, exposing the counterfeits. And because of the specific distribution data associated with NanoGuardian’s forensic-level NanoCodes, you will immediately know of any dose that is not precisely where you intend it to be. Before NanoGuardian, brand-protection technology so revealing simply didn’t exist.

NanoGuardian protects returned goods. The appearance of counterfeit and diverted product in the returns side of the supply chain is escalating. In fact, it is not uncommon for counterfeit and diverted product to be found in genuine packaging. NanoGuardian enables manufacturers and returned goods agents to quickly and easily authenticate returns within minutes, and do so with relatively inexpensive and readily available tools.

Samples of returned product can be quickly analyzed at a NanoGuardian Product Integrity Center, providing a means of detecting diverted product “laundered” through the returned goods process and bringing a stop to this costly problem.

NanoGuardian can validate adverse events. When non-typical adverse events are reported, NanoGuardian can be used to authenticate the product in question and potentially save your brand from erroneous adverse label changes that reduce its competitiveness.

February 26, 2009 — Researchers at the University of Pennsylvania School of Medicine, in Philadelphia, have discovered stem cells in the esophagus of mice that are able to grow into tissue-like structures and form parts of an esophagus lining when placed into immune-deficient mice.1

“The immediate implication is that we’ll have a better understanding of the role of these stem cells in normal biology, as well as in regenerative and cancer biology,” stated senior author Anil Rustgi, MD, professor of medicine and genetics and chief of gastroenterology at Penn. “Down the road we will develop a panel of markers that will define these stem cells and use them in replacement therapy for diseases like gastroesophageal reflux disease [GERD] and to understand Barrett’s esophagus, a precursor to esophageal adenocarcinoma, and how to reverse that before it becomes cancer.”

Diseases of the esophagus are very common, both in the United States and worldwide. “Benign forms include GERD, and millions are affected,” Dr. Rustgi noted.

GERD sometimes can lead to esophagitis, an inflammation of the esophagus. “In some of these cases, esophagitis can lead to a swapping of the normal lining of the esophagus with a lining that looks more like the intestinal lining. That’s called Barrett’s esophagus,” he explained. “This can lead to cancer of the esophagus, which is the fastest rising cancer in the United States, increasing by 7 percent to 8 percent a year.”

To understand normal biology and how injured cells may one day be repaired, researchers set out to identify potential stem cells, which have the ability to self-renew, in the esophagus and to characterize them. The first step was to grow mouse esophageal cells they suspected were adult stem cells. The cells formed colonies that self-renewed, then they grew into esophageal lining tissue in a three-dimensional culture apparatus.

“These tissue culture cells formed a mature epithelium sitting on top of the matrix,” said Dr. Rustgi. “The whole construct is a form of tissue engineering.”

The investigators then tested their pieces of esophageal lining in animals. When the tissue-engineered patches were transplanted under the skin of immunodeficient mice, the cells formed epithelial structures.

In addition, green-stained stem cells in a mouse model of esophageal injury, which mimics what happens during acid reflux, migrated to the injured lining cells and co-labeled with the repaired cells. This indicated involvement of the stem cells in tissue repair and regeneration.

The researchers eventually will develop genetically engineered mouse models to be able to track molecular markers of esophageal stem cells found in a microarray study. The group already has developed a library of human esophageal cell lines and is looking for human versions of markers already identified in mice.

“The ultimate goal is to identify esophageal stem cells in a patient, grow the patient’s own stem cells, and inject them locally to replace diseased tissue with normal lining,” said Dr. Rustgi.

The Penn scientists collaborated with researchers from Massachusetts General Hospital, in Boston, and the Wistar Institute in Philadelphia. The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute.

Reference

1. Kalabis, J., Oyama, K., Okawa, T., et al. (2008). A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. Journal of Clinical Investigation, 118 (12): 3860-69.

A British company has demonstrated an important step for a new sequencing technique.

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A DNA base (red) passes through a protein tunnel lined with a sugar (blue and green bubbles). The sugar slows down the DNA as it moves through the pore, allowing time for the base to be identified.
Photo by: Oxford Nanopore

Speed-Reading DNA Inches Closer

MIT Technology Review, February 26, 2009, by Katherine Bourzac — For DNA sequencing to become a routine part of patient care, it needs to become cheaper and faster. A company called Oxford Nanopore hopes to bring down both the cost and the time required for sequencing using a technique called nanopore sequencing. The company has now made an important demonstration of its technology: for the first time, researchers were able to identify DNA bases with near total accuracy. In addition to identifying the four bases of DNA, the technique can also detect a modified version of one of the bases, which may be responsible for causing cancer and other diseases.

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Speed reader: A DNA base (red) passes through a protein tunnel lined with a sugar (blue and green bubbles). The sugar slows down the DNA as it moves through the pore, allowing time for the base to be identified.
Credit: Oxford Nanopore

The new technique allows for the direct identification of bases without the fluorescent labels and imaging equipment used for conventional high-speed sequencing. Direct reading of DNA should not only be faster and cheaper, but it should also make it possible to perform more complex analysis, says Jeffrey Schloss, program director for technology development at the U.S. National Human Genome Research Institute. The Oxford Nanopore system’s ability to detect the DNA modifications catalogued by an emerging field called epigenetics is particularly exciting, says Schloss. For example, the addition of organic molecules called methyl groups to one of the bases has been shown to play a role in the development of diseases such as cancer. But it is arduous to detect these modifications using conventional sequencing methods, so the full effects and why they happen are still not well understood.

Oxford Nanopore researchers have not yet demonstrated that they can process complete DNA sequences using their system. However, the new results, published this week in Nature Nanotechnology, are an important proof of concept for nanopore sequencing. “They’ve shown the feasibility of all the steps,” says Schloss.

The system that the company used to identify DNA bases is a tunnel-like protein embedded in a membrane very similar to that which surrounds biological cells. The flow of ions across the membrane and through the pore creates a current that can be measured using an electrode similar to those used to study neurons in the lab. By applying a strong electrical potential across the membrane, researchers drive DNA bases through the pore. As each base passes through, it modifies the current flowing across the pore in a characteristic way.

The key to making the method work is controlling the flow of the bases through the protein pore. DNA bases are “too small to be identified on their own: they would fly through,” says James Clarke, a scientist at Oxford Nanopore. So a sugar molecule lining the opening bulks it up so that the DNA doesn’t zip through too rapidly. In previous versions of the nanopore system, this sugar molecule was rather loosely associated with the pore, moving in and out. Company researchers led by founder Hagan Bayley, who is also a professor of chemistry at the University of Oxford, made it possible to read DNA bases one after the other by chemically bonding the sugar to the inside of the nanopore.

Oxford Nanopore can identify bases, but not yet in sequence. The system that it has demonstrated involves passing chopped-up DNA, not whole strands, through the nanopore. The company is now working on a setup for feeding long strands of DNA through the pore one base at a time. To do this, the researchers must attach an enzyme called an exonuclease to the nanopore. They hope that bases will be chopped off one at a time by the enzyme and will pass through the pore to the other side.

“There’s some question [about] what will happen when you put long strands of DNA in front of the nanopore,” says Schloss. “Will it form a hopeless knot?”

This is just one of several unknowns confronting researchers. To make the technology truly scalable and commercially viable, the pores will need to be grouped in large arrays, and the company will need to develop a less complicated way of reading the electrical signals from the pores. Oxford Nanopore says that it is currently working on both of these problems.

A potential pitfall of Oxford’s nanopore-exonuclease approach, says Schloss, is that the DNA will be destroyed as it has been read, making it impossible to resequence a strand to check for errors.

However, there are other approaches to nanopore sequencing that are less destructive. David Deamer, emeritus professor of chemistry at the University of California, Santa Cruz, who first came up with the concept of nanopore sequencing in the 1990s and is a scientific advisor for Oxford Nanopore, points out that this is not the first demonstration of a nanopore system that can identify all DNA bases. Last year, researchers led by Reza Ghadiri at the Scripps Institute, in La Jolla, CA, sequenced a 10-base-long strand of DNA using another nanopore technique. The flow of DNA through the Scripps system, which is based on Deamer’s original concept, is controlled by an enzyme that acts as a ratchet, moving the molecule forward one base at a time. But this system is much too slow, advancing at a rate of one base every 10 minutes, and the Scripps researchers are working on speeding it up.

Oxford Nanopore hasn’t put all its eggs in one basket. It has licensed technology for several nanopore-sequencing methods, including Deamer’s and another that uses an artificial nanopore: a silicon wafer punched with nanoscale holes and lined with carbon nanotubes the conductance of which changes as the DNA passes.

“One of these approaches will have a breakthrough and will be able to sequence at a rate faster and cheaper than what we do now,” predicts Deamer. Neither the researchers at Oxford Nanopore nor those at competing labs are willing to speculate about just when this will happen, or what such a system would cost per genome. But Schloss says it’s possible that one of the groups will meet the National Human Genome Research Institute’s original target year of 2014 for successful nanopore sequencing.