Applied Biotechnology

A luminescent lab mouse, genetically engineered to produce the same protein that makes fireflies’ tails light up, may accelerate progress in coming up with treatments for muscular dystrophy. This bioengineered mouse also has a genetic defect that, like its counterpart gene defect in people, causes the disease.

The luminescence happens only in damaged muscle tissue, and its intensity is in direct proportion to the amount of damage sustained in that tissue. So each glowing mouse muscle gives researchers an accurate real-time readout of just how much the disease has progressed and where.

It adds up to vastly expedited drug research. Tom Rando, MD, PhD, director of Stanford’s Glenn Laboratories for the Biology of Aging and founding director of Stanford’s Muscular Dystrophy Association Clinic, told me. As I wrote in my release about his new report in the Journal of Clinical Investigation about the Rando lab’s invention:

No truly effective treatments for muscular dystrophy exist. “Drug therapies now available for muscular dystrophy can reduce symptoms a bit, but do nothing to prevent or slow disease progression,” said Rando. Testing a drug’s ability to slow or arrest muscular dystrophy in one of the existing mouse models means sacrificing a few of them every couple of weeks and conducting labor-intensive, time-consuming microscopic and biochemical examinations of muscle-tissue samples taken from them, he said.

With an eye to vastly speeding up drug testing while simultaneously dropping its cost, Rando and his colleagues developed the new experimental strain whose glow (you see it through the skin) gives investigators an instantaneous, accurate reflection of what’s going on inside a mouse’s muscles, well before the degenerative changes could have been observed using standard detection techniques - without any need to kill the mouse in order to get the results.

Trivia point: The word “muscle” comes from the Latin musculus, meaning “little mouse.” More than mere coincidence?

Okay, probably not. But I thought it was worth mentioning.

Previously: Aging research comes of age, Can we reset the aging clock, one cell at a time? and Mouse model of muscular dystrophy points finger at stem cells
Photo by Goldring

A million years ago (all the way back in 2006!) I wrote an article for Stanford Medicine magazine about genetic technologies and the eugenics movement in this country during the first part of the 1900s. I still remember it as one of the most fascinating of my articles to research, demanding as it did that I speak with a variety of geneticists and ethicists about the increasing control that humans have over their genetic destiny.

When, last year, I had the privilege of writing about Stanford biophysicist Stephen Quake, PhD, and his work on whole-genome sequencing of fetuses before birth, I couldn’t help but remember that article of yore. What are we getting ourselves into?

Now MIT Technology Review has recognized whole-genome fetal sequencing as one of its “10 Breakthrough Technologies 2013.” Accompanying the designation is an in-depth review of the technology and its implications - which are far more complex than I could have imagined six years ago. The article contains comments from several experts, including Stanford law professor and bioethicist Hank Greely, JD, and Quake:

Quake says proving that a full genome readout is possible was the “logical extension” of the underlying technology. Yet what’s much less clear to Quake and others is whether a universal DNA test will ever become important or routine in medicine, as the more targeted test for Down syndrome has become. “We did it as an academic exercise, just for the hell of it,” he says. “But if you ask me, ‘Are we going to know the genomes of children at birth?’ I’d ask you, ‘Why?’ I get stuck on the why.” Quake says he’s now refining the technology so that it could be used to inexpensively pull out information on just the most medically important genes.

In my opinion, experts are right to consider the impact of this type of technology before it becomes commonplace. The ethical implications of parents learning their child’s genome sequence within a few weeks of conception - and of possibly using that information to make decisions about the pregnancy’s outcome - are substantial. Thankfully, some really smart people have been asking these questions in one form or another for years, even though the answers seem to end up more grey than black and white. From that ancient article I wrote six years ago:

For example, even though sex selection of embryos fertilized in vitro has many people up in arms, there’s no evidence that it’s on track to alter the gender balance in this country: Boys and girls are nearly equally sought after, says [medical geneticist and associate chair of pediatrics Eugene Hoyme, MD]. And although some parents will terminate a pregnancy if the fetus has a genetic or developmental problem that they feel isn’t compatible with a meaningful life, different families draw this line at dramatically different points in the sand. For some, it’s too much to consider having a child with Down syndrome. For others it’s important to sustain life as long as possible regardless of the severity of the condition. Still others might choose to have a child as similar to them as possible, down to sharing disabilities such as deafness.

“Eugenics is here now,” says Stanford bioethicist David Magnus, PhD. “So what? We allow parents to have virtually unlimited control over what school their child attends, what church they go to and how much exercise they get. All of these things have a much bigger impact on a child’s future than the limited genetic choices available to us now. As long as these are safe and effective, why not give parents this option as well?”

Previously: New techniques to diagnose disease in a fetus, Better know a bioengineer: Stephen Quake and Stanford bioethicists discuss pro, cons of biotech patents
Photo by paparutzi

Map making has long been the domain of explorers, cartographers and treasure buriers, but a Stanford cancer researcher has recently gotten into the act.

Garry Nolan, PhD, a professor of microbiology and immunology, has developed a novel method for graphically plotting the data generated by analyzing individual cell characteristics. He uses a customized computer-design program to sort the types and numbers of cells making up individual cancer tumors. The resulting “maps” can identify cancer sub-types and even “family trees” among tumor cells in individual patients, and may one day be used to personalize treatments for cancer and other diseases.

“Our message is that cancers can be organized [and] can be mapped, and we can finally understand which cells a given drug has activity against and map this to the molecular biology of particular cancers,” Nolan said.

Nolan’s cell data is derived using an innovative variation on a common cell-sorting technique called flow cytometry. He has devised a way - which he terms single-cell mass cytometry - to measure dozens of biological parameters, including cell size, DNA content and protein expression in individual cells. Mass cytometry enables a more detailed profile of cells’ molecular makeup and activity than previous technologies.

The potential of Nolan’s work has been recognized. He is the first recipient of the Department of Defense’s Ovarian Cancer Research Program’s Teal Innovator Award, a five-year, $3.2 million grant to advance the understanding and treatment of ovarian cancer. Nolan’s research is also featured in the just-released Fall edition (.pdf) of the Stanford Cancer Institute’s newsletter, SCI News.

Michael Claeys is the senior communications manager for the Stanford Cancer Institute.

How do you catch a drug-safety problem before it trips you up in human trials? Try making a mouse with a human liver - or one close enough to human to predict what the drug you’re testing will do in a person.

A team led by Stanford pharmacogenomic expert Gary Peltz, MD, PhD, in a study just published in the Journal of Pharmacology and Experimental Therapeutics, designed and used just such mice to show precisely how a compound showing promise for fighting HCV (the virus responsible for hepatitis C) would be metabolized in people. Not only that, but these ‘humanized’ mice accurately predicted how the compound would interact with another, already approved HCV drug in human subjects. (With more than 30 percent of all people over age 57 taking five or more prescription drugs at any given time, drug-drug interactions are a serious concern.)

The liver is the body’s chemistry set. In this hardworking organ, batteries of enzymes (molecular machines that do most of the body’s chores) operate in careful sequences like workstations of an assembly line. Together, they manufacture myriad substances and modify existing ones. They also constitute the body’s front-lne detox unit, metabolizing potentially poisonous ingested substances. That includes drugs we consume for medical purposes.

Metabolites - the products of metabolism - can themselves be bioactive, for better or for worse. “It’s often not the drug itself, but one of its metabolites, that is responsible for a drug-induced toxicity,” Peltz told me when I interviewed him for the release I wrote on the new study. So drug developers rigorously test their drugs in animals, typically starting with mice, before moving into clinical trials.

But mice metabolize things differently from humans, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen safety problems, said Peltz. Another big problem is those unanticipated interactions between a new drug a person takes and any other drugs that person may already been taking.

The drug tested in the study, clemizole, is an old antihistamine widely prescribed in the 1950s and 1960s but left on the shelf when newer drugs came along. Stanford HCV authority Jeff Glenn, MD, PhD, has resurrected clemizole after observing that it impedes the virus’s replication. The new study advances clemizole’s prospects for development, because what the drug appears to do in human liver tissue is just what the doctor ordered.

Previously: Hepatitis C virus’s Achilles heel, Immunology escapes from the mouse trap
Photo by primeperry

Researchers around the globe are working to engineer a pain-free method to deliver vaccines and other medications subcutaneously without the use of a hypodermic needle. Some have created patches comprised of microneedles, others have designed a needle modeled after the mosquito’s mouth and another group devised a magnetic jet injection device.

Now researchers in South Korea have developed a device using an erbium-doped yttrium aluminum garnet (Er:YAG) laser to propel a tiny, precise stream of medicine below the skin’s surface. A paper describing researchers’ work was published yesterday in Optics Letters. According to journal release:

The laser is combined with a small adaptor that contains the drug to be delivered, in liquid form, plus a chamber containing water that acts as a “driving” fluid. A flexible membrane separates these two liquids. Each laser pulse, which lasts just 250 millionths of a second, generates a vapor bubble inside the driving fluid. The pressure of that bubble puts elastic strain on the membrane, causing the drug to be forcefully ejected from a miniature nozzle in a narrow jet a mere 150 millionths of a meter (micrometers) in diameter, just a little larger than the width of a human hair.

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Tests on guinea pig skin show that the drug-laden jet can penetrate up to several millimeters beneath the skin surface, with no damage to the tissue. Because of the narrowness and quickness of the jet, it should cause little or no pain, [ Seoul National University Jack Yoh] says. “However, our aim is the epidermal layer,” which is located closer to the skin surface, at a depth of only about 500 micrometers. This region of the skin has no nerve endings, so the method “will be completely pain-free,” he says.

This short video shows a demonstration of the injector firing into the open air without a skin or gel target. The jet, which is roughly the diameter of a human hair, seems dispersed but a target would be placed within the jet breakup distance of a few millimeters, so splash-free injection is achieved.

Previously: Taking the sting out of injections, Researchers turn to mosquito to design painless needle and NIH funds development of painless vaccine patch
Via BBC News

Earlier this year, Stanford electrical engineer Ada Poon, PhD, made headlines when she publicly showcased a tiny wireless chip, driven by magnetic currents, that is small enough to travel through the bloodstream. Now comes news that Poon and colleagues have demonstrated the feasibility of a millimeter-sized, implantable cardiac device that runs on radio waves transmitted from a small power device on the surface of the body.

A Stanford Report story published today discusses the significant engineering challenges that researchers had overcame in designing the device:

Existing mathematical models have held that high-frequency radio waves do not penetrate far enough into human tissue, necessitating the use of low-frequency transmitters and large antennas – too large to be practical for implantable devices.

Ignoring the consensus, Poon proved the models wrong. Human tissues dissipate electric fields quickly, it is true, but radio waves can travel in a different way – as alternating waves of electric and magnetic fields. With the correct equations in hand, she discovered that high-frequency signals travel much deeper than anyone suspected.

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According to their revised models, the researchers found that the maximum power transfer through human tissue occurs at about 1.7 billion cycles per second, much higher than previously thought.

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The discovery meant that the team could shrink the receiving antenna by a factor of 10 as well, to a scale that makes wireless implantable devices feasible. At the optimal frequency, a millimeter-radius coil is capable of harvesting more than 50 microwatts of power, well in excess of the needs of a recently demonstrated 8-microwatt pacemaker.

Researchers say the work is a major step in advancing the development of a new class of medical devices, ranging from swallowable endoscopes to precision brain stimulators, that can be implanted into the body and powered wirelessly.

Previously: Stanford engineers create wireless, self-propelled medical device that swims through blood stream

Have you ever heard of the “cooling glove?” It’s a rapid thermal exchange device, developed more than a decade ago by Stanford biologists Dennis Grahn and Craig Heller, PhD, that takes advantage of specialized heat-transfer veins in the palms of hands to quickly lower the body’s core temperature. As a result, the device can dramatically improve exercise recovery and performance.

A Stanford Report story published today describes how the researchers’ efforts to devise a model for studying heat dissipation led to development of the cooling glove and explains the relationship between overheating and fatigue. In the above video, researchers demonstrate how the glove works and discuss how rapidly cooling one hand can allow athletes to reach their maximum athletic capabilities without using performance-enhancing drugs.

Versions of the glove are currently being used by the Stanford football and track and field teams, the San Francisco 49ers, Oakland Raiders and Manchester United.

Previously: Does HGH help or harm athletic performance?

Winners were announced this week in the DEsign By Biomedical Undergraduate Teams (DEBUT) Challenge, a nationwide contest that invites undergrads to tackle problems in three categories of biomedical design. The video above demonstrates the winner in the “Therapeutic Device” category, the QuickStitch Surgical Suturing Device to Improve Fascia Closure, which was developed by five students at Johns Hopkins University. From an National Institutes of Health press release describing the team’s invention:

QuickStitch is an inexpensive, disposable suturing tool for gastrointestinal surgery that improves safety, efficiency, and consistency in stitching fascia (a collagenous layer underneath the skin that wraps around the internal organs to keep them from pressing against the skin layer). The device aims to improve surgeon performance and patient outcomes by regulating stitch placement and tension, thus helping to avoid the problems of hernias and ischemia that can result from improper stitching after gastrointestinal surgery.

The team won a $10,000 prize, as did the winners in the contest’s two other categories, “Diagnostic Devices” and “Technology to Aid Underserved Populations and Individuals with Disabilities.” Six teams also received honorable mentions. The contest was sponsored by the the National Institute of Biomedical Imaging and Bioengineering. The entire list of winning projects is a fun read.

Previously: New gadget for measuring white blood cells invented at Stanford, Stanford and FDA to collaborate on med-tech education and How Embrace infant warmers are saving lives in developing nations

To promote research and foster conversation on developing sustainable health-care solutions for low-resource environments, the Stanford Graduate School of Business recently launched a global health innovation blog of the same name.

In explaining the motivation for launching the blog and focus of the content, the organizers write:

We created the Global Health Innovation blog to give healthcare innovators, entrepreneurs, and other professionals a place to read and share information about the many challenges of developing and commercializing products and services targeted at underserved populations in developing countries. We also intend to highlight creative solutions being used to overcome common barriers in an effort to inspire and assist the growing community of global health innovators at Stanford and beyond.

Every few weeks, we’ll post a new vignette that tells the story of company or team, a challenge they faced, and the solution(s) they used to address the problem. In some cases, these stories may also focus on lessons learned from unsuccessful experiences. We hope that others who have either faced similar issues or have tried alternative solutions will share their insights by adding a Comment to the post.

The latest post examines the story of SafePoint Trust founder Marc Koska’s efforts to address the threat of unsafe injections, his involvement in developing a low-cost auto disposable syringe and the organization’s ongoing campaign to improve basic health-care in developing countries.

Previously: How a Stanford dermatologist is using telemedicine to reach underserved populations in California, U.S. Chief Technology Officer discusses health-care reform’s effects on innovation and Ask Stanford Med: Answers to your questions on health-care innovation

Among my childhood phobias, a fear of needles is the only one that continues to haunt me in adulthood. So I was interested to read that researchers at the Massachusetts Institute of Technology have developed a new gadget capable of delivering a tiny, high-pressure jet of medicine through the skin without the use of a hypodermic needle.

Popular Science reports:

It’s similar to a normal syringe, except instead of a needle plunger, it uses a Lorentz force actuator, made from a magnet surrounded by a conductive coil. When a current is turned on, the magnetic field interacts with the current to produce a force. That force kicks a piston, which ejects a drug that has been embedded inside the capsule. The speed of the ejection and the depth it will reach can be controlled by altering the current.

To penetrate the skin, the ejection happens at ultra high speeds, almost equivalent to the speed of sound through air. The drug flows through an opening that’s about as wide as a mosquito proboscis, according to MIT News.

Researchers led by Ian Hunter and Catherine Hogan tested a prototype device with two different velocities: One can breach the skin and reach deep into tissue, and another can deliver drugs more slowly, so they can be absorbed by the skin. Different people would need different piston velocities …

While the device won’t be ready for the upcoming flu season, I take some comfort in knowing that the research on making injections less painful is progressing.

Previously: Researchers turn to mosquito to design painless needle
Photo by Indiana Public Media