Over the past few years researchers have taken advantage of unprecedented advances in biology, electronics and human genetics to develop an impressive new tool kit for protecting and improving human health. Sophisticated medical technology and complex data analysis are now on the verge of breaking free of their traditional confines in the hospital and computer lab and making their way into our daily lives.
Physicians of the future could use these tools to monitor patients and predict how they will respond to particular treatment plans based on their own unique physiology, rather than on the average response rates of large groups of people in clinical trials. Advances in computer chip miniaturization, bioengineering and material sciences are also laying the groundwork for new devices that can take the place of complex organs such as the eye or pancreas—or at least help them to function better.
The articles on the following pages offer a glimpse at some of the most promising developments in customized technology for genetics, artificial sight, cancer, implantable health monitors and mental illness. Not everything will necessarily pan out. But collectively they suggest that compact medical technology will play an ever increasing role not only in treating the sick but also in safeguarding the health of those who are well.
The cost of sequencing the human genome keeps falling, but making sense of the results remains a challenge
When the Human Genome Project was launched more than 20 years ago, the effort of printing out the entire instruction book for building a human being was expected to require hundreds of sequencing machines, cost $3 billion and take 15 years. Thirteen years later, in 2003, the first “complete” human genome sequence was announced. But that momentous achievement was still a work in progress. Huge gaps remained in the map of the hereditary material that determines a person’s genetic destiny, waiting to be filled in.
Fast-forward to January 2012, at the International Consumer Electronics Show in Las Vegas. There amid the gaming consoles and flat-screen televisions stood a gene sequencer, a sleek white box the size of a desktop printer. Its inventors say that when the device hits the market later this year, it will crank out an individual’s complete genetic sequence in just a few hours for $1,000, or the cost equivalent of a nice plasma TV.
For years the $1,000 genome has been held out as the tipping point that will usher in a new era of personalized medicine. At that price point, the readouts are supposed to be cheap enough for ordinary doctors to put them to work treating patients with heart disease, cancer or other illnesses based on their own individual genetic risks and drug sensitivities. As gene sequencers like the one displayed become increasingly available, industry watchers argue that the age of comprehensive genetic testing of the human population has finally dawned.
But some say a widespread rollout of the technology would be premature. “It’s not ready,” says Aravinda Chakravarti, a professor of genetics at the Johns Hopkins University School of Medicine. Chakravarti worries that the potential benefits of personalized genomic medicine have been overpromoted. People do not realize, he says, that full genetic scans, whether done through a physician or bought online, are close to useless right now as medical tools.
The main problem is that the technology has grown faster than the researchers’ ability to understand the results it produces. For example, each individual’s genetic readout must be compared with lots and lots of other people’s readouts for doctors to understand which genetic patterns are important indicators of disease and which can be safely ignored. In addition, many diseases are caused by rare mutations that have not yet been identified. Finally, the task of simply sorting through the sheer mass of data spit out by a genome scan is daunting. “Generating the sequence now is fast and cheap,” says Euan A. Ashley, an assistant professor of cardiology at the Stanford University School of Medicine. “But the analysis? Wow. That’s not going to be fast, and that’s not going to be cheap.”
To demonstrate just how complex the process can be, Ashley and a few other researchers at Stanford and at Harvard University analyzed the genome of their colleague Stephen Quake, a professor of bioengineering. It took them six months to figure out how to do it, even though Quake had already sequenced his genome himself, so they had the raw data they needed.
Quake’s family history included several instances of heart disease. Sure enough, the team found that he possessed several genetic variants that have been linked to an increased susceptibility to heart attack. But the genetic analysis produced a few curveballs—including an increased likelihood of a hereditary blood disorder called hemochromatosis, even though no one in Quake’s family suffers from the condition. At this point, it is impossible to say whether the unexpected result reflects a true danger or some kind of mistake in the sequencing process—the genetic equivalent of a typographical error.
Despite these glitches, Ashley is optimistic about the potential for individualized DNA readouts to transform medical care, envisioning a day when a person’s genome is a standard part of the electronic medical record. So far, however, the few patients who have benefited the most from having large portions of their genome analyzed have had rare diseases with genetic variants that were unusual enough to stand out. For the rest of us, our genome awaits—a tale yet untold. —Nancy Shute
Synthetic photoreceptors will restore vision to the blind
Miikka Terho knows the difference between an apple and a banana. He can tell you that one is round and sweet and crunches when you bite it and that the other is long and curved and turns to mush if you let it ripen too long. But if you ask him to tell one fruit from the other without touching, smelling or tasting them, he is at a loss. Terho is completely blind. For three months in 2008, however, he recovered the ability to distinguish an apple and banana by sight thanks to a tiny electronic chip that researchers implanted in his left eye. Though brief, the new technology’s initial success has permanently changed the prospects for Terho and many others like him.
Terho, who works for an athletic scholarship organization in Finland, has retinitis pigmentosa, a genetic condition that destroys the light-sensitive cells lining the retina at the back of the eye. He could see just fine until age 16, when his night vision began to fail. In his 20s his ability to see in the day deteriorated as well. By age 35 Terho had lost central vision in both his left and right eyes. By 40 he could perceive only hints of light at the periphery of his vision.
Everything changed in November 2008, when Eberhart Zrenner of the University of Tübingen in Germany embedded the chip in the retina of Terho’s eye. The chip replaced damaged photoreceptors (known as rods and cones) in the retina. In a healthy retina, photoreceptors convert light into electrical impulses that eventually reach the brain by traveling through several layers of specialized tissue—one of which is made up of so-called biopolar cells. Each of the chip’s 1,500 squares, which are arranged in a grid that measures 0.12 inch by 0.12 inch, contains a photodiode, amplifier and electrode. When light shines on one of the photodiodes, it generates a tiny electric current that is strengthened by the adjacent amplifier and channeled to the electrode, which in turn stimulates the nearest bipolar cell, ultimately sending a signal through the optic nerve to the brain. The more light that shines on a photodiode, the stronger the resulting electric current.
Terho’s retinal implant opened a window on the world for him that measured about the size of an eight-inch-square piece of paper held at arm’s length. Through that window Terho could make out the basic shapes and outlines of people and objects, especially if the contrast between light and dark colors was strong. The implant did not, however, contain enough electrodes to produce sharp images. In addition, the chip allowed him to perceive only shades of gray rather than color because it could not differentiate different wavelengths of light.
Despite these limitations, the implant dramatically changed how Terho interacted with the world within days after his surgery. For the first time in a decade, he was able to see and name objects like silverware and fruit, read letters in large print, approach people in a room and recognize loved ones. Two other patients who received implants around the same time were able to locate bright objects placed against dark backgrounds.
Zrenner had to remove the chips after three months because the design left the patients vulnerable to skin infection: an external pocket-size battery pack delivered power to the amplifiers in the eye through a small cable threaded into the skin, leaving an open wound. Moreover, users needed to be near a computer that wirelessly controlled the frequency of electrical impulses, as well as such aspects of vision as brightness and contrast.
Since 2008 Zrenner has made his implant safer and more portable. The latest model—which has been placed in 10 people so far—is wireless. Underneath the skin a thin cable runs from an electromagnetic coil behind the ear a short distance to the chip at the back of the eye. Placing another electromagnetic coil housed in a small plastic box on top of the skin near the ear completes an electric circuit, which provides power to the implant. By fiddling with knobs on the outer coil, patients can modify brightness and contrast. To improve the technology further, Zrenner wants to implant three chips next to one another in a single retina so that individuals will have a larger field of view.
Although synthetic photoreceptors should prove helpful for any forms of blindness that result from damaged photoreceptors (namely, retinitis pigmentosa, choroideremia, and some kinds of macular degeneration, such as geographic atrophy), they cannot help people with glaucoma or other conditions that degrade the optic nerve.
Another team has also had Zrenner’s level of success in clinical studies. California-based Second Sight has developed a retinal implant—Argus II—that also treats retinitis pigmentosa, albeit with a different approach. Argus II captures images of the world in a tiny camera mounted on a pair of glasses, converts those images to electrical impulses and transmits them to an electrode that sits on the surface of the retina, rather than being embedded in it. In contrast to Zrenner’s implant, Argus II does not mimic the normal excitation of the retina by light waves. Instead it produces a patchwork of bright and dark dots that patients must learn to interpret.
Restoring even grayscale vision is expensive. Currently the Argus II setup is priced at $100,000 per eye and—once fully tested and approved—Zrenner’s retinal implants are likely to cost at least as much. Zrenner must conduct additional clinical trials before European advisory boards will permit him to instruct other surgeons in the procedure. Argus II has been approved for sale throughout much of Europe but not yet in the U.S. The success of the first clinical trials and the speed at which the technology is improving suggest, however, that retinal implants could be more widely available in just a few years. —Ferris Jabr
Zeroing In On Cancer
Bioengineers are developing tiny nanoparticles programmed to detect cancer at its earliest stages
Supersmall particles have the potential to fix some of medicine’s biggest problems. So-called nanoparticles, which are on the scale of nanometers (one billionth of a meter), are so tiny that 500 of them could be lined up across the width of a human hair. Scientists are engineering them to do everything from delivering drugs within specific parts of the body to providing more detailed images of internal organs. Now researchers are fine-tuning them to uncover cancer cells wherever they might be hiding.
Standard imaging tools detect tumors once they have grown large enough to see on a scan. Nanoparticles can find a single cancer cell in a sample of 10 million normal cells. Experimental nanomedicine detection for breast cancer, for example, has been able to pinpoint tumors 100 times as small as those that can be seen via mammography in laboratory studies. Nanoparticles that are outfitted with cancer-specific proteins or genetic material can also help doctors distinguish between malignant growths and run-of-the-mill inflammation or benign lesions.
Gregory Lanza, a professor of biomedical engineering at Washington University in St. Louis, and his team are developing nanoparticles that seek out and signal the presence of newly forming blood vessels that specifically feed the growth of tumors—a key stage in the development of colon, breast and other cancers. Such blood vessel growth does not usually occur in noncancerous tissue. This technology could also theoretically inform doctors how quickly a cancer is growing and thus how aggressive treatment should be.
Sanjiv Sam Gambhir, a professor of diagnostic radiology at Stanford University, and his colleagues are focusing on colorectal cancer, trying to find tiny malignancies that a standard colonoscopy might miss. The group is creating nanoparticles made of gold and silica and then adding molecules that instruct the particle to home in on the particular cancer cells. When the targeting molecules attach to a tumor in the colon or rectum, the nanoparticle minerals scatter the light from a specialized endoscope, betraying the presence of the cancer.
Nanoparticle engineers are also attempting to make nanoparticles that perform multiple tasks, such as highlighting tumors in MRI, PET and other scans and even delivering cancer drugs. Such combination nanodevices could allow physicians to see whether a treatment is getting where it is supposed to go—and whether it is working. Even with current targeted therapies that act specifically on cancer cells while sparing normal cells, doctors often do not have a good sense of how much of the medication has reached the tumor. “The imaging component is what allows you to know you actually delivered the drug—and how much,” Lanza says.
Efforts to bring nanoparticles to the clinic face some obstacles. Scientists will have to prove, for instance, that these minute helpers are safe for human use. But “the single biggest hurdle” for cancer therapy, Gambhir says, is the lack of plausible targets. Nanoparticles can be quite exquisitely designed, but they “aren’t magical,” he notes. Researchers do not know enough about the earliest stages of cancer growth to know which molecules the nanoparticles should be directed toward. Without knowing the targets, “we haven’t even taken the first step,” Lanza says. “We need to walk before we can run.” But with the nanomedicine field worldwide projected by various industry analysts to top $130 billion by 2016, the race to find out is on.
Smart Implantable Devices
New wireless monitors warn patients of an impending heart attack or help them to manage diabetes
Biomedical engineers are developing tiny, implantable monitors that could take some of the guesswork out of how best to treat patients with chronic conditions such as heart disease or diabetes. Several such devices—which send data wirelessly from key regions of the body or the blood to external receivers—are now being tested in the clinic. Eventually implanted monitors could play a more active role in treatment, not solely detecting dangerous arrhythmias, for example, but also jolting a stopped heart back to life. A couple of the instruments that are being developed target two of the most common medical problems:
Heart attacks. Manufactured by Angel Medical Systems in Shrewsbury, N.J., the AngelMed Guardian is roughly the size of a pacemaker and tracks the heart, beat by beat. It is tuned to listen for abnormal patterns, such as a rapid increase in timing or an irregular pulse in people who have recently survived a heart attack (making them at risk for another) but who do not qualify for a pacemaker or implanted cardiac defibrillator. If the device senses another impending attack, it vibrates and causes an external pager to beep and flash, alerting the patient or others to get help. To prevent false alarms, the Guardian needs to detect a problem signal for more than a minute before it sends an alert. These and other cardiac details gleaned from the device can be downloaded wirelessly to a computer for analysis. Angel Medical has licensed its heartbeat-detection technology to a company that makes implanted cardiac defibrillators. The combined technology will allow the device to administer an electric current to the heart if the monitor picks up signs of cardiac arrest or a particularly dangerous arrhythmia, while also sending electrocardiogram results to a physician.
Abnormal glucose levels. A new implantable glucose sensor made by GlySens in San Diego might some day offer millions of diabetics a wireless monitoring system of their own. The device takes near-continuous readings under the skin of a patient’s glucose level—which is then correlated to the level in the blood. The result: far more accurate and more complete information for guiding insulin dosing and timing than can be achieved by testing blood from finger pricks. And because the sensor is implanted, it requires less upkeep than current external monitors.
“We want to give the patient and the family a device where they can forget about the device and just have the information,” says Joseph Lucisano, a bioengineer who is also president and chief executive officer of GlySens. “Treatment of diabetes and many other chronic diseases is all about monitoring, recognizing and optimizing patterns of signals,” he adds. So having a wireless link that delivers “large volumes of data at minimal cost really will enable a lot of things that we probably can’t even anticipate.”
Wireless sensors are likely to be even more subtle in the future. Researchers have developed a thin, flexible instrument that can be applied like a temporary tattoo to skin or inside the body and can collect readings on heart rate, muscle contractions and even brain waves. Being developed by mc10, a company in Cambridge, Mass., that creates flexible electronics, the futuristic circuit is on its way to being completely portable—with an internal power supply and a wireless transmitter. In all likelihood, the combination of wireless monitoring of internal organs with flexible, form-fitting technology will soon give patients and doctors instantaneous information about a wide range of chronic conditions that have long been difficult to manage. —K.H.
Blood Tests for Mental Illness
Levels of particular proteins could offer a new way to diagnose schizophrenia and depression
Sabine Bahn wants to change the way psychiatrists diagnose severe mental disorders. She has spent the past 15 years probing the blood and brains of patients with schizophrenia and bipolar disorder (in which someone’s mood vacillates between mania and depression), searching for proteins that signal a person’s likelihood of developing these conditions. The molecules, known as biomarkers, promise a far more objective way to identify mental illnesses than the usual approach—making diagnoses based largely on patients’ self-reported behaviors.
Although biomarkers have improved diagnostic methods for many illnesses—among them diabetes and heart disease—they have not, so far, proved as helpful for psychiatric diseases. Still, Bahn, who heads a laboratory at the University of Cambridge, and a few other neuroscientists are convinced that biomarkers will soon become an indispensable component of psychiatry’s tool set. Two blood tests—one of which is based on Bahn’s research—are already commercially available.
In 1997 Bahn began scouring brain tissue that had been preserved from schizophrenic men and women who had died. She found that, compared with brain tissue from healthy people, the specimens she examined had unusually high or low levels of at least 50 proteins. Nineteen of the proteins were involved in the operation of mitochondria—the tiny, energy-producing organelles in cells. Bahn also found evidence that the neurons of schizophrenics could not use glucose efficiently, relying on a different molecule—lactate—as an alternative source of energy.
By 2006 Bahn found similar biochemical differences in the cerebrospinal fluid and blood of living people with schizophrenia. In two of her most recent investigations, she distinguished schizophrenic patients from healthy patients with around 80 percent accuracy by examining levels of 51 proteins in the blood. This group of biomarkers includes the stress hormone cortisol and a protein known as brain-derived neurotrophic factor (BDNF) that encourages the growth of new neurons, as well as the establishment of new connections between existing neurons.
Based on Bahn’s research, the Austin, Tex.–based laboratory Myriad RBM has developed a $2,500 blood test for schizophrenia called VeriPsych, which measures the amounts of the various proteins that she has identified. Although the test has not received approval from the U.S. Food and Drug Administration, psychiatrists are allowed to use it as part of their practice. (Some tests restricted to a single lab do not have to be FDA-approved as long as they meet rigorous standards for use in people.)
imilarly, San Diego–based Ridge Diagnostics has developed a biomarker test for depression that the company provides through a North Carolina lab for $745. MDDScore, as the test is called (MDD stands for “major depressive disorder”), searches the blood for 10 biomarkers, including BDNF and cortisol.
Researchers have not yet validated these blood tests in clinical trials—except for small studies funded by the companies themselves. Still, a few psychiatrists have found the tools helpful in distinguishing schizophrenia from a temporary drug-induced psychosis or in helping depressed patients accept the reality of their condition and the need for treatment. —F.J.
This article was published in print as "Tomorrow's Medicine."