Immune reboot: To reboot the immune system, scientists harvest hematopoietic stem cells, like the one pictured here, from a patient and destroy the existing immune system with a round of immunosuppressive drugs. The harvested stem cells are then injected back into the patient. This kind of stem-cell transplant shows promise in treating patients with type 1 diabetes.
Credit: Gary D. Gaugler / Photo Researchers

Some diabetics who received a stem-cell transplant do not need insulin injections even years later.

MIT Technology Review, April 15, 2009, by Courtney Humphries — Patients who underwent a procedure to wipe out the immune system and reconstitute it with their own stem cells remained insulin injection-free for up to three to four years after the procedure, according to a study published this week in the Journal of the American Medical Association. The research provides further evidence that a stem-cell transplant can reverse type 1 diabetes in some patients. Although a stem-cell transplant is a drastic procedure with a risk of serious side effects, this represents the most successful treatment to reverse the disease in humans without the need for ongoing medication.

The report extends research published in 2007 showing that the majority of 15 patients who underwent a blood stem-cell transplant were able to remain insulin-free for more than 18 months. Richard Burt, a coauthor of the study and a specialist in autoimmune disease at Northwestern University, says that “the criticism of the prior study was that maybe this was some kind of extended honeymoon”; he’s referring to a phenomenon in which patients newly diagnosed with type 1 diabetes will see their symptoms improve temporarily as they make health changes. This latest study extends the treatment to an additional five patients and shows that most patients have been able to remain off insulin for a longer period of time. In addition, it shows that patients have increased levels of a biological indicator of insulin secretion–evidence that they are indeed producing insulin on their own.

Type 1 diabetes is a chronic disease in which the immune system attacks the insulin-secreting beta cells in the pancreas; the body eventually fails to produce enough insulin to control blood-sugar levels. Because this form of diabetes is an autoimmune disease, scientists have been looking for ways to stop the immune system’s destructive actions. One idea is to “reset” the patient’s immune system by wiping it out with drugs and then rebuild it with the patient’s own stem cells. Blood or hematopoietic stem cells reside in the bone marrow and are responsible for replenishing blood and immune-system cells. Hematopoietic stem-cell transplant is most often used to treat patients with cancers like leukemia and other diseases of the blood, but it has recently been investigated as a way to treat several autoimmune diseases, including diabetes and lupus.

In this study, which was based at the University of Sao Paulo, in Brazil, patients first underwent drug treatments to boost their blood stem-cell production, making it possible to harvest stem cells from the blood rather than from the bone marrow. The patients were then hospitalized and given chemotherapy that severely impaired their immune systems; they simultaneously received drugs to prevent infections. The stem cells were purified from the blood and then injected back into the patients, where they could travel to the bone marrow and rebuild the immune system.

Twenty of 23 patients were able to go off insulin treatment for an average of 31 months; 12 of those have maintained this state, while 8 relapsed and began taking low doses of insulin. The researchers also measured levels of C-peptide, a by-product of insulin production that is used as an indicator of how much insulin is being manufactured in the pancreas. Burt explains that even on a “honeymoon” period, C-peptide levels will decrease in diabetics, but for patients in this study, “C-peptide levels kept going up and hit their maximum at two to three years.”

A stem-cell transplant would only be effective in newly diagnosed patients who still have some beta cells left to preserve. Some patients have also achieved insulin independence with an experimental treatment that involves transplanting insulin-secreting cells from a donor. However, these patients require immunosuppressive drugs to keep their immune systems from rejecting the donor cells. “This is the first treatment that, after one treatment, patients are on no insulin and require no medications,” Burt says.

Gordon Weir, head of islet transplantation at Joslin Diabetes Center in Boston, says that the results are impressive and that the treatment is “clearly having some effect on the natural course of the type 1 diabetes,” but it’s still too soon to declare this a permanent cure. Furthermore, he says that excitement about the results should be tempered by concerns about the potential dangers of the treatment and confusion about how the stem-cell transplant is actually working. In this study, two patients developed pneumonia because of the treatment; three others later experienced hormonal disorders, and nine patients developed a sperm deficiency.

Weir points out that the treatment regimen involved many drugs–including powerful chemotherapy agents–which may also have affected the diabetes. “We don’t actually know the stem cells had anything to do with this result,” he says. Weir hopes that the trial will spur further studies on the role of the stem cells and ways to make the treatment safer. Burt and his colleagues are now awaiting FDA approval for a randomized trial that would provide more rigorous data about the benefit of this treatment for diabetes.

People who are genetically at risk for Alzheimer’s show differences in brain activity in their twenties and thirties.

MIT Technology Review, April 2009, by Emily Singer — Healthy young people who carry a genetic variant that raises the risk for Alzheimer’s disease show differences in the brain decades before memory problems typically arise, according to research published today in the Proceedings of the National Academy of Sciences. Brain-imaging studies found that carriers had a hyperactive hippocampus, part of the brain central to learning and memory, even when mentally at rest. Scientists involved in the study say that the findings support the idea that the memory part of the brain is overworked in high-risk people, which over time could contribute to the disease.

Researchers used functional magnetic brain imaging to assess brain activity in 36 adults ages 20 to 35, half of whom carried at least one copy of the at-risk variation, and all of whom performed normally on tasks designed to test their cognitive skills. Not everyone who carries the variant, called APOE4, will develop Alzheimer’s. But those who have one copy have a quadrupled risk of the disease, while those with two copies have about ten times the average risk.

According to a press release from Imperial College London,

Differences in the region of the brain involved in memory, known as the hippocampus, have previously been shown in middle-aged and elderly healthy carriers of APOE4. However, the new Oxford University and Imperial study is the first to show hyperactivity in the hippocampus of healthy young carriers. It is also the first to show that APOE4 carriers’ brains behave differently even at “rest.”

Dr. Christian Beckmann, another author of today’s study from the Division of Neurosciences and Mental Health at Imperial College London, added: “Our brains are always active–our minds wander even when we’re not carrying out specific tasks. We were surprised to see that even when the volunteers carrying APOE4 weren’t being asked to do anything, you could see the memory part of the brain working harder than it was in the other volunteers. Not all APOE4 carriers go on to develop Alzheimer’s, but it would make sense if in some people, the memory part of the brain effectively becomes exhausted from overwork and this contributes to the disease. This theory is supported by studies that have found the opposite pattern in people who have developed Alzheimer’s, with these people showing less activity than normal in the memory part of the brain.”


Stem Cells Undo Birth Defects…….and Alzheimer’s?

Repairing damage: Neural stem cells, tagged green with a fluorescent dye, have been transplanted among the brain cells (red) of a mouse born with brain damage after its mother was given heroin during pregnancy. Transplants like this one seemed to effectively reverse the cellular, biochemical, and behavioral defects suffered by heroin-damaged mice.
Credit: Joseph Yanai

Transplanted stem cells restore normal behavior in brain-damaged rodents.

MIT Technology Review, 2009, by Jocelyn Rice — By injecting stem cells directly into the brain, scientists have successfully reversed neural birth defects in mice whose mothers were given heroin during pregnancy. Even though most of the transplanted cells did not survive, they induced the brain’s own cells to carry out extensive repairs.

Transplanted stem cells have previously shown promise in reversing brain damage caused by strokes, as well as by neurological diseases like Parkinson’s, Alzheimer’s, and Huntington’s. But their use in treating birth defects is relatively new. In recent years, a handful of research teams have been developing stem-cell-based therapies for rodents with real or simulated birth defects in the brain.

Joseph Yanai, director of the Ross Laboratory for Studies in Neural Birth Defects at the Hebrew University-Hadassah Medical School, in Jerusalem, says that stem-cell therapies are ideal for treating birth defects where the mechanism of damage is multifaceted and poorly understood. “If you use neural stem cells,” says Yanai, “they are your little doctors. They’re looking for the defect, they’re diagnosing it, and they’re differentiating into what’s needed to repair the defect. They are doing my job, in a way.”

Yanai and his colleagues began with mice that had been exposed to heroin in the womb. These mice suffer from learning deficits; when placed in a tank of murky water, for instance, they take longer than normal mice to find their way back to a submerged platform. And in their hippocampus–an area of the brain associated with memory and navigation–critical biochemical pathways are disrupted, and fewer new cells are produced.

All of those problems are swiftly resolved when the researchers inject neural stem cells derived from embryonic mice into the brains of the heroin-exposed animals. When swimming, the treated mice caught up with their normal counterparts, and their cellular and biochemical deficits disappeared. Yanai announced these findings in 2007 and 2008.

Such dramatic results were surprising, considering that just a fraction of a percent of the transplanted stem cells survived inside the mice’s brains. But they are consistent with an emerging consensus of how adult stem cells perform their many functions through so-called bystander or chaperone effects. Beyond simply generating replacements for damaged cells, stem cells seem to produce signals that spur other cells to carry out normal organ maintenance and initiate damage control.

“The chaperone effect is an important aspect of stem-cell biology that’s simply been under-recognized,” says Evan Snyder, who directs the Stem Cell Research Center at the Burnham Institute for Medical Research, in California, and whose research group coined the term in 2002. “That actually may be the low-hanging fruit in the stem-cell field–taking advantage of this, and not the cell-replacement aspect that we always thought would be the key to stem-cell biology in regenerative medicine.”

Cesar Borlongan, a professor and vice chairman for research in the department of neurosurgery at the University of South Florida College of Medicine, uses a different model to explore the use of stem-cell treatment for brain-damaged infants. By deliberately restricting blood and oxygen flow to the brains of newborn rats, he and his colleagues simulate the effects of an infant stroke–a devastating event that causes untreatable brain injury in newborn humans.

Much like Yanai, Borlongan found that injecting stem cells into the compromised rats’ brains reversed some of the behavioral deficits seen before treatment. For example, the treated rats could balance for longer time periods on a rotating rod.

To bring this kind of therapy closer to clinical tests in humans, Borlongan has experimented with administering the stem cells intravenously. Last July, in the online version of the Journal of Cerebral Blood Flow and Metabolism, he and his colleagues announced that transplanted stem cells produced the same result in rats regardless of whether they were given intravenously or injected directly into the brain.

Yanai has had similar success with intravenous administration in his heroin-exposure model, which he plans to announce at this year’s annual meeting of the International Society for Stem Cell Research, in Barcelona.

The injected stem cells are able to migrate from the bloodstream to the brain for two reasons, says Borlongan. First, the injured brain sends out chemical signals that recruit the cells. And second, brain damage can compromise the blood-brain barrier, which normally regulates which substances can cross the threshold into the brain.

Not everyone is enthusiastic about the intravenous approach, however. Darwin Prockop, director of the Institute for Regenerative Medicine at Texas A&M Health Science Center College of Medicine, cautions that the injected cells can lodge in other organs–particularly the lungs–causing unwanted and even deadly side effects. And according to Evan Snyder, it may be unnecessary to go in through the bloodstream; his group has not seen any major risks associated with direct brain injection, a route that he considers to be clinically feasible in humans.

But all of these therapies involve introducing foreign cells into the body, and therefore, run the risk of provoking a potentially dangerous immune response. In most studies to date, the treated rodents are dosed with powerful immunosuppressants. Yanai is currently exploring personalized treatments to circumvent this issue: cells are extracted from the animal to be treated, coaxed to return to a stem-cell-like state, and then transplanted. Because they originate in the treated animal, the cells are recognized as “self” and ignored by the immune system.

Recently, Borlongan has found that immunosuppressants are unnecessary in the infant-stroke model. Because he treats the rodents at a very young age, their still-immature immune systems appear relatively unfazed by the transplanted stem cells. Borlongan notes that a low-level immune response may actually be useful: by cutting down on the number of cells that survive in the long term, it may reduce the chance that injected cells will reproduce uncontrollably and form tumors.

Nonetheless, according to Prockop, the risk of tumors is a serious concern with any stem-cell-based therapy. And while he is optimistic about the future of cell therapies for treating a wide variety of diseases, he urges caution and conscience when considering severe birth defects. “The big danger is that you can take a child who may be doomed to die in a few years, and make that child a lifelong invalid who needs continuing nursing care,” he says. “So the prospects, if you think about them hard, are extremely worrisome. If you don’t get a complete cure, you may be causing more harm than good.”

A man in his mid-50s fractured his tibia in a ski accident, and 3 months later still had not healed. Patient did not want surgery, and so opted to take teriparitide, and today is back skiing again. (Credit: University of Rochester Medical Center)

University of Rochester Medical Center, April 14, 2009 — Rarely will physicians use the word “miraculous” when discussing patient recoveries. But that’s the very phrase orthopedic physicians and scientists are using in upstate New York to describe their emerging stem cell research that could have a profound impact on the treatment of bone injuries. Results from preliminary work show patients confined to wheelchairs were able to walk or live independently again because their broken bones finally healed.

At the heart of the research is the drug teriparatide, or Forteo, which was approved by the FDA in 2002 for the treatment of osteoporosis. Astute observations led a team of clinicians and researchers to uncover how this drug can also boost our bodies’ bone stem cell production to the point that adults’ bones appear to have the ability to heal at a rate typically seen when they were young kids.

Baseline research presented in February at the Orthopedic Research Society meeting revealed that of 145 patients who had an unhealed bone fracture – half of them for six months or longer – 93 percent showed significant healing and pain control after being on teriparatide for only eight to 12 weeks. These findings were enough to convince the National Institutes of Health to fund a clinical trial underway in Rochester, and if the preliminary data are any indication, researchers may have discovered a new, in-the-body stem cell therapy that can jumpstart the body’s natural healing process in bones.

The clinical implication is significant, as orthopedists can soon have a new tool at their disposal to deal with many common, painful bone ailments including the tens of thousands of painful fractures for which there is no treatment (pelvic fractures, vertebral compression fractures, clavicle fractures), fractures that won’t heal, fractures in patients that are either too sick to have surgery or chose not to have surgery, and even reduce the size of a incision in some surgeries.

Aging Bones Heal Slower

Of the estimated six million fractures in the United States each year, approximately five percent will have slow or incomplete healing. According to J. Edward Puzas, Ph.D., who heads up orthopedic bone research at the University of Rochester Medical Center and is the principal investigator of the clinical trial, a large portion of non-healing fractures tend to occur in older adults.

“In many people, as they get older, their skeleton loses the ability to heal fractures and repair itself,” Puzas said. “With careful application of teriparatide, we believe we’ve found a way to turn back the clock on fracture healing through a simple, in-body stem cell therapy.”

Those especially hard hit are the nearly 60,000 Americans suffering from pelvic fractures, where bracing and immobilization are not an option for an injury that leaves people immobile and in pain before the bone fuses.

“It takes three to four months for a typical pelvic fracture to heal. But during those three months, patients can be in excruciating pain, because there are no medical devices or other treatments that can provide relief to the patient,” said Susan V. Bukata, M.D., medical director of the Center for Bone Health at the University of Rochester Medical Center Bukata. “Imagine if we can give patients a way to cut the time of their pain and immobility in half? That’s what teriparatide did in our initial research.”

Bukata said much more was at stake then just comfort and pain relief. Patients who would ordinarily be confined to nursing homes or require additional medical attention because of non-healing fractures might be able to live an independent life. Bukata and Puzas estimate that if this drug saved just one week in a nursing home, it would pay for itself – and beyond.

“Many people don’t realize that pelvic fracture carries with them the same mortality as hip fractures – in one year, approximately one-quarter of all older women with pelvic fractures will die from complications,” Bukata said. “And during that year of recovery, a patient typically puts a greater strain on our health care system, not to mention their pain and suffering.”

Translational Research at Work

The impetus for the research began in Bukata’s clinic, where she saw painful bone fractures in osteoporotic patients quickly heal within a few months of taking teriparatide. At the time, Bukata also served on a research team at the University’s Center for Musculoskeletal Research, and she began to advocate that the team direct its efforts in an entirely new direction based on the results she was seeing with patients who were taking teriparatide.

“I had patients with severe osteoporosis, in tremendous pain from multiple fractures throughout their spine and pelvis, who I would put on teriparatide,” said Bukata. “When they would come back for their follow-up visits three months later, it was amazing to see not just the significant healing in their fractures, but to realize they were pain-free – a new and welcome experience for many of these patients.”

Puzas and Bukata developed a plan to focus attention in both the lab and clinic to understand if her observations were a fluke or if there was an underlying scientific process producing such life-changing results for patients.

“While we had come to understand how teriparatide builds bone more robustly than the body can on its own, up to that point, we had no clue how the drug would or could help with fracture healing,” Puzas said.

Bukata began prescribing teriparatide to patients with non-healing fractures, and was amazed at her findings: 93 percent showed significant healing and pain control after being on teriparatide for only eight to 12 weeks. And in the lab, Puzas began to understand how teriparatide stimulates bone stem cells into action.

Closing the Gap

When a fracture occurs, a bone becomes unstable and can move back and forth creating a painful phenomenon known as micromotion. As the bone begins healing it must progress through specific, well-defined stages. First, osteoclasts – cells that can break down bone – clean up any fragments or debris produced during the break. Next, a layer of cartilage – called a callus – forms around the fracture that ultimately calcifies, preventing the bony ends from moving, providing relief from the significant pain brought on by micromotion.

Only after the callus is calcified do the bone forming cells – osteoblasts – begin their work. They replace the cartilage with true bone, and eventually reform the fracture to match the shape and structure of the bone into what it was before the break.

According to Puzas, teriparatide significantly speeds up fracture healing by changing the behavior and number of the cartilage and the bone stem cells involved in the process.

“Teriparatide dramatically stimulates the bone’s stem cells into action,” Puzas said. “As a result, the callus forms quicker and stronger. Osteoblasts form more bone and the micromotion associated with the fracture is more rapidly eliminated. All of this activity explains why people with non-healing fractures can now return to normal function sooner.”

“The decreased healing time is significant, especially when fractures are in hard-to-heal areas like the pelvis and the spine, where you can’t easily immobilize the bone – and stop the pain,” Bukata added. “Typically, a pelvic fracture will take months to heal, and people are in extreme pain for the first eight to 12 weeks. This time was more than cut in half; we saw complete pain relief, callus formation, and stability of the fracture in people who had fractures that up to that point had not healed.”

The new clinical research will study post-menopausal women and men over 50 who come to the Emergency Department at Strong Memorial Hospital with a low-energy pelvic fracture. Patients will be divided into two groups — one offered teriparatide, the other a placebo — and followed for 16 weeks to measure the fracture healing process in a variety of ways: pain levels, microscopic bone growth determined through CT scans and functional testing of bone strength, among others.

Eli Lily, manufacturers of Forteo, are providing the medication for the clinical trial. Both Drs. Puzas and Bukata are members of Eli Lily’s speaker bureau.

Adapted from materials provided by University of Rochester Medical Center


Bone Marrow Stem Cells Used To Regenerate Skin

Wiley-Blackwell — A new study suggests that adult bone marrow stem cells can be used in the construction of artificial skin. The findings mark an advancement in wound healing and may be used to pioneer a method of organ reconstruction. The study is published in Artificial Organs.*

To investigate the practicability of repairing burn wounds with tissue-engineered skin combined with bone marrow stem cells, the study established a burn wound model in the skin of pigs, which is known to be anatomically and physiologically similar to human skin.

Engineering technology and biomedical theory methods were used to make artificial skin with natural materials and bone marrow derived stem cells. Once the artificial skin was attached to the patient and the dermal layer had begun to regenerate, stem cells were differentiated into skin cells. The cells are self-renewing and raise the quality of healing in wound healing therapy. When grafted to the burn wounds, the engineered skin containing stem cells showed better healing, less wound contraction and better development of blood vessels.

Skin, the human body’s largest organ, protects the body from disease and physical damage, and helps to regulate body temperature. When the skin has been seriously damaged through disease or burns, the body often cannot act fast enough to repair them. Burn victims may die from infection and the loss of plasma. Skin grafts were originally developed as a way to prevent such consequences.

“We hope that this so-called ‘engineered structural tissue’ will someday replace plastic and metal prostheses currently used to replace damaged joints and bones by suitable materials and stem cells,” says Yan Jin of the Fourth Military Medical University, lead author of the study.

*Artificial Organs is the official journal of the International Federation for Artificial Organs (IFAO), the The International Faculty for Artificial Organs (INFA) and the International Society for Rotary Blood Pumps (ISRBP).


Bone Growth Accelerated With Nanotubes And Stem Cells

From left to right, Brian Seunghan Oh, a materials science postdoc in the Jacobs School’s Department of Mechanical & Aerospace Engineering; Karla Brammer, a Jacobs School materials science graduate student; Jacobs School bioengineering professor Shu Chien; and materials science professor Sungho Jin. (Credit: Image courtesy of University of California – San Diego)

UCSD, Spring 2009 — Engineers at the University of California at San Diego have come up with a way to help accelerate bone growth through the use of nanotubes and stem cells. This new finding could lead to quicker and better recovery, for example, for patients who undergo orthopedic surgery.

In recent years, stem cells have become a hot topic of investigation with studies suggesting revolutionary medical benefits due to their ability to be converted into selected types of newly generated cells. During their research, the group of UC San Diego bioengineers and material science experts used a nano-bio technology method of placing mesenchymal stem cells on top of very thin titanium oxide nanotubes in order to control the conversion paths, called differentiation, into osteoblasts or bone building cells. Mesenchymal stem cells, which are different from embryonic stem cells, can be extracted and directly supplied from a patient’s own bone marrow.

“If you break your knee or leg from skiing, for example, an orthopedic surgeon will implant a titanium rod, and you will be on crutches for about three months,” said Sungho Jin, co-author of the PNAS paper and a materials science professor at the Jacobs School of Engineering. “But what we anticipate through our research is that if the surgeon uses titanium oxide nanotubes with stem cells, the bone healing could be accelerated and a patient may be able to walk in one month instead of being on crunches for three months.

“Our in-vitro and in-vivo data indicate that such advantages can occur by using the titanium oxide nanotube treated implants, which can reduce the loosening of bones, one of the major orthopedic problems that necessitate re-surgery operations for hip and other implants for patients,” Jin added. “Such a major re-surgery, especially for older people, is a health risk and significant inconvenience, and is also undesirable from the cost point of view.”

This is the first study of its kind using stem cells attached to titanium oxide nanotube implants. Jin and his research team – which include Jacobs School bioengineering professors Shu Chien and Adam Engler, as well as post doctoral researcher Seunghan Oh and other graduate students and researchers –report that the precise change in nanotube diameter can be controlled to induce selective differentiation of stem cells into osteoblast (bone-forming) cells. Karla Brammer, a Jacobs School materials science graduate student, will also present these findings in a poster session during Research Expo on February 19.

According to this breakthrough research, nanotubes with a larger diameter cause cells growing on their surface to elongate much more than those with a small diameter. The larger diameter nanotube promotes quicker and stronger bone growth. “The use of nano topography to induce preferred differentiation was reported in recent years by other groups, but such studies were done mostly on polymer surfaces, which are not desirable orthopedic implant materials,” Jin said.

It is common for physicians and surgeons to use chemicals for stem cell implants in order to control cell differentiation, a conversion into a certain desired type of cells, for example, to neural cells, heart cells, and bone cells. However, introducing chemicals into the human body can sometimes have undesirable side effects. “What we have accomplished here is a way to introduce desirable guided differentiation using only nanostructures instead of resorting to chemicals,” said Seunghan (Brian) Oh, who is the lead author of the PNAS article.

The next step for engineers will be to work with orthopedic surgeons and other colleagues at the UC San Diego School of Medicine to study ways to translate this breakthrough research to clinical application, said Shu Chien, a UC San Diego bioengineering professor and director of the university’s new Institute of Engineering in Medicine (IEM). Chien said this effort will be fostered by the IEM, whose goal is to bring together scientists, engineers and medical experts to come up with novel approaches to medicine.

“Our research in this area has pointed to a novel way by which we can modulate the stem cell differentiation, which is very important in regenerative medicine,” Chien said. “This will lead to a truly interdisciplinary approach between engineering and medicine to getting novel treatments to the clinic to benefit the patients.”

Heart alert: An implantable device, shown bottom right, measures a heart’s electrical activity. The device transmits information to an external device (the black box with cable), which tells the patient if he needs to visit the emergency room. This device transmits data to the physician’s workstation (the white box with screen), which tells the doctor what happened during the attack.
Credit: AngelMed

A pacemaker-like device aims to get victims to the hospital faster.

MIT Technology Review, April 14, 2009, by Emily Singer — An implantable device that alerts high-risk patients when they show signs of a heart attack could shorten the time it takes for the wearer to seek medical attention. The device, being developed by AngelMed, a medical-devices company in Shrewsbury, NJ, is already approved for use in Brazil and is now undergoing clinical testing in the United States. While early tests show that it can detect heart attacks, the impact on a patient’s long-term outcome is not yet clear: tests of other cardiac devices have found that detecting problems earlier doesn’t always translate into better health for patients.

AngelMed’s device, called the Guardian, is similar to other implantable cardiac monitors, such as defibrillators. Leads are attached to the patient’s heart to record the electrical activity of the muscle. While existing devices are designed to detect electrical problems in the heart, known as arrhythmias, the Guardian uses novel algorithms to detect problems with blood flow in the heart–the hallmark of heart attacks. Specifically, the device detects something called segment elevation, which causes an abnormality in the electrical current during the time that the heart is recharging between beats.

“Patients often take almost three hours to come to the hospital for a heart attack, and that number hasn’t budged much despite patient-education efforts,” says Michael Gibson, chief of clinical research in the Division of Cardiology at Beth Israel Deaconess Medical Center, in Boston, who is overseeing part of the clinical trial. “Every hour you delay in getting to the hospital increases risk of dying by 1 percent. We feel very strongly that if we can get that time down, we can get risk down.”

A similar approach is used with external electrocardiogram machines in hospitals–in which sensors are placed on the skin–to detect heart attacks. But Gibson and his collaborators found that assessing electrical activity directly from the heart is much more sensitive and can detect changes much more quickly.

When the device detects signs of heart attack, it generates a buzz that the patient can feel on the skin. A receiver outside the body, which wirelessly receives data from the implant, then tells the patient if the problem is severe–meaning he needs to go to the hospital immediately–or if it requires a more leisurely office appointment. “You can bring the device to the ER and show the doctor what was happening when the alarm went off,” says Gibson.

So far, more than 40 patients in the United States and Brazil have received the implant. In the first phase of testing, two patients had a heart attack during the trial, both of which were detected by the device. Researchers are now enrolling patients for a larger trial of 600 to 800 patients. The trial will focus on high-risk patients, such as those who have already had a heart attack.

“I think there is lots of potential for these types of devices,” says William Abraham, director of the division of cardiovascular medicine at Ohio State University, in Columbus. Abraham has done extensive testing with an implantable diagnostic device from Medtronic that monitors heart rhythms.

However, some experts are skeptical that the AngelMed device will make a significant difference in a patient’s clinical outcome. “There’s no question that the earlier you get treated, the better off you are,” says William Maisel, director of the Medical Device Safety Institute at Beth Israel Deaconess Medical Center, who is not involved in the clinical trials. “But the vast majority of patients develop symptoms, such as chest pains or shortness of breath, when they have a problem. The idea that we need an early-warning system–I just don’t see it.”

Maisel adds that patients who have already had a heart attack–the most likely candidates for the device–are also the most likely to recognize and quickly respond to symptoms.

The issue of clinical impact has plagued previous cardiac diagnostic devices. In 2007, a Food and Drug Administration panel recommended against approving an implantable monitor developed by Medtronic to detect heart failure. While clinical trials showed that the device accurately measured intracardiac pressure, which signals when the heart isn’t pumping enough blood, having that information did not significantly reduce the number of patient hospitalizations or ER visits due to heart failure.

However, Maisel says that two groups in particular may benefit from the AngelMed device: people who have heart attacks and don’t feel them–a disorder called silent ischemia that can occur in some diabetics with nerve damage– or “people who have frequent chest pain but not heart attacks, and go to the emergency room unnecessarily.”

Fighting cancer: Ken Offit, chief of the clinical genetics service at Memorial Sloan-Kettering Cancer Center, in New York.
Credit: Memorial Sloan-Kettering Cancer Center

Ken Offit aims to find out why some women escape the disease.

MIT Technology Review, Spring 2009, by Emily Singer — Women who carry mutations in the BRCA1 and BRCA2 genes have a dramatically increased risk of developing breast cancer: a 36 to 85 percent chance of developing the disease during their lifetime, which is three to five times greater than the average risk rate. Ken Offit, chief of the clinical genetics service at Memorial Sloan-Kettering Cancer Center, in New York, wants to know how the other 15 to 64 percent escape unscathed.

Genetic microarrays that allow scientists to quickly screen the genomes of thousands of patients are finally bringing that question within reach. In a new study, scientists around the globe are collecting DNA samples from women with mutations in BRCA2. Researchers will scour their genomes for variations that are more common in carriers who have made it to old age cancer free. If they’re successful, the study could point to genetic pathways that reveal new ways to treat cancer or prevent it before it even begins.

Because genetic variations that protect against cancer are expected to exert only a moderate effect on breast-cancer risk, scientists need to study thousands of women to find them. And because BRCA mutations are rare, occurring in about 1 in 400 women in the general population (and about 1 in 40 Ashkenazi Jewish women), cancer and genetics centers all over the world are collaborating on the study. Offit talks with Technology Review about the genetics of cancer protection.

Technology Review: Tell us about the new study.

Ken Offit: We’re focusing on two extreme phenotypes in breast cancer. At one end of the spectrum are women who have inherited a predisposing mutation which vastly increases the risk of breast cancer and who develop it at early age. At the other extreme are older women who have not developed cancer, despite having that predisposing mutation. We will search for [genetic variations] that are protective against breast cancer.

It’s a very simple study that we’ve been wanting to do for a long time.

TR: Why is the study only now being carried out?

KO: Two factors have finally come together to make it feasible. The technology is at hand: SNP arrays [microarrays that can quickly detect single nucleotide polymorphisms, or SNPs, across the entire genome]. And through international collaboration, we finally have enough women to do the study.

We already have in hand over 5,000 carriers of BRCA2 from around the world. That’s an extraordinary number of individuals coming from virtually every major cancer and genetics center around the world.

TR: Have genetic factors that are protective against breast cancer been found before?

KO: Candidate gene studies have found some protective markers–for example, a SNP in a gene called rad51, which appears to confer some protection in BRCA2 carriers. It’s a gene involved in the process of DNA damage response and repair.

TR: Are there drugs that can protect against cancer?

KO: Sometimes taking drugs like tamoxifen [a drug that interferes with the activity of estrogen and is used to treat breast cancer] can reduce risk in BRCA carriers. But it has risks.

TR: Could the same approach find protective factors for other types of cancer?

KO: In theory, the same approach could be applied to other hereditary cancer syndromes, such as colon cancer, thyroid cancer, or pediatric cancers. The question is whether the same factors that protect women from getting breast cancer or other cancers in the face of strong genetic predisposition will be generalizable to the population at large. We also hope to look at that.

TR: Will the results of the study be useful for genetic screening?

KO: The risk for breast cancer [in BRCA carriers] over the course of a lifetime can range from 30 to 40 percent up to 80 to 90 percent, based on different studies. The hope would be that by mapping modifiers [genetic variants that either increase or decrease risk], we would be able to tell women which end they are closer to.

Women who have mutations that modify risk may well be interested in tailoring their preventive medical management to an adjustment in risk. Someone carrying a series of modifiers that indicate they are at particular risk at early age might elect to have more frequent surveillance or surgical risk reduction.

TR: Will this study lead to new drugs that protect against the development of cancer?

KO: In any gene discovery experiment, the long-term goal is to better understand the biology of the process, which can then serve as the rationale for pharmacologic development. Certainly, the identification of genes that are protective against all the processes in aging, including the increasing cancer risk, would be interesting targets for drug development.