Six-year-old Sierra Bingham had the flu. But the rural Oregon girl didn’t bounce back from the illness like most children do“She just kept vomiting and looking worse and worse,” recalls her father, Jason, of that spring in 2006. “After about two weeks, she woke up and her face was swollen.”
Sierra’s step-grandmother, a nurse, suggested a chest X-ray to rule out a problem with Sierra’s heart, and her parents called their primary care physician that day. They were not overly concerned. Jason and Stacy had two other children, and Stacy — also a nurse — was pregnant with their fourth. They were familiar with sick kids. But the X-ray at the hospital in Baker City netted them an immediate referral to a pediatric cardiologist in Boise to investigate some troubling findings.
“I was sitting in the hospital waiting for the results of Sierra’s X-ray, and I overheard a doctor in the hall on the phone to the intensive care unit,” says Jason. “I was thinking ‘Wow, that kid he’s describing is really very sick.’ And then I realized he was talking about Sierra.” By that night, she was on a ventilator in the intensive care unit.
Sierra was diagnosed with a condition called dilated cardiomyopathy, in which the heart muscle weakens and begins to fail. Although some genetic mutations are known to be associated with the condition, the cause is often unknown. It affects about one child in every 100,000 in this country, and 40 percent of those with symptoms like Sierra’s either die or undergo a heart transplant within two years of diagnosis.
Sierra was already desperately ill.
For about two months, doctors in Boise tried to help Sierra as an outpatient by giving her intravenous medication to help her heart pump better. But after the third trip to the hospital, they decided enough was enough. Stacy and Sierra were airlifted to Lucile Packard Children’s Hospital Stanford. Sierra was placed on the heart transplant list shortly thereafter.
“Our world changed in an instant,” says Jason. “You just don’t assume your kid has a crazy heart disease. The odds of that happening were so slim. It was crazy.”
In 2006, the options for children like Sierra were limited to medications meant to help the heart beat more efficiently and reduce its workload. Children whose hearts became too weakened to support life could be tethered to machines to pump their blood during the weeks and months they waited for a new organ — but even that lifesaving technology was rudimentary for someone of Sierra’s age and size.
Sierra was lucky. She received a donor heart on Aug. 3, 2006, just before she was slated to go on mechanical support. Her heart transplant saved her life.
In many ways, she’s now a typical teen. But she still returns regularly to Packard Children’s Hospital so doctors can monitor her heart function and treat her for organ rejection. Meanwhile, the Binghams have become well known at the hospital — in part because their journey with heart disease hasn’t ended with Sierra.
For a child or adult newly diagnosed with dilated cardiomyopathy today, treatment remains largely the same as it was for Sierra. Watchful waiting coupled with medication is still standard, although options for mechanical support for children have since become widely available and have saved many lives.
But many experts believe better options are coming: They expect research on stem cells to bring about a revolution in care for heart disease patients. These unusual cells, with the ability to turn into many other kinds of cells, could be used to repair damaged hearts and eventually, perhaps, make entirely new organs. And researchers like cardiologist Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute, envision a day when stem cells are used not just to treat heart disease, but to quickly identify which medications are most promising for individual patients, or to pinpoint others that are likely to result in cardiac toxicity.
It’s not a pipe dream. The California Institute for Regenerative Medicine has doled out over $120 million to hasten potential therapies into clinical trials — including $20 million to Wu and Deepak Srivastava, MD, director of cardiovascular and stem cell research at the Gladstone Institutes in San Francisco. And in January 2014, big pharma stepped up with a $12.5 million investment from Johnson & Johnson in Los Angeles-based Capricor Therapeutics Inc. to investigate whether cardiac stem cells can repair heart attack damage.
Interest in the therapeutic use of stem cells in cardiac medicine isn’t limited to California, either. Research groups across the country and around the world are working feverishly to explore how best to use the versatile cells, and patients themselves have reported improvements after some preliminary treatments. In 2011, the National Institutes of Health launched the Center for Regenerative Medicine to speed promising stem-cell-based treatments for a variety of diseases to the clinic by tackling technical hurdles and providing access to well-characterized stem cell lines for study.
At the same time, regulatory agencies like the FDA are working to adapt to a new era in medicine that relies on stem cells — either from human embryos or created from adult cells. Standards — what type of stem cells, how they are used and on whom — will be necessary to codify treatment recommendations and move the field forward. But speed is essential.
“Heart disease remains the No. 1 cause of death for men and women in this country,” says Gladstone’s Srivastava. “One half of people with end-stage heart failure will be dead within two years. People are waiting for these treatments, and they are dying while waiting.”
Nobody knows this better than the Binghams. On May 17, 2012, then-7-year-old Lindsey woke up with a swollen face.
“I can’t put into words the pit I felt in my stomach that morning,” says Jason. “Within days we were right back in that hell.” A visit to the emergency room in Baker City confirmed their worst fears. Lindsey had severe dilated cardiomyopathy. On May 21, Lindsey was airlifted to Packard Children’s Hospital, accompanied by her mom.
The human heart begins beating about 21 days after conception. But most of the heavy developmental lifting is done before then.
The organ forms from a hollow tube made from a type of embryonic tissue called mesoderm. The mesodermal cells give rise to cardiac precursor cells; once formed, the tube loops around itself to the right, and sections along the loop begin to bulge outward to form the atria and ventricles, which are then each bisected by a wall of tissue to form the left and right halves of the heart.
When completed, the heart’s four chambers pump blood through the body in a kind of figure-eight pattern: With the heart at the center, blood circulates first from the right ventricle to the lungs and routes back through the heart for an extra push from the left ventricle before traveling through the rest of the body and returning again to the heart. The atria serve as a staging area for the blood before it enters each ventricle.
It’s the left ventricle that weakened, for whatever reason, for Sierra and Lindsey. To compensate, their hearts began beating faster, and the ventricle slowly enlarged until the girls were in complete heart failure.
When Lindsey came to Packard Children’s, doctors suggested genetic testing to try to find a cause of the family’s seemingly inherited condition. They turned to the Stanford Center for Inherited Cardiovascular Disease, directed by cardiologist Euan Ashley, MD, PhD. Mutations in more than 50 genes have been linked to dilated cardiomyopathy; researchers wanted to investigate each one. So far there’s been no obvious culprit to blame for the girls’ condition, and Jason and Stacy have no sign of cardiomyopathy. The Binghams are desperate to find a reason or a cause, even perhaps an environmental component.
“We want to know that this is not something that we did to our kids,” says Jason. “We’ve had our water tested, we threw out all our furniture and had our carpets cleaned. I don’t know if I hope it’s genetic, but I’d do almost anything for an answer.” The stakes were high. The Binghams now had five children, and a sickening familiarity with the heart transplant process.
The heart is comprised of four main types of cells: cardiomyocytes, endothelial cells, fibroblasts and vascular smooth muscle cells.
Of these, cardiomyocytes are responsible for contracting in a coordinated manner to pump the blood. They’re the ones researchers would most like to be able to use to replace damaged or malfunctioning tissue. But the jury is still out as to the ideal starting material to repair damaged hearts, and approaches may vary according to a patient’s specific problem.
UPS AND DOWNS – Toughing out lives marred by unexplained heart disease: Gage, Sierra and Lindsey Bingham (from left).
Until about 10 years ago it was believed that the heart and brain experienced little, if any, regeneration during a person’s life: You die with the same cells you had as an infant (unless you’re unfortunate enough to suffer a heart attack, which can kill up to 25 percent of heart muscle cells by starving them of oxygen).
More recent research has shown, however, that cell turnover does occur slowly — about 1 percent of cells are replaced each year. It’s not clear, however, which cells give rise to these new ones. Possibilities include existing cardiomyocytes or as-yet-unidentified cardiac precursor cells that hide out in the heart until called into action by aging or damage.
“We’re learning that nature has devised a system that is much more sophisticated than we had imagined,” says Stanford’s Wu. “When you think about it, we are all composed of stem cells that sustain us through our lifetimes; without them we would all die from premature aging. Now the question is ‘What stem cells are involved, and how much renewal capacity do they actually have? Can we make them potent enough or activate them for therapeutic applications?’”
With one child in California and four to juggle at home in Oregon, Jason, an accountant and cattle rancher, found himself traveling back and forth during the first month of Lindsey’s hospitalization in the cardiovascular intensive care unit while Stacy stayed with Lindsey. While Packard doctors, including the director of its pediatric heart failure program, David Rosenthal, MD, and pediatric cardiologist and former director of Packard Children’s heart center Daniel Bernstein, MD, worked to support Lindsey’s failing heart with intravenous medication and oxygen, relatives and friends stepped up to care for the other Bingham kids. In mid-June, Jason, Stacy and their other three children underwent yet another round of precautionary testing to look for potential heart problems.
“We really weren’t surprised, at that point, to learn that Gage, our 3-year-old son, had a slight enlargement,” says Jason, noting physical similarities between Gage, Sierra and Lindsey. But the physicians assured him Gage’s problems were slight. The other two children, 10-year-old Megan and 5-year-old Hunter, had some issues, but no immediate red flags.
Unfortunately, stem cell medicine was not advanced enough to help Lindsey. But researchers like Wu and Srivastava are hopeful that will change within five to 10 years. Their grant from the California’s stem cell institute funds research into using human embryonic stem cells to generate cells like cardiomyocytes to help failing hearts. With the right coaching (in the form of added proteins and special growing conditions) these stem cells, isolated from human embryos, can become any cell in the body, including cardiomyocytes. These homemade heart cells beat spontaneously in a lab dish, and have been shown to integrate and electrically couple with existing cells when injected into the hearts of guinea pigs.
With support from the CIRM grant, Wu and Srivastava are extending these studies to larger animals and plan to file an Investigational New Drug application with the FDA — a necessary step before a product-based treatment can be tested in humans — within the next four years.
Another possible route to therapy is to use a patient’s own cells, collected from skin or other tissue. These cells can be induced to become pluripotent, or embryonic-stem-cell-like, by adding just a few proteins that are normally not present in adult cells. Induced pluripotent stem, or iPS, cells can in turn be nudged to become cardiomyocytes for potential therapeutic uses or to diagnose cardiac problems in specific patients.
Wu’s research has shown that these iPS cells generated from people with inherited cardiomyopathy can give rise to cardiomyocytes that beat differently than those derived from iPS cells from people with healthy hearts. These patient- and disease-specific iPS-cell-derived heart cells also respond differently to various drugs prescribed to patients with heart conditions. Wu has received $1.4 million from CIRM to collect tissue samples from up to 800 patients like Sierra and Lindsey with idiopathic dilated cardiomyopathy (as well as 200 healthy subjects). The iPS cells from the patients’ tissue will be used to create cardiomyocytes to learn more about the disease process in each individual and to test specific drugs.
“This will be the personalized medicine of the future,” says Wu. “Instead of giving a drug to 5,000 patients as part of a clinical trial, we can test the drug in the laboratory on iPS-derived beating heart cells from patients — a kind of clinical trial in a dish. And, if you have heart disease, we’ll be able to test potential drug therapies on your cells rather than using you as a guinea pig as we try to figure out what works best.”
Many researchers agree that in the near term the use of iPS-derived cells for drug screening and disease modeling will provide a more immediate benefit to patients than the use of cells as therapies. In fact, cardiologist Bernstein recently spent a year on sabbatical in Wu’s lab working on the iPS cell project. But as yet, the use of iPS cells to select medications for individual patients is not routine. Instead, Gage was placed on three different medications, and his parents monitored his heart rate and blood pressure daily as physicians worked to find the correct combinations and dosages for their youngest child.
Meanwhile, Lindsey was worsening. On June 29, Jason, then in Oregon, got the call to come to California immediately. Lindsey’s heart urgently needed mechanical support.
Jason got to Packard Children’s Hospital on June 30, just before Lindsey was to receive an external heart pump called the Berlin Heart.
This time he brought Gage along. Gage had been acting strangely in Oregon the previous day and his heart rate had seemed abnormally low — only about 40 beats per minute. Jason thought that, in the stress over Lindsey he might have recorded it incorrectly.
In 2004, the hospital was one of the first institutions to use the Berlin Heart in children in the United States. The pump can prolong a patient’s life during the wait for a suitable transplant organ and allows young patients more mobility than would have been possible with older, much larger machines. But it’s still a temporary fix.
During the surgery, two thick tubes were inserted through Lindsey’s abdomen and up into her heart. Blood cycled out of her heart into the pump, which then gave it the extra push Lindsey’s damaged ventricles were unable to muster. The operation is now routine at Packard, but it means a nearly irreversible step toward transplantation.
While waiting, Jason asked Lindsey’s nurse to take a quick listen to Gage’s heart.
“What happened next was completely unbelievable,” says Jason. “Gage was admitted and he and Lindsey, who had just come out of surgery, ended up side by side in the cardiovascular intensive care unit. They had the crash cart, the defibrillator paddles and more doctors around Gage than around her.”
Gage was in complete heart block, a condition in which electrical impulses from a patch of pacemaker cells on the wall of the right atrium, called the sinoatrial node, fail to propagate correctly across the heart to the ventricles. As a result, the ventricles must trigger their own ungainly, sluggish contraction.
“For six years, Sierra had been the one,” says Jason. “She was the child we were always concerned about. To learn we had a second child with the same problem, we thought we were going to have a mental breakdown. And now a third? At the same time? It was blowing our minds.”
Although researchers are pinning a lot of hopes on possible therapies using embryonic or induced pluripotent stem cells, there are still many hurdles to be overcome. Because the cells are pluripotent, it is possible for them to become any tissue in the body. This is both a blessing and a curse.
“Effective cell therapies will likely require tens of millions of cells,” says Wu. “If we inject cardiomyocytes made from pluripotent cells into a patient’s heart, we have to be sure these contain no other cell types.” Other concerns include the fact that cells derived from embryonic stem cells could spark an immune reaction in the recipient that could lead to rejection, and the need to learn how, when and exactly where to deliver the cells to patients.
In August 2012, researchers from the FDA’s Center for Biologics Evaluation and Research outlined in a paper published in Science Translational Medicine some of the challenges and approaches to working with cell-based therapies such as stem cells. Hurdles include the fact that cells used for therapy are living entities that respond dynamically to their environment, both before and after transplantation. This makes it difficult to establish benchmarks for standardization when preparing the cells, particularly if they are isolated anew each time from individual patients. (Should an investigator aim for a certain cell number? Or a certain length of time the cells are grown in the laboratory? How can the cells’ purity be maintained during the period they are outside the body?) Furthermore, unlike a drug that degrades and is excreted in a (mostly) predictable manner, transplanted cells may migrate or differentiate into various other cell types in ways that could be difficult to predict or track.
Despite these challenges, there are currently dozens of cellular therapy clinical trials at Stanford and elsewhere for cardiomyopathy, angina and heart attack. Some of these trials use a specialized, and well-characterized, subpopulation of adult stem cells from the bone marrow called CD34-positive cells that are known to give rise to the endothelial cells that line the interior of blood vessels.
A 2012 review by the nonprofit Cochrane Collaboration of the outcomes using adult bone marrow stem cells in more than 1,700 patients with heart attacks in 33 clinical trials concluded that this type of treatment can confer “moderate benefit” to at least some patients, although it’s not clear whether the cells help by delivering more blood to the heart or by generating new muscle tissue.
The trial run by Capricor and supported by CIRM and Johnson & Johnson takes another approach. They’re using cardiac tissue samples obtained through biopsy to generate patient-specific, stem-cell-rich bodies called cardiospheres. A preliminary study of the technique (conducted at Cedars-Sinai in Los Angeles) studied the effect on 17 patients who had suffered recent heart attacks. After six months, the researchers reported those patients treated with cardiospheres experienced a significant reduction in scar tissue and an increase in functional muscle mass in the organ, although the organ’s pumping ability appeared unchanged.
The next portion of the trial is expected to enroll up to 274 people who have had heart attacks within the previous 12 months. In this trial, investigators will be using prepared, well-characterized cardiospheres from donors, rather than isolating heart tissue and preparing cardiospheres from each participant. Doing so will allow them to treat patients more quickly, and the use of a standardized product will eliminate some experimental variables and help accurately assess the effect of the intervention.
With Lindsey and Gage both in the CVICU, stem cells of any type were far from Jason and Stacy Bingham’s minds on June 30, 2012.
While Lindsey recovered from her Berlin Heart surgery, doctors surgically implanted an internal pacemaker to help Gage’s heart maintain a healthy, normal rhythm. Then the family settled into a room at the Ronald McDonald House at Stanford to wait for Lindsey’s transplant. This time, the vigil was longer than it was for Sierra.
Heart transplants may be the only answer for kids with dilated cardiomyopathy, but they’re difficult to come by. According to the National Heart, Lung and Blood Institute, about 3,000 people are on the heart transplant list in this country on any given day, but only about 2,000 to 2,500 organs become available each year. For older people whose heart damage was caused by heart attack, there aren’t many options.
“We’ve done a great job with therapeutic interventions at the front end,” says Sean Wu (no relation to Joseph Wu), MD, PhD, assistant professor of cardiovascular medicine at the Stanford Cardiovascular Institute, “and this has saved many lives. But we have little to offer to people who have survived their heart attacks but have lost a lot of their cardiac tissue function. These people have a mean survival of only about three years.”
Sean Wu’s lab is working on a technique in which iPS cells are injected into developing mouse embryos genetically incapable of forming their own working hearts. The researchers have been able to generate entire working organs in these animals with iPS cells. The hope is that one day researchers will be able to grow patient-specific organs-to-order in large animals like pigs simply by using iPS cells created from skin or blood samples.
“This may sound like science fiction,” says Sean Wu, “but maybe, considering the speed of progress in the field, it’s not as far-fetched as it seems.” Noted stem cell researcher Hiromitsu Nakauchi, MD, PhD, recently recruited to the Stanford Institute for Stem Cell Biology and Regenerative Medicine, has been conducting similar studies with positive results.
Growing a new heart from a patient’s own cells is likely to be time-consuming and expensive. But in theory it should solve any problems with rejection because the heart would be an exact match to the patient. Rejection is not rare, and often not inconsequential. Sierra has been struggling with a type of antibody-mediated rejection of her donated heart since about 2011; doctors are treating it with regular intravenous infusions of immunoglobulin that helps remove antibodies attacking the heart.
Most organ transplants have a limited life span, be it five years or 25. Depending on the age of the recipient, future transplants may be necessary. Sierra’s experience had taught the Binghams that life after transplant is still challenging — Sierra must take multiple daily medications to suppress her immune system and prevent or slow rejection. But they also knew that a transplant was Lindsey’s only hope.
On the evening of Feb. 12, 2013, after more than seven months in the hospital— with occasional quick forays to the outdoor fountain or hospital cafeteria — Lindsey and her family received the news they had been waiting for. A matching heart was available for Lindsey.
They celebrated while they waited throughout the night and the next day for the surgery to begin (paperwork, matching of other organs, removal and transportation of the donated heart can take many hours).
And then, just hours before Lindsey’s transplant, the unthinkable happened. A routine checkup for Sierra landed her in the CVICU for dangerously high pressures in her donated heart. Once again, Jason and Stacy found themselves shuttling between two children just doors apart from each other, saving their breakdowns for the hallway.
On Feb. 14, Valentine’s Day, Lindsey got her new heart.
Simultaneously, down the hall, Sierra’s doctors brainstormed ways to try to protect her transplant.
“Seven years ago, I would never have imagined being in this situation,” says Stacy. “We worried about normal kid stuff, like whether they’re liked by their friends at school. Not how long their hearts were going to last.”
Sierra needed a port to simplify the regular intravenous treatments needed to combat her rejection. She was also put on an additional, third, immunosuppressant and released to the Ronald McDonald House. Meanwhile, Lindsey recovered from her transplant.
On Feb. 28, after 264 days in the hospital, Lindsey was also discharged, and on May 30, the family headed home to eastern Oregon. The girls play volleyball and basketball with their siblings. They swim and they jump on the trampoline. They have a dog they named Axelrod after one of their favorite Packard doctors, pediatric cardiologist David Axelrod, MD. By many measures, their lives are normal.
But their time at Lucile Packard Children’s Hospital Stanford continues. Megan and Hunter get annual checkups for cardiac problems. Lindsey is assessed for organ rejection about once every two months, and Gage’s pacemaker is adjusted every three months. Sierra comes in once a month for a 14-hour treatment to remove the antibodies her body makes against her donated organ and to monitor blood pressure inside her heart. And, although there have been some tantalizing hints, the root cause of their condition remains unknown.
The efforts of the physicians at Packard Children’s and untold clinical advances in transplantation, technology and immunology unquestionably saved the lives of three of the five Bingham children. But there’s still more that can be done. In November, researchers from cardiologist Joseph Wu’s laboratory collected blood samples from each of the seven family members to begin the process of making iPS cells to try to identify the molecular basis of the children’s weakened hearts — a process that could take years to complete.
“It could be any of several causes,” says Joseph Wu. “Maybe it’s a problem with the cellular channels that propagate the signal to contract, or maybe it’s a problem with the muscle components themselves. We won’t know until we have their heart cells beating in a laboratory dish and can examine them more closely.” Although identifying a molecular cause of the disorder won’t immediately help Sierra or Lindsey, who now have donated hearts, it’s possible that it may make it easier for clinicians to find the right medicine to help Gage’s heart last as long as possible.
“My goal, as the founder of the Stanford pediatric heart transplant program,” says cardiologist Bernstein of these efforts, “is to put us out of business.”
Researchers from the Stanford Center for Inherited Cardiovascular Disease haven’t given up either. Ashley, who is Jason and Stacy’s cardiologist, also co-directs the newly launched clinical genomics service for patients at Stanford Hospital and Packard with mystery conditions or inherited cancer, cardiovascular or neurological diseases.
“The Binghams and families like them are why we set up the Center for Inherited Cardiovascular Disease at Stanford,” says Ashley. “We gather many experts together in one room and plan the best approach. In this case, we completed regular sequencing of a smaller number of targeted genes including those of the mitochondria (the ‘powerhouse’ of the heart cells) then moved to sequence the genomes of the most affected children. The first pass did not uncover a smoking gun, but we have just launched our newest analysis tools and have them aimed squarely at this target. We remain hopeful.”
Finding a genetic cause would be a relief, but it also extends the long arm of the disease. Should Sierra, Lindsey or Gage have children, it’s possible they will pass along their defective genes.
“I will worry about this for the rest of my life,” says Jason. “I’ll worry about my kids, and then I’ll worry about my grandkids and my great-grandchildren.”
But there’s hope. Although it remains to be seen whether advances in regenerative medicine occur quickly enough to help Gage avoid a transplant, they are at least likely to render a better medical outlook for Jason and Stacy’s grandchildren.
Ideally, they’ll be diagnosed quickly through genome sequencing at or shortly after birth, and the optimal medication and dosage will be determined for each through the use of matched, iPS-derived cells. If necessary, stem cells will be used to strengthen their weakening left ventricles. If transplantation becomes necessary, organs could be grown specifically for them to ameliorate the chances of rejection.
But in the meantime, the Binghams wait.
“The fact is, I still have two kids with transplants, and one who is likely going to need one,” says Stacy. “If the researchers can find a cause for this, or if they could help Gage, that would be wonderful. But I don’t feel like we have the time to sit around and worry. We have five kids, and life just goes on.” SM