Regenerative Medicine: Repairing the Heart

A breakthrough in the use of stem cells for regenerative medicine has just been reported by researchers at Cedars-Sinai Heart Institute. Patients who suffered heart attacks were implanted with cells derived from their own hearts. Some of the scars left by the heart attacks dissolved and new heart muscle cells re-grew, according to a report in the February 14 issue of The Lancet.

Patients involved in the study had all experienced recent heart attacks that damage heart muscle. The first step in the procedure involved inserting a catheter through a vein in the neck under local anesthesia. Using the catheter, researchers withdrew a small sample of healthy heart tissue. The tissue contains some stem cells, but the key step in the procedure is to multiply and purify the small number of stem cells so that they number in the tens of millions.

These cardiac stem cells, multiplied but originally from the patient’s own heart, were then infused back into the site of the heart attack. The result seems to be a nearly 50% drop in the size of the scar and a re-growing of healthy heart muscle, at least as far as could be determined using imaging technology.

It is important to note that this study is a Phase I clinical trial. Its main purpose is to show that there is no unwarranted risk in the procedure. The outcome of this trial, however, shows a real likelihood of benefit. The evidence is strong that scaring is reduced and heart muscle regenerated. It is too soon, of course, to know the long-term benefits.

What is new in this study is the strong likelihood of actual regeneration of heart cells. Whether the implanted cells produced the new muscles or whether they acted indirectly, triggering neighboring cells to divide and regenerate tissues, is still not clear.

The lead researcher in the study, Eduardo Marbán, made this claim about the finding: "This has never been accomplished before, despite a decade of cell therapy trials for patients with heart attacks. Now we have done it. The effects are substantial, and surprisingly larger in humans than they were in animal tests." Marbán is the director of the Cedars-Sinai Heart Institute who invented the procedures and technology involved in the study, including the procedures for multiplying the stem cells.

"These results signal an approaching paradigm shift in the care of heart attack patients," said Shlomo Melmed, MD, dean of the Cedars-Sinai medical faculty and the Helene A. and Philip E. Hixon Chair in Investigative Medicine. "In the past, all we could do was to try to minimize heart damage by promptly opening up an occluded artery. Now, this study shows there is a regenerative therapy that may actually reverse the damage caused by a heart attack."

The study itself concludes with this claim: “Our study provides an initial indication that therapeutic regeneration might indeed be possible in cardiac tissue.”

The goal of regenerative medicine—the use of stem cells to help patients regrow cells and regenerate tissues or organs—has long been central to the dreams that surround stem cell research. Even though this in only a Phase I study and still must be replicated, it seems to be an important step in the development of regenerative medicine.

Many of course will be especially delighted that no embryonic stem cells were directly involved in this procedure. Those who object to the use of human embryos in research will regard these cells as “morally unproblematic.” It is also very significant to point out that because the cells come from the patients, there should be no issue of tissue rejection.

At the same time, it should be noted that the field of stem cell research advances as a whole field. Knowledge gained from one area (for example, using embryonic stem cells) opens the door for advances across the whole field.

The article, “Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial,” appears appropriately in the Valentine’s Day issue of the medical journal, The Lancet.

Chimeric Monkeys? Where Do We Go From Here?

What is a “chimeric monkey”? Why would anyone want to create them? And why should anyone care?

In ancient myth, a chimera was an animal with a human head and, say, the body of a horse or a lion. That’s not what’s going on here.

In biology today, a chimera is an animal that comes from two or more embryos. This happens naturally, when twins are conceived but the two fertilized eggs fuse into one embryo, eventually producing one individual.

In research, scientists create chimeras in order to study how cells function. Mice chimeras are now commonplace in stem cell labs around the world. Researchers add stem cells to an early-stage mouse embryo (a blastocyst). If the experiment goes well, the developing mouse will have cells from two sources: the “host” embryo and the implanted cells. The implanted cells often integrate into the body and brain of the mouse pup. By this test, researchers know that the implanted cells are truly stem cells—or, more precisely, that they are pluripotent, capable of becoming any type of cell in the mouse body.

Caption: Chimero, a chimeric Rhesus monkey produced by aggregating six Rhesus blastocysts. Photo credit: OHSU.

Researchers also implant human stem cells into mice. If they multiply and are fully integrated into the body, it’s pretty clear that they are pluripotent and capable of functioning within a living biological system and not just in a dish in a lab. In that case, the mouse is an “inter-species” chimera. Two embryos, of course, but from two different species, human and mouse.

For all the ways in which mice resemble human beings, there are big differences, some of which are particularly noticeable at the earliest stages of life. So when researchers at the Oregon National Primate Research Center at Oregon Health & Science University tried to put pluripotent monkey stem cells into monkey blastocysts, they failed. At the blastocyst stage, Rhesus monkeys don’t behave like mice.

The Oregon team, led by Shoukhrat Mitalipov, kept trying other approaches, finally discovering a completely different technique. Instead of using embryonic or pluripotent stem cells and adding them to a blastocyst, they backed things up, at least in terms of embryonic development. How far back? All the way to the four-cell stage. When a Rhesus monkey egg is fertilized (in this case, in a lab dish), it divides into two cells, then four. What happens if two cells in one blastocyst were combined with two cells from another blastocyst? Success—but still only partly so.

So they tried another approach, one that seems complex and counterintuitive. Researchers “aggregated” three blastocysts—and “they” began to function as one embryo. Four blastocysts—same result. Five, even six blastocysts. They did this 29 times and produced 29 viable chimeric embryos. Or to quote the original paper: “Remarkably, all 29 aggregates developed to blastocysts…”

Just what will this mean for the field of stem cell research? At the very least, this research points to the complexity of living biological systems. It’s nice to think that researchers can extract pluripotent stem cells, keep them multiplying indefinitely, direct them to develop just the right way, and implant them into the human body to regenerate tissues. If only it were that simple. As the field advances, it is clear that what was once called “pluripotency”—the ability to become any cell type—is anything but clear or simple to define.

All the more reason, I believe, why the field needs to move forward as a whole. It’s morally and scientifically simplistic to say that the field can advance without cells from embryos.

But does the Oregon work suggest a step too far? For many, it may be morally permissible to work with cells derived from blastocysts, perhaps donated from IVF clinics and due to be discarded anyhow. But what the Oregon work seems to signal is that when it comes to primates—including human beings—the cells in the living blastocyst are significantly different from the cells derived from the blastocyst. The cells in the living blastocyst, though dynamic and changing, can be regarded as totipotent, capable of becoming any cell type including the placenta and umbilical cord. Cells derived from the blastocyst—human “embryonic” stem cells or pluripotent cells—have lost part of this potential.

Does this mean that research, in order to go forward, needs access to cells as they exist in living blastocysts? That would be a step clearly beyond federal funding guidelines (the “Dickey-Wicker Amendment”). Even with private funding, it would likely exceed what most Americans can support. In some states and many countries, it would be plainly illegal.

And yet this is exactly what lead Oregon researcher Shoukhrat Mitalipov seems to have in mind. "We need to study not just cultured embryonic stem cells but also stem cells in embryos,” Mitalipov said in a release from the journal Cell. “It's too soon to close the chapter on these cells." Is that OK as long as he sticks to non-human primates?

Mitalipov is clearly right: "We cannot model everything in the mouse." Rodents and primates are different in unexpected ways at the earliest stages. Stem cells inserted in mouse blastocysts form chimeras, but not in primate blastocysts.

Quoting Mitalipov once again: "The possibilities for science are enormous." All the more reason to think this through. As complex as the science might be, the moral and religious implications are even more complex.

I for one need time to think this through. I hope to be back here before long with some more thoughts. For now, let me recommend a statement that I helped prepare a few years ago on the question of chimeras.

The paper, "Generation of Chimeric Rhesus Monkeys," was released on January 5 and will appear in the January 20, 2012 issue of the journal, Cell.