REGENERATIVE MEDICINE

Study the Masters, Grasshopper

Despite Latest Breakthroughs, Stem Cells Are Still Crucial

When a crayfish loses a claw to a predator’s maw, it takes stock of its loss and grows itself a new one. Severed salamanders, too, handily sprout new limbs, each bearing a batch of spanking new digits. Even lowly lizards can regenerate tear-away tails. So perhaps it is understandable that we humans, with our generally inflated sense of species superiority, feel chagrined by our inability to grow replacement parts, as though deprived of some morphological manifest destiny.

That scientists have gained the almost alchemical ability to conjure such transformations is a remarkable sign of their deepening understanding of how genes work.

Now three scientific papers, all published within the past few weeks, offer tantalizing evidence that a human regenerative revolution may be on the horizon. One study showed that red blood cells can be mass-produced from simple starter cells in the lab, an advance that some experts predict could make the Red Cross blood donor program obsolete. Another showed that conventional cells living humdrum lives in the pancreas can be prodded to become specialized, insulin-secreting “beta cells”—the kind that aren’t working or are missing in people with diabetes. A third study showed that muscle precursor cells can be nudged within the body to become brown fat cells. Unlike ordinary fat cells, which contribute to obesity and gave rise to today’s robust liposuction industry, brown fat cells actually burn calories. By boosting one’s supply of them, scientists suggested, a person might be able to get in shape without ever setting foot in a gym.

That scientists have gained the almost alchemical ability to conjure such transformations—changing one kind of cell into another—is a remarkable sign of their deepening understanding of how genes work. Virtually all human cells have the same 25,000 or so genes inside of them; a cell’s identity as muscle or fat or any of the other approximately 200 tissue types comes down to which of those genes are turned on or off—a status once believed to be set in cellular stone. Now it is clear that many cells can be cajoled to change their occupations, though the process requires that countless genetic switches get flipped to precisely the appropriate settings.

The challenge of cellular reprogramming is daunting. Think about that gray, metal electrical box in your basement, but with 25,000 circuit breakers inside instead of 10 or 20, all of them having to be flipped to the proper position to make just one cell behave as the kind of cell you want it to be. How on Earth are scientists figuring out those proper patterns?

One of the best ways, it turns out, has been to watch the Master at work. Master cell, that is, namely the human embryonic stem cell. Embryonic stem cells are the blank-slate cells that are tucked inside microscopic embryos during the first days after an egg cell has been fertilized. They divide—and thus multiply—and over a period of months those millions of offspring cells flip their genes to the proper settings to become all the kinds of tissues needed to make a fully formed person.

In the decade since human embryonic stem cells were discovered, scientists have learned a lot about which gene-activity profiles correlate with various kinds of cell specialization. They have also learned how to culture embryonic stem cells under just the right conditions so those cells and their offspring set their own switches in desired ways, allowing the cultivation of muscle cells, nerve cells, blood cells, and others. In two out of the three recent studies, scientists went a big step further: They turned cells that had already taken on a specialty into cells with a brand new specialty—muscle cells into brown fat cells and ordinary pancreatic “exocrine” cells into beta cells—without any involvement of stem cells at all. Predictably, some conservative commentators who oppose research on embryo cells took the news as evidence that embryonic stem cell research no longer needs to be supported.

There will come a day when embryonic stem cells will seem crude and extraneous for the kinds of work that needs to be done. But that time is not here yet.

But a close look at the research papers reveals that embryonic cells still have a lot to teach before scientists will have gained clinically useful control over human cell fates. In the first study, by scientists at Advanced Cell Technology in Worcestor, Massachusetts, human embryonic stem cells in laboratory dishes were coaxed to multiply en masse and mature into red blood cells, the oxygen-carrying corpuscles that circulate by the trillions in everybody’s body. Celebrating the feat, researchers spoke of a future in which people in need of transfusions might get the life-saving crimson freshly made to order, instead of from donors who might carry viruses or other infectious agents. And indeed, the transformation was impressive: Just as happens naturally in the bone marrow, cultivated stem cells were made to mature into full-blown red blood cells. Those red cells produced the oxygen-ferrying protein hemoglobin and even ejected their own DNA once they fully matured, a neat trick that is unique to red blood cells.

There is a catch, though. Lanza’s cells produce mostly fetal hemoglobin, a variant that is useful to fetuses, which get their oxygen from the placenta, but less than ideal for the already born, who get their oxygen by breathing. In short, these are the wrong kind of red cells for transfusion. And little is known at this point about how to flip the right switches to get these cells to make adult hemoglobin. Clearly, this is a technology that is promising but far from ready for Red Cross approval.

The other two studies are more attractive and scientifically elegant because no stem cells were involved and because they involved the direct transformation of one kind of cell into another while those cells were living inside the body (mouse bodies, by the way, so keep in mind that this work may or may not pan out in people). The potential benefits are obvious: an injection of the right genes into a patient and Presto, those deadbeat pancreas cells are transformed into super beta cells, and that clunker of a pancreas is regulating your blood sugar again! None of the fuss or muss of laboratory dishes. No need for pesky embryonic stem cells. But also, it turns out, no proper regulation of those cells after they’ve made their miraculous transition. For example, in the experiments, led by Douglas Melton at Harvard, in which ordinary pancreas cells were made to morph into insulin-secreting cells, those cells just kept churning out insulin, endlessly. That’s a far cry from what beta cells are supposed to do, which is to increase insulin production after meals, when needed, and decrease it when blood sugar levels go down. A person would be better off with old-fashioned periodic injections of insulin than with these newfangled insulin-churning pancreatic cells.

Similarly, while it’s attractive to think of the weight-loss benefits of a simple DNA-based injection that converts some of your lumbering muscle precursor cells into white-hot, energy-burning brown fat cells, the system as tested in mice so far—by researchers at the Dana Farber Cancer Center—is less than reassuring in terms of having some control over the process. Among the unanswered questions: Might muscle mass decrease as cells once destined to become bicep or tricep changed jobs and became part of the body’s brown fat farm? Would appetites simply increase as we sizzled through calories? Would there be any way to undo the cellular shift, or tweak the newly retuned system, to assure some kind of biological balance?

In nature and in our bodies, as we develop from embryos to babies and as we live out our lives, cellular processes are kept in underappreciated balance all the time by regulatory processes in our DNA—processes that scientists have barely begun to plumb. And there is no better venue for studying these crucial processes than embryonic stem cells—both because that is where they naturally occur, in sequence, as development progresses, and because stem cells can multiply endlessly in the lab, making them the perfect platform for cell biology and genetic studies.

No doubt there will come a day when embryonic stem cells will seem crude and extraneous for the kinds of work that needs to be done. But that time is not here yet. If we want to learn how to gain control over our bodies, how to rejuvenate aging tissues and regenerate ailing organs, we should sit with the masters. Study the salamanders. And stand by our stem cells.

Rick Weiss is a Senior Fellow at the Center for American Progress and Science Progress.

Tags: stem cells

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