Stem Cell Saltarello and the Possible Dream
This is a story that begins with learning to make stem cells dance. And then dares the grandest dreams of all.
When we use the term "stem cell", we mean a cell which can do two things:
- (1) it can make more copies of itself,
- (2) it can differentiate into (grow into) other cell types.
With regards to the ability to make copies -- known as self renewal -- this is an ability *lacking* in many key cell types. Neurons, for example, do *not* self renew (generally speaking). When a disease or injury kills neurons, generally speaking, existing neurons cannot divide and form replacements. This is in part why neurological injuries and diseases are so devastating -- neurons lost are largely neurons gone forever. Similarly, it was generally thought (until recently) that heart muscle likewise does not have significant ability to self-renew; heart muscle destroyed by a heart attack cannot be replaced by the body. In contrast, skin grows back easily, quickly filling in cuts and wounds.
But the ability to multiply is only half of what makes a stem cell a stem cell. The other, critical half, is the ability to differentiate, to become something else, or become many kinds of something else. After all, although skin cells grow, skin cells only become other skin cells. They don't turn into blood cells. Stem cells, on the other hand, *can* become other kinds of cells, as well as making copies of themselves.
"Stem cell" is a category. There are many different kinds of stem cells, with varying ability to multiple and differentiate. The ultimate stem cell, of course, is the initial fertilized egg itself -- the single cell which has the capability to become an entire human being. As it turns out, (handwaving madly, and setting aside things like trophoblast formation) among the first 50-150 cells after that are also still capable of turning into most, if not all, cells in the human body. These near-universal stem cells are known as pluripotent stem cells.
Subsequent to this in development, these pluripotent stem cells specialize. As they specialize, as they proceed down developmental paths, they become more limited in what they can become. A pluripotent stem cell which could once become almost anything, becomes a more specialized stem cell with a more limited set of options. Eventually, our body's cells (almost all) fully differentiate into specific types of adult cells, with a specific ability (or lack of ability) to make more copies of itself.
And then the (scientific) fun began.
Here's where we *really* start to handwave, because, well, the full details are the stuff of books. It's what I've been spending most of my time off clinical duty reading and studying about. But the broad outlines are enough of interest of their own.
Initial work sought to figure out how to steer existing near-universal, or pluripotent, stem cells down to pathways of clinical interest. The body, after all, does this, steering various generations of stem cells down specific pathways to make specific tissues. If scientists could learn the same control signals, they could do the same thing. One could start with pluripotent stem cells and then manufacture new neurons, new heart tissue, new insulin-producing pancreatic islet cells, etc. The implications for human medicine are obvious, such as the kidney repair work featured in Tomorrow, We Fly.
Of course, before you could start making new heart tissue and new neurons and new insulin-making cells from pluripotent stem cells, you had to have a supply of pluripotent stem cells to make things *with*. Not a big deal for the foundational research in mice, since obtaining pluripotent mouse stem cells from mouse embryos is not politically explosive. Obtaining *human* pluripotent stem cells from *human* embryos, however, is an entirely different ethical and political ball game, and a very complex one. But that is not today's story.
Driven to look for alternatives, scientists explored sources of pluripotent stem cells other than embryos. Some worked with pluripotent stem cells that could be purified from amniotic fluid. Others worked with stem cells in cord blood. But among the most radical approaches attempted to find a way to make pluripotent stem cells from scratch. Figure out how to turn already differentiated adult cells *backwards* into pluripotent stem cells. Figure out how to *undo* the differentiation our cells go through. Which, as far as biology knew up to that point, did not happen naturally in the human body, and did not routinely happen (if at all) in nature.
Scientists, however, are not the kinds of folks to let a little thing like "this does not occur in nature" stop them. Biology, especially human medical biology, has long past moved beyond merely describing and exploring how nature works, and deep into trying to make nature do whatever we want it to. Cutting edge medicine has, in many ways, become the discipline of engineering biological systems. So if adult cells did not naturally turn backwards into pluripotent stem cells, we'd just have to figure out how to *make* them turn backwards.
Which, about three years ago, scientists first began to figure out how to do.
Previous studies of how embryonic stem cells work -- among them, many key studies done by scientists in other countires since they couldn't be done here in America -- had identified dozens of genetic control elements -- transcription factors -- which appeared to play some part in making an embryonic pluripotent stem cell an embryonic pluripotent stem cell. Presumably, some combination of these factors might be enough to reprogram an adult cell back into something that acted like a pluripotent stem cell. But which combination? It wasn't clear, since nobody really understood the basic biology of stem cells well enough to predict precisely.
However, if you couldn't completely *predict* which combination of transcription factors would do the job, you *could*, if you were really bold/insane, just start systematically trying combinations until something worked. Thomas Edison was reported to have overcome the challenge of inventing a electric light bulb by relentlessly trying thousands of different materials until he found ones that worked. To handwave truly madly, that's essentially how the first successful reprogrammed stem cells were created. Groups of scientists developed extremely clever experimental systems to let them systematically sort through combination after combination of transcription factors. And they *did* successfuly find combinations of transcription factors that could successfully reprogram adult cells backwards. Backwards into cells that acted in many key ways like pluripotent stem cells.
Put another way: scientists literally figured out how to force adult skin cells to become embryonic-like stem cells, which could then be driven forward again into new heart cells, new neurons, new blood.
This was not a trivial enterprise; the Japanese researchers who made the first breakthroughs started with 24 different candidate transcription factors, and the final successful recipe required four of them. For those playing at home, that's over ten thousand possible combinations -- and there was no guarantee whatsoever when Yamanaka started out that either *only* four were necessary, or that his original set of 24 even included all the necessary ones. But he and other colleagues around the world managed to do it.
This area of science -- the area of generatable, "inducible" pluripotent stem cells -- induced from adult cells -- is still in its extreme infancy. The efficency (until recently) stinks. The list of problems, obstacles, and challenges is a mile long. We're essentially at the same place with inducible pluripotent stem cells as the field of aviation was immediately after the Wright Brothers first flew -- nothing but short flights down windy beaches, and nothing else. *Yet*. But it is a beginning. And beginnings are what we build on.
Generating embryonic stem cells from scratch of course solves the whole ethical and political problem of embryo-derived stem cells. Furthermore, being able to someday do this with a patients' *own* skin cells completely removes the whole immune rejection problem (discussed in greater depth in To Juliet, and to Victory). After all, the new heart cells came from your own skin, so they perfectly genetically match you. So instead of trying to find a compatible bone marrow donor and beat the recipient's immune system into submission to take it; or waiting for a compatible organ donor for new kidneys, new liver, or new heart; we could eventually just take some of the patient's own skin cells, drive them backwards into pluripotent stem cells, drive them forward into new bone marrow or kidney or heart tissue, and patch the existing organs. In a lot of cases, in many diseases, you don't really need a whole new organ; you really just need some new cells to patch up the old organ. And Inducible Pluripotent Stem Cells -- manufactured from the patient themselves -- could very well be the answer.
But as amazing as all that is, there's even more.
As it happens, the same transcription factors and regulatory systems which can drive an adult, differentiated cell backwards into an inducible pluripotent stem cell, are also often very, very important in *cancer*. Which makes sense. A cancer cell, after all, is a normal cell which both changes radically in behavior, and acquires the ability to vastly multiply out of control. An inducible pluripotent stem cell... is a normal cell which changes radically in behavior, and acquires the ability to vastly multiply *under* control. The same transcription factors and control processes appear to be heavily involved in both. Nobody thinks this is a coincidence. So perhaps if you can make an adult cell dance into a ever-growing stem cell, you can figure out how to *stop* adult cells from turning into ever-growing *cancer* cells, and vice versa. Master the dance, and you master the cells, stem and cancer alike. Much of the white-hot, furthest forward edge of cancer and stem cell research -- including much of the not-yet-published work I've been priveleged to be shown at Hopkins/NIH -- is right in this territory.
The basic biology underlying driving cells backwards and forwards through development can potentially repair damaged hearts, cure diabetes, repair demylinated multiple sclerosis nerves, fix busted kidneys, reverse dementia, cure cancer of all kinds, and dozens of other applications. And beyond there lies what may be the beginning of the second great revolution in human lifespan...
The first great revolution in human life expectancy -- the doubling in human life expectancy which occured between the 1850s and now -- was in large part built around germ theory. A whole constellation of ideas -- the importance of providing clean food and water, sanitation, vaccines, sterile technique, antibiotics -- arose from the concept of infection and combating it. And together, they took a whole raft of early killers largely out of the picture. Mothers and infants no longer died of "childbirth fever". Children no longer died of polio, whooping cough, or simple ear or bladder infections. TB, pneumonia, food and water poisoning -- many adult killers too were beaten back. Surgery became possible, and traumatic wounds survivable, without cutting into the flesh inevitably leading to gangrene and death. From John Snow's legendary Broad Street Pump Handle to the latest generations of anti-HIV medications, preventing infection and fighting infection has enabled the average human in the developed world to enjoy almost twice the effective lifespan of their ancestors.
Germ theory totally changed the landscape of disease and death. Beaten back were the infections which killed us before our forties. Now instead, it is largely the cancers and the heart disease and the diabetes -- diseases of worn out or broken cells -- which kill us in our 80s. But mastering the dance of stem cells may let us sweep away today's killers the same way germ theory swept away yesterday's killers. If our knowledge of the dance of stem and adult and cancer cells allows us to routinely patch hearts and kidneys, replace insulin-producing islet cells and demyelinated nerves, force the cancer genie back into it's bottle, life expectancy could start climbing again rapidly, in the same way it climbed when infections began to be tamed on a wide scale.
And way down the line some of the grandest questions of all.
We as individual humans grow old and eventually die. Many of our adult cells "grow old", die, and are not replaced. The thing is, tho, we all began from one single cell -- from the egg and sperm of our parents. And our parents began the same way. And our grandparents began the same way. We all ultimately are the product of a line of cells which has been growing through quadrillions of generations since the dawn of life on earth itself. A line of cells which has been growing and dividing and growing again for billions of years.
The eggs and sperm within the fish of ancient seas eventually became *us*. So there's obviously no inherent limit to how long certain cells can keep going. Some of them, after all, have been going and going for millions of years. There may be inherent limits to how long *specialized* cells can keep going, but if you can *make* new specialized cells from more generalized cells; and if those generalized cells themselves are, functionally, immortal... somewhere down that road, lies clinical immortality in it's truest, literal sense.
There must be, of course, far more to longevity than simply replacing worn-out cells. There is, for example, surely more going on in the brain than the cells that make it up. Do the synaptic arrangements and organization wear out in time, for example? These are questions we have no idea and no answers for... yet. Simply because most people die of cancer or heart disease first. Or their brains are ravaged by the death of neurons we can't replace. But there *are* already documented human beings who remained lucid, coherent and cognitively intact well into their 11th and even 12th decades, proving that the brain in general is biologically capable of operating at least that long, if everything goes right. If we can keep everything else going. The basic biology underlying the dance of stem cells and adult cells and cancer cells may give us the tools to do exactly that.
With radical new stem-cell biology based therapies for heart disease, kidney disease, and everything else; with related ability to make cancer cells dance backwards into silence; we might be able to substantially tame many of today's killers. And no one knows just how much extra life that might give us. But it would be a revolution even if all we did was just allow the average human a full 120 years. If all we did was give the average person an extra forty years.
For too many of the dying patients we are priveleged to serve today, they'd honestly settle for just an extra four.
The research being published by the most advanced laboratories in the world is extraordinarily exciting. The *unpublished* work I've been lucky enough to glimpse at Hopkins and NIH even more so. I've been prototype engines of biomedical discovery that will dwarf the power of anything publically available. I've watched heart cells beat in a dish which were manufactured efficently from skin cells. Even just the news from this morning's headlines. The sheer scope, scale, and power of the biomedical science being developed today is staggering. And so will be the medicine our children will be using from it thirty years from now.
There's always the worry that the hype will outpace the reality. Certainly there are many individual diseases which so far have remained stubbornly untreatable, despite decades of scientific assault. But history, I think, is on our side. When our parents were growing up, life expectancy for cystic fibrosis patients was less than four years. It's now almost forty. Back then, a multiple sclerosis patient could expect to be wheel-chair bound and bed-ridden within a decade, and dead before the age of 40. Now, most multiple sclerosis patients don't die of their disease at all. Between the year I was born and now, the remission rate for children with cancer has been doubled. At this point, a newly diagnosed kid with cancer's chances of surviving at least five years are north of 75 percent, orders of magnitude higher than in our parent's childhoods. Some of the first kidney transplant patients are now entering their 40th year after transplant. And on and on and on. Thirty and forty years ago, our predecessors promised that the basic science they did then, would lead to real cures years down the line. We delivered on that promise. And we're going to go right on delivering.
We're just beginning in our ability to dance back and forth between adult cells, stem cells, and cancer cells. The list of things we might be able to do as we master that dance sounds almost too amazing to be plausible. But look how far we came with far less biomedical knowledge. History makes me confident, with these powerful new tools and exciting new research, we'll go much, much farther.
Patching hearts and kidneys. Repairing nerves. Giving diabetics the ability to make their own insulin. Turning cancers of all kinds backwards. And so much more. This really could be the medicine of thirty years from now. Work that will give dying patients today extra years. Work that might give our children extra decades. And work that might give our grandchildren, or our great-grandchildren, the gift of centuries -- and beyond. This is the prize waiting to be won, by the researchers and clinicians willing to pay the personal price to win them. This is the new world we're fighting for.
And you all are helping us make it happen.
Through your taxpayer dollars, which funded the largest biomedical research enterprise ever built by humanity. Through your fundraisers for biomedical research on top of that, all the walks and the biking, the blogging and the Feasts, and everything else. And most of all, for the countless acts of friendship and love you've given all of us, researchers and clinicans alike, out at the far frontier.
Thanks to you all, we've come amazingly far. Thanks to you all, we're going to go even farther. And so, for every one of you who has ever helped us in this journey: our sincerest thanks. And a promise to pursue the secrets of the great dance of stem cells and human biology, until every one of us gets to dance at our hundred-year birthdays -- and beyond.