11
New Cells for Old
Throughout our lives, we gradually lose cells vital to our continuing health. Many fatal diseases of aging—such as Parkinson’s disease—are caused by the loss of populations of cells responsible for one or another crucial function in the body. Fortunately, therapies based upon stem cell research offer the possibility of recreating our missing cells, good as new; politics stands in our way as much as any remaining scientific obstacles.
After the enormous effort that had been required to organize the conference, it was an incredibly rewarding moment to see the man who was revolutionizing stem cell biology take the podium in front of a packed crowd of colleagues.
It was the second conference I’d run at Cambridge focusing on scientific progress toward the reversal of human aging, so the pressure was on for me to top the success of the first. I’m on the board of the International Association for Biomedical Gerontology (IABG)—one of the few biogerontological societies in the world with an explicit brief to pursue the development of biomedical solutions to aging—and a couple of years earlier I had volunteered to spearhead their tenth conference. I knew at the time what I was getting into. The society would provide little logistical assistance beyond networking opportunities, so I would have little help beyond the support (moral and otherwise) of my beloved wife Adelaide, and that suited me perfectly. With the formal authority of a society already on the progressive wing of the biogerontology community, I wanted to push the envelope a little further, and being left to my own devices meant that I would not have to debate my priorities with a committee.
Despite the society’s mandate, previous IABG conferences had tended to be dominated by the same kind of presentations that I saw at every biogerontology conference I attended (and I try to get to most of them): basic science, geriatric medicine, and work in model organisms that the researchers hoped might someday be translated into a pill to slow down aging in humans. I took on the enormous and exhausting work of running this conference because it would give me the opportunity to highlight work that could contribute to a panel of interventions designed to reverse aging.
IABG 10—the meeting that would be, in retrospect, the first in a series of SENS conferences—was an enormous success. I am saying so myself, but I am making no boast of my own: the enthusiasm with which my colleagues thanked me for my efforts at the end of the week was ubiquitous and unmistakeably genuine. Attendees were surprised and excited by what they had heard, not only on its own merits but because most of it was completely novel to them. This was to be expected: while a typical biogerontology conference invites a roster of speakers almost entirely drawn from within the biogerontological community, I had introduced a strong interdisciplinary element, bringing in researchers working in cancer, diabetes, stem cells, and other fields, whose work would in my mind be critical to the development of effective anti-aging biomedicine but who were almost entirely unknown to researchers prone to pegging themselves in the “biogerontology” slot.
At the same time, those presenters had the opportunity to mix with researchers in whose laboratories the degenerative processes of aging were, if not being reversed, certainly being dramatically delayed in mice and other model organisms. This was work that often hardly raised an eyebrow amongst biogerontologists, who were immersed in a field in which it had been taking place since the first calorie restriction experiments nearly seven decades previously, but which amazed the experimental oncologists and tissue engineers that I had brought in to show the biogerontologists what they’d been missing.
IABG 10 was so successful in meeting my academic goals, and the requests from my colleagues that I run a sequel were so obviously sincere, that I felt sure that I could harness its momentum to make it the de facto inaugural meeting of an ongoing series of academic conferences on SENS science at Cambridge. From then on, however, I knew that the effort would be entirely my own: I could not rely on the support (nor brook the interference, little though it had been) of the IABG or any other society. Challenging as the job of directing such events was, I knew it would be worth it.
On the other hand, I also knew that I had set my own bar quite high with the first conference, and that some of my colleagues would be less inclined to attend a conference not run under the aegis of a recognized biogerontological society. This was all the more so when I was the organizer, because a whispering campaign against my credentials as a scientist had been initiated by some of my genuinely well-intentioned but old-school gerontological rivals shortly after the first conference. So if I wanted to get people to show up to SENS2, and to have the series continue, the quality of the conference lineup would have to be top-notch despite the opposition. I would have to meet an ambitious standard—and I wanted to overachieve.
The Master Cells: Accept No Substitutes
I knew that I would once again want to devote a whole session to embryonic stem cells (ESCs)—the primordial “master cells” from which our mature cells spring, and which play a critical role in our development into complex multicellular organisms from the simple ball of cells that is an early embryo. Thanks to the tragic confusion of the science of ESCs with the ethical, legal, and religious disputes around the status of the embryo in the abortion debate, ESCs are the one plank of the SENS platform with which you cannot help but be familiar. You have doubtless heard that, with the right kind of biochemical stimulation, embryonic stem cells can be coaxed into becoming any kind of cell in the body: nerve, muscle, heart, kidney, the lot.
These resulting, “differentiated” cells can then be used to repair or to replace cells and tissues that are lost to—and whose loss is a central pathological feature of—multiple debilitating, often nearly untreatable diseases, including many of the worst scourges of aging. ESCs will be needed to develop full cures for Parkinson’s disease, spinal cord injuries, juvenile diabetes, amyotrophic lateral sclerosis (“Lou Gehrig’s disease”), heart attack damage, some cancers, and other devastating conditions—including aging itself. Indeed, under the purely pragmatic, engineering definition of aging that clarifies so much about what needs to be done to keep our bodies ageless indefinitely, the net loss of cells is itself a form of aging damage. This makes it a central target of SENS.
However, because media coverage of the issue focuses on the political firestorm rather than on the real, hopeful medical story of ESCs’ enormous potential as medicine, you may still not be clear on the key differences in basic biology and therapeutic potential between ESCs and adult stem cells. There are also important differences between ESCs derived from embryos being stored in fertility clinics and those that can be custom-made for each patient out of his or her own mature cells by fusing them with egg cells (a technique known as somatic cell nuclear transfer, SCNT, to which we shall return). For this reason, I will spend a little time disentangling these issues.
True ESCs are found only in very early-stage embryos called blastocysts, which are the very primitive balls of cells that are formed within just a few days after sperm meets egg. The embryo only remains in this stage of development very briefly; it has developed much further by the time the embryo is implanted in the womb. It is from the blastocyst that every cell in the mature organism must be derived, yet the blastocyst itself has none of these differentiated cells: no neurons, no heart cells, no insulin-producing beta-cells, and so on. So for the embryo to go on to transform itself into an organism with the complex structure of a human being, its cells need the ability to transform themselves into each and every one of those mature cells—a power called pluripotency.
Adult stem cells, on the other hand, are much more limited in their abilities, and also with good reason. These cells emerge in the late stages of development, and are retained in particular tissues during life as a reserve to replenish cell stores. They thus hold on to only the limited repertoire of possible fates that is relevant to their role in that particular tissue. Thus, blood stem cells can become oxygen-carrying red blood cells or any of the many blood-borne immune system cells, but (despite what has been claimed—see later on in this chapter) they cannot form either neurons or heart muscle cells: if asked, a blood stem cell would doubtless indignantly reply, “That’s not my job.” They’re there to fulfill a specific role in the body, and to do it well, but not to be on reserve to heal all damage everywhere. This more limited range of developmental flexibility (or “plasticity”) is called multipotency.1
Indeed, there are many areas of the body for which there are no adult stem cells dedicated for use in repair—and, as you might expect, these include the areas that suffer the worst cell loss during aging. This is the situation, for instance, in much of the brain. For many years, it was believed that the entire brain loses cells over the course of normal aging, and that there was no way for the body to replace these losses. This dogma was overturned a few years ago, largely due to the work of Fred Gage and his coworkers at the Salk Institute, who showed that the brain does indeed harbor stem cells capable of renewing some parts of the brain. This has led to a swing, in the popular imagination, to the impression that the entire brain has the inbuilt capacity, through its adult stem cells, to keep the entire brain young and functional.
In fact, however, that impression is also wrong. Only a small number of areas in the brain produce stem cells capable of developing into new neurons: a sub-subsection of the hippocampus called the subgranular zone of the dentate gyrus, and a part of the subventricular zone, where neurons are created to supply the olfactory bulb (the area of the brain that processes the sense of smell). There’s evidence that some of these cells do attempt to repair areas of the brain damaged by age-related disease, but there’s little evidence that they’re much help. After a stroke, for instance, a few of the stem cells formed in the subgranular zone do change their normal habits and migrate toward the site of damage, but over 80 percent of them die within a few weeks, and the remaining cells replace only about 0.2 percent of the cells destroyed by the incident.2
Why do we maintain the capacity to replace neurons in some areas of the brain and not others, like the cerebral cortex where our long-term memories are stored, or the frontal lobe where our ability to make and stick to plans for our future is centered? Most likely, it’s because the olfactory bulb and the dentate gyrus are the only places where evolution has encountered the need for a regular influx of new cells within the brain’s “biological warranty period.” Both those areas have short-term functions that require the regular renewal of their cell populations. There is no built-in population of adult stem cells to deal with cell loss induced by the ravages of aging and age-related neurological diseases such as Alzheimer’s and Parkinson’s. As you’ll have realized if you still remember Chapter 3, this is because, while these disorders have their seeds in molecular damage that occurs throughout life, that damage does not reach a threshold where function is impaired sufficiently to affect Darwinian fitness in a short, Paleolithic human lifespan.
Another example of a tissue in which cells die but are not naturally replaced is the thymus, a key organ in the immune system which acts to “mature” precursor cells into T cells. Its regeneration using stem cells is at an early stage of development, so there’s not much to tell you yet, but a proof of concept exists in a rare but very serious congenital disease—see the sidebar “Rebuilding the Thymus.” I’ve described the immune system generally, and T cells in particular, at some length in Chapter 10, so you might want to refer back to that chapter while reading the sidebar.
REBUILDING THE THYMUS
The promise of using stem cells to treat thymic involution can be seen in recent advances in treating babies with DiGeorge syndrome—a genetic disorder whose victims are born with a variety of defects, including having a thymus gland that is underdeveloped, or in some cases completely absent (the latter being called “complete DiGeorge”). Complete DiGeorge has, until recently, of ten been a very near-term death sentence: with no ability to pro duce T cells, these babies would die of infections that are trivial to the rest of us, within a few months of leaving their mothers’ wombs.
The obvious way to solve the problem of a missing thymus is transplantation, but that’s a tricky business: to do its job, the tissue needs a very good blood supply and plenty of oxygen saturation, which is difficult to achieve without the natural penetration of tiny blood vessels. There have also long been problems with rejection and graft-versus-host disease: perversely, sometimes a few of the child’s bone marrow cells will “spontaneously” transform into dysregulated T cells that don’t recognize either the child’s own antigens or the thymus tissue donor’s. This leads to a ferocious attack on both, usually killing the child; moreover, often the donor’s T cells would turn on the transplant recipient’s foreign tissues in an equally deadly, reciprocal attack.
Recently, surgeons and immunologists at Duke University developed a protocol using very thin slices of tissue to ensure maxi mum transfer of oxygen, which are engrafted into the child’s thigh to give it a generous, readily accessed supply of blood, along with a novel immune-suppressing drug that targets T cells specifically. The intervention is still experimental, but it’s become progressively better through new innovations and now seems relatively successful. In a 2004 report, the Duke team found that five of the six patients receiving the new therapy were still alive fifteen to thirty months later, a greatly improved survival rate.
If, instead of using transplants of foreign tissue, we could take the child’s own stem cells, coax them into becoming thymus cells, and engraft them, we would eliminate the need for risky immune suppression. Then, if we could encourage these cells to grow in a scaffold in which we could build up a complex organ structure, including a proper blood supply, we could abandon the highly un satisfactory replacement of an organ with a wafer-thin tissue slice in favor of a real organ “transplant.” We may never actually be able to do this in DiGeorge syndrome, for the simple reason that we don’t have enough time—but if a foreign tissue implant can generate viable T cells and increase survival in babies born with no thymus, then I can only see promise in delivering a person’s own cells, taught to become T cells and if necessary coaxed and structured into a more complex tissue, to an existing but atrophied organ, to restore it to youthful functionality.
Similarly, in the heart, cells exist, which some researchers have called “cardiac progenitor cells” or similar names; but, while these cells can be nudged into showing some stem-cell-like molecular signatures in a test tube, they have not been shown to form heart cells in the body. Indeed, some closely related stem cells found elsewhere in the body (mesenchymal stem cells) have the same hallmarks but definitely cannot become heart cells. Whatever the ultimate truth of the matter, what we do know is that neither these nor any other cells in the body step in to heal the massive damage wrought to the heart muscle by being starved of oxygen during a heart attack—as any cardiologist or heart-attack survivor can sadly attest. Again, the reason for this lies in the cold statistical analyzes effectively performed by natural selection after generations of genetic dice-rolling in a premodern environment: heart attacks don’t kill twentysomethings, so by evolution’s calculus it’s not worth investing in a repair system that will almost never be used before its owner is killed by something else.
In the first days of the political debate around embryonic stem cells, some very respected laboratories issued reports of ESC-like flexibility in adult stem cells—of blood-forming cells spontaneously transmuting themselves into liver and brain cells, and perhaps most promisingly of such cells being injected into the hearts of rats given simulated heart attacks, forming new heart muscle tissue, and restoring functionality to the organ. These reports were taken so seriously that several groups began early clinical trials in humans, in which stem cells have been derived from the bone marrow of heart attack victims and then injected into their ravaged cardiac tissue.
But independent laboratories have been unable to confirm these claims. Instead, what may be happening is that the cells are indeed being incorporated into the tissues in question, but are doing so by fusing with the existing cells.3,4,5,6,7,8,9,10 There may be some limited benefit to this: the process of fusion may support the surviving cells in damaged tissues, either by secreting growth factors needed during repair, or by helping new blood vessels to grow into the tissue.11 But, while such effects may help to keep a disintegrating ticker beating for a short while more, it cannot substitute for actually rebuilding heart tissue, either for heart attack victims or for the aged humans whose hearts we wish to rejuvenate.
Indeed, recently the New England Journal of Medicine published the results of the first trials of bone marrow stem cells as a treatment for human heart attack victims that were large enough to give meaningful information about actual clinical outcomes in the patients (as opposed to just collecting safety data and early reports of physician and patient experience). One of these trials12 found no benefit, and the other two13,14 reported what the Journal’s summarizing editorial described as “small, [statistically] significant, but clinically uncertain improvements”15 in treated patients compared to those receiving dummy injections. They reported no evidence either way on the subject of the cells actually transforming into heart muscle cells, but the animal studies mentioned above have at this point dashed previous hopes of such an effect.
Contrast these weak effects with the results of an animal study using embryonic stem cells to treat an induced heart attack. Eighteen sheep were subjected to such an assault, and then allowed to decline for two weeks. During this time, scientists harvested ESCs and nudged them to begin making the transition into becoming heart muscle stem cells. Before the embryonic stem cells had completed their developmental journey, the researchers seeded these cells onto the hearts of half of the group, while for comparison the remaining nine animals were left to slide further down the road to disability.
Where the benefits of adult stem cells had been dubious, the healing influence of ESCs was undeniable (see Figure 1a). The cells took hold in the damaged hearts and were shown to transform into mature heart cells, and the animals experienced a dramatic recovery. In the two weeks since their matched relations had been given the ESC treatment, the control group’s hearts had lost an additional tenth of their blood-pumping ability. By contrast, animals who had received the cardiac-committed stem cells enjoyed a 6.6 percent improvement in pumping capacity.
And if you dig into the details of the study, you find even more reason to be optimistic about the potential for ESCs as a therapy for the heart. For one thing, the scientists in this study waited until two weeks after the animals suffered their heart attack to do anything about the damage to their hearts, and it was during this period that the bulk of the degeneration of the animals’ hearts’ pumping capacity occurred. Early intervention, whether with stem cells or even with more conventional medical duty-of-care, might have prevented a lot of this decline, potentially leading to much better outcomes after ESC treatment.
Figure 1a. Restoration of the heart’s pumping ability by embryonic stem cells. (a) Controls vs. ESC recipients. (b) Controls, ESCs plus immunosuppressive drugs, and ESCs alone. Redrawn.16
Second, the ESCs that were used in this study weren’t even derived from sheep, but from mice—an important point to which we will return later. While the cells clearly did their job—maturing into heart cells, uniting with the native tissue, and restoring significant functionality to the animals’ hearts—it still seems reasonable to think that using cells that were actually from their own species would have yielded a better metabolic and functional match, and, therefore, better outcomes.
And third, the average improvement in the ESC-treated group actually conceals a very positive variation in response to ESCs within the group. Because of the possibility that their immune systems might reject the mouse-derived ESCs and spoil the experiment, five out of the nine treated animals had been given immune-suppressing drugs. It turned out that the drugs were unnecessary: the researchers took slices from all animals’ hearts after the study was over, and there was no evidence of inflammation or attack by immune cells in the hearts of the animals given ESCs, no matter whether they were dosed with immunosuppressive drugs or not.
This is positive news in and of itself, but there was even better news to follow. The reported 6.6 percent recovery of heart pumping capacity in ESC-treated animals was a pooled result, including animals that did and did not receive immunosuppressive drugs. When the researchers broke down the results according to whether animals received these drugs or not, they found that the immunosuppressed animals had actually responded more weakly to ESC treatment than ones whose immune systems were left to carry out their business. The sheep in the ESC-only group healed 25 percent more scar tissue from their original heart attacks than the drug-treated animals, and their hearts recovered over twice as much pumping capacity: about a 9 percent versus roughly a 4 percent gain (compared, again, to a 9.9 percent further loss of functionality in animals not receiving ESCs—see Figure 1b). So, in evaluating the prospects for human use of ESCs, we should look at the stronger results available from an ESC-only approach, rather than the weaker results from pooling these animals together with those given immunosuppressants.
After this study was published, the first head-to-head comparison of ESC versus adult stem cell therapy for heart damage similar to that endured during a heart attack were reported; the results showed clearly the superiority of the ESCs, which transformed into heart muscle cells, achieved long-term incorporation into the animals’ heart tissue, and improved the animals’ heart function, while the bone marrow stem cells had no significant effect.17
And this is only the beginning of the biomedical promise of these amazingly versatile cells. Embryonic stem cells have been used to cure animal models of some of the most fearsome diseases human beings suffer, such as juvenile diabetes,18 spinal cord injuries,19,20 multiple sclerosis (MS),21 cerebral palsy,22 stroke,23,24 Parkinson’s disease,25 a form of paralysis caused by a virus that induces a standard mouse model of ALS,26 and—very recently—macular degeneration (the form of blindness caused by the loss of light-sensing cells in the center of the eye’s retina).27 All of these are diseases where a person’s native, adult stem cell supply fails even to begin to replace the cell loss caused by the disease.
Figure 1b.
Of course, none of these therapies has made its way into the clinic—yet. But there’s every reason to think that they will lead to dramatic improvements in our ability to treat these patients. The balance of preliminary evidence from human trials using fetal cells or cells derived from stem-cell tumors (not true ESCs) in Parkinson’s disease and stroke victims, for instance, already shows a lot of promise that can only be expected to improve with the use of actual stem cells, and recently a study using ESCs in a monkey model of Parkinson’s has confirmed their ability to transform into the required type of neurons, engraft into the appropriate area of the brain, and relieve many of the symptoms of the disease.28 These are exciting times.
Why We Need Them
Because the horizons for the ultimate fate of ESCs as differentiated cell types are wide open, and because of their ability to proliferate indefinitely (unlike adult stem cells, whose replication capacity tends to be more limited), the scientific consensus acknowledges the greater therapeutic potential of ESCs over that of adult stem cells. There are certainly therapeutic uses for adult stem cells; indeed, the only stem cell-based therapies currently in clinical practice are things like bone marrow transplants, which use adult stem cells taken from a donor or from the patient’s own body. But the oft-repeated claims by social-conservative lobby groups that adult stem cells can effectively treat “70 diseases” or “more than 65 diseases” have rightly been called “patently false” and the accompanying information on one prominent such group’s Web site “pure hokum” in the editorial mentioned earlier from the normally diplomatic New England Journal of Medicine.
As things stand, only embryonic stem cells hold the potential—both in terms of the range of cells required, and in terms of the sheer quantity of cells needed to create large tissue grafts and in some cases even whole organs—that will be needed to make young bodies from old ones. And need them we will. In addition to cells lost to heart attacks and neurodegenerative diseases, the truth is that we are losing cells—and the functionality that those cells provide—from our tissues on a continuous basis. Parkinson’s disease, for example, is the result of the loss of neurons in the brain that produce dopamine, a chemical messenger involved in fine control of the muscles. You get a clinical diagnosis when you have lost about half of these neurons, impairing this control enough that parts of your body begin an involuntary rhythmic shaking and your face turns into a staring mask with a fixed blank or even hostile expression. But all of us are losing dopamine-producing neurons every day to aging; people with Parkinson’s just lose them more rapidly, reaching the clinical threshold earlier. Without the ability to replace these cells, we’ll all develop the disease eventually (if, as the refrain goes, something else doesn’t kill us first).
And it’s happening all over your body, and not just for the kind of intrinsic metabolic reasons that are most precisely termed “aging.” You are permanently losing cells every day to molecular damage caused by the reactive by-products of normal metabolism, and even after we undo such damage using the foreseeable biotechnologies of the SENS platform, we will still need to reverse these losses if we are to build ageless humans. Plus, we also lose cells to other causes. We all regularly destroy some naturally irreplaceable cells to minor bumps on the head, moments of oxygen deprivation, and the apoptosis (“programmed cell death”) imposed on cells by the body when it senses that they are doing more harm than good.
Whether these latter cell losses are a part of “aging” is debatable, but fortunately it’s not an issue that we need to resolve in order to get moving on the restoration of old and dysfunctional bodies to the full health and functionality of youth. Replacing these missing cells will play an essential role in anti-aging biomedicine, no matter what the causes of their attrition or their relationship to “aging” in the abstract. Progressive cell loss represents a change away from the healthy ideal of youth, and therefore an anti-aging engineer should work toward fixing it, just as any engineer will work to restore machinery back to the state in which it functions best.
Throwing Away the Key to the Medicine Chest
Adult humans have adult stem cells, not embryonic ones: again, true ESCs only exist in blastocysts. Thus, getting a supply of ESCs for use as cellular medicine involves somehow deriving such cells from early-stage embryos. Fortunately, there is a quite generous—and heretofore almost untapped—supply of such cells that is already being produced by an existing industry: in vitro fertilization (IVF) in fertility clinics.
The chances of any given IVF embryo being successfully implanted and then carried to term as a result of the procedure are still relatively low, so fertility clinics routinely create several embryos from the sperm and eggs supplied by either would-be parents or their donors. That way, they have a supply of embryos available for multiple attempts, without requiring women to undergo multiple rounds of the expensive, very unpleasant, and modestly dangerous hormonal treatments required to extract eggs from them. Typically eight such embryos are left over after every round of IVF, with the result that there were 400,000 surplus embryos frozen in storage in American fertility clinics alone as of 2002. At least 16,000 of these are unclaimed by any donor, an additional 45,000 have a similarly murky status,29 and nearly none of the others will ever actually be used in fertility procedures. These embryos are ultimately discarded, or become sufficiently decayed that they cease to have any potential to form a baby.
This is what makes the debate around the use of embryos from fertility clinics such a frustration to doctors and scientists. These embryos are slated for destruction no matter what we do with them: there is no chance that the vast majority of them will ever be implanted in a womb and undergo the additional development needed to make a baby. The opponents of ESC research and therapy have proposed preventing their disposal by implantation into volunteers who would carry them to term for adoption, but even in that scenario there is no realistic prospect that even one percent of such embryos would be diverted from the rubbish tip. Once created, the fate of those blastocysts that are not actually implanted into a woman is sealed; the only question is whether scientists will be allowed to use their cells for research and as cures.
Actually, the insertion of these cells into the midst of the abortion debate is even more artificial than this makes it sound. Blastocysts are so primitive a stage in embryonic development that they have not yet made the biochemical “decision” to become a distinct human being. This is part of why they have the full flexibility to become any type of cell in the human body—and also why the confusion of stem cell technology with the abortion debate is so ethically misguided. At this early stage, for instance, an embryo could still divide into two separate cell populations, each of which can go on to become a separate, unique person. Indeed, this is exactly what happens when identical twins are formed. Since this ball of cells can still go on to become either one, or two, or even more different people, clearly the unified cell mass that precedes this separation does not embody the identity, the essence, or the soul of any single, personal human being. And while we can stand in justified awe of the potential for life (or lives) locked up in these cells, that should not cloud our ethical vision into thinking of this potential as morally being even in the same ballpark as the actual lives of patients that need its cells for medicine, when it is closest to that of skin cells in a petri dish.
The Nicodemus Solution
Powerful though embryonic stem cells derived from embryos left over from IVF may be, however, they do have one potential disadvantage hanging over their medical use. Cells derived from such embryos will, by definition, be immunologically alien to the patient’s own cells, making them a target for attack by the immune system. Thus, the same kinds of problems that currently plague conventional organ transplantation—the horrors of rejection, graft-versus-host disease, and the dangers of living with an immune system turned off artificially with drugs to preserve the transplant—might possibly be an issue in embryonic stem cell transplants, too.
So far, the evidence suggests that we will be able to manage this issue with little hassle in many cases. Much of our confidence on this front derives from recent experience in actually using ESCs in experimental treatments for various diseases. Most such studies have just assumed that rejection would be a problem, and have preemptively taken steps to prevent it, either by using animals with defective immune systems, or by administering immunosuppressive drugs. But more recently, some studies have been performed using ESCs without taking such steps, and the results suggest that there may have been nothing to worry about in at least some cases. In the sheep heart-attack study I mentioned earlier and in several rodent studies,30,31 ESCs taken even from another species have incorporated themselves into the “patient’s” native tissues and provided substantial regenerative benefits, with no rejection issues.
Such results may mean that ESCs’ state of development is so early and tentative that they may not even distinguish themselves with enough antigens to create a problem across the species barrier—let alone the barrier between individual humans. Additionally, it now appears that ESCs produce their own, very localized immunosuppressive signalling molecules that selectively protect them from immune attack, and even trigger any attacking killer T cells to undergo self-destruction (apoptosis).32 Because these mechanisms involve either direct cell-to-cell contact or factors secreted and used very close to the stem cells themselves, this local immune shielding system is free from the systemwide side effects of taking immunosuppressive drugs.
Moreover, in some specific applications the risk of rejection will be low to begin with, because the tissues where we’ll be delivering the cells are substantially shielded from the immune system. A lot of the nervous system, for instance, is largely inaccessible to immune attack (which is how the virus that causes shingles can hide out there for years after being purged from the rest of the body).
We can also lower the risk of rejection by providing patients with ESCs from isolates (“lines”) that are a match for all of the major antigens involved, which we could readily do in many cases if we are allowed to pick and choose our stem cell lines from among the embryos currently slated for destruction. It has been calculated that a bank of just 150 donor embryos randomly selected from the existing stockpile could do this perfectly for one patient in five, provide a probably usable match for almost two in five, and allow for a long-shot match for almost 85 percent of potential patients—and if we were able to choose specific immunological combinations out of the surplus instead of choosing embryos at random, just ten such donations could give grade-A matches for nearly 40 percent of patients and good matches for over two-thirds.33
But we can’t yet rule out the possibility that rejection may present a barrier to our effective use of ESCs in human medicine for aging and disease. In that case, the good news is that technology exists that already allows us to generate embryonic stem cells that are a perfect immunological match for animals as complex as cattle and monkeys, and several scientific teams say they’re on the verge of being able to do the same thing for humans. I’ve already mentioned it: somatic cell nuclear transfer (SCNT). In SCNT, doctors begin by taking a mature cell from the patient’s body (a “somatic cell”), by for example swabbing the inside of the cheek, and then turn back its clock, releasing it from the strictures of a mature, differentiated complexity and transforming it into a patient-specific embryonic stem cell.
This biological miracle is accomplished by a technique that is incredibly simple. The metamorphosis occurs in an egg cell, provided by a donor. This cell’s nucleus is removed to make way for the one from the patient’s cell. With a biochemical boost or a zap of electricity, the two become one, and the egg begins dividing just as it would if it had been fertilized, kick-starting the production of embryonic stem cells created from a patient’s own genetic instructions, creating a perfect immunological match (see Figure 2). The cells can then be used for medicine just as any ESC would be, but with absolutely no fear of rejection.
Actually, you may well already have heard of this advanced biomedical research under a name more popular with the media: therapeutic cloning. While this term is perfectly scientifically accurate, it has generated an enormous amount of confusion about the nature and purpose of SCNT, splashing political napalm onto the heated fires burning in legislatures and online chat rooms surrounding stem cells. Let me try to extinguish those flames.
To a scientist, the word “clone” means simply a set of genes, cells, or organisms that are identical to one another at the DNA level because they are derived from a single ancestor. We’ve used the word in this strict scientific sense in the “clonal expansion” of T cells, and the “monoclonal antibodies” that are currently used to treat some cancers and will probably be used as part of our panel of engineering solutions to aging. Similar uses of the word occur when scientists speak of a “clone” of common bacteria bearing a gene that turns them into tiny biological factories for the production of insulin for diabetics, or even when gardeners talk about a “clone” of strawberry plants.
Figure 2. How SCNT (“therapeutic cloning”) works.
But say “clones” to even highly educated people who don’t work in a few disciplines of biology and biomedicine, and you evoke images of a sea of indistinguishable, zombielike drones, enslaved to technocrats or created for other sinister purposes. That this confusion is corrupting the debate about this potentially essential life-saving technique can be seen starkly in a speech delivered to the Canadian Parliament on February 27, 2003, during debates surrounding Canadian legislation to regulate stem cell research. Mr. James Lunney, a Conservative party member of Parliament for the Nanaimo-Alberni riding on Vancouver Island, began by saying that “[I]f we took one of [the speaker of Parliament’s] cells, extracted the nucleus and put it into an ovum, one could stimulate it electrically and allow it to grow.” So far, so good. But then Mr. Lunney rocketed off into a grotesque but all-too-common flight of misunderstanding: “The so-called therapeutic clone would be to take the immature model of Mr. Speaker and extract an organ, if he needed one, killing the clone in the process. That is so-called somatic nuclear cell transfer or therapeutic cloning.” Similar outrageous confusions have been perpetrated on the floors of the U.S. Congress and elsewhere in the course of the stem cell debate.
SCNT doesn’t involve making clones of people at all. It involves making blastocysts—balls of cells that, as we’ve seen, have not yet even made the necessary steps to decide whether they will become one, two, or more people. True, these blastocysts could in principle be used to make babies if they were implanted into a woman the same way as is done with blastocysts produced through IVF, but this is a potential, not a fact. When blastocysts are created by SCNT for therapeutic purposes, no egg is fertilized by a sperm; no new, unique DNA identity is created; no embryo is implanted in an uterus; no pregnancy results. Biomedical SCNT creates cell life, but not human life: renewed cells, not new people. They certainly have no organs that we could harvest—including, importantly, no brain, nor even the beginnings of nerve cells. We no more “kill” a blastocyst produced by SCNT when we derive stem cells from them than we “kill” a vat full of replicating skin cells when we throw it out at the end of an experiment. Fundamentally, SCNT would be the basis for therapies that cure you with your own cells, restored to the potential they had in their first moments of existence by the power of the stimulated human egg.
Because they derive from the patient’s own DNA, SCNT cells are an exact genetic match to those in your own body, and are treated as “self” by your immune system.34 Whatever may emerge from further research with ESCs derived from surplus embryos left over from IVF, SCNT cells offer a virtual guarantee of freedom from the specter of rejection, graft-versus-host disease, and a lifetime spent on toxic immunosuppressive drugs.
In preliminary, preclinical research, the new regenerative powers of cells derived from SCNT have already shown their promise. In animal models, SCNT medicine has already been used to cure many of the devastating conditions for which human treatments must still be found, such as Parkinson’s disease,35 heart attack damage,36 and the animal equivalent of the “bubble baby” syndrome (SCID)—rescuing not mere weanlings, but fully developed, adult organisms that had suffered with the disease for their entire lives.37 As we’ve seen, the ESCs taken from more conventionally generated blastocysts have worked some of the same marvels—but some of these studies suggest that, even where rejection doesn’t happen, SCNT may still provide some advantages. And indeed, the results tend to downplay the therapeutic potential of SCNT, because in these studies the scientists have not actually derived the cells from each animal individually so as to provide a perfect match (as we would do for human patients), but have used one line of cells to treat an entire colony of close cousins.
In the Parkinson’s study, for instance, the researchers coaxed SCNT-derived cells to produce neurons suited for use in several areas of the central nervous system (forebrain, midbrain, hindbrain, and spinal cord) and responsible for a broad range of functions. Some of them were the kind that produce the neurotransmitter dopamine, which is involved in fine motor control; as I noted, it’s the loss of these cells that causes Parkinson’s disease. Others were cells whose central functions involve another neurotransmitter called choline, and whose loss is characteristic of Alzheimer’s disease. They were also able to derive cells that secrete other neurotransmitters in the brain (serotonin and GABA); that carry movement-control signals from the spinal cord to the muscles (and whose degeneration is central to motor neuron diseases); and that act as “support” cells to neurons proper, nourishing and protecting them. This was a much wider range of mature cells than had been successfully derived from previous protocols using conventional ESCs.
The team then put these cells to the test in the Parkinsonian rodents (whose dopamine-producing cells had been knocked down to less than a third of their healthy numbers by a toxin), comparing their effects to ESCs derived by the conventional route. Dopamine-producing neurons derived from either protocol formed solid, stable grafts, and improved behavior in their recipients, and there was no sign of rejection of either type of ESC. But even though the SCNT-derived cells came from recipient animals’ cousins rather than their own, individual bodies, these cells performed better than conventional ESC cells, forming larger grafts in their brains, with double the number of transplanted nerve cells surviving eight weeks after transplantation, and the final graft sites containing about 50 percent more dopamine-producing neurons.
And it appeared that they might have been somewhat more effective at restoring function, too. Because all the damage had been inflicted on one side of the brain, chemically stimulating the remaining dopamine-producing cells in the brain caused an imbalance in their motion, with the larger number of intact cells on one side of the brain sending out stronger signals to the legs they control than the more damaged side does. The result was that the animals began to veer to one side, rather like what happens when you push a shopping cart that has a damaged wheel on one side of it. This “rotational behavior” is a key test of the function of the damaged part of the brain. Treating these animals with dopamine-producing cells derived either from conventional ESCs or ESCs created using SCNT reduced this aberrant motion by more than 70 percent, with a hint that the SCNT-derived cells were more effective (see Figure 3).
Because the range of neurons and supporting cells produced using these protocols was so broad, the researchers who performed the study believe that their technique could also be used to treat multiple sclerosis and other “demyelinating” disorders (in which the myelin sheath essential to the correct function of neurons is damaged or destroyed), Huntington’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and other motor neuron diseases.
Figure 3. Embryonic stem cells, and especially SCNT-derived cells, restore normal motion in a Parkinson’s disease model.
There remain technical hurdles to overcome in developing SCNT, but theoretical objections to their ultimate use in human medicine continue to fall. There have been concerns about the mitochondria in these cells, for one thing: SCNT is achieved by replacing the DNA in an egg cell with a patient’s DNA, but this still leaves the egg’s own energy factories providing the juice to keep things going. Many researchers have therefore been concerned that the resulting cells would be dysfunctional due to a mismatch between these mitochondria (created originally from the egg donor’s nuclear and mitochondrial DNA) and the final cell, or that the patient’s body might reject the cells based just on the immune-sensitive parts of the transplanted mitochondria. So far, however, it doesn’t seem likely that this mitochondrial mismatch is going to trouble us. Aside from the fact that these cells have been incorporated successfully into the patient-animals’ bodies without any signs of rejection in studies so far, a very careful study that looked all the way down at specific proteins that are used to monitor for mitochondrial “foreignness” found that the cells were accepted as completely native by all available measures.
Similarly, there are concerns that the “epigenetics” of SCNT-derived cells—the “scaffolding” around the genes in the DNA code, which regulates the expression of those genes—would be abnormal, leading to cancer or dysfunction. Again, however, while this has been a problem with using embryos created using the nuclear transfer technique for making cloned animals, it has not yet appeared to prevent stem cells derived from SCNT from functioning properly when transplanted as a treatment into animals. And indeed, early in 2006, scientists from the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, reported that stem cells derived from SCNT have identical patterns of being transcribed and turned into proteins as do ESCs created by conventional IVF-type fertilization, with any differences attributable to the genetic differences among the animals donating the cells rather than the kind of cell involved.38 Moreover, it appears that the very process of generating stem cells from SCNT blastocysts of necessity imposes a kind of “survival of the fittest” of its own, with any epigenetically inappropriate cells collapsing under their own dysfunctionality; this may explain a large part of why it’s been so difficult to get a high yield of such cells from a given blastocyst. This might pose problems for anyone actually looking to use nuclear transfer to clone a person (a point that should itself relieve those concerned about such a use of the technique), but it appears that epigenetic problems will only make the use of SCNT for medicine more difficult, not prevent its safe and effective use.
Another open question is where we’ll get all the eggs we’ll need to use SCNT widely as an anti-aging therapy. The supply is limited by the number of women prepared to donate their eggs, and the hormone treatments and moderately invasive surgery needed are likely to continue to keep the numbers of such women down for some time. Many people also raise ethical concerns about offering money or other inducements to solicit more donors, especially for a procedure which is not without risk.
Even this, however, may yet be overcome on a technical basis instead of a sociopolitical one. One option would be to take the eggs from other species. Such an approach would not be without technical hurdles: notably, the presence of mitochondria in such eggs that are not just from a different person, but from a different species, might make the cells unable to create and sustain an energy supply. With my background in mitochondrial biology, I recently proposed a solution to this problem should it arise.39 My solution results in the mitochondria of the eventual ESCs being derived from the eventual recipient of the cells, just like the nucleus, so it also avoids the “intra-species” mitochondrial problem I mentioned above.
Another alternative may be to mass-produce egg cells bioengineered from more common cell types, such as skin. Canadian researchers recently reported40 having used skin cells from fetal pigs to produce cells which look—based on gene expression patterns, cellular structure, and some functional abilities—an awful lot like egg cells. Whether these cells have the full range of functions of egg cells remains to be seen, but they—or a more developed version of them—might have the same power to reset the clock in mature somatic cells that conventional eggs do. This would mean that we can bioengineer an almost unlimited source of eggs: human fetal skin tissues, which contain nineteen billion such cells per square inch. Such huge numbers would allow us to avoid entrapment in the battlefields of the culture wars, if we can simply reach agreement on the use of tissues from stillbirths rather than aborted babies.
Frozen Embryos, Frozen Science
This brings me back to my second SENS scientific conference. At the time, you could still smell the ozone in the air from the second in a pair of scientific lightning strikes from a previously obscure group of Korean scientists from Seoul National University, headed by veterinarian Hwang Woo-Suk. A few years after Dolly the sheep, Hwang had claimed to have cloned a cow, and more recently a dog, but his fame came when he announced in the winter of 2004 that he had achieved the world’s first derivation of fully fledged human ESCs using SCNT. This proclamation rocketed him to international fame, but it was just the beginning: a little more than a year later, in the months leading up to SENS2, he reported a dramatic improvement on the technique. In his first report, Hwang had only been able to derive a single stem cell line from the 242 eggs that had been donated—and this line had been taken from an egg fused with DNA taken from the egg donor herself, which was of very limited biomedical use. Now, Hwang was saying that he had created eleven human lines using only 185 eggs, and using DNA taken from completely different people, including potential patients of both genders and many age groups.
Everyone in the field, as well as the popular press, hailed this result as a phenomenal breakthrough, and I was far from alone in seeing its potential for treating not only age-related disease, but aging damage more broadly. I knew that I would want someone to present not only Hwang’s results—with which most attendees would be at least peripherally familiar, due to the enormous press coverage—but what they would mean for scientists working in the field.
Hwang’s result was clearly going to have an enormous galvanizing effect on stem cell research. Because of the political climate in which it had taken place, the impact of the announcement was far greater than could be accounted for by the purely technical breakthrough (great as it might have been) of actually being able to make customized stem cells for healing patients. Stem cell research had been stymied for years by President George W. Bush’s notorious decision, in the summer of 2001, to limit federal government funding of stem cell research to work done using lines created prior to the morning when he announced the policy.
That decision reversed a policy accepted under the Clinton administration, but not yet implemented, that would have plowed NIH funds into ESC research using lines derived either from IVF clinics or from work originally performed with private funds. It came not out of science but from the political maelstrom of the abortion debate, and the antiabortion stance held by President Bush and by his key constituency of the Christian Right. And while it is not accurate to call that executive fiat a “ban” on ESC research, it created an enormous chill over the entire field—and not just because of the direct effects of cutting off funding for research performed on nearly all available ESC lines.
The most obvious problem was the stranglehold it put on direct U.S. federal government funding for embryonic stem cell work. The administration holds the purse strings of a remarkably large share of U.S., and even global, basic research in science, with US$20 billion in research-related funding coming out of the National Institutes of Health alone each year. Bush and his political allies would argue that their policy provides scientists with plenty of opportunity to work with stem cells because of the availability of the approved lines, but that claim ignores the actual state of the lines in question.
The White House originally announced that their policy would allow scientists to work with as many as seventy-eight robust stem cell lines, but when senators put the question to NIH Director Elias Zerhouni, he admitted that only nineteen of these lines were actually viable, available in practice (as opposed to locked up by intellectual property restrictions and similar constraints), and ready for use in stem cell work. By 2004, this number was still no higher than twenty-one. In preliminary research presented at the National Academy of Science on October 12, 2004, fourteen of the lines tested by Carol Ware at the University of Washington were found no longer to grow well and to be hard to separate because of the outmoded way in which ESC lines were derived and cultured at the time. One such line was actually withdrawn from scientific use because of this finding.41
A supply of just twenty-odd lines also fails to represent the genetic diversity of humanity well, so it’s hard to verify whether a given finding is a quirk of that line or, say, of people of a given race. A supply of hundreds of viable ESC lines is the likely minimum for healthy progress in this field of science. Indeed, the present situation is worse than this: because of their age, these lines are accumulating mutations that could skew the results of research performed with them because they no longer even represent the stem cells of those original donors. It also means that we can’t study the stem cells of people with particular diseases, or how experimental drugs affect those processes—studies that would best be done with SCNT, which would let us take the cells of people already known to suffer with a given disease and wind back their clocks to the first moment of their primitive existence as blastocysts. Researchers could then watch the cells as they underwent differentiation into the cells most affected by the disease and then the late-phase changes that happened as their abnormal metabolism intersected with aging processes that happen even in healthy people’s cells.
And not only are the cells of very limited use for basic research: everyone working in the field recognises that these cells will never be usable for actual therapies either. All the lines that are both approved and available are useless for clinical purposes because they were originally cultured using feeder cells taken from mice—supporting cells needed to secrete factors and provide structural support that is essential to keeping them in their primal, unspecialized state. Contact with these cells has tainted them in various ways: one study42 found that their cell surfaces contained a sugar that the body’s immune system recognises as foreign and attacks, and it’s widely expected (though not yet proven) that they may also contain mouse cell proteins and even viruses.
It’s only been in the last couple of years that scientists have developed new techniques that first allowed for the propagation of human ESC lines from human feeder cells, and most recently ESCs generated using no feeder cells at all.43 And, again, it’s at least possible that nothing short of custom-made ESCs produced specially for the patient with SCNT will fully address the potential problem of rejection. Thus, only ESC lines derived well after the 2001 line-in-the-sand can actually be used as medicine for disease and for the full repair of aging damage in the future.
The policy also ripples out well beyond the labs of people actually working with the approved lines. For one thing, the restriction on providing money to unapproved stem-cell work is so aggressively enforced that the NIH has to snatch away grant money awarded even for research completely unrelated to ESCs, if any of that money goes into facilities or equipment also used for work on “banned” ESC lines. You could be testing a cancer drug on rats and have your funding pulled if someone else on campus were sharing the use of gene-expression array equipment with you and were using it for ESC work using lines not approved under the August 2001 decision. That makes it enormously difficult for anyone to carry out work on ESCs other than the sanctioned lines on most university campuses, or in essentially all government research centers. Laboratories in which sanctioned work does take place must expensively duplicate and track equipment, all the way down to sticking colored dots on petri dishes and other glassware, and must generally work in ways that degrade effectiveness.
The policy also erects enormous roadblocks even to privately funded research—research that, in theory, is not the target of the Bush policy. Scientists in industry are first trained in universities, and when those universities can’t carry out ESC work, because of a mixture of lack of federal dollars and the handcuffing of non-ESC work carried out using shared equipment with work on “forbidden” lines, young researchers don’t get trained in the techniques of working with stem cells, let alone get the opportunity to perform original research that would advance the field. This, of course, means that such researchers aren’t available for hire by private firms even if they had the money to bring them on.
And naturally, the political uncertainty swarming around stem cell work makes potential investors reluctant to pour money into companies focused on developing ESC-based cures. At the time, it seemed possible that the United States would follow other countries in making aspects of this research—such as SCNT—not merely ineligible for government funding but actually a criminal act. Investors will stomach most risks, but not political risk, and so they abandoned private-funded ESC research for a number of years.
It briefly seemed likely that the Bush administration’s policy would be quickly brought down by political pressure. Even a very conservative selection of polls shows that the majority of people in the United States and elsewhere are in favor of a fairly open policy on scientific access to ESCs. Even in surveys in which the question is posed flat-out with no mention of potential human benefits, the majority of people say that they support deriving stem cells from surplus embryos from fertility clinics for scientific research.44 When the question mentions the potential for human treatments, this proportion climbs into the 70 percent range. And most people even support SCNT research—a fact that fills me with optimism about their future acceptance of other anti-aging therapies.
So, in the August heat, with the controversy raging and President Bush’s popularity resting on unsteady ground, it seemed possible that public opinion would mobilize against the restrictive policy, and scientists would within reasonably short order be enabled to work with ESCs from a wide range of sources.
Then, the planes hit the World Trade Center.
In a month, everything had changed. Where ESC research had been front-and-center on the national stage in August, it was off the radar screen for almost everyone in late 2001, replaced by the immediate fear of terrorism. As pressure and scrutiny from the wider public melted away, those whose organization, resources, and ideological investment were strong enough to continue to push their agenda on the subject even in the shadow of the ruins of the Twin Towers suddenly became the only voices pushing legislators—and in this case, because of the conflation of the science with the abortion debate, that meant almost entirely forces opposed to ESC research. Anti-abortion groups, who are well organized and well funded, made their case to Washington as strongly as ever, without the usual balancing force of either the public at large or of their usual opponents: pro-choice and civil liberties groups had no particular stake in stem cell science, and the latter had their hands full with presenting the case for preserving Constitutional rights in the face of the threat of terrorism. And while patient advocacy groups might have stood in opposition to blockades on research, such groups were nascent at the time, and lacked the support from pharmaceutical companies that often sustains them, since in this case the companies had no vested interest in promoting the groups’ cause.
Feeling deferential to a newly popular wartime president, handed plenty of unbalanced misinformation by the anti-abortion activists on the religious right that made up that president’s base of support (and had played a significant role in their own sweep into power), and with a leadership dominated by representatives with a social-conservative worldview of their own, the Republican-dominated Congress substantially raised the threat against stem cell science. Parallel bills introduced by Sam Brownback in the Senate (S 245) and Dave Weldon and Bart Stupak in the House (HR 234) sought to ban all forms of “human cloning”—including SCNT performed entirely for scientific or medical purposes.
These measures would not only deny federal funding to, but criminalize, the creation of blastocysts using SCNT—imposing actual jail sentences on scientists performing the work. They would also have imprisoned scientists doing any scientific research using ESC lines derived from SCNT; in the original texts of these bills, this went so far as to threaten both doctors and patients with prison time if they administered or accepted cures using SCNT-derived stem cells. Some language even suggested that people who went abroad to receive treatment with SCNT stem cells could be penalized for it on their return to the United States.
But in the coming months, as the public slowly began to raise their heads out of their foxholes, proresearch and patient activist forces began to countermobilize. They were greatly helped by the voices of prominent patients suffering with diseases likely to benefit from SCNT and those close to them, including Michael J. Fox (Parkinson’s), Kevin Kline (whose son has juvenile diabetes), Christopher Reeve (spinal cord injury), and, most powerfully, Nancy Reagan (whose husband, the former president, died of Alzheimer’s disease). A bipartisan coalition favoring expanded embryonic stem cell access—and in many cases the full legalisation of biomedical SCNT—began to form, including such prominent anti-abortion Republicans as Orrin Hatch, Strom Thurmond, Arlen Specter, John McCain, and ultimately then senate majority leader Bill Frist, and apparently extending even to Bush’s own secretary for Health and Human Services, Tommy Thompson. Meanwhile, prominent scientific organizations (including the National Academy of Sciences, the American Medical Association, the Association of American Medical Colleges, and even the National Institutes of Health itself ), as well as multiple disease-specific charities (such as the Juvenile Diabetes Research Foundation, the American Association for Cancer Research, the Lance Armstrong Foundation, and the American Diabetes Association) endorsed research using new ESC lines and the advancement of work on SCNT.
Hatch’s coalition introduced legislation to legalise SCNT for scientific and medical research, while banning use of the technique as a means of cloning people. They also introduced legislation to allow access to surplus embryos from fertility clinics as a source of stem cells. Slowly, more and more legislators from both sides of the aisle signed on to the pro-research side of the debate. For the next several years, the two forces fought to a standstill, with both bills repeatedly introduced and defeated. This created a legal and scientific limbo that ultimately served the anti-research camp’s agenda: the few scientists working on SCNT remained out of prison but without access to funding, potential private investors continued to wait out the political uncertainty, and the President’s restrictions on ESC research remained in place.
False Dawn
Then suddenly, in 2005, came Hwang’s announcement of relatively high-yielding techniques for creating individually tailored ESCs. The news acted like a juggernaut, smashing through barriers both scientific and political. Technically, the ability to make viable, customized embryonic stem cells tailored to individual patients was a massive breakthrough. Politically, it not only reenergized pro-research forces, but applied a new source of pressure on politicians. Stem cell advocates had long argued that, if the government continued to keep a tight lid on ESC research, the science would be done elsewhere: the United States would simply suffer a brain drain, as American scientists moved to more hospitable climes to pursue their vital work and as foreign graduate students (already chafing under new security restrictions) refused offers from American universities. Now, the prophesy began to come true. The Korean government was ready to back their new scientific star’s work with significant resources; countries as far-flung as the United Kingdom, Israel, Sweden, and Singapore began establishing themselves as well-funded hubs for ESC research; and reports of prominent scientists packing their bags started appearing in the media.
The forces of competition began to work their usual magic. Individual U.S. states, fearful of being left behind, began putting up bills to fund stem cell research within their own borders. Federal politicians not strongly ideologically committed against ESCs—including many free-market-oriented Republicans—became increasingly willing to challenge the agenda of the antiresearch ideologues. A couple of years earlier, fifty-eight senators—most of them Democrats, but with substantial support from key Republicans—had signed a letter asking Bush to rescind his policy; a little over a month after Hwang’s announcement, 206 House members followed suit.
I knew that highlighting these advances, and the opening that they afforded to researchers, would be a great way for me to further my conference’s mission to promote anti-aging biomedical research. Short of Hwang himself, the best person to present the opportunities was Gerald Schatten, a stem cell researcher at the University of Pittsburgh who had been working with Hwang for the last two years, had used his veterinary techniques to clone a monkey, and had signed off on the paper announcing the new SCNT lines in Science. I asked him to present their results and outline the royal road to accessing patient-specific ESCs through Hwang’s team at Seoul National University: a “World Stem Cell Hub” that would generate SCNT cells to order using Hwang’s established facilities and experienced technicians.
I was delighted when Schatten accepted my invitation—but I was positively overjoyed when, not long after, he came back with another e-mail saying that he’d like to bring along a friend. Hwang himself had expressed an interest in presenting at SENS2, he said; he realized that it was short notice, but would I be willing to let him share Schatten’s own half-hour slot in the conference? I, of course, offered instead to give Hwang his own half-hour talk as a featured presenter in the session on stem cells and regenerative medicine. I’d have been happy to do this even if it had required throwing out my original schedule and starting from scratch, begging forgiveness from presenters as I shuffled them around at so late a stage in the planning of a very packed conference schedule; but fortunately I didn’t have to do this, as another presenter had recently been forced to pull out. With hardly any shuffling, Hwang was confirmed.
So it was that, with great pleasure on my part and keen attention from hundreds of my colleagues, Hwang mounted the lecture podium of Cambridge’s Fitzpatrick Lecture Hall.
Of course, as you know full well, unless you spent much of the winter of 2005–2006 in a cave in Nepal, it was all a sham. Within months of electrifying my scientific audience in September, Hwang had been exposed as a fraud.
Bad Wizards and Bad Men
First there were ethical questions about the sources of Hwang’s eggs; then, questions about the viability of four of the eleven stem cell lines that he had submitted to Science. And then, reporters looking at photographs presented with Hwang’s data began to notice some suspicious resemblances between allegedly unique stem cell lines. Hwang brushed these off as the result of a confusion with the Science production staff about which of the numerous photos that he had submitted were to be used as figures in the article.
The case against Hwang quickly picked up momentum. Scientists reviewing the paper’s data noticed suspect similarities in the genetic profiles of the various lines’ cells. Then Schatten requested that his name be retrospectively removed from the paper’s authorship because of “allegations from someone involved with the experiments that certain elements of the report may be fabricated.” And on December 15, one such collaborator came forward with the flat statement that nine of Hwang’s eleven lines were flat-out fakes, sharing identical DNA with one another, and claiming that Hwang himself had admitted the fraud.
As each doubt was raised, Hwang would protest his innocence, variously blaming errors, contamination, and the incompetence of others for each of them—even going so far as to claim that one former collaborator had “switched” some of his lines. But, eight days after his former collaborator claimed fraud, he proffered his resignation to Seoul National University—which was refused, on the grounds that he was now the subject of an internal investigation. He was suspended in February, dismissed in March, and indicted in May for fraud, embezzlement, and violation of bioethics legislation.
The fallout of these revelations was felt at many levels. There was, of course, enormous outrage at the fraud, and great disappointment that Hwang’s breakthrough turned out to be flimflam. And it was a political fiasco, exploited by anti-ESC campaigners to cast aspersions on the entire field.
But Hwang’s fraud had also set the progress of the entire field back by at least a year—an eternity in science. The Bush restrictions on ESC research, amplified by the looming threat of criminalization for SCNT from the American Congress, had kept all but a few research teams from working to perfect nuclear transfer for human patients. Hwang’s claims had further diminished the incentive to put resources into the goal: No one wanted to reinvent the wheel already spinning in Korea, and private firms would no longer have a competitive edge as the first creators of patient-tailored ESCs, using in-house methods that could be kept exclusive as trade secrets or through the patent process.
One private firm, Advanced Cell Technology (ACT), had been courageously soldiering on with the work, producing a great deal of quality ESC and SCNT science (much of it, admittedly, overplayed in the media)—this despite constantly lurching from one financial crisis to the next because of investors skittish over the legal climate of their research. In late 2001, they famously announced the first “cloned” human blastocyst,45 although the DNA that was transferred into the egg cell came from the donor’s own body—in fact, from cells that normally enshroud the egg itself—and the resulting blastocysts couldn’t develop beyond a six-cell ball. They spent much of the next two years perfecting that technique, issuing many publications (most of them on research done in cattle) charting their progress toward teasing out the reasons for the low yield of viable blastocysts in SCNT techniques, and working steadily to perfect the technique for human biomedical use.
In late 2003, insists ACT scientific director Robert Lanza, they were very close to resolving the sticking points in their technique, and could shortly have generated the first viable stem cells tailor-made for patients or for research on specific diseases. With Hwang’s eleven-cell-line announcement, however, investors began pulling their bets out of what was perceived to be an “also-ran” in the race—a blow turned into a haymaker by ACT’s simultaneous setback of losing their main source of human eggs. Cells were put into deep-freeze, and ACT’s human SCNT work shut down.
Equally infuriating is the case of Professor Alison Murdoch and Dr. Miodrag Stojkovic, of the Newcastle Centre for Life, a fertility clinic and research center in Newcastle-upon-Tyne in Britain. These researchers managed to create the first human SCNT blastocysts using DNA taken from the cells of a person other than the egg donor.46 Like the ACT cells, these blastocysts were not fully viable, but in the United Kingdom’s more research-friendly environment, the group had received formal approval from regulatory bodies to pursue work using SCNT-derived stem cells, giving them the green light to perfect their technique. But their publication came on the heels of Hwang’s, and compared to his explosive success, the creation of only three fused cells that actually began dividing, and no actual stem cell lines, seemed to be of no relevance to the progress of the field. They, too, promptly shut down their research on the technique—a decision that Murdoch says cost them at least a year.
It was the same story elsewhere. SCNT research teams in Sweden, and also at three American universities that had raised enough private or state money to set up stem-cell research centers with elaborate financial firewalls separating them from federally funded research elsewhere on the same campuses, either dropped their efforts altogether or put them on hold while waiting to see whether the Korean team’s plans would make their efforts redundant.
But if Hwang’s shot, heard ’round the world, turned out to be a backfire at best, it still served to wake up a lot of people. All over the globe, and especially in the United States, researchers began thinking seriously again about what they could do once they had access to the Korean team’s expertise. It promised stem cells with the miraculous flexibility of the blastocyst, but perfectly matched to patients suffering with the worst of the nightmares of aging: Parkinson’s disease, stroke, scarred and weakened hearts, eyes blinded by the death of light-sensing cells choked in their own waste, limbs withering away as the electrical sparks stopped flowing through nerve cells or muscle cells snapped one by one under the force of their own molecular decay. Labs began contemplating grant proposals. Young science students turned back to stem cell research as an exciting career prospect. The dawn was false—but its rays woke the slumbering forces of science all the same.
Today, after the collapse of Hwang’s house of cards, and in defiance of the Bush administration’s politically driven, morally misdirected obstinacy, the field is undergoing a renaissance. Murdoch and ACT have fired up their programs again. Teams are in hot pursuit of successful SCNT techniques, and the research and cures that they will enable, all over the world. Cutting-edge work is occurring at the Center for Regenerative Medicine at Edinburgh University, Scotland (taking over clinical research from the veterinary work that created Dolly the sheep); at the Karolinska Institute in Sweden; at Shanghai Second Medical University, China; and at several privately funded centers in the United States, including the Harvard Stem Cell Institute, the University of California at San Francisco, and UCLA’s Institute for Stem Cell Biology and Medicine.
The legal climate is shifting, too. In addition to China, Great Britain, and Sweden, SCNT is already explicitly legal in Singapore, Belgium, Japan, Spain, and Israel. And it remains legal in the United States, despite the efforts of Senator Brownback and his allies: the Brownback-Weldon bill has twice failed to make it through Congress, though it was reintroduced in 2005 as S 658/HR1357, the Human Cloning Prohibition Act of 2005. More excitingly, Orrin Hatch’s bipartisan Stem Cell Research Enhancement Act, which would have opened up ESC research using lines derived from IVF surplus embryos, passed both the House and the Senate, and was only blocked from becoming law by a Presidential veto—the first of Mr. Bush’s six-year administration. Hatch’s pro-SCNT bill is also back in play, although no vote is imminent.
Meanwhile, individual U.S. states are moving ahead, doing their best to sidestep the funding and regulatory vacuums at the federal level. SCNT research has been legalized in California, Connecticut, New Jersey, Rhode Island, Illinois, and Massachusetts, and although several other states have also specifically prohibited all SCNT work, many more are permitting work done using surplus IVF blastocysts. A ballot initiative in Missouri that would constitutionally protect scientists’ ability to conduct ESC and SCNT research, and patients’ ability to access cures based on these techniques that are available anywhere else in the nation, narrowly passed in November 2006.
The states are also digging up the funds needed to get work going inside their own biotech sectors. The most famous of these is California’s Proposition 71, a ballot initiative that established the California Institute for Regenerative Medicine and gave it a bond-funded budget of $3 billion to fund ESC work including (but not exclusive to) SCNT research. The actual disbursement of these funds has so far been bogged down by anti-research legal actions and some legitimate questions about oversight and ethics, but legal rulings have been almost uniformly favorable, and Governor Arnold Schwarzenegger has recently stepped in with a bridging loan, to start the Institute’s mandated dollars flowing toward development of SCNT-and other ESC-based cures.
And if California is the most famous case, it is far from the only one—or even the first. That honor goes to New Jersey, which in early 2004 became the first state to earmark state funds for ESC research. Starting in December 2005, New Jersey has put out a total of $5 million in grants awarded to seventeen research institutions for research on stem cells from embryos and other sources, and has set up the $23-million New Jersey Stem Cell Institute. Similar initiatives are starting up in Connecticut, Illinois, Maryland, Massachusetts (despite a failed veto attempt by the state’s governor), and the state of Washington.
Meanwhile, efforts have been under way in the private sector, despite the lack of support, adverse regulation, and a climate of uncertainty that sends all but the steeliest of investors off in search of other opportunities. ACT is one prominent example; another is Geron Corporation, a biotech company most famous for its work on the “youth enzyme,” telomerase (which it is now seeking to manipulate in order to shut down cancers by turning off the telomerase taps—see Chapter 12 for much more on this). Geron has perfected methods of raising human ESCs without feeder cells, and is testing six different lines in animals; excitingly, it expected to be ready to begin the earliest stages of human trials using neural stem cells for spinal cord injuries in the spring of 2007.
Some scientists are also seeking purely technical ways to liberate science from the phony moral dilemma surrounding the use of blastocysts for research into, and as cures for, human disease. There are multiple proposed ways to create ESCs from blastocysts without eliminating the potential for these cell balls to ultimately become human lives. One is parthenogenesis, a label taken from the technical term for “virgin birth.” In this technique, the genes in an egg cell (which naturally contains only half of a full complement, as it is designed to be augmented by those in the sperm cell at fertilization) are doubled up on themselves, thereby generating a complete set of DNA instructions; this allows the egg cell to behave enough like a blastocyst to produce ESCs for the egg donor, without actually fertilizing the egg. Another approach is to take stem cells from IVF clinics’ embryos that have defects preventing them from going forward to make a fetus, or to actually induce such defects into a patient’s DNA before making a blastocyst from it using SCNT, in order to eliminate even its potential to form a human life. Recently, ACT introduced yet another option: using stem cells derived from a single cell plucked from the blastocyst, while leaving the rest of them in place as a potentially viable embryo (as is already sometimes done for genetic testing of IVF embryos before implantation).47 Yet a fourth possible option is to coax adult stem cells into behaving more like embryonic stem cells, using growth factors and other chemical messengers, instead of using the inherent renewing power of the egg to do the same thing.48
I have no doubt that such work is valuable—but primarily because it will tell us more about stem cell biology. The lessons learned will allow us to manipulate ESCs and SCNTs more capably when the legal environment finally unleashes the scientific racehorses, champing at the bit to bring the promise of these cells to fruition. The specific techniques involved will probably not, and most certainly should not, be necessary to bring cures to patients with “official” diseases or to regenerate human bodies deprived by the aging process of their capacity to self-heal. Their perceived necessity is a purely political construct, unrelated to scientific reality or underlying humanitarian need. The real need is to free scientists from misguided interference with the quest to turn the enormous potential of embryonic stem cells, including patient-specific cells created by fusing a patient’s cells with an egg, into therapies for the sick and the old.
Fortunately, this is one area where nearly all my colleagues already essentially agree with me—and not just in biogerontology, but across the medical and basic biological science world. The grant-review scientists at the National Institutes of Health would be delighted to disburse funds to promising ESC and SCNT research around the nation, if their hands were not bound by their president’s executive orders. Everyone not under the blinders of a misplaced sense of moral responsibility to a ball of cells recognises the need for ESC research guided by responsible ethics and regulation, not artificial restrictions created out of confusion, fear, and the grasp of political opportunity.
Certainly, there are scientific hurdles to be overcome before ESCs can be used directly as medicine. We have to develop much more reliable techniques for deriving stem cells, transforming them into the kinds of cells that we need, and making them play the same full range of roles that the corresponding cells growing under the guidance of sophisticated developmental programs within our bodies already do. The nascent field of regenerative medicine is already making surprising progress even using cells and tissues grown from patients’ adult cells: tissue engineers are moving from cells to organs, seeding cells into a biodegradable scaffold that guides them to form into a structurally appropriate engineered tissue and then melts away, leaving functioning tissue behind.49 Human patients have been given functioning urethras, starting with cell-free structural tissue taken from cadavers and seeded with the patient’s cells, which have lasted seven years. Functioning bladders have been engineered and transplanted into Beagle dogs, and rabbits have received, and successfully used, engineered erectile penis tissue. And in the most ambitious work to date, cattle have been given simple kidneys created using SCNT, with DNA taken from an ear clipping. The rejuvenated cells were expanded, growing to fill in every cranny of a complex biodegradable kidney scaffold, and the resulting organ implanted. The artificial kidneys were functional, filtering the blood and producing a fluid with close chemical similarity to normal urine.
But the fundamental impediment to the dream of new cells to replenish bodies worn by the years or by disease is a political one—and so must its solution be.
Action Now for Science and Medicine
Nearly all the anticipated readers of this book are citizens of democratic states. A few live in countries that have already given their scientists the green light to pursue cures with ESCs within careful ethical and regulatory frameworks. If so, congratulations. You can help to lead the race for cures forward further by lobbying your politicians to increase funding for such research.
But probably the single largest share of my readership will be in the United States—the country that still makes the greatest contributions to world scientific progress, where young scientists still flock to chase the advancement of human capacity, and where government and industry funding could, if unleashed, have the greatest impact on the field. The National Institutes of Health need to have the brakes taken off their funding power, and to be allowed to step down on the accelerator—hard.
Your voice can help the scientific process along in a way that the scientists themselves can’t match. Write letters, join lobby groups, educate yourself about local issues and your Congressional representatives’ positions; then vote for pro-stem-cell ballot initiatives and research-friendly politicians. Excellent background information and tools to help you support favorable legislation are available from the Coalition for the Advancement of Medical Research (CAMR) at http://www.CAMRadvocacy.org. You can bring forward the date when animal studies become clinical cures—and when, eventually, the old grow young, their bodies renewed by their own rejuvenated cells and tissues. Scientists need your help now to bring medicine out of the lab and into the lives of suffering patients. When you and your loved ones need their help, you will want to know that you have done everything you could to support their lifesaving work.