CHAPTER 6
What’s Wrong with the Ledas?
As the last chapter shows, the history of cloning has been plagued with fraudulent claims and contested results. Every inch of progress gained has been hard won.
Nevertheless, the greatest problem today in cloning mammals is not social or political or religious objections, but the fact that, biologically and genetically, things usually go wrong in trying to create embryos healthy enough to survive to birth. This problem constitutes what could be called the Master Ethical Objection right now to creating babies by cloning from an ancestor.
The problems of creating human babies are often not appreciated until one starts trying to conceive. A woman’s eggs may be the most fertile as a young teenager, shortly after menstruation begins. She then continues to be very fertile until about age twenty-eight, after which her chances of conceiving with her own eggs start to drop, such that by age forty-five her chances are low. At the same time, especially over age thirty-five, her chances of having a child with a chromosomal abnormality, such as Down syndrome, increase.
Even if a couple successfully creates an embryo, that embryo does not necessarily become a baby. Eggs are fertilized when sperm travel up a Fallopian tube to fertilize a ripe egg, after which the resulting zygote must travel down the Fallopian tube to the uterus. The uterus must then be primed with just the right mix of hormones for the embryo to attach. Later in development, there is a kind of “checkpoint” beyond which most genetically defective embryos don’t pass. Exactly what this checkpoint is, is not well understood, but the fact of it is beyond doubt.
This checkpoint likely came about in human evolution to ensure that only the healthiest human embryos survive to birth. In total, about 40 percent of embryos either fail to implant on the uterine wall or miscarry, and half of those miscarried embryos and fetuses do so because of gross genetic defects.
The point is this: Even creating normal human babies is sometimes not so easy. And when assisted reproduction is needed, things get even more complicated. The reason why we have septuplets and Octomoms is that physicians sometimes put in seven or eight embryos to maximize the chance of getting one healthy, delivered child. When many or all successfully implant and grow in a womb that evolved for at most two fetuses, lack of oxygen and nutrients almost inevitably damage some of the resulting children.
Still, however hard it is to create a child through these methods, the risks and challenges in cloning as of the present are even greater—as we see even in past cloning successes and are reflected in Orphan Black’s Ledas and Castors. So let’s look at how cloning has the potential to go wrong.
DOLLY’S DEATH
Following Dolly’s death, five months before what would have been her seventh birthday, critics claimed that there was something about her unique origination that led to her early demise—that because Dolly’s DNA came from a lamb that had already lived many years, Dolly at birth had DNA whose telomeres were already short. Telomeres are the nongene segments of DNA at the tips of chromosomes, and as they shorten, our cells age and we get age-related problems.
This controversy needs to be carefully sorted out. Every alleged fact about cloning is highly politicized and claims about how Dolly died are no exception.
Wilmut himself cites two reasons for Dolly’s death. First, she was overweight, thanks to all the tourists, scientists, and reporters who fed her treats while visiting her. Second, for her protection, she lived indoors. All the time spent standing on her hind legs begging for treats, along with her extra weight, caused Dolly’s hip to dislocate, which contributed to her death from a progressive, irreversible disease caused by a respiratory infection that sheep living indoors commonly contract.
However, a postmortem analysis revealed that Dolly’s telomeres were in fact consistent with a lamb much older than her six years. So some reduction in her telomeres due to the advanced age of her donor’s udder cells may have contributed to her death. If her immune system was weaker because her telomeres were shorter, some would argue that she had less ability to fight off the lung infection than a younger lamb.
If shortened telomeres were responsible for Dolly’s death, whether directly or indirectly, this risk extends to all clones, and especially those whose ancestor was of advanced age.
MITOCHONDRIA AND CLONING
In the previous chapter, when we outlined how originating a person by cloning differs from sexual reproduction, we said that the genes would not come from both a man and a woman but just one ancestor. That statement was made to contrast sexual reproduction with asexual reproduction (cloning)—but it was not 100 percent accurate. When the nucleus of a somatic cell is transferred from an existing person (an “ancestor”), it must be transferred into something, and that “something” is a healthy egg, from which the original nucleus has been removed. And it turns out that those host eggs contain some DNA.
Host eggs with their original nucleus removed still contain something called mitochondria, literally “grain-like threads” in ancient Greek. These threads are frequently referred to as the powerhouse of the cell; they fuel cellular processes and, when dysfunctional, can cripple the body.
More important for us, human mitochondria contain thirty-seven genes, which a clone embryo would inherit. So, given that humans have between twenty thousand and twenty-five thousand genes, it would seem the statement that a clone’s genes come from just one person is 99.9 percent correct (or, more precisely, 99.9815 percent correct).
Nevertheless, some very bad heritable diseases ride on those thirty-seven genes. So bad, in fact, that in England (but not North America), ethics committees have allowed families with devastating, inheritable mitochondrial diseases to use biotechnology to swap the bad mitochondria in the mother’s egg with healthy mitochondria from a donor, in hopes of eliminating disease that may have plagued a family for generations.
Mitochondria replacement represents a different kind of gene therapy than the standard one, which fixes the lack of a particular, functional gene in a sick kid, because the changed genes are heritable and can be passed on to future generations. This is called germ line gene therapy (adding or replacing a single gene in a way that is not heritable is called somatic therapy). Although some ethicists and scientists think society should not have crossed this ethical bright line (they think somatic gene therapy is dangerous enough, let alone therapy with an impact that continues for generations), champions of germ line gene therapy retort that the whole point of making the change is to get rid of the inheritable disease for all future children of the descendants.
What the existence of those thirty-seven potentially deadly mitochondrial genes means for cloning is that whatever mitochondrial genes, or diseases, reside in the egg used will be inherited by any resulting clones—as well as any offspring they may produce.
PROBLEMS WITH PRIMATE CLONING
It is an axiom of modern medical ethics that before medical experiments on humans can be considered ethical, they must first be tried on (and found nonharmful, and hopefully even beneficial, to) nonhuman animals. To be ethical, an experiment that intended to create humans by cloning would require, first, lots of evidence that scientists could one, safely, and two, reliably, clone monkeys, chimpanzees, and apes. Only after achieving those results in primates might it be permissible, in very carefully controlled circumstances, to try to originate a human by cloning. But so far cloning primates, especially those most similar to us, has not been able to produce one normal primate baby, much less produce them reliably.
Although many species of mammals have been successfully cloned, embryos of chimpanzees created by somatic cell nuclear transfer often have the wrong number of chromosomes and therefore do not implant properly in the host uterus. After the primate embryos were created, their cells did not seem to divide properly.
In cell division, or mitosis, the replication and division of chromosomes is guided by things called spindles. Two key proteins (NuMA and HSET) guide the organization of other proteins necessary for the development of the embryo. In primates, these spindle proteins concentrate near the chromosomes of unfertilized egg cells—the same chromosomes that are removed to make way for the new adult cell nucleus in somatic cell nuclear transfer. The process of removing the old nucleus and inserting a new nucleus seems to damage spindle proteins. In non-primate mammals, these proteins appear throughout the egg cell, making it easier to replace the nucleus by cloning without damaging them.
To find out what went wrong in cloned monkey embryos, a team at the University of Pittsburgh School of Medicine fluorescently labeled the parts active during division of cells. They discovered that the mitotic (as in mitosis) spindles that guide chromosomes in cell division did not function correctly in cloned embryos. More important, they found that either the cloned monkey embryos lacked the NuMA and HSET spindle proteins or the two proteins were not functioning properly. Getting primate embryos (and therefore human embryos) to have these two key proteins, and to then have those proteins function correctly in organizing chromosomes around spindles, may be the key to successful human cloning. Recall that Ethan Duncan brags to Cosima in season two, episode six, that he and his wife, Susan, had “solved the spindle problem.” This is exactly what he is talking about.
In 2007, a team of researchers at Oregon Health & Science University did successfully create a stem cell line from a cloned primate nucleus. They also used somatic cell nuclear transfer, but did so more precisely. They didn’t use the DNA stains and X-ray lighting they had used previously, because they believed these techniques were what had harmed the primate’s DNA. Instead, they used a machine called “Oosight,” which allowed them to see the DNA-carrying structures in the egg. Importantly, the researchers micro-surgically gathered chromosomes at the right time during embryo formation so that the spindle proteins needed for each chromosome were present and functioning correctly. So they were able to successfully clone primate fetuses.
As Ethan Duncan would say—they solved the spindle problem! At least, they would have solved it, if they had been able to show that the babies that resulted would not miscarry and, when born, would be healthy and normal. We don’t know exactly why, but none of the primate fetuses completed gestation to birth. The Oregon team transferred seventy-seven embryos into different surrogates, but no fetus made it to day twenty-five.
One problem is that, to produce a viable fetus, the cycle of the cloned embryo has to perfectly match the menstrual cycle of the surrogate mother, a very difficult task to accomplish. Another problem lies within the embryonic cells themselves: They do not have the right epigenetic programming— supra-genetic instructions that affect gene function—to mature into an actual monkey. Cloned embryonic cells may lack the signals that would turn key genes on, or off, at various stages in gestation. So any resulting primate babies almost certainly are going to be born with major defects, such as the Leda girl Charlotte’s leg problems in Orphan Black.
It’s worth noting that the same team from Oregon Health & Science University also created human embryonic stem cells using the techniques, but the university’s Institutional Review Board (IRB) and Ethics Committee blocked them from creating human embryos this way. This recalls Ethan Duncan’s comment that his “Ethical Oversight Committee” regarded his work creating viable, cloned human embryos as “an ethical failure.” The reasoning for the committee’s judgment in the show is not clear, though one would hope that it didn’t just beg the question and assume that any creation of healthy human embryos by cloning was inherently wrong. (Nor do we know exactly what kind of ethics oversight committee it was. If in America, it would either be an IRB—for research funded with federal funds—or an internal ethics committee of a corporation such as at Merck or Monsanto. England and Canada have similar committees with different names and slightly different mandates.)
Why might this otherwise be an ethical issue? When fetuses don’t have the proper genes turned on or off at the right times, or don’t have the proper number of chromosomes, they will be born with significant problems. For instance, Down syndrome is due to a chromosomal abnormality; so is Turner syndrome in females, as well as Klinefelter syndrome.
Thus, any experiment that cloned human embryos from an ancestor and implanted them in the wombs of real women would run a high risk of creating babies with chromosomal defects, as well as other defects caused by genes not turning on or off at the right times in gestation.
As previously noted, this is the major reason why originating babies by cloning is unethical. There is a very high likelihood that any babies so produced would have major structural abnormalities, problems caused by deep-down irregularities in their genes and cells. As there are many other ways to create human babies, by sex or assisted reproduction, and many other ways to get children, using surrogates or by adoption, there is now no cogent ethical argument for allowing experiments to create human children by cloning.
WHAT’S WRONG WITH THE LEDAS?
In Orphan Black, a lot of things went wrong with clones: The Castor males have a brain disease; several of the Ledas, including Cosima, suffer (or suffered, in the cases of Jennifer, Katja, and another unknown clone from Poland) from fatal or potentially fatal autoimmune respiratory diseases; Charlotte has a condition that causes her leg not to function correctly, possibly of neurological origin.
Exactly what is wrong with the Ledas is hard to determine. We know that the Ledas are supposed to be sterile, but that Sarah is not. We know that high school teacher Jennifer, the German Leda Katja, and the Polish clone suffered from a respiratory/lung illness that killed them. We see Katja spitting up blood. We know Jennifer’s last days were spent at the Dyad Institute, which wasn’t able to prevent her early death.
There are several possibilities here. First, inheriting shortened telomeres from Kendall Malone, who was already middle aged when her cells were used, may be to blame; their immune systems might not be as healthy as a normal young woman’s.
Second, there might have been something in the mitochondria of egg donors that causes these issues. We know that Amelia was a surrogate mother for both Helena and Sarah, but probably the eggs that were used came from other, younger women; young eggs work best, and creating embryos from eggs other than those of the surrogates would give experimenters more control over the whole process. Almost certainly, each of the other Ledas would have come from a different egg; each egg may have come from a different woman and so could have different mitochondrial genes. That would help explain why some of the Ledas are affected and others are not.
Third, something might have gone wrong in the chromosomal reassembly of certain Ledas (like the problems with primates) that affects their lungs and maybe every cell in their bodies.
Fourth, something could have gone wrong with the attempt to make the Ledas sterile. This seems to be the main hypothesis the show suggests. Cosima tells Delphine and Scott that the polyps in Jennifer’s lungs and uterus seem to be from an autoimmune disease. Ethan Duncan says as much to Cosima, with the added regret that “we didn’t foresee the consequences” of using that method to cause sterility, meaning he didn’t foresee that it might also cause illness and/or early death.
Kira’s miraculous stem cells helped Cosima, presumably by pumping up her immune system to ward off the bioengineered polyps growing inside her lungs and uterus (evidence that shortened telomeres, and the attendant immune issues, are to blame). Whether Kira’s stem cells would also help the Castors is unclear.
WHAT’S WRONG WITH THE CASTORS?
The Castors’ autoimmune problems could result from shortened telomeres, as well, but issues with their mitochondria present a more likely answer.
Mitochondrial diseases can be really devastating; they resemble fatal neurological diseases, with symptoms similar to Alzheimer’s, Parkinson’s, muscular dystrophy, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and other terrible, degenerative neuromuscular diseases. When mitochondria become dysfunctional or start to die, this disease process affects every cell in the body. Given the way that mitochondrial diseases manifest, it is very likely that the Castors, either by design or, more likely, by error, have a defect in their mitochondria.
Remember when Scott autopsies the brain of killed Castor clone Seth? Scott examines Seth’s brain tissue under a microscope and exclaims to Cosima, “It’s like Swiss cheese, with amyloid plagues and rapid cell death. He wouldn’t have lived a week.” To which Cosima says, “It’s like Creutzfeldt-Jakob disease.”
Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy, a type of disease that makes the brain swell to bursting while destroying its tissue and leaving spongelike holes. If you think that this disease class is rare or impossible, think again. Most recently, a 2015 issue of the New England Journal of Medicine reported the deaths from a deadly new viral encephalopathy of three Germans who bred squirrels (the virus presumably jumped species somehow).
CJD has a fascinating backstory. German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob first published reports around 1920 of the fatal encephalopathy in humans that now bears their names. In 1976, D. Carleton Gajdusek shared a Nobel Prize with Baruch Blumberg for proving that CJD could be transmitted via brain tissue from one person to another (which, given the close resemblance of the Castors to victims of CJD, could suggest that the Castors were infected by scientists experimenting on them, rather than their disease being mitochondrial). In fact, CJD and other spongiform encephalopathies can be transmitted in various ways: by a virus, by injecting brain tissue of one animal into another, and possibly by eating the dead remains of infected animals. Between 1956 and 1984, some infertile women and very short children received hormones from pituitary glands of human cadavers to treat their infertility and growth issues, respectively. About 1985 (when authorities forbade further injection of such hormones), after many women had strangely died, scientists learned by autopsy that some of these women and also many British adults who had been given the hormones had died young from CJD from the infected hormones.
In 1997, pioneering scientist Stanley Prusiner received a Nobel Prize in Physiology or Medicine for proving, despite decades of skepticism of his colleagues, that a new class of self-reproducing pathogens associated with proteins could transmit lethal encephalopathies. Such proteins, called prions, probably cause CJD and other spongiform encephalopathies to be transmitted from one animal to another and, importantly, are not killed by standard methods of preventing infection, such as boiling or heating over flames.
All the encephalopathies are fatal; after symptoms appear, they lead to death in a few years or less. So what afflicts the Castors is very serious stuff. If it resulted from some mysterious contamination in their origination by cloning, that is a very bad thing. If it was built into them by design, that’s pure evil. That would mean the military clones had been programmed to die as young men.
The most well known of the encephalopathies is Mad Cow Disease, a bovine spongiform encephalopathy (BSE) that was discovered in 1986 to have infected hundreds of thousands of British cattle. In the 1990s, about forty people in England died from Mad Cow Disease. The disease is incurable and from signs of its first symptoms, it takes about fifteen months to kill. It appears that these people did not contract BSE from the infected cows directly, but rather contracted a form of CJD by eating meat from cows fed the remains of BSE-infected sheep. Because the disease may take decades to develop, and can only be verified with a brain autopsy, for which most families refuse to pay, exact figures for Mad Cow deaths are hard to determine. But the autopsies that were performed found infectious prions in victims’ brains, meaning it is almost certainly true that these BSE-causing prions were transmitted from infected meat to the human who consumed it. Alarmingly, cooking the meat did not stop the transmission.
We know that viruses also transmit BSEs, and now we know that prions transmit BSEs in ways hard to stop. So it is therefore possible that a Castor might spread a spongiform encephalopathy to female partners through intimate sexual contact.
In Orphan Black, we learn from the physician at the desert military compound that Dr. Coady’s original project was to cure the Castor men of their degenerative problem. But then, the physician tells Paul Dierden, Beth’s original monitor and a major in charge of the Castors, that a Castor brought back an infected woman, whom Dr. Coady studied. After that, the doctor says, Dr. Coady changed the nature of the research project—from saving the lives of his Castor brothers to something more sinister, involving, as Paul later puts it, “unsanctioned experiments on civilians,” in particular deliberately infecting unsuspecting women with a lethal disease. Dr. Coady told the Castor men to start keeping logs of the women with whom they had sex and to log a sample of their hair (for their DNA).
Toward the end of season three, Dr. Coady tells Paul that “Castors and Ledas have the same defect. It attacks the boys’ brains and the women’s epithelial tissue.” Dr. Coady wants Sarah because she believes Sarah can fight off the infection, a hypothesis Coady proves when she drugs Sarah and transfuses her with two units of Rudy’s blood. Sarah gets feverish and sick but quickly recovers. Still, whether Dr. Coady is correct about the Ledas and Castors having the same disease remains to be seen; Sarah’s lack of sterility and her ability to fight off the Castor infection are not necessarily related.
The show does offer one piece of evidence that they are, however: By comparing blood from a sick Gracie and cells from Seth’s brain autopsy, Delphine helps Cosima and Scott discover that both share a “weird protein,” made to look like an orange mini-monster on the computer screen. This weird protein—possibly a prion—is what has been making the Castor males sick and what they have been spreading sexually to unsuspecting women. The show suggests this may be the cause of sterility both in the Ledas and in the Castor males’ sexual partners.
ORPHAN BLACK AND DARK SCIENCE
One of the best things about Orphan Black is how often it gets the science right. However, not all the science in Orphan Black is correct, and the Castor clones’ likely spongiform encephalopathy is one example that doesn’t check out.
During the sixth episode of season three, “Certain Agony of the Battlefield,” things get a little harder to understand. After being told by the physician that Dr. Coady’s research project on the Castors changed when a Castor brought back an infected woman, Paul blurts out, “It’s a weapon!” Dr. Coady seems to agree. And it is possible that an infectious protein spread sexually could be a “weapon,” say, to sterilize women—especially if one goes with the paranoid thought, held by some in the early days of AIDS, that HIV was created to wipe out gay men and promiscuous black people.
But Dr. Coady goes on to defend herself by claiming that, “It could end all war. In a single generation.” It is unclear how something spread sexually could “end all war.” Then she adds another, seemingly different claim: “The science in that room could change the very nature of humanity.” How that is so also remains unclear.
Of course, other weird stuff has happened in Orphan Black that takes us beyond plausible science—the possibly miraculous healing powers of the stem cells of Sarah, Helena, and especially Kira, for one.
Pluripotent stem cells could one day be wondrous and nearly miraculous, as we discussed last chapter. Henrik is right, in season two, to regard biotechnology as something both life changing and humanity changing. Stem cells could even be seen, religiously, as God’s gift to humanity, a biological treasure whereby a person’s own cells are turned into healing machines to cure his or her sick or injured body. Many people, including this author, have championed a new era of “regenerative medicine” and “personalized genomics” based on use of a patient’s own stem cells. But the FDA has yet to approve stem cell treatments in anything but experiments, and those experiments have failed to uniformly prove great results. Unfortunately, unlicensed American clinics offering therapies based on stem cells (which can operate due to a loophole in FDA regulations), or even more unregulated clinics in Mexico and abroad, prey on those impatient with the slow pace of approval, charging exorbitant fees to gullible patients.
Even taking into account stem cells’ future potential, Kira’s nearly instantaneous healing in the emergency room after being hit by a car, and Helena’s recovery after Sarah shoots her, border on the scientifically unbelievable. It is just not in the realm of possibility and starts to creep over the line into the supernatural.
Two other incidents in Orphan Black cross that line and call for explanation. First, there is Olivier’s tail (which Helena, fascinated by it and considering Olivier an abomination, cuts off), and second, that wormlike thing in Dr. Nealon’s mouth that seems to attack Delphine in the final episode of season three.
In the unlikely event that it were possible to make such biological changes, for example, by genetic tampering with the embyro, they would be somatic changes, not germ-line changes. That is, they would modify the existing genes of a person but would not change his or her germ-line cells and so not be passed on to future generations through sexual reproduction. Even if Neolutionists used cloning to create an embryo with such characteristics (as cloning would give scientists the chance to choose the particular nucleus inserted into the egg and, more important, to modify it there), there is still that checkpoint in human embryonic gestation that genetically defective embryos generally don’t pass. Any embryo with a tail or wormlike tongue would not make it past this checkpoint and, hence, would not be born. And this is not even getting into the medical problem of the immune system, which rejects any kind of foreign tissue, and a wormlike appendage or tail is about as foreign as you can get.
ONGOING MYSTERIES
What is wrong with the Ledas is an ongoing mystery in Orphan Black. Their physical ailments create both problems for the Ledas and a sense of urgency to find a cure. What the eventual cure turns out to be, should they find one, could point to the inherent biological problems of being originated by cloning, or the quite different problems of bioengineered cloned humans being sterile, “weapons,” or something else. Both have a strong scientific basis, but each suggests a different set of ethical questions for the show to explore.