In 1818 Mary Shelley wrote Frankenstein; or the Modern Prometheus, the stunning depiction of a human taking over God’s power of creation of life.  Shelley portrays the inordinate curiosity of young Dr. Frankenstein, his obsession with knowledge for knowledge’s sake, and for the glory of curing human disease, of achieving biological immortality.  Yet in the very instant of success, the human creator rejected outright his creation as “monstrous,” unfit for being, undeserving of human life.
Today, with human cloning, we stand on the threshold of an actual Frankenstein-like event: The cloning of the first human being generated in a test tube with electrical stimulation, without “natural” germ cells, the time-honored sperm and egg.  But today’s world is vastly different from the nineteenth century.  How would we react to Frankenstein today?

In an X-Files take-off, The Postmodern Prometheus, a mad scientist creates a monster by engineering a human with fruit fly DNA. The monster gets loose and causes mayhem in a small rural town. This episode is actually a fair dig at molecular biology, whose practitioners can claim with a straight face that the human genome has a gene for fly wings. Today this Franken-science offers yet more fearful monsters, called “embryonic stem cells” -- monsters that claim to offer replacement organs, perhaps immortality, for us all.  But how did all this monstrous biotechnology get here, exploding as if from nowhere onto the moral and political agenda? 

In some ways the history of reproductive science has actually shaped our views of what conception is, more than we realize.  Let’s review how we reached our current understanding of conception and development of the embryo, and our “natural reproduction” relates to “assisted” reproductive technologies including cloning and stem cells.  Finally, I’ll attempt to share a biologist’s perspective on the moral debate.

History of reproductive technology.
The technological transformation of human reproduction came about through molecular biology, a science that is dizzyingly new. Fifty years ago, DNA was unknown, and animal development was studied by pencil drawings of cut-open hen eggs. When DNA was announced by Watson and Crick as the blueprint for life, biologists wondered what became of DNA as developing organs matured.  Many believed that the DNA blueprint must degrade as organs “differentiate,” their blueprint options narrowed down to one--the liver, say, or the cerebral cortex.  The fertilized egg was capable of generating every essential cell type of the body; but the adult body cells, or “somatic cells,” appeared to have lost this capacity, restricted to their own final type. Muscle cells, it was thought, didn’t need genes to make nerves or kidneys; so they lost them. Only the new body’s own “germ cells”--producers of egg or sperm--retained the ability to generate an entire human being.
In the fifties, however, frogs were developed from adult cell nuclei transplanted into enucleated eggs (eggs with the original nucleus removed.)  Thus, the adult somatic cells indeed retain all the genes from the original fertilized egg, though all but a few are “switched off,” their program unavailable for use. This raised the prospect of creating “human clones,” human bodies recreated in toto from a single adult cell. Science fiction writers had a field day writing about human clones, even farming them for replacement organs.

In mammals, however, the “off switch on” most adult genes seemed more permanent, and many attempts at cloning failed.  We now know that although most mammalian cells retain all their DNA throughout development, their DNA acquires different patterns of “imprinting,” extra methyl groups attached to cytosines, one of the four letters in the DNA code.  These chemical tags act like punctuation marks, organizing how the DNA blueprint is “expressed,” its genes turned on or off.  An adult cell nucleus transplanted into an egg would have to correct thousands of these imprinting marks in order to “reset” its genes to restart the program of development without gross errors.  For this reason many reproductive biologists considered human cloning impossible.

Thus, in effect, reproductive biologists created and maintained the idea that the egg cell is fundamentally different from all other cells, and that adult cell nuclei could never “go back to the egg.”  But biochemical reactions by nature are subtle, involving energy shifts that are relatively slight.  Most enzymes can catalyze their conversions forward or reverse, depending on available substrates and cofactors.  Suppose the methylations of DNA imprinting could be reversed or repatterned.  The egg might not look so different after all; or at least no more different from adult cells than differentiated cells look from each other, say, a nerve cell compared with a liver cell.

Although cloning of adult nuclei was dismissed, there were other compelling reasons for egg technology, such as help for infertile couples.  In 1978 baby Louise Brown was born through “in vitro fertilization” (IVF), the union of sperm and egg in the laboratory, outside the human body. Many religious and ethical spokespeople raised a cry of alarm at this technological transformation of humanity’s most intimate practice, the creation of new life. But in medical terms, in vitro fertilization meant an enormous breakthrough for patients suffering one of humanity’s oldest sources of heartbreak: the failure to conceive a child. Most scientists saw a huge gulf between “assisted reproduction” and human cloning, which still seemed impossible--and which lacked immediate practical application.

In the ‘80s, cell biology looked more and more like applied chemistry, with molecular machines constructing the body as surely as workers built a skyscraper. The differences between body cell and fertilized egg looked ever smaller--and possibly reversible. Meanwhile, the new biotech industry made transgenic creations: Franken-foods and Franken-animals, such as sheep that produce life-saving human proteins in their milk.  These sheep needed their genomes precisely maintained from one generation to the next--in other words, they had to be cloned.

With this need in mind, in 1997 Ian Wilmut achieved the first mammalian clone, the lamb Dolly, from an adult nucleus inserted into an enucleated egg with a jolt of electricity. Dolly was at first largely dismissed as a lucky fluke, or even a fake. It seemed beyond belief that the egg could reset the thousands of imprinting marks--and it doesn’t, always, leading to frequent aborted embryos.  But since then, all kinds of mammals have been cloned, including a monkey and twenty-four “perfect” cows. Can the partridge in the pear tree be far behind?

While the public tried to catch its breath, the technical breakthroughs that made Dolly work enabled dozens of spin-off procedures with even greater potential for medicine. The most exciting is embryonic stem cells, with their potential to replace aging organs. What are all these new technologies? How do they relate to one another, and to the vexing question of human clones?

Reproduction: “natural” and “assisted.”
Most of this new technology centers on the unique properties of the human egg. The diagram (see Figure 1) outlines how human egg cells develop and become fertilized, and how technology can alter the process.

Human eggs develop before birth, from germ-line tissue in the female embryo. During “meiosis I,” the first developmental stage, the chromosomes (twenty-three pairs of two) are each duplicated and recombined with their pair-members.  Then half the chromosomes are expelled in a polar body, which restores the number of copies to two. At this stage--still containing two copies of each chromosome--the human egg remains in suspended development for many years, until the monthly onset of ovulation.

Human sperm, by contrast, undergo one round of duplication and two rounds of division, leaving just one copy of each chromosome when the sperm matures. At fertilization, as the sperm penetrates the egg, this event signals the egg to undergo its second round of division, expelling half its chromosomes again to leave one copy of each. The fertilized egg now has a full set each from father and mother.  It undergoes repeated cell divisions as an embryo.

If all this egg development and embryogenesis sounds baroquely complex, it is.  Perhaps that’s why only about one in four embryos conceived “naturally” survive until birth.  The womb is a harsh place for early embryos; only those that develop perfectly survive.   Reproductive scientists now believe that one reason for the high rate of developmental errors in embryos conceived outside the womb is that the petri dish is less hostile to imperfect embryos; doctors try to implant embryos that the womb would reject.

It should be remembered that all egg technology is difficult and involves tedious procedures.  Human eggs are tiny, and finding them in the human reproductive tract was an incredible technological feat in itself.  Some research has focussed on growing eggs in tissue culture, but with little success so far.  So what kind of incentives are there to continue such research?

When human eggs were first isolated, in vitro fertilization to assist infertile couples seemed the one reasonable application. But other applications gradually arose--some obvious, some less so, and some just plain weird. For would-be mothers who could not produce healthy eggs, “egg donors” were sought. Notices appeared on the boards of Ivy League colleges, soliciting eggs. Of course sperm banks were long known, but eggs proved a rarer and therefore more valuable commodity, earning sums that can pay a significant part of one’s college bills. (Unfortunately, however, egg donation also jeopardizes the donor’s own future fertility.)

The formation of embryos in a dish led to speculation about male pregnancy. In rare cases, embryos have implanted in the abdominal cavity of a woman lacking a uterus, and normal baby developed to term. In male monkeys, abdominal implantation has been successful. Could human males undertake this? No country now performs this legally, although a mistaken press release from a hospital led to thousands of inquiries.

Meanwhile, as IVF became routine, hundreds of unused embryos accumulated in freezers. Their existence led to questions: Were there uses to which we could put these embryos, other than creating human beings?

The breakthrough--first accomplished in the ‘80s in mice, and just recently in humans--was the conversion of unused embryos into “embryonic stem cells.” Stem cells are a form of tissue culture that retains the capacity of the original embryo to differentiate into any cell type, any tissue, possibly even whole organs.  Their imprinting patterns remain close to those of the original fertilized egg.
From a medical standpoint, with long lines of people waiting for livers and kidneys, this prospect was enormously exciting. But a problem remains. No embryo produced by IVF will have the exact genetic composition of potential organ recipients; and therefore, tissue rejection would limit the effectiveness of stem cells for most people.

For women, there may be a solution: embryos by “parthenogenesis,” the commencement of embryonic cell divisions from an unfertilized egg. The first step of this process was just reported by a commercial firm last November, although the exact nature of their achievement remains controversial. Parthenogenesis is attractive from a moral standpoint, since the absence of the sperm’s contribution of imprinted signals on its DNA means that such “embryos” would lack half the imprinting pattern needed for development and could never become human beings. But the incomplete imprinting might prevent full development of organs as well--and for men, the process will be unavailable. 
Suppose instead that we replace the egg’s nucleus with the nucleus of a skin cell from the organ recipient?  Now the replacement organ would develop with full genetic compatibility to the eventual recipient. Thus, from a practical standpoint, stem cell technology leads inevitably to cloning embryos from adult cells. In effect, the great science fiction dream (or nightmare) is at hand: The cloning of human beings (if an embryo is a human being) to mine them for spare parts.

And what if unexpected applications arise? Suppose some one wants to implant one of those “pre-stem-cell” embryos. If college students can sell their eggs, why can’t film stars sell their skin cells to would-be parents?

Moral and political dilemmas.
So much for what science is able to do with human eggs, today, and might accomplish tomorrow. But what ought we to do; what should be legal in a modern society?  Some religions claim to offer clear answers, while others sound less than clear; not surprising, since all the world’s major religious traditions arose long before the existence of human eggs was known or imagined.  Meanwhile, in modern democracies the medical enterprise has become our secular state religion.  To save a child’s life, anything is permissible--even to generate embryonic siblings and pick the one from the dish whose tissue type matches.

Politically, the debate has split both parties along unpredictable lines. Senator Orrin Hatch concludes that the embryo becomes “human” only once it implants in a uterus; before that, it’s fair game for stem cells. Does this mean he now supports anti-pregnancy methods that prevent implantation? Across the aisle, Senator Tom Harkin proposes to ban "reproductive cloning" (nuclear transfer to make a new person) but exempt "therapeutic cloning" (nuclear transfer to make stem cells).  This measure, he says, will “open the door to move ahead” with research to turn stem cells into replacement organs. But nuclear transfer is nuclear transfer--surely the practice of it will only hasten the day when humans are cloned.

The biomedical establishment seems to favor Harkin's line.  Researchers have so far largely condemned human cloning, while quietly pursuing “nuclear transplantation” to “replace old eggs”--so long as the egg then combines with a sperm. Half a clone is better than none.

Modern democracies generally aim for the Socratic maxim, “Justice is helping friends and harming no one.” In other words, we help our fellow citizens and loved ones while trying not to hurt anyone else. So who gets harmed in human cloning? The immediate problems may be medical--some cloned animals develop defects related to the problem of “imprinting.” A moratorium on human clones is certainly wise, to make sure we sort this out. If these technical problems get solved, what then?

What about stem cells? There may in fact be a stronger argument that stem cell creation physically harms some one, an embryonic human that never gets to fulfill its potential existence. How real is this harm? Can we simply define life’s start at a convenient point, like Senator Hatch, or like researchers who argue that embryonic life begins in week two, with development of the nervous system?

Another view is that all of these technologies and their discussion inevitably cheapen human life and degrade the worth of all human beings.  An advisor to President Bush, professor Leon Kass, makes this argument.  While acknowledging the benefits of medical science, “achievements for which we must be grateful,” we now find that “human nature itself is on the operating table.”  Kass argues that even in our rapidly changing society, “we limit so-called reproductive freedom by proscribing incest, polygamy, and the buying and selling of babies.”  Kass would include on this list of unthinkables abortion and all forms of assisted reproduction, especially human cloning.

Kass and other ethicists point to relatetd quasi-reproductive technologies which, they argue, could replace embryonic stem cells and provide the same hypothetical medical benefits.  Recently we have discovered “adult stem cells,” undifferentiated cells found in tissues throughout the adult human body.  Adult stem cells retain some of the undeveloped character of egg cells, including some of the patterns of imprinting.  These cells, we hope, may some day develop replacement organs while avoiding the dilemmas of egg technology.  On the other hand, such stem cells with their half-way imprinting might also make ideal candidates for commercial cloning of human adults. 

Why is cloning so bad?  Kass speaks of the “narcissism of those who would clone themselves,” and the “grotesqueness” of those who would clone others.  If a person giving birth to her own twin sounds like the ultimate incest, that must be pondered, in a world where even incest and zoophily find proponents on the Internet.  Ultimately, Kass argues, assisted reproduction turns children into “artifacts” of scientists, instead of the organic products of erotic human beings.  Mechanical, unthinking human cloning will ultimately lead to eugenics and inbreeding.

Behind these arguments, however, a biomedical scientist may fail to hear a concern concrete enough to deny the entire field of reproductive medicine.  Before the advent of modern medicine, was human life indeed valued more than it is today?  Especially infant life?  Long before unclaimed embryos languished in freezers, all societies have practiced disposal of unwanted progeny. In the time of Socrates, unwanted infants were exposed on the Acropolis. In Rousseau’s France, they were left to foundling homes with 90% mortality. Today we abhor these practices, but we do terminate pregnancies--a practice unavailable safely in previous times--and we argue about the rights of a week-old ball of cells. Might this be considered moral progress? Today, organ transplant physicians make life-or-death decisions based on the lack of donors--and desperate patients go to China to buy organs from executed prisoners. Would stem cell replacement organs offer an improvement?

In the X-Files, The Postmodern Prometheus, Scully and Mulder eventually capture the fly-gene monster.  In the end they release him in a night club in the Big City, the ultimate American refuge for outcasts and everything new and strange. Will the Big City welcome human clones? Let’s hope we work this one out before artificial wombs and AI’s make tomorrow’s headlines.

Resources
1. Green, Ronald M., 1999. “I, Clone,” Scientific American, www.sciam.com/1999/0999bionic/0999green.html
2. Kass, Leon R.  “Why We Should Ban Cloning Now. Preventing a Brave New World,” The New Republic Online, www.thenewrepublic.com/052101/kass052101.html
3. Leutwyler, Kristin, 1999. “Dolly’s Legacy,” Scientific American, www.sciam.com/explorations/1999/062199dolly/index.html
4. American Society for Reproductive Medicine (ASRM), 2001. www.asrm.com/index.html
5. Hicks, K., and Slonczewski, J. L. KAP Genetics and Development, 2001. www2.kenyon.edu/depts/biology/courses/biol14/welcome.htm
Note: Portions of this article were published previously in the Observer at Kenyon College, and subsequently in Analog Magazine.