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It's Hard to Make a Human

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Why Clones Fail

Watching Colin Clive cobble together a slab-headed Boris Karloff out of spare body parts always seemed a little simple to working biologists. Now it turns out that starting with living tissue isn't going to easy, either.

A living organism, any organism, is incredibly complex, and works according to a complicated biological protocol. Forget Boris Karloff -- babies in the womb face a perilous pathway to birth, fraught with potential errors, and Mother Nature has a more ruthless record than any professional abortion doctor.
For which we should all be grateful...

Efforts in Italy and the United States to clone a human are creating an uproar on all sides. Fertility expert Severino Antinori, a professed Catholic, is ignoring the criticism of his church and worldwide protest from scientists. Together with Pavos Zanos and Avi Ben-Abraham, Antinori is gleefully soliciting volunteers for a self-financed project, and has reportedly received six hundred applications so far.

Three years ago, Richard Seed, a physicist, publicized his own independent effort to clone a human. Now, a religious group called the Raelians have announced their own human clone project, based on religious beliefs that humans are actually cloned extraterrestrials.

In testimony before the U.S. Senate, Zavos has claimed that his group has all the knowledge necessary to clone a human -- and that there will be no collateral harm. All deny that they will need to create dozens or hundreds or even thousands of failed embryos to get one success. They also dismiss the very distinct possibility that even their "successes" will turn out to be abnormal.

These self-styled pioneers are running into a stiff headwind not just of ethical concerns, but of news from many involved in cloning large animals, that the clones are very likely to be sickly or malformed. ("Cloning Linked to Genetic Errors," by Gina Kolata, the New York Times, March 25, 2001.)

Current cloning technology involves discarding very high percentages of embryos, as much as ninety-nine out of a hundred, something unacceptable in experiments with humans. Antinori and Zavos claim to know how to avoid this.

I doubt very much they have solved all the potential problems. These so-called pioneers are arrogant at best; at worst they could do real damage to the cause of genetic medicine. They may also be too incompetent to conduct any useful research.

Should human cloning research be banned? That's another article, but in short, no; too many research programs rely on useful laboratory techniques that could be labeled cloning by zealots, and banned as well.

Should scientists like Antinori and Zavos be allowed to proceed? I doubt that anyone will be able to stop them. They might be willing to move from country to country, outracing laws enacted against their work, until they end up in a backwater nation with no laws or lawmakers to speak of, and can proceed with their miserably ill-conceived experiments.

Or, they'll do nothing, but continue to mouth off to the world at large, grinning in gratification at all the attention they receive, and discrediting the more cautious, serious work of their betters.

Some scientists involved in cloning research believe that full-term artificial clones are malformed because of technical glitches in the laboratory cloning process. This involves rapid genetic reprogramming of the donor nuclear DNA by the host egg. Nobody understands all aspects of this reprogramming, which sets the nuclear DNA into an early, non-dedicated state of naiveté, ready to help create an entire individual rather than a single kind of tissue. The process is so extraordinary and complicated that many scientists believe this is where the majority of mutational errors will occur.

While this is certainly likely, other, more complicated factors could come into play.

Full-term clones may fail to thrive because scientists have completely gone around the extensive judging and abortion of potential offspring that occurs in nature.

Today's view of biology is just beginning to absorb the requirements of thinking of life as an incredibly complicated and interrelated system, self-regulating, and in many cases as creative as the human brains that study it. Biology is one of the last bastions of humanocentric thinking -- adhering to the belief that being able to learn and adapt creatively, using complicated mental or mind-like processes, is a uniquely human talent.

But however creative life is, the process of manufacturing a large animal in an egg or a womb is extremely difficult. Errors frequently occur, even with robust DNA and healthy, natural growth processes. Nature's first response to major errors, in the early stages of embryonic development, is to reabsorb -- to miscarry in a gentle and largely unobtrusive fashion. More serious spontaneous miscarriages can occur at later stages, usually within the first trimester for humans -- the first three months of development. These fetuses are often malformed, or have some less obvious defect that triggers the mother's abortive response.

Caring for a full-term infant that is likely to die, or to never become a productive member of the community, is simply a waste of time and effort in nature. The mother, freed of her defective offspring, is able to give reproduction another try. (In God's abortion clinic, no protestors are allowed.)

How do errors arise? Older theories assert that DNA is the final and exhaustive template of embryonic development, the exact blueprint and dictatorial, top-down master builder of the eventual organism. In fact, it is not.

So-called blueprint DNA is carried in the nuclei of an embryo's developing cells. These cells coordinate and assign each other different tasks, which means they express different molecules from the same DNA. Over time, cells use these proteins to become different kinds of tissue. Knowing when and how a cell's eventual role in the organism -- its "fate" -- becomes fixed, is key to understanding development.

Further complications arise. Metabolic organelles called mitochondria have their own loops of DNA. (It's now generally accepted that mitochondria are highly adapted descendants of certain kinds of bacteria, who have established a slavish symbiotic relationship with eukaryotic cells.) Mammals and most if not all other large animals inherit their mitochondria from their mothers, not their fathers. (Mitochondria from sperm cells are destroyed soon after fertilization.) Host egg mitochondrial genes can migrate to nuclear DNA even after birth, reducing the fidelity of any cloned copy.

Nature doesn't seem at all fanatical about genetic purity, unlike certain would-be clone masters.

Embryonic stem cells are naïve cells with their whole life and development ahead of them. They are capable of becoming any kind of tissue in the final organism. Once they have grown into their final role, however, very few cells are capable of reversing that development. (Some cells appear to be more flexible than was once thought, but none will ever again have total flexibility.)

DNA now seems more like identical sheets of blueprints carried around in the pockets of trillions of workers, laboring from the bottom up to construct an immense skyscraper. The master builder doesn't exist, apparently -- only the workers. Individual cells toil in time-honored and traditional ways, talking to each other, constrained by codes and protocols and timing cycles within the DNA, but still capable of making judgment calls within their range of expertise.
Nuclear DNA, all by itself, can't possibly "understand" or predict all the contingencies that arise during development, at the cellular level. Speaking metaphorically, the code within the DNA cannot be made flesh without the expert feedback of some of the very mechanisms it codes for. This allows the growth of a developing organism to continue despite variation in levels of nutrition, minor injury and repair, and those most pernicious companions to any building project: mistakes.

What DNA allows, and relies upon, to complete any and all construction projects, is a certain degree of cellular freedom, in short, bottom-up judgment.
Cells are themselves incredibly complicated organisms, with their own needs and "desires". They are strongly constrained by many factors, not the least being molecular orders expressed from their own nuclear DNA, but they also receive instructions from nearby cells—signals that tell them, to a great extent, when to divide or not divide, where to go, what to attach to, and what to do next.

Cells are also told when to die. Cellular suicide, called apoptosis, is essential to the developing organism. In humans, fingers are formed from a mitten-like, early-stage hand by the death of tissues between the developing finger bones -- a kind of sacrificial sculpting. The remaining cells attach and close off, most of the time. By far the great majority of cells cooperate fully. However, some cells may resist these signals and cause problems. (Webbed fingers and feet are not uncommon.)

Why some cells resist the instructions of their peers is important to understanding not just embryonic development, but diseases like cancer.

The skyscraper analogy is pretty useful, though of course not exact. Skyscrapers aren't made of the workers who build them, but our bodies are. (And no successful skyscraper depends on trillions of engineers and welders diving off the top and splatting on the surrounding sidewalk.)

Birth is a collaborative process, with many layers of accounting and bookkeeping. In the womb, at every major stage of development, the embryo is sending persuasive and reassuring signals to the mother. From an early stage, the embryo deceives the mother's immune system into believing that it is not foreign tissue. The father's contribution to the embryo's mix could otherwise provoke an intense immune attack. Later, the growing fetus transmits signals that serve notice that successful stages of development have been reached. These are like applications for permits to finish construction, having met necessary goals in a timely fashion.

Very likely, such signals cannot be sent unless masses of cells have differentiated correctly and formed the required tissues and organs. If the mother's requirements for timely and correct embryonic development are not met, the mother may starve the embryo, or otherwise induce miscarriage.

Some of the signals and responses may be internal to the embryo. If it does not meet its own goals, the embryo will stop its growth, and either be reabsorbed or aborted.

All these tests, internal and external, must be passed for the embryo to get its certificate of approval -- permission to proceed to full term.

Similar processes occur in externally developing eggs, bird eggs, for example. Some simply never hatch, their defective embryos graciously exiting the highly critical stage of nature even before the curtain rises.

In mammals, potential egg cells within the ovaries of the unborn female are judged and weeded out as the ovaries develop. This egg reduction (an internal "candling" and "addling") is crucial to later reproductive success.

Sperm editing is much less rigorous in males -- defective sperm rarely reach their targets, and the female provides plenty of obstacles in her reproductive tract to eliminate weaklings and gimps. Lymphocytes then move in and gobble up the dead and dying losers in this awesome, microscopic marathon.

The obstetrical statistics are sobering. Almost a third of all human pregnancies begin as twins, but in the great majority, only one infant is born, the other -- presumably the weaker -- dying and being reabsorbed. Textbooks on human birth defects are even more sobering. Despite all these judgmental processes, a fair number of infants go to term with defects that greatly reduce their chances of survival, or of living fully productive lives. The textbook photos of sad and sometimes nightmarish products make up a catalog of all possible developmental mistakes.

Not all these unfortunate failures can be traced to bad genes. Genes can be expressed incorrectly, leading to cascades of errors. Sometimes, fetuses may simply be too persuasive in avoiding the negative judgment of the mother's permitting process; they almost literally lie their way into being born. Or, the mother's own "inspectors" are dangerously lax.

More subtle, but perhaps most sobering of all, is the litany of defects large and small that can be found in apparently healthy and fit humans. Each of us carries some kind of defect, or potential defect, however minor. These can manifest at different stages in life, and are often but not always caused by a mutated or deleterious gene, or miscommunication between complexes of important genes. They may be as tiny as a tendency to form moles (little communes of dissenting skin cells), or as heartbreaking as the wide spectrum of learning disabilities called autism.

They can also be as potentially lethal as a tendency to develop cancers.

These subtle, post-birth difficulties may reflect bad genes, but may also result from hidden developmental mistakes, not easily attributed to any particular genetic anomaly.

The workers screwed up, and the skyscraper lacks one or two floors, windows fall out too easily, or it doesn't survive the stress of an earthquake.

Back to cloning. Using current techniques, ninety-nine out of a hundred cloned embryos die even before they are inserted into their host mothers. That's much higher than the failure rate of fertilized eggs in nature.

But the surviving cloned embryos are selected for implantation not by their mothers, but by scientists, who remain relatively clueless about the complexities of development and birth. (No one yet fully understands these processes, and claims otherwise reveal the worst kind of medical hubris.)

Candidate cloned embryos are inserted artificially in the host wombs, and then nursed, with drugs and other unnatural incentives, to reach full term. In this environment, the mother's role as a natural selector of offspring is reduced or eliminated. The result: even apparently healthy offspring have a good chance of becoming sick after birth, or have hidden malformations that severely reduce their lifespan.

No one ever thought cloning would be easy. But clearly, scientists will have to learn to interpret these signals and permitting processes in their experiments, to achieve the much higher success rates of nature.

Medical science has often been called a double-edged sword, allowing both healing and abortion. But nature is far harsher than any medical doctor.

If we wish to supplant or replace nature, we will have to recreate the ruthless early judgment of that most natural and loving of institutions, the mother.

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