March 15, 1999

Creature Clones from Dark and Stormy Nights
Mary Had a Little Lamb
Frankenstein at the Minnesota Meeting
Time Out to Chill Out

Creature Clones from Dark
and Stormy Nights

   The whole question comes down
   to this: can the human mind master
   what the human mind has made?

Paul Valéry

In a way I was surprised that someone in his station, an engineering technician for pacemakers and other high-tech medical implants, would react as he did. After all, the patriarch of Minnesota's multibillion dollar medical technology industry, Earl Bakken, has often acknowledged that he owes his early inspiration to watching Dr. Victor Frankenstein's juiced-up patchwork monster on the silver screen.

The monster's animating force was an electrical shock delivered by a lightning bolt. Bakken, an electrical engineer by training, couldn't get this dynamic out of his mind--electrical currents and their effects on human physiological systems, on life itself. Thus the first transistorized cardiac pacemaker and its progeny.

But my brother's reaction to all the hubbub about human cloning is probably not atypical. Maybe it has something to do with androids, the human-like robots that filter through sci-fi movies and TV series like Star Trek. Or images of human replicas produced via pod technology in the sci-fi thriller Invasion of the Body Snatchers.

I suppose you want to have some confidence as to where you stand with others who generally look like you. A human clone, to many people, throws a monkey wrench into evolution. Not really an android. No gears or circuits behind the cosmetic shell. But not quite one of us, either. Not the product of an egg from Ms. XX and a sperm from Mr. XY in happy union and hatched the old-fashioned way.

I've never had a visceral apprehension about cloning. Not cellular, PC, animal or human. It may mean that, in the end, I will be among the first to be delivered up when the androids or the clones take over. But there it is.

My introduction to cloning came in the forerunner of the building where I now work, the Basic Sciences & Biomedical Engineering Building. Its forerunner was the Zoology Building. My first course in that building was one in American history taught by David Noble in 1969. Noble used to dress up like the historical figures of the day and act the part before us. Thomas Jefferson comes to mind.

A decade or so later, in the same amphitheater classroom, Robert McKinnell moved the subject from the historical Jefferson to the contemporary frog.

McKinnell, a professor genetics and cell biology, taught a course called "The Biology of Cancer." At the time he was making the news with his pioneering frog experiments. He had come up with an improved method for cloning frogs. The technique he used, nuclear transplantation, was originally developed in the early 1950s. It involved injecting the nucleus from one cell into an embryonic cell from which the nucleus had been removed.

Nuclear transplantation technology helped to make McKinnell a leading spokesman on cloning. Today, nuclear transfer, as it is now called, is at the heart of the current surge in embryonic stem cell research and animal cloning.

In his book Cloning: Nuclear Transplantation in Amphibia  (1978), McKinnell wrote that if cloning makes any contribution in the late 20th century, it "will not  be the replication of new individuals of political or scientific note, as is so often depicted by the media, but it will be a better understanding of how a common genome comes to be expressed in one environment as liver and in another environment as brain."

That is, it will be a boon to the study of developmental biology. And so it has, with mouse, sheep and cow clones (including a calf named Mr. Jefferson) now center stage in probing the mysteries of cellular differentiation, organ and systems architecture, and reproduction.

Human clones, waiting in the wings, may have to wait a while longer. It turns out that scientists working with monkeys have hit a barrier. But such barriers have a track record of falling before the steady onslaught of new knowledge. And we have a track record of taking after our cousins on matters of perceiving possibility: monkey see, monkey do.

Mary Had a Little Lamb

Mary had a little lamb, its fleece was slightly grey,
It didn't have a father, just some borrowed DNA.

It sort of had a mother, though the ovum was on loan,
It was not so much a lambkin, as a little lamby clone.

And soon it had a fellow clone, and soon it had some more,
They followed her to school one day, all cramming through the door.

It made the children laugh and sing, the teachers found it droll,
There were too many lamby clones, for Mary to control.

No other could control the sheep, since their programs didn't vary,
So the scientists resolved it all, by simply cloning Mary.

But now they feel quite sheepish, those scientists unwary,
One problem solved, but what to do, with Mary, Mary, Mary...

"Mary Had a Little Lamb" revisited

Meanwhile, electricity continues to animate, just as it did in the laboratory of Victor Frankenstein and the imagination of Earl Bakken and in their inventions. The nuclear transfer technology used to clone mammals today employs a mild electric current to bring about the matrimony of the recipient egg cell with its new nucleus and genetic material.

It was two years ago that the sheep clone Dolly made her debút to an astonished and bewildered world. I once worked for a geneticist of the nothing-is-impossible school and so have been cultivated to consider that nothing is impossible. In my experience, incredulity is much more common than surprise in bioscience circles.

The Halloween following Dolly's debút, the National Library of Medicine opened a major exhibit entitled "Frankenstein: Penetrating the Secrets of Nature."

"Frankenstein, the tale of a young man of science who creates a monster by animating human flesh, represents an enduring myth that has gripped our imaginations for almost two hundred years," said Elizabeth Fee, Ph.D., Chief of NLM's History of Medicine Division in a press release.

"This exhibition provides a serious historical examination of the many meanings of the Frankenstein legend. It starts with Mary Shelley's rational but tragic creature who searches vainly for human companionship and explores the different meanings of the celluloid monster of 1930s Hollywood and its continuing echoes in popular culture. We also see this exhibition as an opportunity to recognize some of the social, ethical, and philosophical concerns raised by such scientific endeavors as cloning, xenografting, the Human Genome Project, and other new developments in biomedicine."

The haunting scenarios of the human clone drummed up during Robert McKinnell's frog experiments in the 1970s have made their way to the birth canal.

That's an apt metaphor. I'm not sure that the Frankenstein story could have been created by a man. Given her circumstances, you get the feeling that Mary Shelley had no choice but to write it and would have even without the aid of a nightmare.

What she wrote was Frankenstein, or the Modern Prometheus. The novel's title, explained critic Caryn James in the New York Times  four days after the paper broke the story about Dolly, is a warning that still resonates in the era of cloning. Victor Frankenstein is the "scientist as Prometheus, who stole fire from the heavens and gave it to man, only to be slapped down by Zeus."

Ever since Shelley's book was published in 1818, wrote James, artists have continued to portray genesis as a "divine right or a natural event" that is tampered with only at great cost. The monster tells Frankenstein, "I ought to be thy Adam. But I am rather thy fallen angel." Adam and Eve gave God enough fits. "What business does man have fooling around with creation?" James asked rhetorically.

Mary Shelley wrote her classic during what Radu Florescu, author of In Search of Frankenstein , called the "haunted summer of 1816." Consider this:

• She was recovering from the death in infancy of her first child the year before and had plenty of anxiety about her infant boy born that year and expectations of more kids to come.

• Percy Bysshe Shelley, her poet husband, was likely under the influence of laudanum or tincture of opium. Not a sensitive husband or engaged dad.

• She was cooped up in the Villa Diodati on the shores of Lake Geneva with Percy and his bizarre companions which included Lord Byron and Byron's dandy, John Polidori, a physician know affectionately as "Polly-Dolly" (also the names of two sheep clones, it turns out).

• Percy preferred Byron's company to hers.

• Mary's half-sister and Byron's mistress who Percy also fancied, Claire Clairmont, was pregnant. Mary once characterized her as "the bane of my life."

• The weather was lousy. Lots of storms that summer.

• Byron prophesied the end of the world in his poem Darkness.

All this on top of the fact that Mary was the child of two famous people, the political philosopher William Godwin and the radical feminist Mary Wollstonecraft who died giving birth to Mary. And that her famous "nightmare" that inspired the tale took place amid nightly readings and discussions of Gothic literature and the latest scientific advances.

One of those advances was witnessed by the wife of the Italian physician Luigi Galvani. She happened to notice that the legs of an experimental frog twitched when its nerves came into contact with a metal scalpel that had picked up an electric charge. She dutifully reported her observation to her husband who deduced that nerves themselves transmit electric impulses. Another contribution by the frisky frog to higher-primate presumption.

So the "Birth of a Monster" was practically inevitable in such a mind, predisposed as it was to fantasy, packed with grim and sobering experiences, and preoccupied with generating and sustaining life.

Mary had a monster. The monster was created by her central character, physician-scientist Victor Frankenstein, who expressed second thoughts before his laboratory creation went on a rampage: "I doubted at first whether I should attempt the creation of a being like myself or one of simpler organization."

"Well, THERE'S his mistake," wrote Caryn James. "He should have started with a sheep."

Frankenstein at the Minnesota Meeting

I attended my first Minnesota Meeting March 8th with this column in the blastocyst stage of its development. The speaker provided the electrical current that gave it feet.

The speaker was Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania and former director of the Center for Bioethics at the University of Minnesota. His is without a doubt the most familiar voice associated with the expanding bioethics field.

Caplan has a gig going that no one can touch in an era of jaw-dropping genetic discovery, wrenching end-of-life decisions, and self-copy. He is every bit the promoter in his field that P.T. Barnum was in his. And he's as nimble at the podium as anyone you'll ever see. His marketing zeal is reflected in his center's Web site, bioethics.net, which requires you to download a 5 MB "Bioethics Console" just to get in. You are invited to fill out an information request form while you're waiting. (What's all this commotion about privacy?)

The title of Caplan's talk was "The Ethics of Making Babies: And Other Moral Dilemmas In the Brave New World of Medicine." At the urging of one of the meeting's floor lieutenants, I agreed to join the questioners following Caplan's talk on reproductive technologies and cloning.

I asked: "Dr. Caplan, would the public apprehension about cloning be any different today if Mary Shelley had written about, say, a 'secret garden' instead of a monster of human creation two centuries ago?"

Caplan answered: "Well, I'm tempted to say, certainly the Pennsylvania state legislative delegation is apprehensive, and they don't know anything about Mary Shelley or where their genes are. It took nothing to terrify them. But of course, that would be casting aspersions on politicians which we wouldn't do in Minnesota.

"I think that the myths that come to us almost from the Greeks--arrogance and the misuse of knowledge myths, and what we see when we look at legends in the bible about what happens to people who push their knowledge, even Adam and Eve eating the apple--I think these are deep seated worries that human fallibility and to some extent greed--that human nature is such that you can't trust.

One of the things that a senator said not too far from here, Tom Harkin [D-Iowa], is that once science gets going, you can't stop it. There's nothing to do about cloning 'cause it's out of the bag and it's sort of gonna go where it goes. He had this Gulliver model of science kind of squishing everything in its path as it stomped around the countryside.

I actually believe that science, technology and medicine are great things. I've said a number of times I wouldn't argue for turning back. I think a lot of the European attitudes ["Frankenfears"] about things like genetically engineered foods are silly. They don't make any sense in a world that's short on food. You want to sort of use this to get food.

But, no, I think the myths go deeper. I don't think its the science fiction or the Frankenstein myths. I think they represent deeper impulses."

Caplan said we "need to be proactive." He fears a lot could ultimately be lost if consensus is not sought and science continues to proceed on its merry way without involving the public at many levels.

On an international level, we should be "trying to push bioethics into our high schools and into our churches and religious groups. There's no reason that the things we've be talking about shouldn't be in the curriculum of all these different countries. There's been almost no real effort to support, by industry or government anyplace, good bioethics curriculum work...to get younger people to think about it. They're interested. They're going to face a lot of these challenges, and they should have parts of classes, or their teachers should know where the resources are to move on this. That would be an assist in the international area, to get young people talking to one another -- Internet Web site, that kind of thing."

Some background before some of these young people end up, say, in legislatures and assemblies. At a meeting with Pennsylvania state legislators recently, Caplan asked "Where are your genes?" A quarter thought they were in their brains, which Caplan thought was "a very optimistic evaluation." A quarter thought their genes were located in their "nether regions," whatever they are. Half had no idea.

"If you don't know where your genes are, you're not rippin' ready to go to start regulating human cloning," Caplan said. "There's room for improvement here."

Time Out to Chill Out

For almost 30 years now journalists and commentators have coupled the standard "raises ethical questions" line and the Frankenstein myth in trying to keep up with the blitz of breakthroughs in reproductive technology and biomedicine.

It is understandable why Arthur Caplan takes issue with what he calls "Harkinism," the notion that once it's out of the bag it's gonna happen and nothing we do will stop it. In an essay published in The Human Cloning Debate  (1998), he writes that there is "something terrifying about Harkinism. If accepted it means that there is really no point in debating or arguing about the ethics of any biomedical advance."

But Caplan disputes both the widely perceived "ethics lag" and Harkinism. In his view, they are both wrong. "It is simply not true that ethics has not had or cannot have an impact on what biomedicine does, or what biomedicine becomes. While the influence is not always obvious, once one looks closely it can be detected."

Ethicists, he argues, have played a role in a number of critical areas including:

• informed consent requirements in recruiting human subjects for research

• prohibitions on research on retarded children living in institutions and upon fetuses "except when it might be for their benefit"

• the inclusion of more women in clinical trials

• prohibitions against embryo research and fetal tissue transplantation, and

• the halting of research involving recombinant DNA in the 1970s "until sufficient oversight could be applied to experiments."

Make no mistake, we want these dark fantasies, and today we want them delivered through visual media. No one is going to stop us from having them. The "man-child" of our time is not a Gothic monster stomping around the countryside so much as the TV-addicted simpleton Chauncey Gardiner played by Peter Sellers in the satire Being There. "I like to watch," he says of TV over and over again.

We like to watch. By watching, our attitudes are influenced, and just maybe our neural networks are reconfigured ("Evolving Brainscapes in an Electronic Age"). After all, the age of the silver screen is less than a century old, and the age of the ubiquitous electronic screen is only a half century old.

The bioethics enterprise has been closely linked to academic research centers since its inception. Its greatest opportunity for growth is in the community at large, perhaps foremost, as Caplan suggested, in the schools. In the schools, bioethics discussions can serve as a rational counterweight to the power of entertainment media to play on our darkest fantasies and deepest fears, as Mary Shelley did in her time, and as Michael Crichton does today.

Writer and film director Crichton recently launched a strident defense of his art in "Ritual Abuse, Hot Air, and Missed Opportunities" published in Science  (March 5) based on a speech he gave in January at the meeting of the American Association for the Advancement of Science.

A physician-scientist by training, Crichton defended movie-making that in his case includes Jurassic Park, Contact, and Sphere  against charges of

• deliberately negative portrayals of scientists

• inaccuracy and made-up plot devices

• lack of positive stories, and

• lack of depiction of the scientific method.

Crichton's response? Chill out. If you make a movie taking into full account all of the above, nobody will come to the theater to watch it. Movie-making is about fantasy-making. We like to watch.

Science misunderstands media. You can never convey "a sense of real science through movies or TV shows," he argues. "You can only do that by exposing real scientists, with wit and charisma, to the waiting public in the media and the classroom."

Scientists themselves are in the best position to explain what they do and what it means. It is time for the scientific community to embrace rather than disdain its members who write for newspapers and magazines or appear in studio or online.

It should be considered part of their job to guide us in "the great adventure of our time" and help us understand the promise, the risk, the danger, and the hope.

    --William Hoffman    hoffm003@tc.umn.edu