In the Ethics Storm on Human Embryo Research

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In the Ethics Storm on Human Embryo Research

Wednesday, September 29, 1999

[by Wade in the New York Times.]

On the white paper tablecloth, Brigid Hogan is sketching a diagram with

the children's Crayolas the restaurant has thoughtfully provided. The

daughter of two artists, she draws rapidly and precisely. The structure of

an embryonic lung billows across the table. Words like " sprouty, "

" breathless, " " branchless, " playful names for the genes that control the

process, appear alongside arrows and curlicues.

Watching this gentle English biologist reach for another Crayola, it is

hard to believe she could ever occasion a threat, let alone one Congress has

deemed so severe that it has thrice passed a law to thwart it.

A leading expert on the embryology of the mouse, Dr. Hogan was the

scientific co-chairwoman and principal author of a National Institutes of

Health report on human embryo research.

The report, published in 1994, presciently described the benefits to be

expected from the study of embryonic stem cells, the primordial human cells

that were first isolated last November, and it said biologists should be

allowed to derive the cells from the surplus embryos created in fertility

clinics. Some biologists hope the cells will provide a universal repair kit

for human tissues.

The idea of destroying human embryos, even surplus ones, was daring

enough, but the report went on to recommend letting embryos be created by

mixing eggs and sperm in a dish, a procedure that could help treat

infertility.

President Clinton swiftly repudiated the notion of creating human

embryos for research purposes. And Congress was so perturbed by the report

that for the last three years it has specifically forbidden the National

Institutes of Health to pay for any research in which a human embryo is

destroyed.

The agency now believes it can legally finance researchers to use the

cells, though not to derive them, under rules recommended by a group of

experts, including Dr. Hogan. The guidelines are expected to be issued

imminently but abortion opponents hope to have Congress override them.

A clash of competing values was perhaps inevitable as biologists

started to part the veils around the mystery of life's earliest moments. The

report by Dr. Hogan and her colleagues, who included ethicists as well as

biologists, precipitated the maelstrom because it was a ringing scientists'

manifesto, a public declaration of the various types of human embryo

research that were about to become technically feasible and the medical

benefits to be expected from each.

Dr. Hogan works at Vanderbilt University Medical Center in Nashville

and holds a coveted fellowship from the Medical Institute, a

munificent patron of biomedical researchers.

In her office overlooking a graceful courtyard on the Vanderbilt

campus, she seems far removed from the political fray set off by her panel's

report.

" I think it is a tremendous shame that people funded by the National

Institutes of Health cannot work on embryonic stem cells, " she said. But she

has no present plans to do so herself. Apart from one foray into human

embryology, an attempt to derive stem cells from fetuses, her chief interest

has always lain with the mouse.

As a scientist, her purpose is to understand how embryos develop. For

the most part, that requires genetic manipulations that would be

unacceptable with human embryos. But because people seem to be constructed

with a very similar set of genes, research by mouse embryologists like Dr.

Hogan is laying the groundwork for understanding and repairing the many

human imperfections caused by defects in the embryo-shaping genes.

Dr. Hogan's interests in embryos are esthetic as well as practical.

Ever since she was a girl growing up near High Wycombe, a town 28 miles

northwest of London, she has viewed embryos as things of particular beauty.

" I carry a picture of a mouse embryo in my wallet to look at if I'm feeling

low, like people carry pictures of their family, " she said.

She studied biochemistry at Cambridge University and did postdoctoral

work at Massachusetts Institute of Technology on sea urchins. But the

genetics of sea urchins are not well understood, and besides, she said, " You

don't feel that warmly about the sea urchin embryo. " On returning to

England, Dr. Hogan switched to the mouse, which was then becoming easier to

study because of new advances.

Although scientists are supposed to be able to reproduce another's work

by following the recipes given in published articles, there are often

details of technique that never get written down. Dr. Hogan soon realized

that there was a whole body of arcane lore, known only to specialists, about

how to mate mice and manipulate their embryos. During a meeting at the Cold

Spring Harbor Laboratory on Long Island, a leading teaching center for

biologists, she mentioned to its director at the time, , the

idea of holding a course there to teach researchers how to do mouse

embryology.

Dr. abruptly left the table where they had been talking, leaving

her to wonder what she could have said to offend him. But a few minutes

later, the time necessary to visit his business office, Dr. returned,

saying, " It's all organized. " Dr. Hogan began teaching a summer course, now

in its 16th year.

Dr. 's enthusiasm was not mirrored at the National Institute of

Medical Research in London, where she then worked.

" At Cold Spring Harbor, everything is organized to get things done, "

she said. " In the N.I.M.R., people thought you were a nuisance if you asked

for anything. "

During Christmas vacations, the institute's building was closed for two

weeks, and those who wanted to work had to bring in their own heaters. Dr.

Hogan recalled how her ankles would burn while the rest of her shivered. She

decided one Christmas Eve that she could not be competitive in such

circumstances. Writing round to friends, she heard of a job at Vanderbilt,

where she moved in 1988.

With a group of 11 people, including graduate and postdoctoral

students, she is trying to reverse-engineer the mouse by analyzing the

genetic program that guides its development from an egg. Mouse researchers

now have many powerful techniques at their disposal. They can remove a gene,

creating a strain of " knock-out " mice that by their physiological defects

may reveal what the gene is meant to do. Or they can replace a gene with one

that makes a blue stain that shows when and in which tissues the gene is

active.

With colleagues at Vanderbilt and elsewhere, Dr. Hogan has found that a

particular gene, known as BMP-4, must be switched on if the embryo is to set

aside germ cells for the next generation of mice.

She is also studying the development of organs like the lung and the

lens of the eye.

Both require interactions between cells belonging to two of the three

sheets of tissue of which the early embyro is formed.

These interactions are governed by specific genes, whose roles she is

trying to define.

Though she focuses on the mouse, Dr. Hogan is keenly interested in how

the techniques she and colleagues have developed may be applied in medicine.

Now that human embryonic stem cells have been isolated, they allow

human embryos to be manipulated with the same mastery as mouse embryos,

although of course most of the changes made to mouse embryos would be

ethically unacceptable in humans.

Dr. Hogan agrees with researchers who believe that human embryonic stem

cells are likely to be useful in repairing ordinary tissues in adults or in

a fetus. But she opposes the use of altered embryonic stem cells to make

changes to an individual's germ line, as is done routinely in making

knock-out mice.

" I think the technique is far too risky and is unlikely to ever be

perfected to the stage when it is absolutely 100 percent reliable, which is

what one would have to insist on, " she said.

Sitting at a dual-eyepiece microscope, Ray Dunn, one of Dr. Hogan's

graduate students, shows a visitor the magical moment when the mouse embryo

changes from a blob to a being. Up to six days after fertilization, the

embryo is a tiny white opalescent cylinder, still far more like an egg than

an animal. But by the eighth day it has billowed out into a tier of buds and

whorls, visibly destined to form head, heart, limbs and tail. Human embryos

look much the same, though they have a more flattened-out appearance.

Though embryologists are far from being able to understand how a mouse

or human is put together, the problem does not seem insoluble. Five families

of signaling genes, many used over and over again at different stages of

development, seem to control a major part of the mouse embryo's development.

When all the developmental genes and their functions are known and

entered in the databases, won't the mystery of life be dispelled and its awe

destroyed? Dr. Hogan doesn't think so. The embryo, she said, " is to me the

most beautiful thing in the world, quite exquisitely beautiful, and the idea

that one could eventually describe how it is formed and grows just in terms

of molecules and genes and pathways doesn't detract from the beauty at all,

makes it more awesome, in fact. "

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editor: Lenny Schafer east coast editor: , Ph.D.

schafer@... CIJOHN@...

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