By Craig Farrand

To the layman, news stories of scientific and medical breakthroughs can become quite staggering; pioneering medicines and techniques have revolutionized the way in which people think about their own body. Or of a body within a body.

In the micro-world of prenatal medicine, the discoveries and advances are no less astounding - and have changed not only the public perception, but even the medical perception of the developing fetus.

But where their predecessors could only observe, offer opinions and wait for delivery, today's doctors are literally entering the world of the fetus, not only getting a close-up view of the developing patient, but also taking surgical steps to correct - and even prevent - defects and deficiencies in postnatal life.

Not surprisingly, however, stepping into the womb is fraught with its own dangers and challenges- the first of which is painfully obvious. the patient is only six inches long - about one twelfth the size of a full-grown person - and weighs only about four ounces - about one-six-hundredth the weight of a full-grown person.

Yet therein lies part of the story of fetal surgery: the development of microscopic instruments and techniques that allows the team of physicians to apply their knowledge and skill in ways never envisioned even a generation ago. Such are the challenges that face doctors working on the cutting edge of fetal surgery - using procedures that cross three distinct physiological environments: the mother, the womb and the fetus inside.

Not only does the risk simultaneously involve more than one patient, but the hazards inherent in any medical procedure are also magnified by the very nature of the core patient's tiny size.

Still, researchers at the WSU School of Medicine have found ways of meeting those challenges - and in the process have not only repaired defects that had been historically out of reach, but also have opened the door to possibilities never envisioned. They can even offer hope to some families faced with the prospect of terminally-ill babies.

Fetal surgery is a relatively new entry into the medical lexicon. Although the first successful transfusion of blood into a fetus was performed in 1963, and the testing of amniotic fluid (amniocentesis) has been practiced for more than 20 years, the arrival of actual surgical procedures in the womb came only in the past 10 years.

Together, these four men are literally writing the book on fetal surgery - in both the application and the techniques used. That they work as a team in 1996 is part story of natural progression and part story of good timing.

The story begins in the 1960s, with that first fetal blood transfusion. Ironically, however, the record is pretty well blank for the next 20 years. Although the development of ultrasound and its widespread use in the 1970s gave doctors their first good "real-time" look at the developing fetus, there was little they could do to correct any defects they discovered.

In the late 1980s, Dr. Michael Harrison of UCSF performed the first true fetal operation - open surgery to correct obstructive uropathy. Wayne State followed UCSF and performed open fetal surgeries several years later. Collaboration continued between UCSF and WSU and in 1994 Wayne State began using in utero endoscopy s techniques to operate on the fetus without opening the womb.

For Dr. Evans, these procedures are the culmination of years of study in fetal medicine. Working at Hutzel, he was instrumental in the development of chorionic villus sampling (CVS) and other prenatal diagnosis techniques bringing embryonic screening to parents whose family histories might indicate genetic disorders.

His goal, of course. is obvious: to allow parents to have and raise healthy children.

"There's probably nothing worse that can happen to a family than to lose a child," he said. "We've seen hundreds, if not thousands of women who have lost a baby - and it always has an effect. That's one of the things that drives us to offer the kinds of prenatal diagnoses we do.'

Today, Dr. Evans is director of the division of reproductive genetics and director of the Center for Fetal Diagnosis and Therapy at WSU/Hutzel Hospital where he has helped WSU become a premier perinatal research

For Dr. Mark Johnson, an ob/gyn and genetics specialist who serves as associate director of Hutzel's division of reproductive genetics, the attraction to fetal surgery came as a graduate student at the University of Minnesota.

"I was attracted to genetics by the study of malformations and maldevelopment," he said. "And I became interested in finding out how and why things happened. In the end, I realized that if you can fix a problem during the early stages of development, then the prognosis and outcome can be significantly improved."

"A good example is diaphragmatic hernia," Johnson said. "In and of it self, it's an inconvenience; it's just a hole in the diaphragm and the bowel gets up into the chest cavity.

'If it happens to you as an adult, it's not a big deal: Doctors do surgery, pull the bowel down and patch the diaphragm.

"But in the developing embryo, it is a big deal because it unbalances the delicate series of events that drive normal development," he said. "So if you're a fetus and your guts are in your chest, your lungs can't develop; they can't inflate and the fetus actually dies from lung hypoplasia or inadequate lung tissue."

In short, while the hernia itself may not be an immediate danger, the long term impact of the hernia on fetal development is - and that means fetal surgery.

But what kind of surgery - open or in utero?

Both methods are employed by Wayne State surgeons. One calls for the fetus to be partially extracted from the womb, while the other involves surgery through the uterine wall, using fiber optics, needles and miniature instruments. The method depends on the problem that needs correcting, however, certain problems are not suitable for in utero surgery.

Certainly a remarkable achievement by anyone's standards, open fetal surgery is one that has been witnessed by Dr. Alan Flake firsthand - more than 75 times. And his first exposure came as part of Harrison's San Francisco team.

"We started doing real invasive surgery in San Francisco," Dr. Flake said, adding that the team's first successes were in the area of repairing diaphragmatic hernias - not surprising, given Harrison's view of the "downstream effect."

By the mid-'90s, Dr. Flake was ready to move on - to the only other center in the world exploring fetal surgery applications and techniques: Hutzel Hospital and the Wayne State School of Medicine.

"I thought there was a real opportunity here to build various fetal clinical programs," Flake said about his arrival in 1994 and his appointment as director of fetal surgery at Children's Hospital/WSU.

"Everything really was in place and all I had to do was bring my expertise. Mark Evans had built a good fetal therapeutic program prior to my arrival," he said. "I felt like I would be the final piece of the puzzle by offering open fetal surgery as well as other capabilities."

"As a pediatric surgeon, I'm used to it," he said. "I'm used to working with magnification and small instruments."

What Flake also brings to the table is his work in the area of genetic therapy: invading the fetal world to alter the otherwise inevitable development of harmful or even deadly malformations.

During this procedure, however, the tissue of the father - which was only a 50 percent genetic match - was placed into the developing fetus' abdominal cavity three times in a two week period, beginning at 16 weeks.

"Because of the unique development properties of the fetus," Dr. Flake said, "there is a time during gestation when its own system is immunologically immature and will accept outside cells as its own.

"The possibilities for such prenatal stem cell therapy are enormous; we could use this procedure to eliminate sickle cell anemia, or other immunodeficiency problems," he said.

Still, Dr. Flake has reservations about the procedure's ultimate use. "The possibilities are there, but it doesn't mean we'll pursue every one," he said. "In the end, it's going to be a matter of making choices based on what is appropriate for a particular patient and on what society is willing to pay for."

Not surprisingly, only those conditions that lent themselves to open surgery were initially good candidates for any kind of intervention - and with good reason. Although an amniocentesis needle could enter the womb, very little else could, and vision was limited to whatever primitive monochrome images early ultrasound equipment could produce.

The diaphragmatic hernia case was one of the first to be treated at Wayne State. The first successful surgeries repaired the hole in the diaphragm; however, a new approach was introduced two years ago. Instead of repairing the hernia directly, doctors tied off the fetus' trachea. Once returned to the uterus, the fetus' lungs then began to fill normally with fluid, forcing the intruding organs back into their abdominal spaces. Only after the birth of the baby would the hernia itself be repaired.

Even today, open surgery techniques are contemplated for some conditions, but the clear advances in fetal intervention are now coming in utero: going inside the uterus to perform surgical procedures with minuscule instruments and fiber-optic systems.

That's where Director of Fetal Endoscopy Ruben Quintero comes in: perinatologist, part designer, part research and development engineer, Dr. Quintero has spent his career in dogged pursuit of the techniques and

Working in a world reminiscent of "Fantastic Voyage" - a movie in which a team of scientists were shrunk to cellular size and then inserted into the body of a human being - Dr. Quintero's goal in life seems to be to illuminate the issue of fetal surgery.

Literally.

"I think my role in the group, my contribution to the world of fetal therapy," he said, "has been the development of endoscopic techniques - both to diagnose and to treat birth defects and other conditions.

"There's a team of people involved, and my role in the team is in the use of endoscopes and so-called minimally-invasive surgical techniques to treat these babies."

The key to his work is the use of endoscopes - or in this case, fetoscopes - that can introduce lights and cameras into the human body. In fact, in today's language, the phrase fetal endoscopy has been replaced with the simple word "fetoscopy."

But the development of ultrasound changed all that.

"Now we could see the fetus on the ultrasound," Dr. Quintero says, 'and we used this technology instead

That left the fetal endoscope collecting dust on most shelves, except at the handful of medical centers still interested in doing research - which is right where Dr. Quintero found it and pursued an almost one-man campaign to deliver the fetal world in a way never before seen: up close and in living color.

And after years of experimentation, Quintero got his chance to prove the technology in 1991. A pregnant patient in Texas arrived on the scene with a condition that existing medicine couldn't deal with; ultrasound couldn't adequately diagnose the possibility of a birth defect.

"I was then approached by my colleagues," he said, "who asked if we could offer her trans-cervical fetoscopy - and I said no, because I thought the risk was too high.

So the incentive was there from that time on to develop other ways of improving our diagnostic capabilities. And the first step was to develop a trans-abdominal technique, using extremely thin endoscopes that we could pass down the shafts of an amniocentesis needle.

Since those first steps, Dr. Quintero is now a recognized leader in the micro- world of fetal surgery- a world in which the smallest needle is as thin as pencil lead and the largest is still thinner than the pencil itself. But his world - and that of the medicine being practiced - no longer ends just within the uterine wall: New techniques, procedures - and his instruments - now enter the fetus itself.

Working with manufacturers to develop a wide range of instruments reduced to fit the applications - scalpels, clamps and any other equipment that might be necessary - Dr. Quintero has become. quite literallv, the reigning expert in the field.

Today, the use of the fetal endoscope - or scopes - is critical to the kinds of surgery being performed by doctors at Wayne State, and the list of possible conditions being addressed continues to grow.

The prognosis in such a case, Dr. Johnson said, is not good. Not only does the blockage cause obvious internal pressure, but it also can permanently damage the kidneys if it goes untreated. At the same time, the blockage can begin to affect the entire amniotic environment, causing additional problems. Because the amniotic fluid is essentially fetal urine by the 14th week, the blockage ends its replenishment; the remaining fluid is reabsorbed, the amniotic sac closes in on the fetus, the cushioning effect of the fluid is lost and the baby is slowly compressed within the uterus and subsequently deformed.

The solution, then, is to provide a temporary shunt to the amniotic sac for the urine to enter the amniotic sac, and also to explore a more permanent solution - in utero.

Already, Drs. Quintero and Johnson have performed this procedure enough to understand a little better each time what it takes to successfully invade the otherwise secure uterine world - and to also set the stage for a next possible step: repairing the urethra.

The fetal surgery team is presently taking the fetal endoscopic technology directly into the bladder to open the passage.

"Maybe it's just a matter of widening an underdeveloped opening; maybe it will be a matter of using a small laser to cut away tissue. Whatever the case," Dr. Johson said, "we'll continue to learn from everything we do and try to establish the kinds of therapies within the womb that will make for a healthy baby."

Several years - and dozens of visits later - a toddler comes bounding into the doctor's office, mother in tow. It's time for another checkup, another lesson to be learned, another chapter to be written in an open-ended book being authored by Drs. Flake, Evans, Johnson and Quintero.