HARNESSING THE POWER OF CREATION

Advances spark birth of hope, controversy

6/23/2008

BY JENNI LAIDMAN
BLADE SCIENCE WRITER

Sharon Saarinen and Alana Saarinen read together in Alana’s bedroom in their West Bloomfi eld, Mich., home.

Sharon Saarinen and daughter Alana, who was born from in vitro fertilization, play in Alana’s bedroom in West Bloomfield, Mich.

Alana Saarinen is an adorable, curious, shy, clever, devilish, affectionate girl. In short, a normal 3-year-old.

She may also be entirely new to biology. She may carry DNA from three people.

The cheerful girl in pigtails was born of her parents' fifth attempt at in vitro fertilization -- the meeting of sperm and egg in a laboratory dish, the "birthplace" of more than 1 million children worldwide in the last 26 years.

But Alana is more than a much-treasured personal victory over infertility -- long and painfully fought -- for Paul and Sharon Saarinen of West Bloomfield, Mich.

She represents a revolution born of the human embryo.

The revolution's advance is often silent, crystallized within the private decisions of desperate couples and inventive fertility doctors. At the same time, it is a scientific revolution of unusual public prominence, the subject of presidential electioneering, Congressional debates, dire predictions, and papal prohibitions.

At the heart of the debate are more than 400,000 human embryos kept on ice across the United States -- including hundreds in Toledo. Suspended in liquid nitrogen, these tiny balls of cells, a little smaller than the dot of an i, are human potential incarnate. Take them from frozen limbo, put them in a womb and they may become babies.

But take the embryos apart -- a notion that for some remains a moral horror -- and grow the cells in dishes, and they could be fantastic tools that may one day be used to treat spinal cord injury, Parkinson's disease, multiple sclerosis, and a host of other illnesses.

Or scientists could skip the whole mixing of sperm and egg, and custom-make an embryo through cloning, creating another source of human stem cells with all their remarkable potential.

There are even some who believe -- although research suggests the risks are potentially devastating to mother and child -- that clones can become babies, the human manifestation of the research that brought us Dolly the sheep in 1996.

But the birth of some human Dolly is the future. The present is dazzling and puzzling enough.

While we barely noticed, this embryonic revolution remade the world of human reproduction. Ever-since-Eve notions of procreation are almost quaint in the face of a multibillion-dollar industry where sperm and egg introductions are carefully engineered, where even the laziest, most misshapen sperm can win the most lustrous egg, where eggs and embryos are graded, fawned over, chosen or rejected.

Today, parents can chose their child's sex. They can make sure their infant is free of not only many diseases that harm babies, but diseases that kill adults as well, such as Alzheimer's, some forms of breast cancer, and Huntington's. They even can select among their embryos to find one that can save the life of an existing child, choosing the genetic match that will allow cord-blood donation, for instance.

Technological developments are expanding a woman's reproductive options: those with sagging, tired eggs can look into rejuvenating therapies; the career-minded can freeze her eggs for a better day, and a woman facing cancer soon may be able to preserve her chance at childbirth by freezing an ovary.

Other advances now allow couples to donate their embryos to science, in hopes that we'll someday harness the power of creation itself.

The 'Embryo Emperor'

On a busy street corner in Chicago's Lincoln Park, in a unremarkable building that bears not a trace of its auto dealership past, works one of America's leading candidates for the title of Embryo Emperor -- should one ever be named.

His name is Yury Verlinsky.

A stocky man, he's wearing a gray knit sport shirt under a pinstripe jacket. He answers questions with bursts of: "yes-yes-yes,'' and when he answers his cell phone, releases a stream of "da-da-da" in his native Russian. His company, Research Genetics Inc., grossed about $9 million last year from its fertility services, Mr. Verlinsky said.

While a national ban prevents federal funding of research on human embryos, and the debate rages on the embryo's moral status, Mr. Verlinsky claims to have created more stem cell lines than anyone on Earth.

In June, Mr. Verlinsky announced the creation of 50 new stem cell lines. By summer's end, Mr. Verlinsky revealed there are 80 lines, and shows no signs of slowing down.

There are some who doubt Mr. Verlinsky's stem cell team could have created and properly described the number of cell lines he claims. Still, the work at his lab demonstrates the role that fertility clinics are playing in the embryonic revolution.

A few fertility specialists make headlines. Panayiotis Zavos, who operates fertility clinics on the Mediterranean island of Cyprus and in Lexington, Ky., says he's going to clone human beings.

Evidence suggests only one team has ever successfully cloned human embryos -- a group in Seoul, South Korea. That team did not use the embryos to create a pregnancy, but to extract a new stem cell line.

But Mr. Zavos, whose Web site prominently features links to his many interviews with famous television journalists, 16 photographs of himself, and an advertisement for a tax service, says he has cloned an embryo and put it in a woman's womb. The pregnancy failed, he said. His claim was neither proven nor published in a scientific journal.

Then, last month, Mr. Zavos announced he had put human DNA into cow eggs to see if the DNA could be used for cloning. When the cow eggs divided, he said, he knew the DNA was suitable for cloning in a human egg. Although this research was scheduled for publication in a scientific journal, the publisher rejected the paper after Mr. Zavos announced his experimental results.

Mr. Zavos' cloning work is condemned in the scientific community, where attempts to clone to create children are viewed as extremely dangerous to the mother and child.

Irving Weissman, the Stanford professor who chaired a panel on cloning for the National Academies of Science in 2002, said cloning in mammals demonstrates the dangers that await those who attempt it in humans.

Of the 17,500 mammalian cloning attempts his panel studied, only 0.8 percent led to a live birth.

"Many of them were so genetically abnormal -- they had an abnormal placenta and abnormally large offspring, huge genetic defects -- so not only were they going to die, they were now threatening the life of the mother," Dr. Weissman said.

In some mammalian cloning experiments, more than half of the mothers died. Among the few clones born, many of those didn't survive a day, so severe were their birth defects.

Nevertheless, Mr. Zavos talks as though he's immune to such disasters in a science that's far from mature.

"What we're doing is, we're creating human clone embryos. We do not kill them. We do not dismember them. We merely test and check to see that they're healthy. Then we transfer them in utero to treat a disease called infertility. ... Why is it so wrong that we who create life are the bad guys?"

Assisted reproduction

While stem cells and cloning roil the world of embryo research, they are only the latest and most publicized controversies since Louise Brown became the world's first "test-tube" baby in England in 1978.

In fact, by some standards, many fertility clinics are better at baby making than Mother Nature.

A few studies suggest that only 20 to 40 percent of eggs fertilized through natural conception survive long enough to implant in the uterus. Among those that do implant, some 10 to 30 percent miscarry. In Michigan and Ohio alone, there are a number of fertility clinics that beat those statistics.

Someone takes home a baby from IVF Michigan -- the largest fertility practice in either state -- in 47.4 percent of all IVF attempts in women under 35. The statistics are from 2001, the most recent information published by the U.S. Centers for Disease Control and Prevention. IVF Michigan includes the Toledo Fertility Center in Sylvania, six clinics in Michigan, a clinic in Lebanon, and another in the United Arab Emirates.

Nationally, IVF clinics are successful about 35 percent of the time for women younger than 35.

Of course, by Mother Nature's rules, doctors cheat. While natural conception normally relies on a single egg at a time to make a baby, fertility clinics induce a woman's ovaries to produce many eggs. Then, the fertility doctor can put back as many fertilized embryos as he and the parents deem appropriate.

For many couples, it's a dream come true.

But fulfilling the hopes of those who ache for a child may have, at times, disquieting consequences. Critics howl that this field is rife with cowboys who pay scant attention to ethics, who conduct experiments without proper consideration for the children they are making. There is hardly a law, state or federal, to stop them. New technologies are used to create babies before the methods are tested thoroughly in animals, before their safety is well-established, critics say.

In 2001, Sharon Saarinen stepped into the middle of a roaring debate over one of these controversial reproductive techniques when she began her fifth attempt to have a baby.

She was 36. After four failed attempts at in vitro fertilization, her fertility doctor told her to give up. The eggs she made had holes in them. They would not make a baby. Let it go. Save your money. Accept.

Mrs. Saarinen didn't accept.

Sharon Saarinen and Alana Saarinen read together in Alana’s bedroom in their West Bloomfi eld, Mich., home.

"I wanted a baby. I was going to do what it takes to get one. It's called desperation. You don't care. You don't see anything. You just want the baby.''

She changed doctors and began treatment with Dr. Michael Fakih at IVF Michigan, perhaps the region's most aggressive fertility center.

Dr. Fakih didn't counsel retreat. He had something he wanted to try -- a procedure developed at St. Barnabas Medical Center in Livingston, N.J.

He wanted to give her eggs extra fuel.

Typically, the egg's chromosomes, huddled inside the nucleus, are blamed for poor egg performance. For instance, older eggs are more likely to have damaged chromosomes, creating genetic conditions like Down syndrome, or severe chromosomal errors that kill the developing embryo.

But Jacques Cohen of St. Barnabas theorized that what really ails some eggs is outside the nucleus. He believes that their failure to thrive arises somewhere in the gelatinous sea in which the nucleus floats: the cytoplasm.

The cytoplasm is far more than a pool in which the nucleus swims. It is full of equipment. It holds scaffolding that extends and dismantles. Message systems shuttle commands from the nucleus to the cell membrane and back again. Other units suck up accumulating waste products. And peppered throughout this complex space are the mitochondria. These are the cell's power plants, pumping out a steady stream of ATP -- adenosine triphosphate -- a chemical the cell uses to fuel its complicated machinery.

In some women, something in the cytoplasm, maybe many things, is awry, the theory goes. Even if the egg fertilizes, the newly formed embryo may lack the gumption to divide. No division, no baby.

To counteract this theoretical egg weakness, Mr. Cohen tried injecting cytoplasm from the egg of a donor into a less-robust egg. The hope was that something in the donor cytoplasm -- maybe the mitochondria, maybe something else -- would energize the troubled egg.

Cytoplasm transfer is what Dr. Fakih proposed to Sharon Saarinen.

He acknowledges there was a chance that DNA from the donor egg could get into her egg. It's not the kind of DNA that determines traits like intelligence, hair color and a tendency to blush. This was mitochondrial DNA, rings of 37 genes handed down from mother and mother alone. This DNA directs the functions of the energy-producing mitochondria.

But a squirt of donor cytoplasm can add another source of this inheritance. Children born via cytoplasm transfer can carry DNA not only from mom and dad, but from the woman who made the donor egg from which the cytoplasm was taken. Females born from this technique could, theoretically, pass the donor mitochondria onto their children.

Is this dangerous? No one really knows. Dr. Fakih, who used the procedure in the birth of 10 babies, said this extra inheritance is benign.

"It doesn't really hurt," Dr. Fakih said. "The babies that were born were all healthy. They're using 99 percent of their own DNA.'' In fact, it's not even certain that every child born of the procedure carries donor DNA. Mrs. Saarinen is currently waiting for test results which will tell her if her daughter, Alana, carries the extra DNA in her cells.

But other experts in reproduction say there is no evidence to support a view that this extra genetic contribution is harmless.

News that some of the infants born from cytoplasm transfer carried extra DNA unleashed a flood of criticism. The U.S. Food and Drug Administration notified clinics that future attempts at the procedure must be treated as an experiment and would require FDA supervision.

"You need to have some hard evidence to suggest that what you're doing is safe. I don't think they have that,'' said Justin St. John from the University of Birmingham Medical School in Great Britain. Dr. St. John uses pig eggs to study the role of mitochondria in reproduction.

Tatiana Sharapava conducts a genetic procedure at the Reproductive Genetics Institute in Chicago. Yury Verlinsky, head of the institute, claims to have created 80 new stem cell lines.

His work suggests an important role for mitochondria, but he warns that the creation of mitochondria in the egg is a complex process that shouldn't be altered lightly.

"If this was a drug, it would have to be tested in cell culture systems and animal models. That doesn't seem to be happening in IVF. And that's what I find quite shocking," he said.

For others, the issue of cytoplasm transfer crossed a critical ethical boundary. It created a genetic alteration that could be passed on for generations, something that many agree should never be done.

"This is really, in my judgment, sort of a revolutionary change,'' said Mark S. Frankel, director of the Scientific Freedom, Responsibility, and Law Program for the American Association for the Advancement of Science.

"We're producing changes in [people's] genetic makeup way down the line without any real knowledge of the consequences," Mr. Frankel said.

One problem is that patient pressure drives the fertility industry, he said, without regard to larger consequences.

"This is the history of the fertility industry. It's basically unregulated, basically conducting experiments on human beings without any oversight," said Mr. Frankel.

"The infertility industry in the United States is the wild, wild West," said Arthur Caplan, a bioethicist at the University of Pennsylvania. "Tell me five laws [it] has to live with that don't have to do with screening for microbes and HIV."

But the fertility industry is not without regulation, its supporters say.

"Reproductive medicine is regulated the same way as every other kind of medicine in this country, through a patchwork of state government regulation, federal regulation, and self-regulation," said Sean Tipton, a spokesman for the Association of Assisted Reproductive Medicine.

States license the physicians, the federal government regulates new drugs and devices used in the practice of medicine, and professional societies credential the specialists in the field.

Mr. Tipton argues that, instead of being left unsupervised, reproductive medical practitioners actually face more regulation than their peers in other fields.

Every IVF clinic in the country has to submit its success rates to the Society for Assisted Reproductive Technologies, which turns the information over to the U.S. Centers of Disease Control and Prevention. Those data are published in the CDC's annual report on assisted reproduction, which is available on the Internet.

No other medical specialty has to report their results in this fashion, Mr. Tipton said.

"I used to talk about the myth of an unregulated fertility industry. I now call it the big lie,'" he said.

While the reporting requirement is real, the penalty for failing to report success data is mild. The fertility clinic at the Medical College of Ohio, which opened in 1999, has never been part of the CDC annual report on reproductive success, although clinic director Lynda J. Wolf said her clinic did file the information this year for 2002. This data won't be published until December.

The penalty for ignoring this law is to be listed in the CDC report as a non-reporter, which MCO was labeled as in 2000 and 2001. A clinic can also lose membership in the Society for Assisted Reproductive Technologies if it fails to report its data.

Joyce Zeitz, executive director of this society, says MCO did lose its membership for awhile, but is again a member. MCO spokesman Matt Lockwood said Dr. Wolf maintains that she has faithfully met all reporting requirements.

In any event, failure to meet this requirement has had no impact on the operations of the MCO clinic, Mr. Lockwood said.

Antonio Borrello holds his daughter, Gianna Borrello, while his wife, Theresa Pavone, listens to him talk about the in vitro fertilization procedure that was used to create Gianna.

Regulating new practices

What evokes the most comment from critics is the fact that no government agency supervises the introduction of new medical techniques into fertility practices.

When a fertility clinic introduces a new practice such as cytoplasm transfer there is no requirement for FDA review, no requirement that the procedure be tested first in animals, no requirement that patients sign a form acknowledging that they understand that they are part of an experiment.

Yet, the lack of FDA intervention for new treatments is not uncommon in medicine. Surgeons, for instance, can alter their techniques without patient consent or FDA approval.

But reproductive medicine may need more supervision, some say.

"There is not sufficient oversight of these clinics. Look at what's at stake here. We're talking about human lives," said Mr. Frankel of the American Association for the Advancement of Science.

All of this is beside the point for Sharon Saarinen. What matters is the little girl in her lap quietly singing and tending her three baby dolls.

"I get angry at reporters or other doctors who say she's going to be ill, she'll have a disease. They don't know that," Mrs. Saarinen said.

Mrs. Saarinen talked to a genetic counselor at Dr. Fakih's urging. "She said, 'I can't tell you how rare it is that your daughter would ever have a disease.' " She was told most problems would have shown up at birth.

Among the handful of cytoplasm transfer pregnancies produced by Jacques Cohen's group, there were two cases of a genetic anomaly called Turner syndrome. One miscarried and one was aborted. Mr. Cohen reported that this genetic defect is a common chromosomal abnormality leading to about 70 percent of first trimester miscarriages.

In a paper published in Reproductive BioMedicine Online, the research team said that while it was possible the mutations arose from the technique, there was not enough data to draw solid conclusions.

But Mrs. Saarinen had already drawn her conclusion. Cytoplasm transfer was God's way of giving her a baby.

"God gave me this child," she said. "I have her because God gave me her. That's the bottom line."

Shifting regulations

A year after Alana's birth, Mrs. Saarinen wanted to try again.

She was shocked at what Dr. Fakih told her: He could no longer conduct the cytoplasm transfer procedure that she credited for Alana's birth. The FDA required the procedure take place under its review.

"I couldn't understand why. It was just so frustrating. I went in, got a procedure, and she's healthy. What's the problem?"

Dr. Fakih had another idea. If she really wanted to try cytoplasm transfer again, she could travel to his clinic in Beirut -- a trip that would only increase the expense of her fertility treatment, which often cost more than $10,000.

So she went to Lebanon. This time, it didn't work. She only made three embryos. None produced a pregnancy.

She was lucky, she said. She could afford a trip overseas to try the procedure that gave her Alana.

"That's what bothers me about this whole thing now. ... There's got to be other women in my position. What are they going to do? Do they all have to go to Lebanon?"

Her friend, 40-year-old Theresa Pavone, was already in her position.

Her quest for a child was an emotional nightmare. Twice IVF brought her life-threatening pregnancies. The embryo lodged in a fallopian tube instead of the uterus. The first of these tubal pregnancies put her in the hospital. She was hemorrhaging.

"She's dying," her husband yelled as he watched his wife vomiting, twisting in pain, in the hospital emergency department.

The second tubal pregnancy resolved more easily, but neither brought her the child she and her husband, Antonio Borrello, longed for.

With her sense of loss and failure came the emotional beating created by the hormones used in fertility treatments. They are designed to induce the ovary to produce more than the normal, single egg during the monthly ovulation cycle.

Again, Dr. Fakih had a plan. This time, rather than using cytoplasm from a donated egg -- the procedure that Sharon Saarinen believes gave her Alana -- he proposed using cytoplasm from one of Ms. Pavone's own eggs.

This new procedure seemed to have no risks at all.

"We don't know if this will work. We don't know what it will do. But we figured, how is it going to hurt?" Mr. Borrello said.

Giana was born in April.

Does the procedure really do any good? Or would the couple have succeeded at IVF without it? It may be too early to say. The method awaits publication in a peer-reviewed scientific journal. No one has repeated the work, and no one has done any research that demonstrates that this form of cytoplasm transfer succeeds any better than chance.

But the world of human embryo research is one of hope. Hopes fulfilled for parents, who praise physicians willing to take chances to end the despair of childlessness.

For the couples, the risks may seem a small and reasonable trade-off for the rewards of parenthood.

For others examining the human embryo for its potential, hope too is part of the equation -- hope that embryos that are no longer needed for reproduction can offer treatments to those for whom medicine has had little to give.