Sunday, August 15, 2004

FAMILY: UC Irvine biologists Anne Calof, left, and husband Arthur Lander hold daughter Sophia at their Laguna Beach home. Their first child died from a genetic defect that sent the parents searching for the cause. EUGENE GARCIA, THE ORANGE COUNTY REGISTER MORE PHOTOS RELATED STORIES •Facts about Cornelia de Lange Syndrome

By GARY ROBBINS
The Orange County Register

LAGUNA BEACH

Sophia's got a sweet tooth. It's a warm day and the toddler wants "eye keem."

Her mother Anne brightens. "She's saying ice cream." Sophia's dad Arthur catches on and brags a bit. "She's 19 months old and knows 200 words. We wrote them down."

The list lies on their kitchen table, an affirmation of love and pride. You expect this from parents. The surprise is that there's a little girl sitting here, jabbering away.

A ghost brought immense pain to this home four years ago, the kind that underscores the fragility of life and makes some couples forsake ever having another baby.

As they eased into middle age, Arthur Lander and his wife Anne Calof were betrayed by biology. Their first child, Isabel, died a month after she was born, claimed by an unknown gene that randomly disrupts and destroys and, in rare instances, kills.

Arthur and Anne asked, "Why us?" They also wanted to know: "Which gene?"

The ghost had struck parents who could strike back.

Both are developmental biologists at the University of California, Irvine, where they run comfortably cluttered labs that are abuzz with the business of figuring out how genes and cells control life.

Arthur and Anne joined the hunt for the one gene in 30,000 or so that sometimes goes awry, causing the birth defect that killed Isabel.

"We wanted to honor our daughter's memory," Anne said.

In the quiet ways of science, the mutant gene has been unmasked, a discovery hastened by one of Arthur's hunches and refined by Anne's study of mice.

But that's not paramount on this warm day. With a fresh sense of what it means to be human and humane, they had a second child. Her name is Sophia Rose Lander. And right now, she wants eye-keem.

COME TOGETHER

Arthur always wanted kids. Anne - not so much.

She was focused on building a career in science, a field that can be subtly hostile to women. Only five years ago, the Massachusetts Institute of Technology admitted that it had a history of marginalizing female researchers.

The issue began to surface at MIT in the early 1990s, when Arthur was on the faculty. Anne was looking for a permanent faculty position. The market in greater Boston was tight. She refused to compromise.

"I didn't want a girl job - a non-tenure track job that became disposable when the financial situation in a department changed ...I wanted security and the chance to build my own research program and train scientists."

The remark is pure Anne. She is a get-to-the-point workaholic who walks fast and talks faster, often piling several ideas into one long sentence.

Opportunity awaited at the University of Iowa, which had an opening for a developmental biologist. Anne took the job, which meant she and Arthur would spend the first years of their marriage 1,000 miles apart.

Arthur regularly flew to Iowa, where he filled Anne's refrigerator with fish stew and other dishes he prepared, a skill he picked up out of necessity. As a kid, he cracked wise once too often about his mother's cooking, leading her to snap: learn to cook for yourself. He did, later turning his touch with food into one of the most popular courses at UCI, "Science in the Kitchen."

The visits weren't enough. Arthur and Anne wanted to be together.

Arthur thought, "Should I go to Iowa? Should Anne come to MIT?"

He recalled this in the way he says most things, with the sort of calm, unhurried demeanor of announcers on National Public Radio.

The solution to their problem was UCI, which was undergoing a boom in the biological sciences. Arthur studies how cells communicate, especially as it applies to cancer and birth defects. Anne explores the nervous system, focusing on how genes get various portions of the brain grow to their appropriate size.

Irvine needed scholars in both areas. The campus offered them jobs. In 1995, UCI became their home. They occupy offices on the same floor of McGaugh Hall, in offices less than 100 feet apart, sitting at desks that, at times, each seem on the verge of collapse from the weight papers and reports.

Arthur, a physician-trained-scientist, thought, "Finally, we can think about having a family."

Anne, the daughter of an Air Force pilot, remained ambivalent until she came to feel that "having a child would make our relationship fuller and deeper."

It took awhile. But in mid-1999, when she was in her early 40s, Anne became pregnant with Isabel. Expectations soared:

"I'm obviously going to have a child that goes to Yale like Arthur did or Reed College like I did and get a Ph.D, and if this child doesn't get all As, I'm going to be disappointed."

Things seem good. .

TROUBLED TIMES

A sick feeling washed over Arthur and Anne during the ninth week of the pregnancy. A grainy black-and-white ultrasound showed that the inch-long embryo that would become Isabel had a shiny bubble that extended from her neck all the way down her back.

"It's a sort of non-specific bad sign," Anne said. "It's frequently, but not always, correlated with some developmental disorder."

There are no tests for most disorders of this type, which fed their anxiety.

The bubble eventually disappeared. Their anxieties did not. For reasons that weren't yet clear, Isabel was growing too slowly. She ended up being born a month early -- Feb. 28, 2000 -- and weighed less than three pounds. She also needed immediate surgery at UCI Medical Center in Orange to fix a problem in her gastro-intestinal tract.

The bad news piled up.

A new ultra-sound revealed that Isabel had grossly undersized kidneys. If she lived, she would need dialysis and probably a transplant.

"I think we just cried for about an hour," said Anne.

The root cause of Isabel's problems emerged a few days later when tape and tubing were moved away from her tiny pink face. A geneticist noticed signature signs of Cornelia de Lange Syndrome, which can cause such things as down-turned lips, a short, upturned nose, lowered ears and small stature and head size.

Some people with the birth defect also have shortened or missing limbs, heart defects and eye problems. But all suffer from mental retardation, which is typically moderate to severe. And the defect usually makes it hard to verbalize. Some sufferers never talk. Many are in chronic pain.

Anne and Arthur were crushed with sadness, whip-sawed by uncertainty.

"We were trying to figure out if this diagnosis was a death sentence, or just a sentence of terrible," said Anne.

They weren't alone in their sorrow, something Arthur came to understand more deeply:

"There's knowing this stuff is out there. And then there's realizing other people share the same kind of experiences. You don't really learn that last part unless you go through it yourself."

A BATTLE JOINED

Tap, tap, tap.

Sitting in Anne's hospital room, Arthur worked his laptop, searching the Internet for anything he could learn about a syndrome that afflicts about one in every 10,000 newborns. It was exasperating. There are several thousand kinds of birth defects. Most are like Cornelia de Lange Syndrome in the sense that they're obscure, with no clear cause.

He pressed on. Arthur's not the type to give up. While studying at Yale about 20 years ago, he auditioned for parts in plays, one of his passions. He had little success; directors didn't like his Brooklyn accent. Arthur responded by producing two musicals, which he also wrote and directed.

If one door is closed, try another. This is how Arthur thinks.

Soon, a door opened. He learned that there was a geneticist at Childrens Hospital of Philadelphia who was trying to find the mutant gene that causes the syndrome. Ian Krantz, it turned out, was the only scientist in the country whose entire laboratory had this mission.

Arthur introduced himself by e-mail, beginning a collaboration that took on deeper meaning on March 30, 2000. That day, Isabel died without ever having left the hospital.

By then, Arthur and Anne had decided to join the search for the mutant gene. Such a discovery could lead to a way to confirm or diagnose a disease that is hard to study because it typically does not run in families.

Science is not a solitary enterprise. It's a collaboration in which people contribute in many ways. Arthur and Anne's involvement reflects that.

They became science advisors to the Cornelia de Lange Syndrome Foundation, a family support organization. Anne joined the board of directors. And they got directly involved with Krantz, providing him with a sample of Isabel's blood to see if he could tease out DNA to look for genetic clues. They opened their personal medical records up for review, and plunged into the real heart of research -- swapping ideas in the dense argot of biology. Arthur got and sent e-mails with phrases like, "We have linkage to 5p13.2 with marker D5S426 ..."

Anne underwent an epiphany:

"I used to think basic research was somehow better than applied research, but now I've changed my mind," she wrote in Current Biology. "Now it seems entirely worthwhile to focus one's scientific curiosity on problems whose solutions will have a direct impact on our lives and the lives of our children."

WHERE, OH WHERE?

A typo, of sorts, causes many diseases, including this defect.

Our 30,000-plus genes are composed of four chemicals that are known by the letters A, T, G and C. The letters are arranged differently in each gene, determining its function.

A change in any one of these letters -- a chemical typo -- can produce a mutation that's harmful, even deadly. And locating the mutation can be like trying to find a single misspelled word in "War and Peace."

Krantz was looking for the gene, and the misspelling, when Arthur and Anne came into his life.

The situation wasn't hopeless; they knew they were looking for a gene that can cause widespread problems, narrowing the search some. But Krantz spent significant time looking at pieces of genes on the wrong chromosome.

That's the biological equivalent of trying to find someone in Irvine when you should be looking in Miami.

Early on, he was groping about and the National Institutes of Health knew it, rejecting Krantz's first two requests for $1.5 million to broaden the search.

"This is part of the problem with rare genetic syndromes," Arthur said "NIH will give you money if you convince them you'll have the answer in five years."

Arthur helped re-write the grant proposal, which reached NIH at a time when the sequencing of the human and mouse genomes was ripping along, helping expose the potential cause of myriad diseases, including birth defects. This time, the grant was approved.

By 2002, things were improving. And not just in the lab.

Arthur and Anne decided to take another chance on having a family. Love delivered on Oct. 2, 2002, when Sophia entered the world, healthy.

Having Isabel "reinforced our desire to have children," Anne said. "It sounds sappy and hard to understand but you learn so many things from your child. You realize someone doesn't have to be perfect for your to love them."

YOU'VE GOT E-MAIL

It's often a hunch that moves science forward, an inner voice that says, "What about this?"

Arthur got that feeling one afternoon last fall while using his iMac to comb a mouse data base for genes that might cause far reaching birth defects. Mice are very similar to humans genetically, making them ideal for study.

He wrote "IDN3" on a piece of paper and circled it. The gene's make-up seemed capable of altering many tissues and organs, like the birth defect.

"You should definitely pay attention to this one," Arthur told Krantz by e-mail, playing that hunch.

Krantz was following the same path. The e-mail simply accelerated the search a bit. He wrote back on Dec. 11, saying, "We're on the cusp of discovery ... Let me break the suspense, the gene turns out to be IDN3."

The breakthrough was confirmed two weeks later. Two weeks later, the breakthrough was confirmed. A genetic scourge had been exposed three days before Christmas.

Arthur was elated, but downplayed his role: "I'm sitting here playing back seat driver. He's in the lab, sequencing stuff ...I was right, but I said five other things, too."

The contribution was deeper than that. Earlier this year, Arthur and Anne performed a series of experiments on mice that graphically illustrated that IDN3 is the kind of gene that causes this birth defect, a finding that gave weight to the scientific paper Krantz submitted to Nature Genetics. The journal recently published the paper, announcing the breakthrough.

Scientifically, Anne and Arthur have moved on. They're trying to create a strain of mice that have the syndrome, an essential step toward opening the disease to much broader study.

Emotionally, the couple also are in a different place, something that was evident last Christmas.

Arthur is Jewish. Anne is Christian. They never used to make a big deal of the holiday. This time, they bought a tree.

"We set (the tree) up on the patio and strung lights and ornaments while Sophia toddled around, pulling things off and getting tangled up in the lights," Arthur says. "She laughed and cooed when we illuminated the tree for the first time. It felt like family should feel."