UAA molecular biologist stumbles upon her own son's birth defect

Jocelyn Krebs got the call every parent dreads.

Her son was 19 months old when it came, but "I'd known for awhile that something was up with him," she says of now 4-year-old Rhys (pronounced Reece).

As a molecular biologist, Krebs studies exactly how a one-cell fertilized egg develops into an incredibly complex adult. She's intimately aware of all the ways this miracle can go awry.

Success requires that biological "traffic signals" turn genes on and off at precise moments in all the right places. An example: DNA has to be able to make heart cells and kidney cells. In a heart cell, you want all the kidney genes turned off.

Figuring out these "traffic signals," or epigenetics, is Krebs' area. When she came to UAA as a young researcher in 2000, this fast-emerging field was seen as the gateway to untangling mishaps as divergent as birth defects and cancer.  Discoveries have continued with dramatic speed and results.

But here's the stunner. Krebs' own work on a particular genetic defect called Williams syndrome -- caused by 25-30 genes missing on chromosome No. 7 -- turned out to be her son's exact problem. It occurs in 1 out of 8,000 births. Either an egg or sperm carry the defect, caused by an error in the normal process of genetic exchange that occurs during meiosis.

In Williams, the brain can be up to 25 percent smaller, with characteristic areas of over- and underdevelopment. Patients have insufficient elastin, a protein that makes blood vessels flexible, often resulting in life-threatening heart conditions. High blood calcium levels lead to seizures. Facial features are distinctive, characterized by ear-to-ear grins. Personality traits include extreme friendliness, even toward strangers.

Conversely, remarkable gifts in language and music can also result.

The challenge is figuring out which missing genes are having which effect.

"I am probably the only person, EVER, that when the geneticist called to say, 'It's a deletion on chromosome seven,' knew exactly what that meant. I went, 'OHHHHH, NO, it can't be!'"

The fact that she was even studying Williams syndrome was serendipity. She came to UAA with cancer research in mind: "Like everyone, I have it in my family."
But another UAA researcher, Tim Hinterberger, happened to have a colony of frogs, and she had one graduate student working with them. That student produced a paper that led Krebs toward a gene called Williams Syndrome Transcription Factor (WSTF). WSTF is part of a "chromatin remodeling complex."

To put this into context, if you took the DNA out of all the cells in your body, it would stretch end to end all the way to the sun. To fit that genetic material into each cell, it has to be compacted 100,000 times.

"It gets folded and folded and folded in a very organized way, NOT like wadding a bunch of spaghetti into a very tight space." Chromatin is the name for this compacted DNA plus the "traffic signals" that are intimately involved with it.

In development, when a body needs access to one of those packed-away genes, a chromatin remodeler helps make it accessible. Krebs was originally interested in WSTF in its role as part of a chromatin remodeling complex. But as she investigated the gene further, she came to understand what an interesting disease Williams syndrome is.

"Now," she says, "I could learn how epigenetics controls development by understanding where human development goes awry in Williams syndrome."

Her work with WSTF started about three years before Rhys' diagnosis.

Krebs has learned a lot. In June, she published a paper linking WSTF to defects in neural crest cells. "This was a big surprise. People hadn't thought to look for it there."

Neural crest cells are embryonic stem cells that appear very early in development when the embryo "looks like a little fat cigar, just starting to identify the different parts of itself that will become tissues like the brain and spinal cord." Instead of doing that, neural crest cells migrate to different parts of the body.

"Cells are calling to them, chemically," Krebs explains. "Some get called to a region that becomes the heart," and they form part of the aorta. "All the bone, cartilage and cranial nerves of the face come from the neural crest. They give rise to the thyroid and parathyroid, regulators of calcium levels in the body."

When the neural crest cells don't arrive at their intended destination to do their job, genetic havoc ensues.

In Krebs' lab, suppressing WSTF in frogs-an excellent animal model for human genetics-led to the death of neural crest cells. That opens the door to conceiving of therapeutic interventions, even if they are a long way off right now.

"One could imagine," Krebs says, "trying to provide a developing fetus with that gene product in the region it needs it, to rescue neural crest cells from failing to migrate and thrive."

Coping with Rhys' disability was a tough assignment, even for a molecular biologist familiar with genes and their complexities.

"For two years, I kept thinking, 'He'll never do this, he'll never get to do that.' But just this year, I stopped doing that.

"My son loves the outdoors. We take him on little hikes. We joke that he's a little botanist - he loves looking at leaves and trees."

And just recently, Rhys has started putting two- and three-word sentences together. "My favorite," Krebs says, "is 'Put Frey down!' "(That's his 9-month-old brother.)

"My son is doing great!"

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NOTE: A version of this story appeared in the Anchorage Daily News on Sunday, Dec. 16, 2012. This story was also pursued by KTVA Channel 11; find a link to the report here.