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COMPLETING THE PICTURE
After working for several years on the causes of chromosome
abnormalities, Lisa Shaffer now focuses on their consequences.
She's especially interested in subtle abnormalities such as
deletions, in which a small piece of a chromosome is snipped out
and lost. Like aneuploidy, most deletions can be traced to mistakes
during early egg development. Unlike aneuploidy, they seem to occur
as often in young parents as in older ones.
They're also harder to pinpoint. Aneuploidy is fairly easy to
diagnose: drench the cells in a chromosome-specific stain, put the
stained cells under a microscope, and count the chromosomes. That
technique can reveal huge deletions, but it rarely catches those
smaller than 10 megabases, a length of DNA that could encompass
dozens of genes.
Shaffer detects losses a fraction of that size with a technique
called microarray analysis. A microarray is the size of a standard
microscope slide. Spotted on it are known segments of human DNA. To
run a test, the lab crew puts on the slide small samples of the
patient's DNA and DNA from a known, control individual. Each sample
carries a fluorescent label: green for patient DNA, orange for
control DNA. The two samples compete to bind with their matching
sequences in the spots on the slide. If the samples have the same
number of copies of a segment, the matching spot will fluoresce
yellow (combination of the green and the orange.) If the patient
has a deletion-one copy of a segment instead of two-more of the
control DNA will bind and the spot fluoresces orange. If the
patient has extra copies of a segment, the matching spot fluoresces
green. A tidy graph of the color of each spot shows clearly where
the patient and control DNA differ.
In 2003, Shaffer and fellow WSU Spokane geneticist Bassem
Bejjani put microarrays to work diagnosing chromosome and genetic
abnormalities for their new company, Signature Genomic Laboratories
(see sidebar, "Trust your crazy ideas"). They do some pre-natal
testing, but most of their clients are doctors who are treating a
child with mental retardation or birth defects for which the source
of the problems has not been identified. It might seem too late to
run chromosome tests on a 6-year-old, but Shaffer says that's not
the case at all.
"It's important to make a diagnosis," she says. "The first
reason is because parents want to know what's wrong with their
child. They also need to understand how it happened, because they
may be at risk for it happening again, or their family members may
be at risk for having a similar child. And then for some chromosome
abnormalities, there are certain medical problems you need to
anticipate. By anticipating them, the child can receive treatments
and have a better quality of life."
A few years ago, she discovered that children with a deletion
called 1p36 (loss of DNA from band 36 on the short arm [p] of
chromosome 1) had poor hearing. That was a major finding, because
many kids with a 1p36 deletion don't talk. "Maybe they don't
speak because they can't hear," says Shaffer. "If
they have hearing problems, let's get them hearing aids so they can
hear, and hopefully they'll develop speech."
She is now exploring 1q42 deletions (loss of DNA from band 42 on
the long arm [q] of chromosome 1). The company's tests have
identified nine children with this deletion. With the permission of
their parents, Shaffer took a closer look at the symptoms and
genetic characteristics of seven of them and one other child from a
previous study.
She found that although their deletions are in the same region
of the chromosome, the kids aren't all missing exactly the same
chunk of DNA. They also don't have exactly the same symptoms. All
have mental retardation or developmental delay, but it ranges from
mild to severe. All have defects in structures along the body's
midline, such as cleft palate; but again, some have much more
severe problems than others.
By diagramming the eight deletions and lining them up next to a
map of the intact chromosome, Shaffer was able to identify what she
calls their "smallest region of overlap" (SRO)-the piece all of
them are missing. That piece accounts for the symptoms the children
have in common. It contains only five genes, all of which have been
identified. Shaffer also found that the child with the mildest
symptoms is missing a big piece to the left of the SRO but little
to the right, while the child with the most severe symptoms is
missing a big piece to the right of the SRO but little to the left.
That's a clue that at least one gene to the right of the SRO is
involved in the more severe symptoms.
Shaffer is eager to find out more about the genes in and around
the SRO. "That's really exciting, to bring all the pieces
together," she says. "The genes are the final piece. We have the
deletion, we're dealing with that-but what's missing, and why is it
important? If we can identify the gene targets, maybe there's a
treatment."
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Trust Your Crazy Ideas
When Lisa Shaffer and fellow geneticist Bassem Bejjani came to
WSU Spokane from Baylor College of Medicine in 2002, they had an
idea for a new company: they would use microarray analysis to
provide faster, more accurate assessment of chromosome
abnormalities than anything that was then available. Microarray
technology had been standard in research labs for years, but had
never been applied to clinical uses before.
 Lisa Shaffer and Bassem
Bejjani. Photo by Robert Hubner.
"No one had taken it to the level of bringing it to the patient,
so you could use it for diagnoses," Shaffer recalls. "We were the
first to use array-based testing for chromosome abnormalities."
With a big initial investment from Spokane's Sacred Heart
Medical Center, she and Bejjani launched Signature Genomic
Laboratories in the summer of 2003. Now, five years on, the company
has 68 employees, new office and lab facilities in north Spokane,
and a growing roster of investors. To date it has analyzed DNA
samples from more than 24,000 individuals from all over the world-a
huge database that has led to the discovery of several previously
unidentified syndromes and boosted Shaffer's ability to study a
range of chromosome problems.
The company deals with families through their physicians, who
draw the necessary blood samples and are informed of the results.
Signature's genetic counselors are on call to talk with the doctors
about what those results mean.
Shaffer says the company's ability to identify rare conditions
has been a boon to parents who feel very much alone before learning
that others are dealing with the same problems they are. Families
have gotten in touch with each other through Signature, sometimes
even holding "reunions" to share their experiences. Shaffer attends
such gatherings when she can.
"I'm always telling them they know more than I do," she says.
"They live with it every day. I'm learning from them."
She is nearing the end of a year-long leave of absence from WSU
she took to work as Signature's CEO. She wants "to get the company
to a point where someone else can take over and I don't need to be
here every day" -and then get back into the lab.
"The reason why I went into science was not to run a business.
It was to help people and to work directly with the families. Which
Signature does, but I do more of the business stuff, so I'm removed
from the part that I like."
In one corner of her office hangs a ceramic tile inscribed with
an image of a light bulb and the words "Trust your crazy
ideas."
"I thought it was perfect, because I was called crazy," she
says. "I was told that there were too many hurdles to overcome;
that you can't take [microarrays] to the level of the patient, that
it has to remain a research tool. And I kept saying, 'Why? I don't
understand why.'"
She and Bejjani were right, and now other companies are
scrambling to catch up.
"Now we've got a bunch of people copying us, but that's OK.
That's what happens. We're still the leaders."
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