Wang and Jeremy Nathans at work in
In the late 1980s, many molecular biologists took
up fishing, and Jeremy Nathans was one of them. “It's
common now, but back then finding genes by high throughput
sequencing was just beginning, depending as it did
on development of automated genome sequencing machines,” he
says. “So we went looking for genes important in
retinal development. There was no other way to find
them aside from sequencing.” Several of the genes
that early search uncovered looked interesting, but
only one—Frizzled—turned out to be the equivalent
of Melville's great white whale, an elusive muse
that Nathans and his students have pursued intensely
through the ensuing years, with powerful results.
All Frizzled proteins appear to serve as cell surface
receptors, and one, Frizzled-4, and its ligand, Norrin,
play a central role in vascular development in the
eye and ear, Nathans and colleagues discovered. Moreover,
defects in the Frizzled-4-Norrin signaling pathway
create serious retinal blood vessel disorders, some
leading to blindness. Learning that hasn't come easily,
says Nathans, “though it's all obvious, of course,
after the fact.” It's taken his lab several years
to conclude that the congenital Norrie disease—which
produces complete blindness and progressive deafness—and
familial exudative vitreoretinopathy (FEVR) are related.
Though FEVR may impair vision only slightly, and
by that mildness seem far removed from Norrie, the
Nathans lab found both are tied to Frizzled-4-Norrin
signaling gone awry.
“The common path was a wild guess,” says Yanshu
Wang, who has worked with Nathans for 17 years, first
as a graduate student, then as a postdoc and more
recently as a Howard Hughes Institute research specialist. “But
it turned out to be right.”
As a postdoctoral fellow, Wang showed that the Frizzled
family of genes was conserved across species from
nematodes to humans, suggesting a major role in development. “At
that point we had no idea what the function of the
gene was,” says Wang. “I'd chosen to work on Frizzled-4
mostly because it was expressed in the retina, and
this is a retina lab.” The Frizzled-4 knockout mice
had problems—esophageal enlargement and dysfunction,
progressive hearing loss, cerebellar degeneration,
ataxia. And though their retinas looked nearly normal,
Wang discovered, after examining the tissue, that
Frizzled-4 knockout mice completely lacked intraretinal
capillaries. To compensate for that loss, arteries
and veins had proliferated madly and were swollen,
distorted and bleeding.
Soon after, a group of researchers in Nova Scotia
linked mutations in Frizzled-4 to a hereditary eye
disease characterized by retinal bleeding—familial
exudative vitreoretinopathy. Though FEVR exists in
both mild and severe forms, both involve some degree
of capillary failure, hypervascularization and bleeding,
just like Wang's knockout mice.
Intrigued by the parallels between the human disease
and symptoms that Wang noted in the mice, Nathans
combed the clinical literature, looking at other
eye diseases related to vascular development, such
as diabetic retinopathy and macular degeneration.
But when he came to literature on Norrie disease,
he made an intuitive leap. Like FEVR, Norrie disease
is characterized by pathologic growth of new blood
vessels. Unlike FEVR, its damage is far more dramatic.
People with Norrie disease are often born blind.
And though Norrie disease is linked to a mutated
gene—Norrin—its gene product, is a secreted protein,
not a receptor. Could Norrin and Frizzled-4 be related?
Was a common pathway involved?
The Nathans lab swung into action. Nathans asked
postdoctoral fellow Qiang Xu to look for biochemical
connections, and the results astonished lab members.
Not only did Frizzled-4 bind very tightly to Norrin,
but when Xu did a gene activation assay and added
an Lrp co-receptor to Frizzled and Norrin, the assay
lit up like a Christmas tree. “We got a thousandfold
response compared to the usual tenfold or hundredfold
response that ensues when a Frizzled is combined
with signaling ligands like Wnt,” says Wang. The
results were so dramatic that Nathans repeated some
of Xu's experiments himself just to be sure. “Jeremy
wanted to look for anything that might be an artifact,” Wang
says. “He said, ‘It's too good to be true.'”
Keeping an eye on the clinical literature helped
reveal connections that might otherwise have eluded
him, Nathans adds. And collaborations with clinicians
have also been important. “A lot of the work we do
would not have happened without their insights.”
Jeremy Nathans mulls over tech transfer and the basic scientist.
We see that you have a number of patents filed
with the Office of Technology Transfer.
Yes, we've filed a
few patents—Genentech has
licensed four of them— but so far there are
no products on the market.
Because you haven't produced anything that's
The sort of work we do is not that valuable
from an intellectual-property point of view.
Our job is to do the long-term foundational
work that biotech and pharmaceutical companies
can't afford to do. Our role is to help the
field become mature enough so that they can
then go into it.
Is that happening now in retinal research?
Yes, I think it is. One way I measure the
success of what we do is to see how many pharmaceutical
companies develop research programs in this
area. My sense is that the number is increasing.
For a long time, many companies weren't interested
because the retina was viewed as too complicated.
But that's changing.
Your work with the Norrin-Frizzled-4 pathway
seems promising in terms of drug development.
We think it may be. One thing we're looking
at is whether or not this pathway is used beyond
the period of retinal development. If so, it
could lead to a more precisely targeted drug
therapy. The vascular inhibitors that have
been tested so far need to be injected directly
into the eye because they have systemic side
effects, but that method of delivery is a problem
because of the risk of infection. By contrast,
the Norrin-Frizzled-4 system only seems to
affect the vasculature in the ear and the eye.
If that specificity holds up in the adult,
perhaps a drug that acts on the Norrin-Frizzled-4
pathway could be taken as an oral medication.
Although the drug would be everywhere, it would
only be active in the eye and ear.