Lights on, brain off

If you’re a night owl like me, then those first rays of
sunshine in the morning often seem to make you feel even groggier than you did
when you went to bed. But scientists have found a new, efficient way to use
simple beams of light to literally—not just metaphorically—shut down the brain.

Ed Boyden, a research
professor at the Massachusetts Institute of Technology, and his colleagues have
discovered two new light-sensitive proteins that, when implanted into neurons,
prevent those cells from activating in the presence of certain wavelengths of
light. Arch, found in a species of bacteria, is sensitive to yellow light,
whereas Mac is of fungal origin and responds to blue light, the scientists
report
in the Jan. 7 issue of Nature.

Arch
A mouse neuron expressing Arch

These proteins, Boyden says, will not only provide
scientists with a powerful but reversible way to study specific brain regions,
but may also provide promising new gene therapy treatments for diseases caused
by overactive brain cells. One of the most drastic examples of such a disorder
is epilepsy,
in which spontaneous activity by neurons can sometimes spread throughout the
entire brain, causing violent seizures and occasionally death.

These aren’t the first light-sensitive proteins, or opsins,
that neuroscientists have adapted to their purposes. For some time, researchers
have been using opsins to both selectively activate and inhibit brain cells, a
field known as optogenetics. As we reported last month,
such techniques allow scientists to study the function of specific brain cells,
such as those involved in memory or disease, with greater detail and precision
than previously possible.

Opsins work because they are ion channels; when activated,
they allow charged particles into a cell. In the case of ChR2, blue light
causes an influx of charged particles that mimic what naturally occurs when a
neuron is told to fire. Halorhodopsin, on the other hand, adds chloride ions to
a cell’s interior that make it unable to send a signal. Halorhodopsin, however,
quickly becomes inactive in the presence of light, whereas the new proteins,
which allow protons into cells, “reset” themselves and can shut off cells for
very long periods of time. “These are an order of magnitude better,” Boyden
says. “They allow for near-digital turning off of neurons in awake animal
cortexes.”

In the Nature
paper, Boyden and his colleagues demonstrate the use of Arch and Mac in awake
mice, but he says that the team has also conducted tests in nonhuman primates
with no apparent side effects yet.  They
are also “very eager” to begin studying prototype therapies in mouse models for
epilepsy, chronic pain, brain injuries, and other brain diseases, he adds.
Opsins are normally implanted using gene therapy, in which a retrovirus is used
to insert the opsin-producing gene into the relevant brain cells. In recent
years, scientists have significantly improved their gene therapy techniques—for
instance, they can now target the right cells by altering the protein coat of
the virus or by adding different DNA promoter regions to the implanted
gene—Boyden says, and thus the risk of side effects such as cancer has dropped
dramatically.

Another benefit of the new long-lasting proteins, he adds,
is that scientists can now precisely and reversibly shut off small regions of
the brain to study their roles in activities like cognition and attention—essentially,
a “high-throughput scan for the brain.” Previously, scientists have obtained this
information largely by looking at lesions, but these are relatively large and
haphazard and provide no information about timing. “It’s like pulling the power
cord of a laptop. You don’t know if it’s the lack of a power or the processing
input causing the problem,” Boyden says. “We believe this will have a
significant effect on neuroscience.”

—Aalok Mehta

Image courtesy of Brian Chow, Xue Han and Ed Boyden / MIT

Alzheimer’s gene therapy trial takes another step

Those who take care of someone with Alzheimer’s or follow
developments in the field are well aware that there are no good treatments for
the disease. The handful of drugs that have been approved for use in
patients—such as donepezil, sold under the name Aricept—only
manage symptoms; they do not reverse or even slow the loss of nerve cells that ultimately
leads to death.

Now scientists are testing
a treatment that does show promise for arresting the progression of
Alzheimer’s. Twelve sites around the country are recruiting patients for a
Phase II trial of CERE-110,
a gene therapy treatment. In this approach, doctors perform surgery to implant
a virus into the brain; the virus then inserts new genetic material into nerve
cells that stimulates them to overproduce nerve growth factor (NGF). This
protein promotes nerve growth survival; increased levels of NGF have reversed
nerve cell degeneration in monkeys and rats.

Phase I trials,
conducted over the past five years, have shown that the gene therapy is safe for
people and does not cause side effects such as cancer or immune reactions,
which had occurred in prior gene therapy trials. Because Phase I trials test
primarily for safety, however, information on how well or if the treatment
works is pretty sparse. The Phase II trial will test the effectiveness of the
therapy in a total of 50 people with mild to moderate Alzheimer’s, with half
receiving the treatment and the other half serving as controls by getting
“sham” surgeries. If the trial were successful, the latter group would be
eligible to receive the full treatment.

Directly tackling the
underlying causes of Alzheimer’s has proven extremely difficult. Last year, for
instance, a highly touted and 1,700-subject Phase III trial
of flurizan
, a drug
that targets the amyloid protein clumps that form in Alzheimer’s, failed to
show a significant benefit. Bapineuzumab, an experimental vaccine against
amyloid proteins, showed positive effects
only in a select group of patients
in a recent Phase II trial.

It will be several years before the results of this trial
are reported, but scientists and patients have a good reason for optimism, as this has been a breakthrough year for gene
therapy. Recently researchers restored
color vision
in two color-blind monkeys using gene therapy. Earlier this
month, scientists also announced that they had halted the
progression
of a devastating brain disease,
X-linked
adrenoleukodystrophy, in two young boys.

-Aalok Mehta

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