| Computing + Proteomics = Big Jump Forward
Synthetic biologists have re-engineered E. coli proteins to bind to target
molecules then signal their success by fluorescing. It takes “trillions upon
trillions” of computer simulations — or about two days, given the power of
today’s computers and some clever programming — to create the re-engineering
blueprint for a protein for a specific target molecule. It takes a further ten
days to “machine” or physically reconfigure the amino acids in the protein to
match the specification in the blueprint, and to add a fluorescent molecule.
To demonstrate that the technique can be applied to a wide range of targets,
Duke University researchers have created proteins that detect TNT, glucose, and
serotonin. Optical fibers coated with TNT-sensing protein and attached to an
unmanned underwater vehicle could help the Navy find discarded munitions in the
ocean. A computer monitors for fluorescence, which occurs if the vehicle
encounters TNT molecules in the water.
A glucose-sensing protein under development could be used to monitor diabetic
patients during operations or in intensive care. Instead of having a nurse take
blood samples every two to four hours (with the attendant risks of exposure and
error, not to mention the possibility of missing a rapid rise in levels between
blood tests) the surgeon inserts a protein-coated optical fiber through a
catheter, and an attached computer sounds the alarm whenever the fiber detects a
dangerous blood sugar level.
Having proved they can make the proteins, the researchers are now
focusing on making them more stable and robust, before application testing
begins, in about a year.
US and German researchers have made artificial DNA that glows when it
combines with a specific sequence of natural DNA, making possible DNA chips that
directly sense individual DNA molecules, such as those of antibiotic-resistant
bacteria.
In the absence of other single strands, a single DNA strand will tend to
“mate” with itself by bending like a hairpin. The researchers added fluorescent
dye to a single DNA strand. The dye stopped fluorescing when the strand brought
the dye into contact with the base guanosine by folding into a hairpin. But the
hairpin opens when it comes into contact with another strand, for example, from
a bacteria, and the dye again fluoresces. By detecting the fluorescence,
observers would be detecting and precisely locating the bacterium. A DNA sensor
based on this approach could be in practical use in two to five years.
A different approach to DNA detection uses carbon nanotubes and probe DNA
molecules to sense trace amounts of DNA. When a targeted DNA type (from E. coli,
for example) is present, it attaches to the probe DNA, which makes electricity
flow more easily through the nanotubes. This detector could be used in practical
applications within two years, according to the researchers. A NASA spinoff
company, Integrated Nanosystems Inc., is commercializing the system, which they
hope could lead to a handheld, instant DNA scanner. If you are a “Trekkie,”
think “tricorder.”
References: Unknown (2003). “Chip Senses Trace
DNA.” Technology Research News, July 31; Unknown (2003). “Glow Shows
Individual DNA.” Technology Research News, September 15; Knapp, Louise
(2003). “Microscopic
Detectives on Patrol.” Wired News, August 23.
Molecular Imaging
Molecular imaging tools will enable doctors to spot disease instantly and
accurately, without resort to scalpel or biopsy needle. Unlike conventional
imaging tools like x-rays and MRIs, which provide only gross
anatomical/structural information, molecular imaging provides cellular-level
functional data. Cellular change can warn of a disease condition well before it
shows up as a gross structural abnormality, such as a tumor, and enables the
physician more accurately to identify a disease from its unique molecular
activities.
Molecular imaging has already begun to change medicine at a very fundamental
level, by redefining diseases in terms of their molecular signature rather than
their gross anatomical structure or location. But it will change it even
further, as the technology becomes able to scan continuously for molecular signs
of disease, as well as helping diagnose, treat, and continually monitor the
effects of treatment.
In an in-depth review of the state of the art, Technology Review‘s
Joan Hamilton quotes a Harvard researcher: “We’re not doing incremental work.
These are leapfrog advances”; and a GE Medical executive: “molecular imaging has
the potential to change the game;” and a biotech executive: “There is a quantum
leap around the corner.”
An example that provides a peek around the corner is the fluorescent protein
described in the previous article. Another is Theseus’ Apomate
molecular-imaging agent, which enables physicians to observe apoptosis — cell
death — as it occurs, and thus to determine whether a particular therapy (to
destroy a cancer, for example) is working, or the extent of ongoing damage to
tissue, for a therapy intended to save the tissue. Apomate is a an
engineered synthetic protein with a radioactive isotope that shows up under a
scanner. Dying cells in a patient injected with Apomate light up under
the scanner. Lung cancer patients in a European trial are given Apomate
at the beginning of chemotherapy, to determine whether tumor cells are dying. If
not, the treatment can be discontinued and other approaches explored.
Apomate is also being used experimentally to identify heart-attack
victims who continue to lose heart cells long after the attack, making them
possible candidates for eventual heart failure — and preventive treatment; and
to identify unstable plaques in coronary blood vessels, that could give early
warning of heart attacks. Apoptosis imaging could become part of the standard
battery of tests for patients presenting with chest pain.
For molecular imaging to reach its full potential, it must first be made able
to focus sharply on a very small number of target molecules. One attempt to do
this uses high-resolution MRI and CT scanners to diagnose early molecular signs
of stroke, schizophrenia, Alzheimer’s, and other ailments.
Another method adapts traditional colonoscopy to diagnose colon cancer, using
a molecular imaging agent engineered from a fluorescent protein that lights up
in the presence of an enzyme found only in malignant polyps. The idea is to
inject imaging agent into a patient, then use a fiber-optic scope to look for
fluorescence. This would permit instant diagnosis, without biopsy. Researchers
are currently testing the procedure on mice.
Another approach, being applied to breast cancer diagnosis, is to exploit the
natural fluorescence of biological tissues stimulated by certain wavelengths of
light. Healthy and cancerous tissues fluoresce differently, and the idea is to
thread a fiber-optic sensor through a biopsy needle, insert the needle into the
breast, light up the tissue through the optical fiber, and collect and analyze
the fluorescence emitted by cells at the needle’s tip. The procedure is being
tested on women undergoing breast cancer surgery. Trials with women undergoing
breast biopsy are planned for 2004.
Molecular imaging has the potential to do more than diagnose, more than
change the way doctors practice medicine; it may change medicine itself. Indeed,
that revolution already has begun, with the arrival last May of Velcade,
a drug that combats a rare blood cancer,. Velcade was developed using
engineered tumor cells that glow brightly under an optical scanner when the
pathways are active. In tests on mice, the chemical theory behind the drug was
proved experimentally, lopping weeks or months off the time it takes drug
developers to establish which candidate drugs work, and which don’t.
One company calls this the beginning of the “see and treat” era. Molecular
imaging agents can not only identify and localize disease, but can also be
engineered to carry a toxic payload to kill the disease-causing agents. They not
only can be — they have been: Zevalin, a radioactively tagged antibody that
finds and binds directly to a protein on rogue white blood cells that cause
non-Hodgkin s lymphoma, received FDA approval last year for patients who have
not responded to other treatments.
This does indeed have all the appearance of the start of a revolution in
medicine, though regular HFD readers will recognize it as just a point on the
exponential acceleration curve of a revolution already under way.
Reference: Hamilton, Joan O’C. (2003). “A Sharper
Picture of Health.” Technology Review, September.
Breathalyzer Mk.II
Scottish scientists are examining the role of lipids — or rather, their
absence — in causing a breakdown in communication between brain cells,
resulting in schizophrenia, autism, dyspraxia, dyslexia, attention deficit
hyperactivity disorder, and depression. They use a simple bag to trap breath,
then look for evidence of oxidative stress wrought by free radicals.
Damage caused by free radicals can lead to a loss of some types of fatty
acids in the brain, in turn leading to problems with brain function and
behavior. The researchers have discovered that some people with mental illness
may also be under oxidative stress, and are looking for drugs to reduce
oxidative stress in the brain. Simple fish oil supplements, rich in omega-3
fatty acids, are one known natural source. They have discovered that certain
“marker gases” in the breath can give advance warning of excessive oxidative
stress. Acetone, for example, is a marker for diabetes, and they are on the
trail of breath markers for lung disease.
Breath analysis is totally noninvasive, easier than a blood or urine test,
and administrable almost anywhere.
Reference: Mackenzie, Hector (2003). “When Bad Breath
Means Bad News.” Wired News, August 20.
Spotting Subtle Change in MRI Images
A 350 KB program called a change detection system, or CDS, developed by US
Department of Energy scientists for defense surveillance images, can show the
tiniest differences between MRI or other digital medical images. It aligns
images to within a fraction of a pixel, compensating for differences in camera
angle, height, zoom, and other distortions that confound other methods;
revealing, for example, tiny retinal changes that signal macular degeneration,
in a matter of seconds. The program is small enough to run on a handheld
computer.
Reference: Delio, Michelle (2003). “Software Spots
Devilish Details.” Wired News, August 18.
Rapid Diagnosis of Infectious Diseases
Faster and more sensitive tests for influenza, pneumonia, adenovirus, herpes,
West Nile virus, SARS, and other infectious diseases may result from a
combination of two existing products: one is a technology that simultaneously
tests for multiple viruses or other pathogens; the other, a technology that uses
micro-electronics and molecular biology to conduct genetic identification and
analysis. The combination is anticipated to allow automated testing of patient
samples within hours, and “greatly improve the ability for health care providers
and labs to detect infectious-disease agents.”
Reference: Gertzen, Jason (2003). “San Diego firms to
develop new disease tests.” Milwaukee Journal Sentinel, September
11.
Blood Test Might Measure Pain
A simple blood test could measure pain. A pain researcher claims his test has
already been shown to work in headache sufferers. His test measures the relative
amounts of three neurotransmitters, but he has refused to identify them,
apparently for commercial reasons. He claims that in unpublished research
involving 60 people, half with mild headache, his test successfully identified
all the men with headache, and 93 per cent of the women. Other pain experts seem
deeply skeptical of these claims, which nevertheless were sufficiently
intriguing to merit mention in the New Scientist.
Reference: Coghlan, Andy (2003). “Blood test tells
how much it hurts.” New Scientist, September 12.
Self-care: Asthma Monitor
Researchers at Brunel University in the UK have developed an alternative to
the peak flow meter. The “Asthma Alert” device requires only normal breathing to
measure the rate of change in concentration of exhaled carbon dioxide, and can
even be used by very small children. “Instead of a number scale that has to be
interpreted, [the device] will have a screen that advises asthmatic patients on
their asthma status and gives instruction on how to adjust their medication if
required,” said its co-inventor. “Its simplicity, reliability and low cost will
make it ideal for patients to monitor their own asthma and be in control of the
disease. It will also be of immense benefit to general practitioners, who will
now be able to diagnose asthma far more accurately.” The device may be ready for
commercial launch in about 18 months.
Reference: Woodman, Richard. “Simple Asthma
Monitor New Monitor Could Help Patients Control Asthma.” Reuters, August
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