Diapeutics: Molecular Imaging and
Pharmacogenomics
“Genomic profiling may tell me I have the likelihood of having cancer, but it
can’t tell you where it is or how it will respond to treatments,” says the
Director of the Center for Molecular Imaging Research, run jointly buy
Massachusetts General Hospital and Harvard Medical School. “That’s where
molecular imaging comes in.” The technology essentially involves engineering
molecules to bind to disease target molecules which can then be detected by PET
scanners.
Some 20 million X-rays, CAT scans, and MRIs are administered annually for
oncology diagnostics alone, according to one analyst cited by Penelope Patsuris
in Forbes. Many of those are likely to be replaced by molecular PET scans
in a few years. When that happens, it will “transform how disease is treated,”
since it can diagnose a disease well before the onset of symptoms and monitor
whether a drug is working, and it can detect cancer better than biopsies.
For instance, Herceptin is designed to target breast cancers with the
Her-2 protein, but only about half of women who test positive for Her-2 in a
biopsy respond to the drug. “That may be because Her-2 may only be expressed in
the biopsy area and not elsewhere in the tumor,” a researcher told Patsuris. “By
measuring Her-2 with molecular imaging, we’d have a better idea of how much
Her-2 is present in a tumor and how well patients will respond to
Herceptin.”
The inevitable replacement of the blockbuster drug business model by the
individually tailored drug model already in the process of being enabled by
molecular imaging and pharmacogenomics has drug company executives worried.
“It’s hard to persuade drug firms that they can still make money using
diagnostics that can shrink their customer base, when the cost of developing one
new drug can reach $1 billion,” writes Bernadette Tansey in the San Francisco
Chronicle. But Genentech, maker of Herceptin — the first
pharmacogenomic drug — sees it as a win-win-win for patients, insurance
companies, and pharmaceutical firms.
Pharmacogenomics and molecular imaging, Tansey’s article suggests, could
reduce the cost of drug development and lower health insurance premiums by, for
example, revealing latent value in drug candidates that might otherwise be
discarded, reviving drugs pulled from the market due to side effects, and
identifying new patients who will take a drug earlier as well as longer because
it keeps them well.
Even without sophisticated molecular imaging, Genentech was still able to
pre-identify patients most likely to do well on Herceptin, and thus was
able to show strong survival benefits with a clinical trial in 469 women in less
than 20 months; without pre-identification, the trial would have needed 2,200
patients and would have taken over ten years. “Herceptin delivered $425 million
in 2003 revenues to Genentech — not a $1 billion blockbuster, but a solid
mainstay of the firm’s growing cancer franchise,” says Tansey, and that’s not to
mention its contribution to the design of next-generation drug Omnitarg
that could help the patients who don’t have excess Her-2 receptors.
Biomarkers for patients who might benefit from lung cancer drugs
Iressa or Tarceva might limit their market to as little as 10 to
15 percent of patients with the most common form of lung cancer, said stock
analysts who, perhaps not disinterestedly, saw “no reason for [drug makers] to
rush this.” Genentech, which has an interest in Tarceva, flatly
disagrees. And at least one member of the investment community is “sold on the
molecular diagnostics approach” and predicts the demise of what he calls
“blockbuster-ology.”
Genentech’s CEO told Tansey: “We’re starting to have a menu of therapies that
can be aligned with a menu of diagnostics. That’s the kind of thing that could
change the world.”
Reference: Patsuris, Penelope (2004). “The
Future Of Digital Imaging: Catching Disease Before It Catches Us.” Forbes,
May 3.
Reference: Tansey, Bernadette (204). “Genentech
a big believer in diagnostics: ‘Personalized medicine’ can help patients and
drug firms.. San Francisco Chronicle, May 17.
Making Cancer Mortal Through RNAi
An international team of researchers has discovered how to keep normal cells
from aging — and how to make cancer cells grow old and die, reports Shaoni
Bhattacharya in New Scientist. The method is to add a protective
molecular “cap” to the telomeres at the ends of chromosomes to protect them from
damage, and to remove the cap that naturally exists on up to ten percent of
cancer cells.
Telomeres maintain the structure and stability of chromosomes as they
replicate during cell division, but they shorten with each division and
eventually become so short the cell dies. Using immunofluorescence to light up
various molecules in cancer cells, the researchers always found the protein
molecule RD51D near the telomeres. When they used RNA interference to block the
action of this molecule, the cancer cells suffered substantial damage and most
died within seven days.
Reference: (2004) “Secret of eternal
life may give cancer cure.” New Scientist, April 30.
Genomics Advances
The rat is the third mammal to have its genome sequenced, and work is
proceeding to sequence the cow, honeybee, sea urchin, monkey, and others, at
Baylor University. The lead researcher, who also played a prominent role in the
Human Genome Project, thinks that in three years genomics will be in use “at the
bedside” to diagnose and treat genetic anomalies in patients. “Progress is
happening slower than we would like, but it’s coming along,” he told
BusinessWeek‘s John Carey, adding: “I’m pretty upbeat now.”
Reference: Carey, John (2004). “Genomics: ‘We’re
Steadily Marching‘.” BusinessWeek, May 6.
Bionic Spine Beats the Real Thing
An artificial spinal disc expected to be available in the US from Johnson
& Johnson in the next 12 months may be better than the real thing, says
Daniel Rosenberg in the Wall Street Journal, and almost certainly an
improvement over spinal fusion, which involves bone grafts and metal implants.
The new discs would reduce the 350,000 such procedures carried out annually in
the US.
The J&J artificial disc, Charite, is already sold in Europe to
treat “single level” lumbar-disc disease. The new disks should reduce or
eliminate wear and tear on vertebrae above and below, which tends to happen with
fusion, and may give patients a wider range of motion than fusion, as well as
increased motion sooner after surgery, no need for bracing, and no need for a
bone graft painfully taken from another part of the body.
Charite is designed to last 40 years, and will likely increase demand
for back surgery from patients (and some doctors) who now avoid fusion.
Interestingly, although the product is not advertised and not easy to find on
the Internet (according to one doctor), many patients are already asking about
it.
The price is estimated to be around US$11,000, slightly more than fusion.
Medtronic is expected to have a competing lumbar disc on the US market in 2007,
as well as an artificial cervical disc for treatment of severe neck pain —
which Medtronic thinks presents a bigger business opportunity.
Disc replacement may not make fusion obsolete, since the new discs may not be
viable for older patients, obese patients, and anyone with poor bone stock,
according to one doctor. And even newer treatments, such as disc nucleoplasty —
“an outpatient procedure in which a patient’s disc is injected with a catheter
that uses radio waves to break up tissue” — may prove to be a better
alternative to surgery.
Reference: Rosenberg, Daniel (2004). “Artificial
Spinal Disc Offers Cure Touted as Improvement Over Fusion.” Wall Street
Journal, May 12.
Spinal Cord Repair
Rats with spinal cord injuries regained 70 percent of their normal walking
function with a three-part treatment hailed as a breakthrough in paralysis
research at the University of Miami School of Medicine. The study involved
hundreds of rats with crushing injuries to the thoracic region of the spinal
cord, which mainly causes loss of control of the legs and is the most common
form of spinal cord injury among people in the United States.
The researchers transplanted Schwann cells from the peripheral nerves, where
regeneration does occur, to create a bridge across the damaged area of the
spinal cord and promote the growth of axons and their protective myelin sheath.
They also injected cyclic AMP, a messenger molecule that guides the nerve cells
to grow their connecting fibers, and Rolipram, which prevents the
breakdown of cyclic AMP and allows it to be effective over a longer period.
(Rolipram, an antidepressant, is also being investigated as a possible
treatment for multiple sclerosis.)
Rats that received the treatment regained 70 percent of their walking
function after eight weeks. They could step consistently, and had better fine
motor control and coordination. They also had more tissue in their spinal cords
than a control group, suggesting the treatment also stopped the secondary tissue
loss that normally occurs after a spinal cord injury, not to mention a 500
percent increase in nerve fibers in the graft area.
The study’s principle investigator was not ready to speculate to a Reuters
correspondent about a date for human trials.
Reference: Unknown (2004). “Paralysis Study:
Walking Improves.” Reuters via Wired News, May 23.
Industrial Biotech, GM Microbes
The young industry of industrial biotechnology uses genetically modified
organisms to manufacture chemicals. Craig Venter, of Human Genome Project fame,
has joined the fray by inventing a method of sequencing the genomes of all the
microorganisms in an environment — such as the Sargasso Sea, where he found
1,800 new microorganisms, some of which may one day prove useful in the
industry.
Other environments being trawled for candidates include hot springs, ocean
beds, soda lakes, and the Arctic tundra, reports a lengthy article in the
Economist magazine.
“It does seem likely,” says the Economist, “that industrial
biotechnology will shake up the chemical industry” in the short term, and has
the potential to shake entire economies over the longer term by, for instance,
eliminating reliance on fossil fuels, or ameliorating global warming.
A French company, Metabolic Explorer, uses a database of biochemical pathways
from multiple organisms (“as many as it can get”) and a computer model of the
metabolism of E. coli to determine how to genetically re-engineer the bacterium
to use specific pathways to produce a desired product. It has already applied
its method to produce an amino-acid animal-feed supplement with a market worth
$1.4 billion a year.
A Wisconsin company has used a similar technique to produce an amino-acid
supplement used by many people with arthritis. Other products being made, or
about to be made, by such methods include other amino-acid supplements, vitamin
supplements, antibiotics, anti-influenza drugs, foundation creams for cosmetics,
and “even the solid rocket-fuel that is used in air-to-air missiles.”
One consultant estimates about five percent by value of the world’s chemical
output is already biotech-based and will likely double over the next six years.
But “the really serious money” will flow when the field turns up the heat on
bulk chemicals and fuels, as it is now starting to do. Already, Metabolic
Explorer can turn glucose into acrylate, a feedstock for the plastics industry.
Cargill is developing microbes modified to produce a dozen chemicals that are
precursors for plastics. A Michigan State University researcher who invented
biotech rocket-fuel has developed bacterial enzymes to make a form of nylon.
A joint-venture between Cargill and Dow Chemicals produces a cost-effective
polymer made from lactic acid made, in turn, from maize-derived glucose.
Metabolix grows a specialist plastic inside genetically engineered bacteria.
DuPont’s Sorona plastic is “half biotech and half traditional.”
The industry’s Holy Grail is a way of producing glucose — the “crude oil” of
industrial biotech — really cheaply. In North America, industrial glucose is
derived, at considerable expense and with considerable waste, from maize starch.
A way is being sought to turn the bulk of the plant’s dry weight — cellulose —
into glucose, biologically, using enzymes found in many bacteria and fungi.
Novozymes, a Danish company, is making progress on this problem and intends to
turn the glucose into ethanol, a substitute for gasoline. Over the next few
years, they hope to bring the price of ethanol down to competitive with gas. A
Canadian company, Iogen, has already opened a commercial-production
cellulose-to-ethanol plant.
Reference: Unknown (2004). “Sea of
dreams: Genetically modified microbes will lead to a revolution in industrial
biotechnology.” The Economist, April 29.
Underground Pharms
Drugs can be “manufactured” at industrial scales by genetically modified
“transgenic” plants, but fear of cross-contamination with regular crops is
holding back the use of this method. For example, writes Kristen Philipkoski in
Wired, “the USDA recently rejected Ventria Biosciences’ request to plant
120 acres of rice that would be genetically modified to contain two human
proteins that fight infection: lactoferrin and lysozyme.”
An Indiana entrepreneur and Purdue University now propose to take the
“pharming” business underground — to an abandoned limestone quarry, creating
“what is basically a greenhouse in a cave” and reducing the chances of cross
contamination. Although it will be more expensive — requiring power for heat
and light — than pharming in the open, it will add other benefits by giving
researchers experimental control over environmental variables.
Apparently, underground acreage is not a problem — “there are literally tens
of thousands of acres of available space,” a researcher said. Purdue is
developing a ventilation system that will filter out insects and pollen, but one
sceptical environmentalist told Philipkoski that anything less than a
hermetically sealed facility would eventually allow transgenic plant pollen to
escape. In any event, “there’s always the risk of mixing them at some point
along the production chain, as happened in 2000 when a genetically modified corn
product called Starlink, approved only for animal feed, accidentally made
its way into Taco Bell tortillas. The resulting lawsuits essentially sunk that
program.
Reference: Philipkoski, Kristen (2004). “Drug Farms
Forced Underground.” Wired News, May 27.
Designer Baby Stem Cell Donors
Five so-called “designer babies” have been “created” at a Chicago laboratory
through embryo tissue typing, to serve as stem-cell donors for siblings with
leukemia and a potentially lethal anemia. The embryos were screened for
compatibility with their siblings through pre-implantation HLA testing, an
offshoot of the pre-implantation genetic diagnosis method used to screen and
select embryos for genetic diseases such as Down Syndrome and for gender. The
latest cases are the first instances in which embryos were tissue-typed but not
screened genetically for diseases.
Healthy embryos that were not matches for their siblings were frozen for
potential future use, but because there was always a possibility they would be
discarded in the future, a Catholic Church officer and a member of President
Bush’s Council on Bioethics were both troubled. The doctor did not share their
concern, noting that in vitro fertilization frequently produces a surplus
of embryos, and that the current research was about saving the lives of very
sick children. A medical ethicist said: “Of all the reasons people have babies,
this would seem to be a wonderful reason. Most reasons are either mindless sex
or selfish reasons.”
The results of the treatments of the sick children will not be known for some
time.
Unknown (2004). “Babies Born With a
Mission.” Associated Press via Wired News, May 4.
Designer Anti-AIDS Virus
Lawrence Berkeley National Laboratory researchers have engineered an HIV
virus to adhere to normal HIV and preventing it from turning into AIDS, reports
Kristen Philipkoski in Wired. The treatment has worked in computer
simulations and in the petri dish. It was so easy and inexpensive, said one of
the researchers, that “If I can do it, anyone can do it,” adding: “That’s going
to be a problem.”
They say the treatment would prevent AIDS from arising even in patients who
otherwise would have developed the disease after a decade of latency, and
predict that HIV would not become resistant to the virus.
The treatment was made by removing the harmful parts of an HIV virus and
replacing them with DNA strings that inhibit its ability to kill immune cells.
It adheres to natural HIV and spreads along with it, even from person to person.
This is “synthetic biology,” the synthesis of biological elements, usually at
the molecular level or below, into machines.
A corporate lab, Virxsys, is already in phase I (safety) clinical trials of a
similar treatment, with human subjects.
Reference: Philipkoski, Kristen (2004). “Designer Virus
Stalks HIV.” Wired News, May 13.
Anti-AIDS Bacterium
Researchers at the University of Illinois in Chicago have shown in petri dish
experiments that harmless lactobacillus bacteria naturally present in human
mouths could stop newborn babies from contracting HIV via milk from HIV-infected
mothers. The bacteria bind to a sugar present on the surface of at least seven
different HIV-1 strains of the virus.
In the tests, one lactobacillus strain reduced the level of HIV infection by
over 99 percent. If it passes through animal testing and succeeds in human
trials, the treatment would have an enormous impact: It is cheap, it needs to be
administered only once because the bacteria maintain themselves in the gut, and
it could be given to babies routinely even if a doctor is not sure whether the
mother is infected.
Reference: Randerson, James (2004). “Friendly mouth
bacteria could block HIV.” New Scientist, May 26.
Anti-obesity Shock Therapy
A laparoscopically inserted, pacemaker-like implant device sends small,
unfelt electrical shocks to the muscle wall of the stomach to give a feeling of
satiety. It is much safer than, and less than one-fifth the cost of, lap band or
gastric bypass surgery, but it is not as effective in some patients.
About 450 patients, mostly in Europe, where the device is approved, have
received the implant. However, reports Louise Knapp in Wired, “Its
success rate . . . has been hit-or-miss,” with some patients responding “almost
miraculously, losing 40 percent of their excess weight” and others not
responding at all. One problem is that merely feeling full does not stop the
“binge eating” to which some morbidly obese patients are prone. The lap band or
gastric bypass, in contrast, effectively prevents binge eating.
The implant procedure takes less than an hour followed by a few hours of
hospital bed rest, compared to a three hour procedure and up to four days in
hospital for a gastric bypass. The doctor can set the intensity, frequency, and
pattern of the electrical pulses. Clinical trials are underway in the US.
Reference: Knapp, Louise (2004). “Electric Shocks to
Fight the Flab.” Wired News, May 25.
Obesity Drug
In 1996, University of Texas MD Anderson Cancer Center researchers discovered
a drug that “makes fat mice thin and healthy, and it could do the same for
humans” writes Kristen Philipkoski. Cancer tumors and fat both rely on blood
vessels to sustain them, therefore the anti-angiogenic approach already being
applied to cancer treatment might also work for obesity, they reasoned. They
eventually found a peptide that specifically attaches to fat blood vessels and
blocks them, thus starving and killing the fat cells.
In tests, mice not only lost 30 percent of their weight, but also became
“healthier all around.” Baboon tests are next, and human trials could take place
in three to five years. Compared to current treatments such as Xenical,
which essentially tries to prevent absorption of fat, the new method works
faster and (in the mice) with fewer side effects.
Reference: Philipkoski, Kristen (2004). “Blood Feud Kills
Off Fat Cells.” Wired News, May 10.
Fat to Bone
A team of researchers from Louisiana and North Carolina have converted stem
cells in human fat to human bone cells when transplanted into a mouse. A Danish
team has independently reported similar success.
The method involves extracting human fat through liposuction, separating out
the stem cells, and culturing them in the lab. The cells are then placed onto a
chip of artificial bone, which is implanted under the skin for six weeks. After
removing the bone chip from the experimental mice, the stem cells were found to
have converted to living human bone cells and were growing on their own.
Some significant hurdles remain before human clinical trials could be
considered.
Reference: Unknown (2004). “Center
reports stem-cell breakthrough.” Associated Press via USA Today, May 6.
Stem Cell Bank
The world’s first embryonic stem-cell bank, opened in May in the UK, will
store “tens of thousands” of stem cell lines and supply them to researchers
developing stem cell therapies. Opponents, reports Reuters, have condemned the
bank “as a storage site for dead babies.” The bank is being funded by the
Medical Research Council and the Biotechnology and Biological Sciences Research
Council. Its first two stem cell lines were developed separately by researchers
at King’s College London and the Center for Life in Newcastle.
Reference: Unknown (2004). “1st Nat’l Bank of
Stem Cells.” Reuters via Wired News, May 19.
Regenerating the Pancreas
A new study in mice confirms that insulin-producing beta cells in the
pancreas can regenerate themselves, repairing the ravages of type 1 (juvenile)
diabetes, which destroys them. Previous studies have suggested that embryonic or
adult stem cells could also be coaxed to become beta cells, but the new study
found no evidence that adult stem cells are involved in the regeneration of beta
cells.
It is still unclear whether beta cells could replicate themselves in
sufficient numbers to be useful.
Reference: Unknown (2004). “Insulin-Making
Cells Regenerate.” Associated Press via Wired, May 5.
Dendrimers Against Cancer
“Smart” nanodevices made from dendrimers are being developed at the
University of Michigan to deliver a lethal dose of an anticancer drug to
cancerous cells while leaving normal cells unharmed. Working examples of four of
five nano-components that make up the “tecto-dendrimer” nanodevice have so far
been made, and work is under way to assemble them into the final product. The
components perform cancer cell recognition, diagnosis of cancer cause, drug
delivery, reporting tumor location, and reporting cancer cell death.
In vitro and in vivo tests of the four completed components
have been successfully conducted using the KB cell line, a human epidermoid
cancer.
Reference: A University of Michigan website. (Current as of
May 5, 2004.)
Hypothermia Therapy
Therapeutic ultra-profound hypothermia — cooling the body to just above
freezing — slows metabolism and “translates into more available time on the
operating table, less potential for blood loss, and fewer post-op
complications,” writes Wil McCarthy in Wired. But that’s just for
starters.
Current cooling techniques — blood coolers, ice-water baths, cold caps,
water-circulating pads — may reduce core temperature down to 90 degrees F., and
going any lower can result in catastrophic circulatory dysfunction. But a small
company called BioTime has developed a process that cools the body to 35 degrees
F. — “the brink of freezing” — without causing damage and allowing much longer
states of “suspended animation,” as it were.
It does so by using a blood-volume expander, in common use to maintain blood
pressure and chemistry in the wake of massive blood loss, which also has the
properties of an antifreeze. Since the product, Hextend, is already on
the market as a blood-volume replacement, it could receive US Food and Drug
Administration approval for use in therapeutic hypothermia in three years, with
beneficial impacts on long surgeries.
In tests on baboons and other animals, after two hours at 35 degrees, with
all vital signs stopped, the animals were “easily” brought back to life from two
hours of absolute clinical death, with no subsequent sign of physical or
neurological damage over a period of weeks, the company claims. For test animals
cooled for more than three hours, the success rate drops below 50 percent, but
even those may be acceptable odds for a patient facing otherwise certain death
from an almost inaccessible brain tumor.
BioTime is also developing a cryoprotectant, HetaFreeze, to freeze
tissue grafts without causing cell damage. It has been tested with skin and
hair, and may eventually allow the freezing of whole organs. Treated with
cryoprotectant and suspended under high pressure in liquid nitrogen, the organ
tissue becomes vitrified without damage, and can be thawed and grafted onto a
living animal.
While BioTime, says McCarthy, “goes out of its way to distance itself from
cryonics” (freezing the dead in hopes of resurrection when science catches up),
its work is clearly heading in the same direction, intended or not.
Reference: McCarthy, Wil (2004). “The Doctor Will
Freeze You Now: How low-temperature surgery could kick-start the cryo game.”
Wired, Issue 12.05, May.
Biodegradable Drug-eluting Stent
In preliminary tests, Conor Medsystems new drug-eluting stent has shown it is
about half as likely to clog up with scar tissue than others on the market.
Instead of being simply coated with drugs to prevent the buildup of scar tissue,
the Conor stent packs the drug inside a polymer mesh that biodegrades slowly,
providing a steady dose of the drug for a longer period than today’s drug-coated
stents.
These results are from a small-scale trial. A large study is under way in
Europe, and a large US trial is planned for this Fall.
Reference: Hamilton, David P. (2004). “Conor
Drug-Eluting Stent Shows Promise in Early Tests.” Wall Street Journal, May
25.
Personalized Medicine
A new electroencephalogram (EEG)-based system records the firing of neurons,
blood flow, and other brain activity to gauge the effectiveness of
antidepressants. A disposable strip of electrodes affixed to the forehead
measures activity in the frontal lobe, where (it is claimed) depression often
manifests itself, and a computer analyzes and displays the results.
“You can see changes in the brain 48 hours after the patient takes the drug,”
said one of its developers, adding that its use could cut human clinical trials
of antidepressants by 80 percent. It can also be used as a “clinical trial of
one” to determine which of 25 common antidepressants on the market is best for
an individual patient — a great boon since most antidepressants take at least
two weeks to alleviate symptoms, if at all. The device will not be sold at first
for such use, however; rather, it is being sold to pharmaceutical companies to
help evaluate antidepressants.
One sceptical psychiatrist said, however, “There’s no data to show that it
[depression]’s coming from the frontal lobe. There are changes in many other
parts of the brain.” She is sticking to her PET.
Reference: Unknown (2004). “This Is Your Brain
on Drugs.” Reuters via Wired News, May 30.
Aloha, Telesurgery
A Hawaiian hospital has begun telecasting live surgeries over a broadband
link to allow specialists worldwide to observe and consult with its surgeons
during emergency and other procedures. The island state’s patients won’t need to
travel thousands of miles to the US mainland or abroad for operations, and
medical students will be able to view the live surgeries. By not sending
patients on long journeys to hospitals elsewhere, the hospital’s revenues will
increase, the financial cost to patients and insurers will be less, the risk to
patients needing urgent treatment will be lowered, and students will get better
training.
The hospital has partnerships with physicians at the University of California
at Los Angeles and Stanford University. It is also attracting more patients from
Pacific rim countries. It is now exploring robotic surgery with other hospitals,
surgeons, and the medical school.
Reference: Sawada, Kristen (2004). “Kapiolani’s
telesurgery will reach doctors worldwide.” Pacific Business News, April 30.
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