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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 5 of 5. This is the beginning of the thread.
Posted by jrbecker on May 17, 2004, at 8:42:16
a good overview of depression research on the horizon...
May 14, 2004, 3:48PM
Depression research finds mental health experts optimistic
By DAVID KOHN
Copyright 2004 Baltimore SunHusseini Manji just wants his rats to be happy. But that's not an easy thing to make happen. Many have been genetically engineered to be fretful and melancholic, to give up easily when faced with problems.
But Manji is determined; he gives his disheartened rodents a range of experimental drugs, including one that lowers chemicals released during stress and another that strengthens the brain's neuronal support system.
Manji isn't an overenthusiastic animal lover. He's a psychiatrist at the National Institute of Mental Health who knows that if he can get his rats to be more curious, or swim longer in a pool of deep water, he might eventually be able to help some of the 20 million Americans suffering from depression.
Manji, 44, is part of a new wave in depression research. Using fresh insights into how this often-devastating disease harms the brain, he and others are developing innovative drugs.
These new approaches go far beyond current treatments, most of which work by increasing levels of the neurotransmitter serotonin. Over the past decade, researchers have linked depression to other neurochemicals and have found evidence that structural defects in the brain might play a role.
He helps oversee NIMH's extensive depression-research program. In labs on the Bethesda, Md., campus of the National Institutes of Health, Manji and his colleagues examine depression from a variety of angles. In addition to rats, they study genes, neurons, primates and humans.
The most commonly used antidepressants are drugs such as Prozac, which increases brain levels of serotonin, a chemical that effects mood, anxiety and cognition. Introduced 17 years ago, selective serotonin reuptake inhibitors are safer than older antidepressants and have fewer side effects.
But SSRIs work well for only half those who take them. And even when successful, they regularly cause gastrointestinal and sexual problems. Last month, the FDA warned that SSRIs might cause suicidal thoughts, particularly in children.
A quarter of the 6 million Americans who take antidepressants aren't helped by any medicines, whether SSRIs or their predecessors.
"There's a huge need for new drugs," Columbia University neurobiologist Luca Santarelli said. He is one of many scientists working on drugs that stimulate the growth of new nerve cells in key parts of the brain.
Studies in animals and humans have shown that this neuronal sprouting, as it is called, can lift depression. Known as neurogenesis, this recently discovered phenomenon could play a crucial role in the next wave of medicines.
"This could be the key to treating depression," said Princeton University psychologist Barry Jacobs, a leading proponent of the neurogenesis theory.
Current antidepressants stimulate neurogenesis in the hippocampus -- a brain region involved in mood and anxiety -- but do so indirectly and slowly. These drugs typically take three to six weeks to improve mood, an eternity for a deeply depressed person. Santarelli and others are looking for molecules that trigger neurogenesis without such a lag.
The search has spurred scientists to examine relatively overlooked neurochemicals.
Many researchers have focused on stress hormones. Released when animals are under pressure, these chemicals help put the body and brain on alert. Many depressed people have high stress-hormone levels, and scientists think these compounds could trigger the disease. This theory has received a recent boost from studies finding that excess stress hormones can shrink the hippocampus, the opposite of neurogenesis.
For some people, depression might be "a stress response that gets stuck in the `on' position," said NIMH researcher Dr. Philip Gold, who is studying a drug that lowers brain levels of the key stress chemical corticotropin-releasing hormone.
Gold thinks the compound, antalarmin, might work especially well in melancholic depression, a subtype in which patients are overagitated and anxious.
Several pharmaceutical companies are also working on anti-CRH compounds. Because these drugs and the Prozac class of medicines work by different neurochemical pathways, they aren't likely to have the sexual and digestive side effects, and might work faster, scientists say.
"We think it has legs," said Jim Cassella, head of clinical research at Neurogen Corp., a Connecticut biotech company working on a CRH antagonist. The company hopes to begin human trials next year.
Another possible target is glutamate, a neurotransmitter that sends excitatory messages, telling the brain to pay attention. Too much glutamate overstimulates and damages nerve cells, and researchers suspect that this chemical system goes awry in depression.
Manji and colleagues are interested in two glutamate blockers: memantine, an Alzheimer's drug, and riluzole, used for Lou Gehrig's disease.
"It's likely that depression is actually several different biological conditions," said Dr. Dennis Charney, head of depression research at NIMH.By understanding the neurochemicals that contribute to the disorder, researchers hope to delineate those differences. NIMH is trying to find genetic markers for each subtype.
Researchers at Emory University are focusing on brain scans, trying to pinpoint specific brain circuits affected in various forms of depression. The ultimate goal is to better match drugs with patients. Now, psychiatrists must guess, trying one drug after another until they hit on one that works.
While some researchers try to lower glutamate and stress hormones, others work to boost other neurochemicals that seem to soothe depression. Chief among these is brain-derived neurotrophic factor, a compound that acts as a powerful support system for neurons.
Some researchers suspect that by triggering neurogenesis and improving overall neuronal health, BDNF can alleviate depression. Current antidepressants also raise BDNF, but they take weeks.
Roche is looking at the substance and has teamed up with a small biotech company, Memory Pharmaceuticals, to study a drug that could quickly raise brain BDNF levels. The companies are testing the compound on animals.
Manji is also trying another way to boost BDNF: sleep deprivation. Scientists have long known that lack of sleep is a potent and almost immediate antidepressant. Because sleeplessness has obvious side effects, it's not a viable treatment. So Manji and his NIMH colleagues are trying to trick certain brain regions into staying up while the rest of the brain (along with its owner) sleeps.
In an experiment set to begin this spring, scientists will inject sleeping depressives with a BDNF-boosting drug during key sleep periods, when the brain is acutely responsive. If the method works, it could literally cure depression overnight.
Not all of these ideas will pan out. Antidepressant research is notoriously frustrating. What cheers up rats -- even those bred for despair -- doesn't always revive unhappy humans. And, because depression is so complex and subjective, what works with one group of humans often fails with another.
But most scientists are confident that some of the research will end up helping patients.
Posted by SLS on May 17, 2004, at 8:55:33
In reply to future research hopeful for vanquishing depression, posted by jrbecker on May 17, 2004, at 8:42:16
I've been waiting such a long time.
:-(
- Scott
Posted by finelinebob on May 17, 2004, at 9:22:15
In reply to future research - I wish they'd hurry up already!, posted by SLS on May 17, 2004, at 8:55:33
Posted by SLS on May 17, 2004, at 10:04:38
In reply to **future** research?! ***rats!!!*** (nm), posted by finelinebob on May 17, 2004, at 9:22:15
When I was a research patient at the NIMH, I had the honor of witnessing the incorporation of lab rats into the pool of data collected for the betterment of mankind. It was a difficult thing for me to justify the application of painful procedures to, and the sacrificing of, so many animals. It was a bit of a moral dilemma for me, and I guess it still is. It becomes especially difficult when you start moving up the tree of evolution. Dogs? Chimps? Would we be so willing to use Neanderthals in this way were there to be any still walking the earth? Unfortunately, I can't participate actively in any sort of deliberation of this matter. My life depends on this type of research. Ethics and morality are luxuries I can't afford.
Just something to think about.
- Scott
Posted by jrbecker on May 17, 2004, at 10:37:01
In reply to Re: **future** research?! ***rats!!!***, posted by SLS on May 17, 2004, at 10:04:38
> When I was a research patient at the NIMH, I had the honor of witnessing the incorporation of lab rats into the pool of data collected for the betterment of mankind. It was a difficult thing for me to justify the application of painful procedures to, and the sacrificing of, so many animals. It was a bit of a moral dilemma for me, and I guess it still is. It becomes especially difficult when you start moving up the tree of evolution. Dogs? Chimps? Would we be so willing to use Neanderthals in this way were there to be any still walking the earth? Unfortunately, I can't participate actively in any sort of deliberation of this matter. My life depends on this type of research. Ethics and morality are luxuries I can't afford.
>
> Just something to think about.
>
>
> - Scottperhaps in the future, you won't have to feel so guilty about preclinical research (see below).
http://www.technologyreview.com/articles/print_version/freedman0604.asp
The Silicon Guinea Pig
Technology Review
By David H. Freedman
June 2004Can silicon microchips mimic living organisms? Some researchers believe they can provide a fast, cheap way to screen thousands of drugs for toxic side effects.
A different animal: This chip provides a realistic simulation of a lab animal's metabolism.
At first glance, Michael Shuler’s chip could pass for any small silicon slab pried out of a computer or cell phone. Which makes it seem all the more out of place on a bench top in the Cornell University researcher’s lab, surrounded by petri dishes, beakers, and other bio-clutter and mounted in a plastic tray like a dissected mouse. The chip appears to be on some sort of life support, with pinkish fluid pumping into it through tubes. Shuler methodically points out the components of the chip with a pencil: here’s the liver, the lungs are over here, this is fat. He then injects an experimental drug into the imitation blood coursing through these “organs” and “tissues”—actually tiny mazes of twisting pipes and chambers lined with living cells. The compound will react with other chemicals, accumulate in some of the organs, and pass quickly through others. After several hours, Shuler and his team will be closer to answering a key question: is the compound, when given to an actual human, likely to do more harm than good?This so-called animal on a chip was designed to help overcome an enormous obstacle to discovering new drugs: there is currently no quick, reliable way to predict if an experimental compound will have toxic side effects—if it will make people sick instead of making them well. Testing in animals is the best drugmakers can do, but it is slow, expensive, often inaccurate, and objectionable to many. To minimize the number of animal tests, drug companies routinely screen drug candidates using cell cultures—essentially clumps of living human or animal cells growing in petri dishes or test tubes. The approach is relatively cheap and easy, but it gives only a hazy prediction of what will happen to a compound on the circuitous trip through the tissues and organs of an animal.
Shuler is among a handful of researchers who are developing more sophisticated cell cultures that simulate the body’s complex organs and tissues. MIT tissue engineer Linda Griffith, for one, has built a chip that mimics some of the functions of a liver, while Shuichi Takayama, a biomedical engineer at the University of Michigan, has built one that imitates the behavior of the vasculatory system (see “Other Animal-on-a-Chip Efforts,” below). But while such efforts have produced convincing analogues of parts of human or animal bodies, Shuler has gone a step further. Working with colleague Greg Baxter, who launched Beverly Hills, CA-based Hurel to commercialize the technology, Shuler has combined replicas of multiple animal organs on a single chip, creating a rough stand-in for an entire mammal. Other versions of Shuler’s chips attempt to go even further, using human cells to more faithfully reproduce the effects of a compound in the body.
Drug companies are interested, and no wonder: they routinely make thousands, even tens of thousands, of compounds in hopes of finding one that is effective against a particular target. Chips such as Shuler and Baxter’s could mean a cheap, fast, and accurate way to weed out compounds that would eventually prove toxic, saving companies years and millions of dollars on the development of worthless drugs. According to a recent study by Tufts University’s Center for the Study of Drug Development, for each drug that reaches market, the drug industry spends an average of $467 million on human testing—the vast majority of the money going to drugs that fail, either because they aren’t effective or because they prove toxic. If more failures could be identified before animal testing even began, companies could focus more of their time and money on the winners. “Everyone in the industry hopes to have surrogates for animals and humans when it comes to testing compounds,” says Jack Reynolds, head of safety sciences for Pfizer, the world’s largest pharmaceutical firm. “This is the sort of technology we’d want in our toolbox.”
OTHER ANIMAL-ON-A-CHIP EFFORTS
Project Leader Group Technology
Dawn Applegate RegeneMed
(San Diego, CA) Chips lined with human liver tissue for drug screening
Linda Griffith MIT
(Cambridge, MA) Liver on a chip for drug screening
Paul Kosnik Tissue Genesis
(Honolulu, HI) Chips with vascular and ligament cells for developing tissue replacement
Shuichi Takayama University of Michigan
(Ann Arbor, MI) Cell-culture chips with channels that mimic the vasculatory system
William Wang Pharmacom
(Iowa City, IA) Drug-screening chips that will include cells from the brain and other organs
Silicon life support: A brick-sized pump sends a nutrient-rich fluid through an "animal on a chip" (bottom right).Poison Pills
The toolboxes of drug developers are already stocked with a host of simple cell-culture tests aimed at quickly predicting which would-be drugs will have toxic side effects. The problem with these tests is that they’re often too simple. A typical scenario: researchers squirt a solution containing an experimental medication into petri dishes where live cells harvested from a rat’s lungs float in a nutrient-rich broth. If the cells die, the researchers table the compound and try another; if the cells survive, they begin the lengthy and expensive process of testing the compound on mice, rats, and other animals. But the compound’s failure to kill the lung cells offers little insurance that it won’t make people sick.When a person takes a drug, its active ingredient goes on a wild ride to get to the target cells: it might be absorbed by the gut, broken down by enzymes in the liver, hoarded for weeks by fat cells, screened out by a brain membrane, and whirled through the whole ordeal over and over again by the blood. When that happens, an otherwise harmless compound can accumulate in a particular organ until it reaches toxic levels. Or it can be transformed into a different compound altogether, which itself is toxic. Pfizer’s Reynolds estimates that, of drug candidates that end up proving unsafe, approximately 40 percent acquire their toxicity after being converted to other compounds in the body.
One reason that conventional cell-culture tests often mislead researchers is that they don’t present the complex brew of enzymes and other chemicals that a drug can encounter and react with in the various tissues of the body. And simple cell cultures don’t reveal how much of a drug actually gets to different types of cells, in what form, and for how long. Indeed, nearly half of the drugs that seem safe in cell-culture testing prove toxic in animal tests; and even more fail when they encounter the complex tissues and organs of humans. Researchers hope, however, that cell cultures that better simulate the conditions in the body will do a far better job at spotting toxic drugs, reducing the reliance on animal and human testing. “The holy grail of the industry is to be able to predict toxicity from a cell culture,” says Peter Lord, head of mechanistic toxicology in preclinical development at Johnson and Johnson Pharmaceutical Research and Development.
A cultured approach: Cornell University’s Michael Shuler takes cell cultures to a new level.Tiny Plumbing
Michael Shuler is a 57-year-old, lanky chemical engineering professor who has nurtured a side interest in biological processes since junior high school. By 1989 he had become interested in toxicity testing, and he had been pondering the unreliability of conventional cell cultures when an idea occurred to him: could you make a cell culture that replicates the journey through the various organs? He recognized it as a chemical engineering problem: glass chambers lined with different types of cells and hooked up via tubes to each other and to a pump that sent fluid through them would far more realistically simulate a body, and tests employing them might predict what happens in living animals much more accurately.After several months, Shuler and students had constructed a bench-top conglomeration of cells and plumbing providing a crude working model of a set of mammalian organs. It sort of functioned, but Shuler knew there was a big problem with its fidelity: almost all of the chemistry in the body takes place in tissues packed with minute canals and chambers, where critical reactions hinge on the ability of various chemicals to concentrate in some places and diffuse in others, depending in part on the microscopic geography. Mixing everything up in big beakers would distort that delicate balance. Plus, at this size the system wouldn’t be practical or cheap enough for large-scale testing.
Meanwhile, molecular biologist Greg Baxter had just joined Cornell’s Nanobiotechnology Center as a research scientist. His specialty was microfluidics—essentially, microscopic plumbing on a chip. On his second day he buttonholed Shuler at his lab, wondering if he had any projects that could benefit from ultraminiaturization. Funny you should ask, said Shuler.
It took just two meetings to hammer out the basic chip design and a year to produce the first prototype. To build one of the devices, the researchers carve minute trenches that look like faint scratches into a thumbnail-sized silicon chip; these trenches serve as fluid-carrying pipes. Producing microfluidic features on chips for testing chemical reactions and imitating biological processes is not new. But by combining their skills in chemical engineering and microfabrication, Shuler and Baxter add a significant twist: they’ve engineered the sizes, lengths, and layout of all the trenches in an attempt to closely duplicate the fluid flows and chemical exposures that cells experience in real organs.
The trenches act as surrogate blood vessels, carrying chemicals within and between the chip’s ersatz organs, which are themselves composed of trenches that are tightly spiraled or snaked into dense clots roughly half a centimeter wide. Thousands of living cells are fixed to the floor of each organ’s trenches. A brick-sized external pump circulates a nutrient-rich fluid—a stand-in for blood—through the chip. When a test compound is added to the fluid, its silicon journey is roughly analogous to what it would undergo in a live mammal, thanks to 13 years of fiddling with each organ’s size, pattern, and interconnects, and with the sizes and shapes of the various trenches. “We wanted the cells’ environment to be as realistic as possible, from the delivery of nutrients and the removal of waste products to the mechanical stresses that it experiences,” says Shuler.
After a test compound has circulated through the chip for several hours, the cells in the chip are monitored, either with a microscope or via embedded sensors that can test for oxygen and other indicators. Do the cells absorb the compound? Does it sicken or kill them? As in an actual animal, each organ or tissue plays a specific role in the chip. The liver and gut break some compounds down into smaller molecules, for example, while the fat—jammed not only with cells, but also with a spongelike gel—often retains compounds, allowing them to leak out later. A “target” organ or tissue is usually included to demonstrate the ultimate effects of the compound; this might be a cancer tumor, or an especially vulnerable tissue, such as the lung’s, or bone marrow.
The chips, of course, will have to be extensively tested before drug firms will use them widely. Still, early signs are encouraging. Shuler ran one experiment with naphthalene, a compound used in mothballs and pesticides. Excessive exposure causes lung damage, but you wouldn’t know it from standard cell-culture tests. That’s because the culprit isn’t naphthalene itself but rather two chemicals produced by the liver when it breaks naphthalene down. If you knew that and splashed those by-products directly on lung cells in culture, you’d observe such a severe response that you’d conclude even slight exposure to naphthalene is extremely dangerous. But that’s wrong, too; as it turns out, fat cells yank much of the toxic compounds out of the system. Shuler’s chip convincingly mimics this chain of events, yielding a realistic measure of the damage.
Such precise simulation promises to help drug companies improve their screening of drug candidates—and waste less time and money on those that will ultimately fail animal tests. According to Baxter, the chips are ready for such an application right now, and six large companies are currently talking to Hurel about adopting the technology. Shuler, aided by a team of students and collaborators at Cornell and elsewhere, is working on further shrinking and automating the technology. The goal: a sheet-of-paper-sized bank of 96 chips that plugs into a robotic lab setup that very rapidly adds test drugs and monitors the results. The system could not only replace conventional cell cultures but also reduce a reliance on animal experiments, in which researchers must use a great number of animals to test different doses of a drug, and must monitor those animals over time to pick up subtle side effects. “We’re talking about running a test in one or two days that would take months with animals,” says Shuler. Shuler projects a per-chip production price of about $50 complete with cells, compared to the hundreds or even thousands of dollars it takes to acquire and maintain a single lab animal.
Kind of Human
Chips that replicate the functioning of animals will likely be the first versions of the technology to make a commercial impact. But the hope is that once those prove to accurately predict the results of animal tests, human-on-a-chip versions will provide a good indication of how toxic a drug is likely to prove in human trials.Animal testing plays that role now, but not very well. Four out of five drugs that make it through animal testing end up failing in human clinical trials, usually because of safety concerns. Part of the problem is that mice can’t tell you they have headaches, blurred vision, or stomach cramps. But the larger issue is simply that animals’ organs, and the processes that take place in them, are not identical to those of humans. No one knows how many drugs that would have been safe in humans were shelved because they sickened some animals. (Penicillin, for instance, is toxic to guinea pigs but fortunately was also tested on mice.)
Chips containing simulated human tissues and organs could also allow researchers to work out complicated multidrug schemes for treating various diseases without putting patients through agonizing rounds of trial and error. Shuler, for instance, is zeroing in on anticancer cocktails. He incorporates human cells from uterine or colon tumors in his chips, setting up a more realistic model of a particular type of cancer. He can then test the ability of various combinations of chemotherapy drugs to kill the cells without sickening the rest of the system. “To find good combination therapies, you need to run a lot of tests to determine the right doses and the order in which the drugs are given,” he explains. “It’s the sort of problem we can get our hands around with this technology.”
Neither Baxter nor Shuler claims that the animal on a chip is any sort of panacea for the complex and deeply challenging drug-development process. For one thing, the chips still have to prove in large-scale tests that they really do a better job than conventional cell cultures of predicting toxicity. But if they measure up, then the pills you take ten years from now may very well arrive thanks to the sacrifices of a silicon lab rat.
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David H. Freedman is a freelance journalist based in the Boston area and the author of five books. His last story for Technology Review was “The Virtual Heart" (March 2004).
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