2005 August 31 Wednesday
Estrogen Lowers Free Radical Production In Female Rats

Estrogen's effect of lowering free radical production might explain why pre-menopausal women are at lower risk of stroke than same age men.

Estrogen’s role as an inhibitor of toxic free radicals in cerebral blood vessels may be a key reason why premenopausal women have a lower stroke risk than men.

According to UC Irvine School of Medicine researchers, estrogen has a powerful and positive influence on women’s health by increasing the energy production efficiency of mitochondria – the tiny power plants that provide cells the energy they need to function. And in doing so, the hormone inhibits the mitochondrial production of free radical oxygen molecules. Previous studies have shown that excessive amounts of these radical elements in the body, through a process called oxidative stress, can damage blood vessels and lead to stroke or degenerative disease.

In the UCI study, Dr. Vincent Procaccio of the Center for Molecular and Mitochondrial Medicine and Genetics and colleagues discovered estrogen receptors in vascular mitochondrial cells. To see how mitochondria functioned with deficient estrogen levels, they removed the ovaries from test rats, which suppressed any hormone influence, and identified a significant increase in radical oxygen molecule levels and a decline in the capacity for mitochondria to produce energy. In rats treated with doses of estrogen, however, vascular mitochondria produced energy more efficiently with lower amounts of damaging free radicals.

This effect is probably a product of natural selection. But why? Why would estrogen have been selected for to cause this effect? Why wouldn't testosterone cause the same effect? Or why wouldn't mitochondria always work more efficiently and produce less free radicals even without hormones present?

“We want to find out more how estrogen can protect blood vessels in the brain,” said Procaccio, also an assistant professor of pediatrics. “And when we gain a fuller understanding, we hopefully can figure out how best to realize potential benefits of hormone replacement therapies. Also, learning the mechanisms by which estrogen is beneficial to brain circulation may give us new ideas about how to protect against stroke.”

Spurred by recent findings of the Women’s Health Initiative, there is growing debate over the effects of estrogen and the risk of cardiovascular disease and stroke. While women aged 30 to 50 have about five times less risk of stroke than men, this difference disappears when women reach menopause. Research studies show that estrogen protects animals from experimental stroke, but recent clinical trials with certain hormone replacement therapies in older women did not show protection from stroke.

Study results appear on the online version of Molecular Pharmacology. Chris Stirone, Sue P. Duckles and Diana N. Krause of the UCI Department of Pharmacology assisted with the study. The National Institutes of Health provided support.

Another question: If women live with less free radical production until they hit menopause then why do they catch up with men on stroke rates? They should have less total accumulated free radical damage by the time they lose the estrogen that keeps free radical production down. If that is the mechanism by which stroke risk is lower in women then shouldn't their stroke risk remain lower due to less accumulated damage? Even once they start accumulating damage at the same rate as men they still have less damage accumulated and hence their total accumulated damage should continue to lag.

The KEEPS study just getting underway will investigate whether early estrogen supplementation can prevent the increase in heart disease due to menopause.

New Haven, Conn. -- Researchers at Yale School of Medicine and seven other national institutions are recruiting patients to participate in the Kronos Early Estrogen Prevention Study (KEEPS) to look at the effects of estrogen on heart disease prevention.

The study will explore whether beginning hormone therapy in women during the menopausal transition (ages 42 to 58) protects against atherosclerosis, the major cause of heart attacks. Results from a prior study of older women called the Women's Health Initiative (WHI) estrogen plus progestin trial suggested there were few benefits of estrogen on atherosclerosis. The National Institutes of Health halted the study in 2002, but KEEPS will explore issues raised by WHI. Women in WHI were postmenopausal, with a mean age of 62.7, yet most women begin hormone treatment much younger, at the onset of menopausal symptoms.

"Once atherosclerosis is present, it is already too late to prevent it," said Yale principal investigator Hugh Taylor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale. "We think estrogen can help to prevent the disease if started early enough."

Prior to the WHI, most data suggested that hormone replacement therapy was associated with a high degree of protection (30 to 50 percent reductions) against coronary heart disease, mortality and osteoporotic fractures, in addition to a small increase in breast cancer risk.

Once effective anti-cancer treatments are developed the trade-offs of hormone replacement therapies will shift much more clearly toward use of hormone replacements. Also, future cheap DNA testing will allow more accurate predictions of the relative risk of cardiovascular diseases and cancers. Those with lower cancer risk and higher heart disease and stroke risk will be the best candidates for hormone replacement.

But my preferred future solution to the increased risk of heart disease and stroke with age would be to use cell therapies and/or gene therapies to repair the circulatory system. Make the circulatory system young again.

Update: As Sheila reminds me in the comments, a previous post of mine reported evidence that estrogen might not continue to benefit blood vessels in old age. See my post "Estrogen Becomes Vasoconstrictor In Old Age". But perhaps an increase in arginine in the diet could restore the vasodilation effect of estrogen as I discuss in that post.

By Randall Parker 2005 August 31 02:01 AM  Aging Studies
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Calorie Restriction Will Add Only A Few Years To Human Life Expectancy

The benefits of calorie restriction (CR) for humans have been overstated.

Severely restricting calories over decades may add a few years to a human life span, but will not enable humans to live to 125 and beyond, as many have speculated, evolutionary biologists report.

"Our message is that suffering years of misery to remain super-skinny is not going to have a big payoff in terms of a longer life," said UCLA evolutionary biologist John Phelan. "I once heard someone say caloric restriction may not make you live forever, but it sure would seem like it. Try to maintain a healthy body weight, but don't deprive yourself of all pleasure. Moderation appears to be a more sensible solution."

Biogerontologist Aubrey de Grey has been making this argument for years. He expects humans to get a much smaller percentage gain from calorie restriction as compared to much smaller creatures.

"With mice, if you restrict their caloric intake by 10 percent, they live longer than if they have unlimited access to food," Phelan said. "If you restrict their intake by 20 percent, they live even longer, and restrict them to 50 percent, they live longer still; but restrict their intake by 60 percent and they starve to death."

Calorie restriction is not a panacea according to Phelan. I agree. A real panacea would make your body young again and not just slow down the rate at which you get old.

"Humans, in contrast, will not have rodent-like results from dramatically restricting calories," he said. "Caloric restriction is not a panacea. While caloric restriction is likely to be almost universal in its beneficial effects on longevity, the benefit to humans is going to be small, even if humans restrict their caloric intake substantially and over long periods of time."

Phelan developed the first mathematical model demonstrating the relationship between caloric intake and longevity, using representative data from controlled experiments with rodents, as well as published studies on humans, diet and longevity. He and Michael Rose, professor of ecology and evolutionary biology at the University of California, Irvine, published their findings in a journal article titled, "Why dietary restriction substantially increases longevity in animal models but won't in humans," published in the August issue of the peer-reviewed journal Ageing Research Reviews.

Phelan says CR might deliver as much as a 7% increase in life but 3% is more likely. So you get two more years.

Their mathematical model shows that people who consume the most calories have a shorter life span, and that if people severely restrict their calories over their lifetimes, their life span increases by between 3 percent and 7 percent -- far less than the 20-plus years some have hoped could be achieved by drastic caloric restriction. He considers the 3 percent figure more likely than the 7 percent.

"The trade-off between calories and longevity appears to be close to a linear relationship, but the slope isn't very steep," said Phelan, whose model predicts the relationship between calories consumed and life span.

Phelan thinks it is not worth it to go through life feeling hungry.

Phelan's conclusion is that the few extra years of life are not worth the suffering necessary to achieve them.

The vast majority do not have the will power to do this in the first place. I bet even if the benefit of long term calorie restriction was shown to be 20 or 30 more years few people could bring themselves to follow a CR diet.

But suppose CR would buy you 2 years of additional life starting in, say, 2034. Well, if rejuvenation therapies hit the market in 2035 then that extra two years could save your life.

"Do you want to spend decades severely limiting what you eat to live a few more years? You will be unhappy and then your life will end shortly after mine ends," Phelan jokes.

Scientists have known for six decades that cutting the caloric intake of rodents by 40 percent or 50 percent results in dramatically longer lives for them.

"You can practically double their life span," Phelan said. "The same result has been found in fish, spiders and many other species. If it works for them, some thought, it should work for us; I'm here to tell you it doesn't."

Phelan, co-author of the book, "Mean Genes," conducted his dissertation at Harvard University 10 years ago on caloric restriction and on why it works in extending the lives of rodents.

"When you restrict the caloric intake of rodents, the first thing they do is shut off their reproductive system," said Phelan, citing a finding from his dissertation. A normal rodent reaches maturity at one month of age, and begins reproducing its body weight in offspring every month and a half. If humans shut off reproduction by severely limiting calories, "our reduction in wear and tear on the body is minimal," he said.

Rodents on CR have continuous bad moods.

The rodents placed on severely restricted diets bit people who tried to hold them, and had an unpleasant demeanor, unlike the more docile animals given more "normal" amounts of food, Phelan said.

"I think about food all the time," he said. "I'm not going to be so extreme that I become the mouse that bites anyone who touches me. My advice about food is be sensible, and don't be a fanatic about it because the payoffs are not worth it."

While the relationship between how much you eat and your life span is not so dramatic, there are very real costs of being overweight -- including greater risk for heart disease and other life threatening illnesses, Phelan said.

The human data factored into the mathematical model include the caloric intake of people in Japan, and their longevity, compared with sumo wrestlers, who consume more than twice the normal male diet, and men in Okinawa, Japan, who consume less than the average Japanese male.

We need rejuvenation therapies. The idea of finding a way to slow aging with CR or sirt1 or the latest hope Klotho all seem like misplaced hopes to me. Klotho may eventually deliver the same (limited) benefit as CR but without the perpetual hunger and might be worth taking some day. But we really need gene therapies, cell therapies, immunotherapies that can remove extracellular junk, and other therapies that can do repair.

By Randall Parker 2005 August 31 01:08 AM  Aging Studies
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2005 August 29 Monday
Stanford Researchers Induce Adult Stem Cell Growth

Stanford researchers have discovered a way to get adult stem cells to divide that probably will simultaneously lower the risk of the stem cells going cancerous.

Out of the tousled tresses of a long-locked mouse, Stanford researchers have discovered a technique to turn on certain adult stem cells at will. Their new method not only transforms shorthaired mice into shaggy critters but also could open the door to finding ways to use stem cells to treat a host of tissue-related diseases and conditions, including cancer.

"Any area that requires tissue regeneration could be potentially impacted by this finding," Dr. Steven Artandi, an assistant professor of medicine (hematology), said of the research, which was published in the Aug. 18 issue of the journal Nature. Artandi is the senior author of the paper that focuses on stem cells in the mice's skin tissue, though it has implications for other stem cells as well.

The key to controlling these stem cells lies within an enzyme, telomerase, which has long been known to play a crucial role in keeping chromosomes intact when stem cells divide and in the formation of cancer. There is recent evidence, though, that the enzyme may play additional roles in the cell that are not well understood.

To better understand the role of telomerase, Artandi's lab developed a genetically modified mouse, which enabled them to stuff additional telomerase into the mouse's cells. The added enzyme was equipped with a genetic switch that would activate telomerase, or more specifically a telomerase component called TERT, when the mouse was fed a chemical trigger.

TERT activates stem cell growth.

Similar to the board game Mouse Trap, in which one trigger sets off a chain of events ending in the capture of a mouse, the chemical trigger fired up the TERT, which kicked the stem cells into action, which built up the hair follicles, which started growing hair nonstop, which ultimately yielded the shaggy mouse.

You might be thinking: Hey, some day will a variation on this technique but developed for humans regrow hair on receding hairlines?

Adult stem cells in hair follicles are only intermittently active, so hair normally grows in corresponding spurts. When active, the stem cells proliferate and expand, building up the follicle and producing cells that make new hair. After a while, the follicle reverts to a resting state and hair growth ceases. But all that changed when Artandi and Kavita Sarin, lead author of the paper and a Stanford graduate student in genetics, flipped the switch on the TERT gene. The stem cells woke up and stayed up.

The finding is particularly striking because the TERT protein was acting independently from its normal role in the telomerase complex. "TERT can activate stem cells and cause them to proliferate," Artandi said. The introduced TERT was present in other tissues besides the mouse's skin, where it was also affected by the chemical trigger. "We see other effects as well from TERT activation, and we're working on those tissues right now," Artandi said.

Here's the extremely exciting part of this technique: Essentially they created a telomerase knock-out stem cell line. Without the ability to regrow telomeres the stem cells probably lack the ability to develop into cancers. Without telomerase acting to grow longer telomeres (caps on the ends of chromosomes) cancer cells might eventually run out of telomeres therefore stop dividing.

Telomerase consists of the protein TERT and an RNA component, TERC. Together, they enable telomerase to perform what until now has been its only clear function: patching up chromosomes after the rigors of cell division.

Chromosomes are never completely copied during cell division but are shortened a bit at each end, where material is left out of end caps called telomeres. Eventually, when the telomeres dwindle too far down, the cell stops dividing or dies.

Though present in only modest quantities in most cells, telomerase is abundant and vital in stem cells, where ample stores of telomerase keep the telomeres nice and long, allowing the cells to keep dividing without limit.

This endless dividing of cells is fine when it's just happening in stem cells. We rely on those new cells to repair injured and worn out tissues throughout our bodies. But in 90 percent of human cancers, telomerase—normally so rare outside of stem cells—is plentiful and active, facilitating the uncontrolled growth of tumors.

"We're interested in what telomerase is doing in cancer," Sarin said. That and the hope of learning more about stem cells—as well as learning more about what TERT might be up to aside from telomere rebuilding—is what prompted the study.

The ability to turn on adult stem cell division by knocking out one component of telomerase while increasing the availability of another teolomerase component simultaneously increases the supply of adult stem cells available for stem cell therapy and decreases the odds of getting cancer from stem cells.

To be certain it was TERT alone that was triggering the stem cells, Artandi's team crossbred mice to eliminate the presence of the RNA component, TERC. Since TERC is crucial to rebuilding telomeres, when the mice grew shaggy even with no TERC around, it was clear the follicle stem cell stimulation was due solely to TERT and that the telomere repair function of telomerase played no role.

"This is really an unanticipated effect for TERT, one that's independent of the conventional telomerase complex," Artandi said.

The findings have gotten the attention of other telomerase researchers. "It's very interesting and very tantalizing," Carol Greider, one of the co-discoverers of telomerase, was quoted as saying in an article in the New York Times on the findings. Greider is at Johns Hopkins School of Medicine and was not involved in the study.

Artandi and Sarin stressed that the potential for therapeutic treatments arising from their work is highly speculative at this stage. That caveat aside, they noted many diseases and conditions could benefit from renewed tissue, including chronic ulcers of the skin, Parkinson's disease, Type-1 diabetes, osteoarthritis and some spinal injuries. Deafness caused by the loss of hearing hair cells, the sensory cells that respond to sound, also could benefit.

Said Artandi: "It's a very long list, and it really touches on many of the principal diseases that affect people, especially with advancing age."

By Randall Parker 2005 August 29 02:35 AM  Biotech Stem Cells
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Hormone Replacement Therapy Delays Menopausal Skin Changes

Replacement hormomes used from the earliest stage of menopause reduces the development of wrinkles and skin rigidity.

Long-term hormone therapy used earlier in menopause is associated with fewer wrinkles and less skin rigidity in postmenopausal women, Yale School of Medicine researchers report in the August issue of Fertility and Sterility.

"These benefits were seen in women who had consistently used hormone therapy and had been in menopause for at least five years," said Hugh S. Taylor, M.D., associate professor in the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

"We don't believe hormone therapy will make wrinkles melt away once they're already there, but the results of our study shows that hormone therapy can prevent them. Hormone therapy makes wrinkles less severe and keeps skin more elastic," Taylor added. Taylor and his co-authors compared 11 women who had not used hormone therapy to nine long-term hormone therapy users. Demographics including age, race, sun exposure, sunscreen use, tobacco use and skin type were similar. The researchers made visual assessments of wrinkle severity at 11 facial locations. A plastic surgeon with no knowledge of which women were using hormone therapy rated the number and severity of wrinkles using a Lemperle scale.

The team also measured skin elasticity using a durometer.

They found that rigidity was significantly decreased in hormone therapy users compared to nonusers at both the cheek (1.1 vs. 2.7) and forehead (20 vs. 29). Average wrinkle scores were lower in hormone users than in non-hormone users (1.5 vs. 2.2) on the Lemperle scale.

Taylor said that what is happening in the skin may be reflective of the functioning of other organs such as the heart and bone, which might also be benefiting from estrogen therapy. The results suggest that hormone therapy keeps the skin looking younger and healthier and may have cosmetic benefits if started early. Hormones seem to keep the skin healthy, but can't reverse present skin damage.

Both male and female hormone replacement therapies for anti-aging might increase cancer risks. But if true that is yet another argument for development of effective anti-cancer treatments. Once the various types of cancer become easily curable we will be able to get the benefits of hormone replacement therapies while avoiding many of the risks.

By Randall Parker 2005 August 29 02:13 AM  Aging Studies
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2005 August 28 Sunday
Cell Fusion Reprograms Adult Cells Into Embryonic Cells

Fuse an adult cell with an embryonic cell and the embyronic cell reprograms the nucleus of the adult cell to have embryonic behavior.

Researchers have developed a new technique for creating human embryonic stem cells by fusing adult somatic cells with embryonic stem cells. The fusion causes the adult cells to undergo genetic reprogramming, which results in cells that have the developmental characteristics of human embryonic stem cells.

This approach could become an alternative to somatic cell nuclear transfer (SCNT), a method that is currently used to produce human stem cells. SCNT involves transferring the nuclei of adult cells, called somatic cells, into oocytes in which scientists have removed the nuclei.

The immediate use of this technique will be for research on how to reprogram adult cells into a fully dedifferentiated state.

The researchers said that -- while the technique might one day be used along with SCNT, which involves the use of unfertilized human eggs -- technical hurdles must be cleared before the new technique sees widespread use. It is more likely that the new technique will see immediate use in helping to accelerate understanding of how embryonic cells "reprogram" somatic cells to an embryonic state.

The researchers published their findings in the August 26, 2005, issue of the journal Science. Senior author Kevin Eggan and Howard Hughes Medical Institute investigator Douglas A. Melton, both at Harvard University, led the research team, which also included Harvard colleagues Chad Cowan and Jocelyn Atienza.

In theory, researchers can induce embryonic stem cells to mature into a variety of specialized cells. For that reason, many researchers believe stem cells offer promise for creating populations of specialized cells that can be used to rejuvenate organs, such as the pancreas or heart, that are damaged by disease or trauma. Stem cells also provide a model system in which researchers can study the causes of genetic disease and the basis of embryonic development.

This result was already demonstrated with mouse adult somatic cells and mouse embryonic cells. So, again, the result isn't a surprise.

Eggan, Melton and their colleagues decided to pursue their alternative route after other researchers had shown that genetic reprogramming can occur when mouse somatic cells are fused to mouse embryonic stem cells. The scientists knew that if their studies were successful, it would provide the research community with a new option for producing reprogrammed cells using embryonic stem cells, which are more plentiful and easier to obtain than unfertilized human eggs.

Human skin cells were used.

In the studies published in Science, the researchers combined human fibroblast cells with human embryonic stem cells in the presence of a detergent-like substance that caused the two cell types to fuse. The researchers demonstrated that they had achieved fusion of the two cell types by searching the fused cells for two distinctive genetic markers present in the somatic fibroblast and stem cells. The researchers were also able to further confirmed that fusion occurred by studying the chromosomal makeup of the fused cells. Their analyses showed that the hybrid cells were "tetraploid" – meaning they contained the combined chromosomes of both the somatic cells and the embryonic stem cells.

The fact that the resulting cells have nucleuses from both cells means these cells probably can not be used for therapy.

One of the key findings from the study was that the fusion cells have the characteristics of human embryonic stem cells. "Our assays showed that the hybrid cells, unlike adult cells, showed the development potential of embryonic stem cells," said Eggan. "We found they could be induced to mature into nerve cells, hair follicles, muscle cells and gut endoderm cells. And, since these cell types are derived from three different parts of the embryo, this really demonstrated the ability of these cells to give rise to a variety of different cell types."

But this is an important step toward the goal of making pluripotent stem cells (i.e. stem cells that can become any cell type) without destroying embryocs.

Furthermore, Eggan noted that genetic analyses of the fused cells revealed that the somatic cell genes characteristic of adult cells had all been switched off, while those characteristic of embryonic cells had been switched on. "With the exception of a few genes one way or the other -- which is perhaps because these cells are now tetraploid -- the hybrid cells are indistinguishable from human embryonic stem cells," he said.

"The long term goal for this experiment was to do cell fusion in a way that would allow the elimination of the embryonic stem cell nucleus to create an embryonic stem cell from the somatic cell," said Melton. "This paper reports only the first step toward that goal, because we end up with a tetraploid cell. So, while this does not obviate the need for human oocytes, it demonstrates that this general approach of cell fusion is an interesting one that should be further explored."

The researchers also performed fusion experiments using pelvic bone cells as the somatic cells and a different human embryonic cell line, to demonstrate that their technique was not restricted to one adult cell type or embryonic cell line.

In both cases, the researchers observed extensive reprogramming of the somatic cells. "We were surprised at how complete the reprogramming was," said Eggan. "I think we were expecting that there would be more 'memory' of the adult state than the embryonic in the hybrid cells. It was quite clear that when we looked at these hybrid cells, they had completely reverted to an embryonic state."

The challenge is how to eliminate the extra nucleus.

Melton said that the remaining technical hurdle is figuring out a way to eliminate the embryonic stem cell nucleus in the hybrid cell, causing it to have a normal number of chromosomes. One problem, said Melton, is that the nucleus in stem cells is large, occupying nearly the entire cell. Thus, it is not practical to physically extract the nucleus, as is currently done with oocytes, which have a relatively small nucleus. An alternative approach of destroying the embryonic stem cell nucleus with chemicals or radiation would induce the cell's suicide program, called apoptosis, he said.

Melton emphasized that "at this at this stage in our understanding, the hard fact is that the only way to create an embryonic stem cell from a somatic cell is by nuclear transfer into oocytes. Taking advantage of this current capability -- such as colleagues in South Korea and other countries are doing -- is critical if we are to maintain the progress necessary to realize the extraordinary clinical potential of this technology."

But this technique has immediate value in research to figure out how a cell nucleus gets reprogrammed into a less differentiated state.

Eggan added that the most realistic current promise of the fusion technique is in studying the machinery of genetic reprogramming of somatic cells by embryonic cells. "It is extremely difficult to study the reprogramming process using eggs, because in the case of humans it is very difficult to obtain eggs in any quantity and difficult or impossible to genetically manipulate them," he said. "But embryonic stem cells can be grown in large quantities. We can isolate the components of the reprogramming machinery, and we can genetically manipulate the cells to analyze the reprogramming process."

The ability to understand the process of dedifferentiation of a nucleus into a pluripotent state would provide an excellent basis for the development of more precise and reliable techniques for producing pluripotent cells. The use of Somatic Cell Nuclear Transfer (SCNT) to put adult cells into denucleated eggs is really a hack and a hack that does not work well.

Leave aside fact that some people have ethical objections to SCNT. Some animals created via SCNT have health problems. We need much greater control of cellular dedifferentiation than SCNT provides. We need to understand what SCNT does to cells. But now scientists can study what cell fusion does to adult cells and this will make the study of the process of dedifferentiation easier to do.

Update: Other researchers claim to have solved the problem with the extra nucleus from the embryonic stem cells.

Other researchers already claim to have solved the problem of the extra chromosomes. Yuri Verlinsky and his colleagues at the Reproductive Genetics Institute in Chicago, US, claimed in May to have achieved the same as Eggan, but by reprogramming with ESCs stripped beforehand of their nuclear DNA. Without this extra genetic baggage, the cells have real potential for therapy.

They claim to have a research paper explaining how they did this headed for release.

Several teams are working on the extra nucleus removal problem.

They do not mention that several teams, including ones in Illinois and Australia, have said in recent interviews that they are making progress removing stem cell DNA from such hybrid cells. None of those teams has published details of their results. But several leading researchers have said they believe it will be feasible to remove the extra DNA.

Technical means will be developed to avoid ethical objections to the use of embryos to extract embryonic stem cells. Promoters of stem cell research would do well to refocus their efforts toward supporting a large increase in funding stem cell research in general rather than fight the human embryonic stem cell political battle.

By Randall Parker 2005 August 28 11:01 PM  Biotech Stem Cells
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2005 August 26 Friday
Monkeys Prefer Gambling Risk To Sure Reward

Human gambling problems probably have very ancient roots.

DURHAM, N.C. -- Duke University Medical Center neurobiologists have pinpointed circuitry in the brains of monkeys that assesses the level of risk in a given action. Their findings -- gained from experiments in which they gave the monkeys a chance to gamble to receive juice rewards -- could give insights into why humans compulsively engage in risky behaviors, including gambling, unsafe sex, drug use and overeating.

The researchers, Michael Platt, Ph.D., and Allison McCoy, published their findings in the advanced online version of Nature Neuroscience, posted August 14, 2005. The research was sponsored by the National Institutes of Health, the EJLB Foundation, and the Klingenstein Foundation.

In their experiments, the researchers gave two male rhesus macaque monkeys chances to choose to look at either of two target lights on a screen. Looking at the "safe" target light yielded the same fruit juice reward each time. However, looking at the "risky" target light might yield a larger or smaller juice reward. The average juice reward delivered by looking at either target was the same.

To their surprise, the monkeys overwhelmingly preferred to gamble by looking at the risky target. This preference held, regardless of whether the scientists made the risky target reward more

variable, or whether the monkeys had received more or less fruit juice during the course of the day.

This result is another knock at the foundations of economic theories that assume perfect rational utility maximization by market actors.

"There was no rational reason why monkeys might prefer one of these options over the other because, according to the theory of expected value, they're identical," said Platt. The researchers also tested whether the monkeys were simply responding to the novelty of the risky target.

Well, the theory of expected value is wrong. Monkeys, like homo sapiens, are not homo economicus.

I wonder if manufacturers who sell products that are sometimes great and sometimes terrible attract repeat buyers who keep hoping for a repeat of that successful thrill.

"We wondered whether the monkeys preferred the risky target because the experiment was dull and boring, and they wanted the variability," said Platt. "But when we made the task more interesting by changing the color of the lights on each trial, the monkeys didn't care anything about it."

Monkeys, like many humans, like to gamble in games where the odds are stacked against them.

In fact, when the researchers made the average payoff for the risky target less than for the safe target, "we found that they still preferred the risky target," said Platt. "Basically these monkeys really liked to gamble. There was something intrinsically rewarding about choosing a target that offered a variable juice reward, as if the variability in rewards that they experienced was in itself rewarding."

Even when the researchers subjected the monkeys to a string of "losses," the high of a "win" appeared to keep them going, said Platt.

"If they got a big reward one time on the risky choice, but then continued to get small rewards, they would keep going back as if they were searching or waiting or hoping to get that big payoff. It seemed very, very similar to the experience of people who are compulsive gamblers. While it's always dangerous to anthropomorphize, it seemed as if these monkeys got a high out of getting a big reward that obliterated any memory of all the losses that they would experience following that big reward," said Platt.

The researchers inserted microelectrodes into the posterior cingulate cortex of the brain to further studied monkey gambling.

Confident that they had developed a valid animal model that would reveal insights into the brain mechanism for assessing risk, the researchers next explored the neural circuitry that governed that assessment. They threaded hair-thin microelectrodes into a brain region called the posterior cingulate cortex, which studies in humans and animals had implicated in the processing of information on rewards. They then measured the electrical activity of neurons in the region as they administered the same behavioral task to the monkeys.

"We found that the neurons behaved very similarly to the monkeys," said Platt. "That is, as we increased the riskiness of a target, the neurons' activity would go up in the same way the monkey's frequency of choosing that target would go up. It was amazing the degree to which the activity of these neurons paralleled the behavior of the monkeys. They looked like they were signaling, in fact, the monkeys' subjective valuation of that target," he said. Further analysis of the neuronal activity indicated that, indeed, the neurons were reflecting the risk value the monkeys placed on the target, rather than an after-the-fact response to the payoff.

Where does this sort of insight lead to? Picture in the future microelectrodes inserted into the brain to deliver jolts to cancel out the feeling that some gamble is worth taking.

While Platt and McCoy believed they have isolated one component of the neural machinery of risk, they do not believe they have mapped the entire circuitry.

"We don't think the posterior cingulate cortex is by any means the only area that's important for assessing risk, for deciding what's valuable and for actually making a choice based on that valuation," said Platt. "We think that this is just part of a whole circuit that's involved in that process." However, he said, pinpointing a key region involved in risk assessment will enable further studies to map that circuitry.

"It's going to be interesting to trace this circuitry to see which parts of the brain are signaling something about subjective utility and which parts of the brain are signaling information about true reward and punishment experiences," said Platt.

The animal study results can help map where to place electrodes to cancel out the desire to gamble (not that the researchers made such a claim).

He emphasized that such animal studies are a highly useful complement to human studies and genetic studies using mice. Neuroimaging studies in humans performing such tasks can identify brain regions involved in making decisions based on risk, he said.

"And then, using these animals, we can do electrophysiological studies that allow us to understand how the fundamental processing units of the brain -- single nerve cells -- actually process information about reward and risk and uncertainty; and how that information might contribute to the actual decision process that results in the monkey's choice," said Platt. What's more, he said, the monkey studies allow manipulation of the circuitry using drugs to determine how the circuitry might malfunction in human disorders.

The monkey model of desire to gamble also makes for a convenient lab model for the development of pharmaceutical agents to dampen down the gambling impulse.

"For example, it is believed that people who have low levels of the neurotransmitter serotonin might be more risk prone and impulsive," said Platt. "Disturbances in such neurotransmitter systems might be the basis of pathological conditions like pathological gambling, obsessive-compulsive disorder and depression. We can do pharmacological manipulation of the serotonin system in monkeys to see how it influences risk perception and risk preferences, and whether we see changes at the level of the single neurons that we're studying."

Plus, if monkeys can be genetically engineered to be less prone to gambling then some day the same will be doable with offspring genetic engineering.

What's more, said Platt, the studies with monkeys can guide studies in mice, in which scientists can make genetic alterations in the mice and study the behavioral effects of those alterations. Such studies could contribute to understanding of the genetic basis of compulsive behaviors and other such behavioral disorders.

With greater understanding comes greater powers to manipulate. How about a virus genetically engineered for surreptitious injection into a political opponent to make him a reckless gambler? Risks with illicit affairs or foreign policy adventures might help bring down the politician. Then again, if recent experience serves as a guide, perhaps not. Hmmm....

By Randall Parker 2005 August 26 04:45 PM  Brain Economics
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Public DNA Sequence Databases Reach 100 Gigabases Of Data

The big public DNA sequencing databases have hit the 100 gigabase mark.

The world’s three leading public repositories for DNA and RNA sequence information have reached 100 gigabases [100,000,000,000 bases; the ’letters’ of the genetic code] of sequence. Thanks to their data exchange policy, which has paved the way for the global exchange of many types of biological information, the three members of the International Nucleotide Sequence Database Collaboration [INSDC, www.insdc.org] – EMBL Bank [Hinxton, UK], GenBank [Bethesda, USA] and the DNA Data Bank of Japan [Mishima, Japan] all reached this milestone together.

Graham Cameron, Associate Director of EMBL’s European Bioinformatics Institute, says "This is an important milestone in the history of the nucleotide sequence databases. From the first EMBL Data Library entry made available in 1982 to today’s provision of over 55 million sequence entries from at least 200,000 different organisms, these resources have anticipated the needs of molecular biologists and addressed them – often in the face of a serious lack of resources."

100,000,000,000 DNA letters sequenced sound like a lot? I find this disappointing. The human genome is estimated to be in the neighborhood of about 2.9 gigabses. So 100 gigabases is only enough to represent the DNA sequences for about 34 people. Suddenly sounds a lot less staggering.

All this information from many organisms helps scientists in many ways. However, in 5 or 10 years DNA sequencing costs will drop down to $1000 or perhaps even $100 per person. Then literally hundreds of millions of people will get their DNA sequenced and orders of magnitude more sequencing of other species will get done.

Cheap DNA sequencing would lead very quickly to the identification of DNA sequences that contribute to many disease risks, longevity, personality, intelligence, and assorted abilities and aspects of appearance. Identification of genetic variations that contribute to differences in disease risks and longevity will help guide the genetic engineering of stem cells to create stem cells which maximize longevity and health improvements.

With cheap DNA sequencing drug side effects due to genetic variations would become much more avoidable and drug development efforts would hit fewer failures in late stage testing due to harmful side effects in small portions of populations. Hence the rate of drug development would accelerate.

Money spent by government DNA sequencing projects doing sequencing of organisms with today's technology would be better spent on more research to develop cheaper sequencing methods. Though efforts already underway promise cheaper DNA sequencing methods in the not too distant future. Check out previous posts in my Biotech Advance Rates for reports on efforts to cut DNA sequencing costs by orders of magnitude.

By Randall Parker 2005 August 26 03:45 PM  Biotech Advance Rates
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2005 August 24 Wednesday
Testosterone Replacement Therapy May Up Prostate Cancer Risk

While the evidence is by no means conclusive a small study of prostate cancer patients suggests that testosterone therapy increases the risk of prostate cancer.

Researchers in the United States say that prostate cancer developed in 20 men within months to a few years after they began testosterone supplementation, to correct a deficiency of the hormone.

Dr. Franklin D. Gaylis from the University of California at San Diego Medical Center, says that there are several anecdotal case reports, small studies, and observational studies such as theirs, that raise concern but do not as yet, provide conclusive evidence.

A major method of treatment for prostate cancer is the use of drugs that knock out the body's production of testosterone. This typically adds a few years to the lives of prostate cancer sufferers until the prostate cancer mutates into a form that is called "hormone refractory" or "androgen independent". At that point the cancer cells no longer need testosterone in order to grow.

That such a large fraction of the men developed prostate cancer in the first year of testosterone use suggests testosterone contributed to the development of prostate cancer.

To describe the characteristics of prostate cancer in men taking testosterone, researchers reviewed 20 cases of prostate cancer that developed among men taking testosterone. A majority of these cancers developed during the first two years on testosterone, and roughly one-third developed in the first year. Prostate cancer was detected by abnormalities in both prostate-specific antigen (PSA) levels and findings on digital-rectal exam (DRE) in 40% of men, by abnormal DRE alone in 35% of men, and by elevated PSA alone in 25% of men.

A lot of old guys have very low testosterone levels.

Testosterone therapy products have been approved by the U.S. Food and Drug Administration for treating a limited number of conditions, particularly hypogonadism associated with low testosterone levels. Hypogonadism occurs in men of various ages, and most clinical studies of the therapy so far have been in younger men. Recent studies have shown that a significant percentage of otherwise healthy older men have testosterone levels consistent with hypogonadism. Data also suggests that low testosterone in elderly men is associated with a loss of lean body mass and muscle strength and increased central body fat. There may also be decreased bone density and mental dysfunction associated with low testosterone levels. For these reasons an increasing number of elderly men are being treated with exogenous testosterone. However, the risks of administering testosterone to elderly men have yet to be defined.

I am skeptical of the notion that hormone replacement therapies can provide net benefit for most aged people. Testosterone is not that hard to synthesize. Therefore its decline may not be due to damage to pathways that make it. The aging body does not lose the ability to synthesize the complex cholesterol molecule from which testosterone gets made Cholesterol is a 4 ringed polycyclic aromatic hydrocarbon with some chains hanging off it. Relatively minor modifications and pruning of those chains (which my aging brain can no longer remember) produce testosterone, estrogen, and the other sex hormones and corticosteroids. Therefore the decline in testosterone in aged men might be a product of evolutionary selective pressures to lower the risk of prostate cancer and possibly to lower the risks of other types of cancers as well.

If we had effective and safe cures for prostate cancer and other cancers that feed off of sex hormones then some of the hormone replacement therapies might provide a net benefit. Also, as genetic screening for cancer risks becomes more advanced then it might turn out that some aging people with the right genetic variations can derive a net benefit from replacement hormone therapies.

This reminds me of the research on thyroid hormone levels and breast cancer. Women with underactive thyroids have less risk of getting breast cancer.

Researchers at The University of Texas M. D. Anderson Cancer Center have found that women with a common thyroid gland disorder appear to have a reduced chance of developing invasive breast cancer, according to a study published in the March 15 issue of Cancer, out online Feb. 14.

In a retrospective case-control study of 2,226 females, researchers found that women with primary hypothyroidism (under-active thyroid) had a 61 percent lower risk of developing invasive breast cancer. Additionally, women newly diagnosed with breast cancer were 57 percent less likely to have the under-active thyroid gland condition compared to a control group of healthy women.

Also, women with underactive thyroids who did get breast cancer got less aggressive forms of breast cancer on average.

"Women with a history of hypothyroidism had many more stage I and II breast cancers and very few stage III diseases," lead researcher Massimo Cristofanilli, MD, tells WebMD. "Overall, their disease was less aggressive." He is with The University of Texas M.D. Anderson Cancer Center.

When our aged cells get run at youthful speed the cells are more likely to spin out of control and go cancerous. We need to repair or replace our old cells so that we can turn up the accelerators on our bodies and function once again at youthful levels. We also need great, fast, safe, and effective cures for cancer and treatments that tell pre-cancerous cells to commit cellular suicide. Cancer is a major obstacle in the way of rejuvenation.

By Randall Parker 2005 August 24 04:04 PM  Aging Drugs
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2005 August 22 Monday
Biomedical Research Seen As Capital Expenditure

Real estate investment banker Robert Klein, who initiated and providing funding for California's $3 billion Stem Cell Research and Cures Initiative which won 59% of the vote in a statewide referendum, argues that medical research costs should be seen more like an investment and less like an expense.

To Klein, medical research should be viewed as a part of the public infrastructure, like a dam or a bridge. "You've got to stop 'expensing' research," he says. "You've got to put it in the state constitution and authorize state bonds for it as a capital asset." The approach protects controversial areas of study and allows the state to account for costs over decades instead of every year. With this philosophy, Klein proposed a way for citizens to demand long-term funding. For nine months he worked with scientists, patient advocates and a team of prominent lawyers, and they eventually crafted Proposition 71 for the 2004 ballot.

Think of it this way: If potholes in the roads were causing damages to vehicles that far exceeded the cost of fixing the potholes then the political cry would go out to fix the potholes. Well, the cost of diseases and aging - both for expensive treatments and for the costs of disability - run into the trillions of dollars per year. So why do the US National Institutes of Health get less than $30 billion dollars per year while US federal, state, and local governments spend somewhere in the neighborhood of $700 to $800 billion per year for medical care and nursing care? Why does the private sector spend even more while the government also spends money to provide income to old folks who are too aged to work?

While we can not allocate money to repair and rejuvenate bodies as quickly as potholes can get repaired we can allocate money to achieve repairability of human bodies within the lifetimes of most of us. The idea of developing the means to grow replacement organs or send in cells or gene therapy to do repairs of tissue is no longer the distant imagining of science fiction. Such therapies are already available for a few diseases and more are under development. For example, two teams in Pittsburgh Pennsylvania and Innsbruck Austria have working cell therapies for repairing sphincter muscles to cure urinary incontinence.

The faster we develop therapies built upon the rapid advances in biotechnology the sooner we will start reaping the return on our collective investments in therapies that repair and rejuvenate aged, malfunctioning, and diseased body parts.

In 2003 health care spending made up 15.3% of the US economy and is projected to rise to 18.4% by 2013 with further increases beyond 2013. Currently US federal biomedical research spending (almost $29 billion out of an almost $11 trillion economy) amounts to less than a third of a percent of GDP. Why spend over 30 dollars delivering care with today's lousy treatments for every dollar spent on research to develop newer, better, and more cost effective treatments? Imagine we spent $30 dollars on car repairs for potholes for every dollar we spent fixing potholes. Our current policies are about that dumb. Effective treatments will be cheaper treatments. Also, effective treatments will boost productivity and economic output by boosting the level of function of the labor force and by allowing people to work more years. Biomedical research will pay back many times over.

My modest proposal: Fix medical research spending levels as a fixed percentage of major medical entitlements spending programs. For example, make Medicare and Medicaid each spend 10% or even 15% of their budgets on biomedical research. When their entitlements spending for provision of care goes up then their funding of research should go up in tandem by proportionate amounts. A 10% allocation of medical entitlements program spending to research would more than double current biomedical research funding. If the same pattern was repeated by other Western governments the increase in biomedical funding would greatly accelerate the rate of progress in developing therapies.

By Randall Parker 2005 August 22 01:37 PM  Aging Debate
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2005 August 18 Thursday
In Vivo Bioreactor Grows Replacement Bone In Rabbits

Needed replacement bone pieces can be grown in a special layer on the surface of other bones.

An international team of biomedical engineers has demonstrated for the first time that it is possible to grow healthy new bone reliably in one part of the body and use it to repair damaged bone at a different location.

The research is described in a paper titled 'In Vivo Engineering of Organs: The Bone Bioreactor' published online by the Proceedings of the National Academy of Sciences.

Researchers from Imperial College London, the Massachusetts Institute of Technology and Vanderbilt University hope their discovery, which takes advantage of the body's natural wound-healing response, will transform treatments for serious bone breaks and diseases.

New Zealand White rabbits were used to test this procedure. The researchers successfully transferred the bone to another location in the rabbits to repair a bone injury at the other location.

The periosteum layer on the outside of bones has stem cells which can be coaxed into growing replacement bone.

This new research, however, takes a new approach that has proven to be surprisingly simple. Long bones in the body are covered by a thin outer layer called the periosteum. The layer is a little like scotch tape: the outside is tough and fibrous but the inside is covered with a layer of special pluripotent cells which, like marrow cells, are capable of transforming into the different types of skeletal tissue. Because of this, Dr Stevens and her colleagues decided to create the bioreactor space just under this outer layer.

They created the space by making a tiny hole in the periosteum and injecting saline water underneath. This loosened the layer from the underlying bone and inflated it slightly. When they had created a cavity the size and shape that they wanted, next the researchers removed the water and replaced it with a gel that is commercially available and approved by the FDA for delivery of cells within the human body. They chose the material because it contained calcium, a known trigger for bone growth. Their major concern was that the bioreactor would fill with scar tissue instead of bone, but that didn't happen. Instead, it filled with bone that is indistinguishable from the original bone.

Here is the really cool part: This approach might work for growing replacement tissue for organs such as the liver and pancreas.

"This research has important implications not only for engineering bone, but for engineering tissues of any kind," said researcher Robert S. Langer, Institute Professor at the Massachusetts Institute of Technology and a pioneer in the field of tissue engineering. "It has the potential for changing the way that tissue engineering is done in the future."

The scientists intend to proceed with the large animal studies and clinical trials necessary to determine if the procedure will work in humans and, if it does, to get it approved for human treatment. At the same time, they hope to test the approach with the liver and pancreas, which have outer layers similar to the periosteum.

While some organ fail too quickly to allow patients to grow new organs to replace them for some types of organ failure the decline of organ function takes months or years and the problem is diagnosed long before the organ reaches an advanced stage of failure. Plus, advances in embedded nanosensors will lead to much earlier identification of failing organs to provide even more time to grow replacements. Therefore the ability to grow replacement organs within one's own body using one's own cells (which will not suffer from immune rejection) would have great value.

An essential component in Strategies for Engineered Negligible Senescence (SENS) is the replenishment of adult stem cell reservoirs in the body with youthful adult stem cells. Imagine then a two stage process for rejuvenation of organs. First, add youthful stem cells to an existing old organ. Then induce the growth of a new replacement organ in a layer created on the surface of the existing organ. Then once the replacement organ develops to full size remove the old organ.

We still need the ability to grow organs outside of a human body. However, for those cases where replacement organs can grow inside one's body we might gain the ability to grow organs much sooner by use of this "in vivo bioreactor" approach.

By Randall Parker 2005 August 18 10:48 AM  Biotech Organ Replacement
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2005 August 17 Wednesday
Hormone Oxyntomodulin Causes Weight Loss By Appetite Reduction

Hormone oxyntomodulin may provide the solution to obesity.

A hormone found in the small intestine has provided a crucial breakthrough in developing new drugs to tackle the growing obesity epidemic, claim scientists. Obesity now affects more than half of all UK adults, costing the UK up to £3.7 billion a year in sickness absence and treatments.

In an article published today in Diabetes, the world's top diabetes research journal, a team from Imperial College London and Hammersmith Hospitals NHS Trust has used injections of oxyntomodulin, a naturally occurring digestive hormone found in the small intestine, to reduce body weight and calorific intake in overweight volunteers.

The injections boost existing levels of oxyntomodulin, normally released from the small intestine as food is consumed, signalling to the brain that the body is full and has had enough to eat.

Professor Steve Bloom, senior researcher at Imperial College London and Hammersmith Hospital, says: "The discovery that oxyntomodulin can be effective in reducing weight could be an important step in tackling the rising levels of obesity in society. Not only is it naturally occurring, so has virtually no side effects, it could be ideal for general use as it can be self administered. Despite this, we still need to conduct larger clinical trials to test its effectiveness over longer periods."

The researchers found that over four weeks, injections of oxyntomodulin three times a day in 14 volunteers reduced their body weight by an average of 2.3kg. They also found that daily energy intake by the test group was reduced by an average of 170kcal after the first injection, to 250kcal at the end of four weeks. The average recommended intake is 2500 kcal per day for men, and 1940 for women.

The researchers also found that volunteers in the study group had lesser appetites without a reduction in food palatability.

Note the unfortunate need to inject the hormone. In the longer run I can imagine a way to avoid the need for injection. Cells genetically engineered to make oxyntomodulin could be implanted in the body With sufficiently sophisticated genetic engineering the cells could be designed to only secrete the oxyntomodulin when some activating drug is taken. That would provde a way to avoid the risk of excessive skinniness and even starvation.

The subjects receiving oxyntomodulin had less leptin and adipose hormones in their blood.

The study found that leptin, a protein responsible for regulating the body's energy expenditure was reduced in the study group. They also found reduced levels of adipose hormones, a hormone which encourages the build up of adipose tissues, a type of tissue where fat cells are stored.

The lead researcher has unsurprisingly wasted no time in creating a company to commercialize this discovery.

Professor Bloom has set up a spin-out company, Thiakis, to commercialise this discovery, and run further trials.

Expect obesity to be rare 20 years from now. It is a lot easier to solve than a lot of other behavior disorders because the bloodstream carries messages to the brain that change whether we feel full or sated or hungry. Behavioral problems that occur entirely within the brain are much less tractable.

By Randall Parker 2005 August 17 11:49 PM  Brain Appetite
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Happiness Comes From Relative Comparisons Of Wealth

While level of physical healthiness is the biggest determinant of happiness, comparison of financial success with others of the same age group is the second largest source of happiness and unhappiness.

PHILADELPHIA, PA--Financially richer people tend to be happier than poorer people, according to sociological researcher Glenn Firebaugh, Pennsylvania State University, and graduate student Laura Tach, Harvard University. Their research is focused on whether the income effect on happiness results largely from the things money can buy (absolute income effect) or from comparing one's income to the income of others (relative income effect). They present their research in a session paper, titled "Relative Income and Happiness: Are Americans on a Hedonic Treadmill?," at the American Sociological Association Centennial Annual Meeting on August 14.

Firebaugh argues that, in evaluating their own incomes, individuals compare themselves to their peers of the same age. Therefore a person's reported level of happiness depends on how his or her income compares to others in the same age group. Using comparison groups on the basis of age, the researchers find evidence of both relative and absolute effects, but relative income is more important than absolute income in determining the happiness of individuals in the United States. This may result in a self-indulgent treadmill, because incomes in the United States rise over most of the adult lifespan.

"If income effects are entirely relative, then continued income growth in rich countries today is irrelevant to how happy people are on the whole," says Firebaugh. "Rather than promoting overall happiness, continued income growth could promote an ongoing consumption race where individuals consume more and more just to maintain a constant level of happiness."

Firebaugh tested what he refers to as the hedonic treadmill hypothesis, which uses a comparison of age-based cohorts. The hedonic treadmill requires a specific type of relative income effect--one where "keeping up with the Joneses" means continually increasing one's own income, because we can be sure that the Joneses are increasing theirs.

This suggests a reason why some find socialism attractive: People want to be freed from the competitive need to keep up with others. Socialists want to eliminate the ability to get ahead so that they no longer have to worry about the need to keep up others in order to preserve their happiness. Therefore the lure of socialist policies stems from innate genetically determined features of how the mind works.

The researchers' measured the age, total family income, and general happiness of 20- to 64-year-olds using analysis from the 1972-2002 General Social Survey. They controlled for health, education, effects of getting older, race, and marital status. Happiness was measured using a self-report response of "very happy," "pretty happy," or "not too happy."

While income is important in determining happiness, Firebaugh's data found that physical health was the best single predictor of happiness, followed by income, education, and marital status. The researchers found a relative income effect--the richer you are relative to your age peers, the happier you will tend to be.

Aside: This is yet another argument for the development of Strategies for Engineered Negligible Senescence or SENS. SENS therapies will rejuvenate the body and make everyone healthier. Since healthiness is the most powerful determinant of happiness rejuvenation therapy will greatly increase happiness for entire populations.

"We find with and without controls for age, physical health, education, and other correlates of happiness," said Firebaugh, "that the higher the income of others in one's age group, the lower one's happiness. Families whose income earners are in jobs with flat income trajectories are likely to become less happy over time. Thus the relative income effect observed here implies adverse effects for some individuals over the working years of their life cycles."

On the other hand, the longer people live the more they will feel unhappy due to losing out to more successful people their same age. The range of incomes and accumulated assets will get wider with passing years due to differing levels of ability, motivation, and luck. However, if everyone walks around in youthful bodies comparison between oneself and people of one's own age group will become more difficult. How to tell who is your age or 50 years older or younger than you?

But comparison of relative wealth as a source of unhappiness will be solved by advances in neuroscience. People will use drugs, gene therapies, and cell therapies to reprogram their circuits for determining their level of happiness. For example, I predict that people setting out to achieve some goal (e.g. getting an advanced degree or starting a business or leaning to play a musical instrument) will get their own brains reprogrammed to cause them to get more of their sense of happiness from how well they are progressing toward that goal and less from comparison with other people.

One of the problems posed by cheap worldwide communications technologies is that they increase the pool of people to which people compare each other. Someone in Pakistan or Yemen or South Africa can compare their material possessions to those in Britain or America or Taiwan and find more people who are far better off than them. Therefore satellite TV and the internet are probably sources of increased unhappiness (and likely resentment) among the poorer folks who have access to such technologies. Super poor people in places like Bangladesh or Niger probably feel less unhappiness about relative levels of wealth than moderately poor people in places like Egypt or Indonesia.

Update: Another point: If rich peope were to hide their wealth by living in places that are either obscure (plant trees and bushes and live in small remote valleys in rural locales or perhaps on private islands) or in homes that are outwardly modest looking then the happiness of an overall population would be raised. Also, if wealth gets concentrated into a small number of countries and the poorer folks are kept from emigrating to those countries then again relative differences in levels of wealth would be less obvious and poorer folks would probably feel happier.

By Randall Parker 2005 August 17 03:22 PM  Brain Economics
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2005 August 15 Monday
First Gene Therapy Success Against Muscular Dystrophy In Mice

A rare gene therapy success is reported in mice with muscular dystrophy.

PITTSBURGH, Aug. 15 – Researchers from the University of Pittsburgh report the first study to achieve success with gene therapy for the treatment of congenital muscular dystrophy (CMD) in mice, demonstrating that the formidable scientific challenges that have cast doubt on gene therapy ever being feasible for children with muscular dystrophy can be overcome. Moreover, their results, published in this week's online edition of the Proceedings of the National Academy of Sciences (PNAS), indicate that a single treatment can have expansive reach to muscles throughout the body and significantly increase survival.

CMD is a group of some 20 inherited muscular dystrophies characterized by progressive and severe muscle wasting and weakness first noticed soon after birth. No effective treatments exist and children usually die quite young.

Despite gene therapy being among the most vigorously studied approaches for muscular dystrophy, it has been beset with uniquely difficult hurdles. The genes to replace those that are defective in CMD are larger than most, so it has not been possible to apply the same methods successfully used for delivering other types of genes. And because CMD affects all muscles, an organ that accounts for 40 percent of body weight, gene therapy can only have real therapeutic benefit if it is able to reverse genetic defects in every cell of the body's 600 muscle groups.

Aside: If a virus can get into all the muscle groups of the body it is no wonder that some kinds of viral infections make your muscles ache all over.

Think about what the passage above says about the state of gene therapy in the year 2005. Delivering a single large gene is too difficult. Well, gene therapies for rejuvenation will need to fix dozens and perhaps hundreds of genes. Some of those genes are large. We need much better gene therapy delivery vehicles.

The researchers use a couple of approaches to make the gene therapy work for CMD.

By using a miniature gene, similar in function to the one defective in CMD, and applying a newly developed method for "systemic" gene delivery, the Pitt researchers have shown that gene therapy for muscular dystrophy is both feasible and effective in a mouse model of especially profound disease. Using this approach, the team, led by Xiao Xiao, Ph.D., associate professor of orthopaedic surgery and molecular genetics and biochemistry at the University of Pittsburgh School of Medicine, report that treated mice had physiological improvements in the muscles of the heart, diaphragm, abdomen and legs; and they grew faster, were physically more active and lived four times as long as untreated animals.

The miniature gene they speak of here might be just the portion of the gene that gets translated into a protein. Many mammalian genes have what are called "introns" and "exons". The introns do not get translated into proteins but rather are spliced out in the process of going from gene to protein. The "exons" therefore can be combined into a gene that is smaller than the naturally occurring gene but which probably (barring some regulatory role for the "introns") can be made to work just as well.

"While we have much farther to go until we can say gene therapy will work in children, we have shown here a glimmer of hope by presenting the first evidence of a successful gene therapy approach that improved both the general health and longevity in mice with congenital muscular dystrophy," said Dr. Xiao.

The most common form of CMD, and also one of the most severe, is due to a genetic mutation of laminin alpha-2, a protein that is essential for maintaining the structures that surround muscle cells and is an integral link in the chain of proteins that regulate the cell's normal contraction and relaxation. If the protein is defective, or is lacking, this outside scaffold, called the extra-cellular matrix, disintegrates, and the muscle cells become vulnerable to damage.

One limit to their approach is the use of a virus to deliver genes. The adeno-associated virus (AAV) which they mention below is only 4675 DNA letters long. While the virus gets transported well into muscle cells (and muscle cells age and need gene therapy for rejuvenation) the Adeno-Associated Virus (AAV) just can not carry much DNA into a cell.

Simply replacing the defective gene with a good laminin alpha-2 gene is not possible because its size makes it impossible for researchers to get it to squeeze inside viral vectors – disarmed viruses that are used to shuttle genes into cells. But the team found a good stand-in in a similar protein called agrin that when miniaturized could be inserted inside an adeno-associated virus (AAV) vector. Dr. Xiao's laboratory is known for its work developing this vector, which they have previously shown is the most efficient means for delivering genes to muscle cells.

In the current study, the authors show that two strains of AAV, AAV-1 and AAV-2, were effective in transferring the mini-agrin gene to cells in two mouse models. The AAV-1 vector was given by systemic delivery – a single infusion into the abdominal cavity – a method the authors only recently described and which they used for the first time in this study to transfer a therapeutic gene. The AAV-2 vector was delivered locally, given by intramuscular injection to different muscles of the leg. With both approaches, muscle cells were able to assimilate and copy the genetic instructions for making mini-agrin. Once produced, the mini-agrin protein functionally took the place of the laminin alpha-2 protein by binding to the key proteins on either end, thus restoring the cell's outside scaffolding and reestablishing the missing link to key structures inside the cell.

I'm less excited than the authors because I want vectors (delivery vehicles or carriers) for gene therapy that can delivery much more DNA into each cell for more extensive reprogramming.

Clearly, the authors are most excited about the impressive results achieved in their experiments using systemic gene delivery, which proved there could be significant therapeutic improvements and even be life-saving. Yet they say their results are far from ideal and more work lies ahead.

"It's probably not realistic to expect that we can achieve complete success using the mini-agrin gene, which while somewhat similar, is structurally unrelated to laminin alpha-2. Unless we address the underlying cause of congenital muscular dystrophy we're not likely to be able to completely arrest or cure CMD," added Chungping Qiao, M.D., Ph.D., the study's first author and a research associate fellow in Dr. Xiao's lab.

Future directions for research include finding a way to engineer the laminin alpha-2 gene. For this study, the authors chose to use the mini-agrin gene because researchers from the University of Basel, Switzerland, had already demonstrated it could improve the symptoms of muscular dystrophy in a transgenic mouse model, which has little clinical relevance. The Pitt researchers might also explore approaches that combine genes that promote both muscle and nerve growth, as well as focus on improving the AAV vectors.

In addition to Drs. Xiao and Qiao, other authors are Jianbin Li; Tong Zhu, M.D., Ph.D.; Xiaojung Ye, M.D., Ph.D.; Chunlian Chen; and Juan Li, M.D., all from the department of orthopaedic surgery; and from the department of cell biology and physiology, Romesh Draviam and Simon Watkins, Ph.D.

Gene therapy does not get as much press as cell therapy. Yet gene therapy is crucial for rejuvenation. We will be able to replace many cells and organs using stem cell therapies and also tissue engineering techniques combined with stem cells to grow replacement organs. But the toughest problem for rejuvenation is the brain. We need to rejuvenate all the cells which are already in the brain. We will do part of that job by sending in immunotherapies that attack extracellular junk. Also, stem cells will help some. But to fix aged neurons, glial cells, and blood vessels in the brain we are going to need gene therapies that can deliver lots of genetic instructions to carry out repair and to replace damaged genes.

Another problem with viral gene therapy delivery mechanisms is the immune system's tendency to quite correctly recognize viruses as invaders. One way around that problem might to be to develop methods to very briefly suppress the immune system. If the viruses move out of the bloodstream pretty quickly then immune system suppression drugs might not need to suppress the immune system so long as to put one at risk of a major infection. Or perhaps the immune system could be trained to recognize a particular and not naturally occurring variation of AAV as self.

AAV still can play a role in rejuvenation therapies. One way to get around its size limitation might be to send in lots of small genes in successive AAV packages. Other way might be to genetically engineer AAV packaging proteins to form larger cases to carry larger genes into cells. Therefore the report above is a good step in the right direction and the researchers should be applauded. We just need many more such steps to produce successively better gene therapy techniques.

Thanks to Andy Price for pointing out this report. Says Andy "The cool thing for everyone (SENS) here that this treatment gets to ALL muscle groups.". His reference is to Strategies for Engineered Negligible Senescence or SENS.

By Randall Parker 2005 August 15 08:47 PM  Biotech Gene Therapy
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Moderate Prenatal Alcohol Exposure Slows Down Baby Brains

Moderate prenatal alcohol exposure too low to cause recognizable Fetal Alcohol Syndrome makes the brains of the resulting children less able to carry out complex tasks.

  • Prenatal alcohol exposure is often linked to slower cognitive reaction times and poorer attention.
  • A new study investigates cognitive function and speed as tasks become more complex.
  • Findings indicate that alcohol-exposed children can perform as well as other children on simple tasks, but as tasks become more demanding and challenging, processing speed slows down significantly.

As the kids grow up they are unable to advance to learning the increasingly complex tasks necessary for advanced education and intellectually complex occupations.

Decades of research have left little doubt that prenatal alcohol exposure has adverse effects on intellectual and neurobehavioral development. A recent study of the effects of moderate to heavy prenatal alcohol exposure on cognitive function confirms earlier findings of slower processing speed and efficiency, particularly when cognitive tasks involve working memory. Results are published in the August issue of Alcoholism: Clinical & Experimental Research.

"Prenatal alcohol exposure is often associated with slower reaction times and poorer attention in infancy, and some of these deficits may be at the core of poorer academic performance and behavior problems often seen later in childhood," said Matthew J. Burden, postdoctoral research fellow at Wayne State University School of Medicine and corresponding author for the study. "In cases of fetal alcohol syndrome (FAS) … lower IQ scores are common, often reaching the level of mental retardation. This is because alcohol consumed by the mother has a direct impact on the brain of the fetus. However, full FAS is not required to see this impact; it is just less obvious to detect across the array of exposures found in fetal alcohol spectrum disorders (FASD), which include effects of prenatal alcohol at lower drinking levels."

Julie Croxford, graduate research assistant at Wayne State University, says there is a need for researchers to look at the damage caused by prenatal alcohol exposure at lower-than-heavy levels of drinking. "In the past, much focus was placed on studying the full-blown FAS," she said. "More recent research has considered those individuals damaged by lower levels of exposure. This is an important focus."

For this study, researchers assessed 337 African-American children (197 males, 140 females) at 7.5 years of age; selected from the Detroit Prenatal Alcohol Longitudinal Cohort, the children were known to have been prenatally exposed to moderate-to-heavy levels of alcohol. Their mothers were originally recruited between September 1986 and April 1989 during their first prenatal visit to a maternity hospital clinic. The children were assessed on processing speed and efficiency in four domains of cognitive function – short-term memory scanning, mental rotation, number comparison, and arrow-discrimination processing – using a Sternberg paradigm, which examines speed of completion as problems become increasingly more difficult.

"We chose these four domains because they allow us to study distinct aspects of cognition within the same cognitive framework," said Burden. "This helps to distinguish potentially specific deficits from those that are more global in nature; that way we get a better understanding of how prenatal alcohol exposure affects cognitive functioning many years later in childhood. We used the Sternberg paradigm because it indicates how fast an individual generates the correct response to a number of problems, providing an overall measure of speed; and it examines the rate at which response times increase as problem difficulty increases, providing a processing efficiency measure."

Although the alcohol-exposed children were able to perform as well as the other children when tasks were simple – such as naming colors within a timed period – when pressed to respond quickly while having to think about the response, their processing speed slowed down significantly.

"This suggests that processing speed deficits are more likely to occur within the context of some cognitive demand," said Burden. "We also found that prenatal alcohol exposure was associated with poorer efficiency on number processing, a finding consistent with past research showing more specific adverse effects in the arithmetic domain. Arithmetic performance may be relatively more compromised with prenatal alcohol exposure than other types of intellectual performance, such as verbal abilities. We also looked at how processing speed related to other aspects of cognition, working memory in particular. Prenatal alcohol exposure had some impact on both speed and working memory, but the effect on working memory was partly accounted for by the deficits in speed – in other words, slower performance contributes in part to poorer working memory."

"The conclusion drawn here is that the reaction-time deficits associated with prenatal alcohol exposure are seen more in demanding/challenging cognitive tasks that involve the integration of working memory," said Croxford. "The real-world implications of this are that children exposed prenatally to alcohol may be able to perform simple tasks, but may struggle with tasks that are more challenging and require complex cognition and the use of working memory. This is likely to mean that these children may be more and more challenged the older they get by the demands placed on them within the school system and within their day-to-day social interactions."

Researchers controlled for many other variables and still found the effect.

Both Burden and Croxford noted that this study also examined the impact of "confounding" factors such as home environment, socioeconomic status, and current maternal drinking levels, which researchers believe may contribute to the poor outcomes seen in children exposed to prenatal alcohol.

"In this study, we accounted for more than 20 of these potentially confounding influences in the analyses," said Burden. "The effect of alcohol exposure in utero persisted above and beyond any other influences present."

What this means, said Croxford, is that alcohol itself causes specific, identifiable and permanent deficits in brain development and physiology. "This reinforces the current public health message that women should not drink alcohol during pregnancy," she said.

Burden said that he and his colleagues will continue to examine the long-term effects of prenatal alcohol exposure on the same children. "In addition to neuropsychological and behavioral measures, we will also be using electrophysiological techniques such as event-related potentials and neuroimaging (fMRI) to more directly connect cognitive performance with brain function," he said.

Look ahead 20 years. Imagine that implantable nanosensors can detect and record a pregnant mother's alcohol consumption. She could be checked periodically by passing a reading device over her body to read the records of her embedded nanosensors. If she has consumed alcohol or taken harmful drugs or smoked cigarettes or eaten food that contains toxins all this could be detected.

Well, assuming that becomes possible do you suppose some governments in more industrialized countries might require all pregnant women to have nanosensors implanted in them? The argument for why this would beneift society is easy to make. Why should pregnant women have a legal right to harm the cognitive development of their fetuses? The rest of us suffer the consequences (lower academic achievement, lower earnings, lower taxes paid, more state aid received, more behavioral problems, and probably more crime) if women do harm to their developing fetuses. So why shouldn't the fetuses be protected from avoidable harm by use of state powers?

As I see it the more we can measure ways that people harm each other (e.g. pollution or drug abuse while pregnant or while nursing or by child abuse) the more ways we should intervene to stop that harm. Now, an obvious argument to make is that fetuses are not yet legal humans and therefore do not have rights to protect. Even if one accepts the moral argument (and many don't) I still see a utilitarian argument for protecting fetuses from damage since we all benefit. I also see a rights-based argument: Fetuses that are not cognitively impaired by drug and alcohol exposure are less likely to develop into adults who have behavioral problems that cause them to violate the rights of others.

Update: Before anyone tells me that they can't imagine their government imposing fetal nanosensor monitors on women keep in mind that there are nearly 200 national governments in the world and most of them are not Western and not liberal. China has the biggest population in the world (though India will likely eventually surpass it by mid 21st century) and China imposes a One Child policy on its entire population. China is on course to become the largest economy in the world. Other East Asian countries similarly do not share Western conceptions of the proper role of government.

By Randall Parker 2005 August 15 05:08 PM  Brain Development
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2005 August 12 Friday
Success Predicted For Cellular Dedifferentiation Efforts

Cellular dedifferentiation means turning a cell from a specialized state (e.g. muscle cell or liver cell) into an unspecialized cell that has the ability to become other cell types. At the most extreme dedifferentiated state embryonic stem cells are so dedifferentiated that they have the ability to become all more specialized cell types. This extreme state is called pluripotency. Ethical opposition to the use of cells harvested from human embryos to create pluripotent cell lines has led scientists to look for other ways to create pluripotent stem cells. A major figure in stem cell research says a number of labs are getting close to announcing successful techinques for dedifferentiating cells.

"Just a few years ago, it was beyond the reach of the existing science at the time ... almost like alchemy, where you're trying to turn lead into gold," said Dr. Robert Lanza, vice president of medical and scientific development at Massachusetts-based Advanced Cell Technology.

But today, new tools have changed the landscape: "Our group, and I know at least two or three others, are playing with different techniques, and it's very clear that something is going on here. We're definitely getting reprogramming," Lanza said.

The article cites a number of experimental approaches being pursued to cause dedifferentiation. However, I expect better methods which provide more precise control and more consistent outcomes to eventually replace some of the earlier techniques.

Success may come soon. Lanza says look for research reports on dedifferentiation in the next year.

What's more, researchers are hinting that yet more dramatic studies will be coming out in the weeks and months ahead.

"You'll start seeing publications in the next year," Advanced Cell Technology's Lanza said.

I've long argued that dedifferentiation is a solvable problem and that it would not take decades to solve. Plus, solving it will provide a great deal of information with many practical uses. W

Lanza is a very credible source for such an optimistic assertion as Lanza and ACT colleagues were the first to clone a human embryo in 2001. In other words, he's an accomplished stem cell researcher and has a major human embryonic stem cell research achievement to his credit.

Even if you resent or disagree with the religious folks who morally oppose the harvesting of embryonic stem cells from human embryos you should see Lanza's latest claim as good news. If fully pluripotent stem cells (i.e. capable of becoming all cell types) can be created without destroying embryos then a larger fraction of the populations of Western countries will support research into uses of pluripotent stem cells. Increases in public support for stem cell research of any type are beneficial to the cause of developing rejuvenating therapies and disease cures.

US President George W. Bush's chief bioethicist Leon Kass is even willing to accept removal of a single cell from an embryo to create pluripotent stem cell lines of the technique can be demonstrated to pose no risk to the eventual baby that could develop from such an embryo.

The next alternative is to use a biopsy, that is, cell removal from still-living embryos, presumably in ways that will not do damage to that embryo. We now practice, at least on a small scale, what’s called preimplantation genetic diagnosis, where couples are at risk of a child with a genetic disease known to run in the family. At the roughly eight-cell stage, one or even two cells are taken out for genetic testing. And maybe 10,000 babies have already been born, more or less healthy, following this procedure. ... If you take out a couple of cells and you test them, and the embryo is shown not to carry the genetic disease of concern, that embryo is then transferred to a woman, and if all goes well, nine months later you’ve got a baby free of the disease. The thought is that maybe you biopsy these embryos, and you take out the individual cells, not for genetic testing, but to try to produce stem cell lines from them.

No one has yet converted a single blastomere from an eight-cell embryo into a stem cell line. That’s a scientific challenge. But the council was quite concerned about the ethics of this. We didn’t think that one could justify putting a child-to-be at additional risk, not for its own benefit. Until it could be proved by animal studies, or by much longer studies of preimplantation genetic diagnosis, that embryo biopsy is really risk-free to the child who results from all of this, the council is unprepared to pronounce this particular approach as ethically acceptable at this time.

While that techinque may turn out to be useful it still involves going down a path of fertilizing an egg from a woman with a sperm from a man to start a pregnancy in order to get a pluripotent stem cell line. But that cell line does not genetically match any single existing person's DNA sequence. What we really need most of all is the ability to turn our own cells into more flexible and youthful cells so that we can create fully immunologically compatible cells. Plus, if I'm going to have neural stem cells injected to help rejuvenate my brain I don't want someone else's stem cells which have different characteristics due to genetic differences and which therefore might gradually alter my personality.

By Randall Parker 2005 August 12 09:18 AM  Biotech Stem Cells
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2005 August 10 Wednesday
Stem Cells Seen As Crucial For Rejuvenation And Life Extension

The idea that stem cells will be used to rejuvenate aged bodies shows signs of becoming the conventional wisdom among stem cell researchers. Writing in the journal EMRO reports of the European Molecular Biology Organization two recent articles address this prospect. First, researcher Nadia Rosenthal examines "Youthful prospects for human stem-cell therapy" for both disease prevention and life extension.

It is the year 2053. A mere century after James Watson and Francis Crick resolved the structure of DNA, scientists at the forefront of medical research have just announced the first successful regeneration of a human heart. After re-routing the blood of Jón Sigurdsson, a terminal heart-failure patient, to an advanced cardiac assist device and removing most of the damaged organ, doctors thawed a frozen tube of Jón's personalized stem cells—established in 2013 from embryonic stem cells created through somatic nuclear transfer—and injected them into his chest. Thanks to a sophisticated cocktail of growth factors, the new stem cells target the damaged area and rapidly get to work, perfectly rebuilding a youthful heart. Several weeks later, Jón is discharged in excellent health. Regenerative medicine provided him with a new kidney ten years ago, and subsequent double knee regeneration gave him renewed mobility. Now his new heart will soon have him running a six-minute mile again. Jón Sigurdsson is 100 years old.

Rosenthal foresees a future in which stem cell-based therapies rejuvenate aged parts of the body and allow much longer lifespans. Stem cell research seems inevitably to lead to such thoughts. Stem cell researchers want to develop youthful, genetically undamaged, and flexible stem cells. Once they accomplish this for a wide range of stem cell types it is hard to avoid the conclusion that many parts of the body could be repaired by sending in youthful cells to gradually replace the old cells. She even discusses the future use of stem cells to dissolve scar tissue and build new 3 dimensional scaffolding for tissue types which have suffered decay in larger scale structures.

Most of the rest of the article is a tour through recent advances in stem cell research and what they portend

Reproductive cloning is not envisioned in humans, but the lessons learned from cloned animals may be important for therapeutic applications of nuclear transfer. Large deletions involving millions of base pairs have been found in ageing post-mitotic tissues, such as the heart (Vijg, 2004), thus removing large numbers of genes, which leads to cellular degeneration. If such defective nuclei from senescent tissue were used to generate personalized stem cells for therapy, they could cause more harm than good. Moreover, nuclei from patients with inherited diseases, such as haemophilia or muscular dystrophy, may first need to be manipulated to correct the genetic defect before they can be used in clinical settings.

Such a transfer, with subsequent manipulation of genes in human ES cells using human viral vectors and other techniques, could be used on aged nuclei to avoid creating stem cells with dangerous mutations. Any strategy for introducing genetic changes must be applied with care, however, due to the possibility of these genes randomly integrating into the host genome, causing even more serious mutations. To circumvent this danger, techniques for gene-specific modifications that are routinely performed in mouse ES cells have recently been applied to human ES cells, thereby providing the opportunity to correct genetic mutations in stem cells derived from nuclear transfer before administering them to patients.

Adult stem cells are being found an increasing number of locations the human body and in other mammals. At the same time, the tools we have for identifying adult stem cells still leave much to be desired.

In parallel with studies on ES cells, a concerted search for similar adult stem-cell lineages has yielded a flood of recent publications. These challenge the classical concept that stem cells in the adult are present in only a few locations, such as the skin or bone marrow, and are committed to differentiate into the tissue in which they reside. Nevertheless, rigorous criteria are required to distinguish an adult stem cell from partially committed cells with limited potential. True stem cells are self-renewing during the lifetime of an organism and they undergo asymmetric division, so that one daughter cell maintains the stem-cell lineage while the other daughter cell matures into a specialized cell type. The criteria for defining stem cells in the adult are still difficult to satisfy experimentally. There is no predictable location for stem cells in most adult tissues, and we still have only limited tools for identifying them.

For purposes of regeneration we need to know a lot more about adult stem cells. Most obviously adult stem cells are an important source of cells for use in regeneration therapies. However, less obviously, we need to know all the types of adult stem cells and all their locations in the body in order to develop and deliver youthful replacement adult stem cells into all the reservoirs that hold them. Therefore we absolutely need to delineate all the differences between the many different kinds of adult stem cells.

The emotional political debate about the limitations and advantages of embryonic stem cells versus adult stem cells and ethical arguments about embryonic stem cells tend to distract attention from the fact that we need to solve many problems in adult stem cell manipulation. Regardless of how replacement stem cells are made they have to get converted into the various adult stem cell types in order to replace aged stem cells of each type with more youthful cells. Well, how to create adult stem cells of each needed type? How to grow them in sufficient number? How to cheaply and easily test to know that a conversion to a needed cell type succeeded? Then the created cells must get delivered to all the many (and probably mostly still undiscovered) stem cell reservoirs in the adult body. How to get stem cells to go just where we want them to go? Will they have affinity for their natural habitats? Or will they require methods of injection or ways to tag them to give them affinity for the desired target areas? All these problems need solutions.

We need many new technologies to make manipulation of all stem cell types easier. We need automated ways to separate out the many stem cell types from other cell types and to nurture and grow them. We need ways to rejuvenate stem cells. Stem cell research does not exist in a vacuum separate from other avenues of advance in biological sciences and biotechnology. We need advances in DNA sequencing technology to make it cheap and easy to test the DNA of stem cell lines for correctness and completeness. We need gene therapy techniques that can repair and improve the genome of stem cell lines.

Rosenthal's article reviews many recent reports on adult and embryonic stem cell research. In is worth reading in full.

Another article in EMRO reports by Anthony D. Ho, Wolfgang Wagner & Ulrich Mahlknecht of the University of Heidelberg, Germany is entitled "Stem cells and ageing" with the provocative subtitle "The potential of stem cells to overcome age-related deteriorations of the body in regenerative medicine".

Although the vulnerability to infectious disease and cancer is caused by a decline of the immune system, the latter is in turn a product of interactions among haematopoietic stem cells and the microenvironments in the bone marrow and the thymus, as well as in the mucous lining of the bronchus and gut systems. Hence, all ageing phenomena—tissue deterioration, cancer and propensity to infections—can be interpreted as signs of ageing at the level of somatic stem cells. As the regenerative prowess of a living organism is determined by the ability and potential of its stem cells to replace damaged tissue or worn-out cells, a living organism is therefore as old as its stem cells.

These researchers outline a number of technical obstacles which make identification and study of non-embryonic stem cells difficult.

Lab tests which can measure a stem cell line's regenerative potential are needed.

Furthermore, by contrast to ESCs, which can be derived from cell lines established from 4- to 7-day-old embryos, somatic stem cells are elusive. The need for in vitro assays to identify human haematopoietic progenitors increased with the advent of haematopoietic tissue transplantation to treat leukaemia. Any assay to measure stem cells must compare the properties of the cells analysed in vitro with those of repopulating units tested in vivo after a lethal dose of irradiation—an experimental approach that is obviously not possible in humans (Ho & Punzel, 2003).

The problem with stem cells in older bodies does not appear to be so much diminished numbers as diminished abilities in those stem cells which remain.

Various studies have indicated that even though similar HSC concentrations could be found in young and old bone marrow, it is the functional ability per cell in the repopulation model that shows a significant reduction with increasing donor age. HSC senescence is regulated by several genetic elements mapped to specific chromocytes (Chen, 2004). These elements may differ among species, strains and even individuals in the mouse model. In humans, HSC senescence and related pathological effects might not be as obvious as in the mouse model because individual primitive HSC clones can produce progeny that sustain life-long mature blood cell production, which is especially obvious after bone marrow or HSC transplantation.

The older the donor of bone marrow cells for transplantation (e.g. for leukemia) the worst the chances of success.

The success of any bone marrow transplantation correlates with the quantity of HSCs in the graft, which are able to reconstitute the blood and immune system after myeloablation. On the basis of our extensive experience in HSC transplantation since 1984, we have found that age represents the main variable and worst prognostic factor for clinical outcome of transplantation. Recent evidence indicates that there is a decline with age in the quantity and quality of the CD34+ cells harvested. There is also a change in the ratio of fat to cellular bone marrow with age, which has been well known since the turn of the twentieth century. One way to overcome this problem would be to expand the human HSC population ex vivo before transplantation. There have been numerous such attempts, but progenitors with self-renewal capacity are very demanding. Reports of successful expansion of HSCs derived from human marrow in the laboratory have thus far been controversial. By contrast, CD34+ cells derived from umbilical cord blood have been shown to be expandable to a limited extent, which is another indication that the potency of HSCs declines with ontogenic age.

As we age we all would benefit from infusions of youthful stem cells carefully selected to have few DNA mutations. We'd gain stronger immune systems, less risk of anemia, and probably stronger bones as well. More generally, the development of genetically sound and youthful stem cells for all the stem cell reservoirs of the body would partially reverse aging and substantially increase life expectancies.

By Randall Parker 2005 August 10 06:12 PM  Aging Reversal
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Higher Vitamin D Reduces Aging Bone Fracture Risks

The current US Recommended Daily Allowance of Vitamin D for bones is too low.

With an aging population, and with people living longer, experts say bone fractures will become a bigger and more costly problem unless more is done to prevent them. Osteoporosis (reduced bone mineral density) is most common in older adults, particularly women. It is a major risk factor for bone fractures, which can cause significant suffering while carrying high economic costs. While vitamin D has been shown to reduce the risk of fracture in the elderly, a study recently published in the Journal of the American Medical Association (JAMA) raises the question of how much vitamin D is enough.

The Recommended Dietary Allowance (RDA) of vitamin D for older adults is between 400 and 600 International Units (IU) per day. In their review of the existing literature, a team of scientists including senior author Bess Dawson-Hughes, MD, director of the Bone Metabolism Laboratory at the Jean Mayer USDA Human Nutrition and Research Center on Aging at Tufts University, found that this dose was not effective in reducing nonvertebral fracture rates among study participants. The researchers concluded, though, that higher daily doses, in the range of 700 to 800 IU, may reduce the risk of fracture by approximately 25 percent.

Dawson-Hughes and her colleagues analyzed the results of seven experimental trials that all compared fracture rates among subjects 60 years of age and older given vitamin D supplements (with or without calcium supplements) to those among similar subjects given only calcium or placebo. Each study lasted between one and five years, and looked specifically at hip fractures or other fractures that did not involve the spine. The researchers found that only subjects receiving higher doses of vitamin D supplementation had significantly fewer fractures than did subjects in the comparison groups.

"In the future, we may need to reconsider the current recommended daily values of vitamin D for older adults," says Dawson-Hughes. She adds, "We also need to look more closely at the possible role that calcium supplementation may have in mediating the effects of vitamin D. Fractures in the elderly can lead to severe health consequences, including death. One promising prevention strategy may be dietary supplementation with both calcium and vitamin D."

Another meta-analysis on vitamin D published in JAMA last year found that older adults can reduce their risk related to falls by more than 20 percent by ensuring they get enough vitamin D. Dawson-Hughes, an author on that paper, noted that "vitamin D may also improve muscle strength, thereby reducing fracture risk through fall prevention."

Reduction of broken bone risk and improved muscle strength are not the only reasons to up your vitamin D. See my post "Vitamin D Could Decrease Overall Cancer Risk 30%".

At best vitamin D can reduce the rate of decay of bones with age. Your bones are still going to age unless something more is done. In the future stem cell therapies to rejuvenate the cells that build up bones will also reduce the risk of bone fractures by putting in place cells that can make bones young again. Plus, the youthful and carefully selected and modified stem cells will have much lower risk of going cancerous. We need to accelerate the rate of progress in stem cell research.

By Randall Parker 2005 August 10 05:32 PM  Aging Diet Studies
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2005 August 08 Monday
Gene Expression Patterns Studied In Young And Old Brains

A research team with members from UC Berkeley, the Max Planck Institute in Leipzig Germany, Harvard, and Lawrence Berkeley National Laboratory have examined gene expression patterns of different regions of young and old human and chimpanzee brains using DNA microarrays and found that the frontal cortex where most higher levels of thinking get done ages more rapidly and in ways distinct from other parts of the brain.

No matter how healthy a life one leads, no person has managed to live much longer than a century. Even though the advances of the modern age may have extended the average human life span, it is clear there are genetic limits to longevity. One prominent theory of aging lays the blame on the accumulation of damage done to DNA and proteins by “free radicals,” highly reactive molecules produced by the metabolic activity of mitochondria. This damage is expected to reduce gene expression by damaging the DNA in which genes are encoded, and so the theory predicts that the most metabolically active tissues should show the greatest age-related reduction in gene expression. In this issue, Michael Eisen and colleagues show that the human brain follows this pattern. A similar pattern—which, surprisingly, involves different genes—is found in the brain of the aging chimpanzee.

The authors compared results from three separate studies of age-related gene expression, each done on the same type of DNA microarray and each comparing brain regions in young versus old adult humans. In four different regions of the cortex (the brain region responsible for higher functions such as thinking), they found a similar pattern of age-related change, characterized by changes in expression of hundreds of genes. In contrast, expression in one non-cortical region, the cerebellum (whose principal functions include movement), was largely unchanged with age. In addition to confirming a prediction of the free-radical theory of aging (namely, that the more metabolically active cortex should have a greater reduction in gene activity), this is the first demonstration that age-related gene expression patterns can differ in different cells of a single organism.

Since the paper was published in PLoS Biology you can read the full paper online for free. One section of the paper referring to other studies on brain aging makes mention of some depressing results from another study on brain aging.

Exactly how macromolecules damaged by ROS may lead to aging has been studied in detail in recent years, and the human brain has been intensively examined in this regard because of its overall importance in human senescence. For example, up to one-third of the proteins in the brains of elderly individuals may be oxidatively damaged, and these damaged proteins have been shown to sometimes have diminished catalytic function [3,6]. One recent study of aging in the human brain demonstrated that oxidative damage to DNA can be caused by mitochondrial dysfunction, and tends to accumulate preferentially in some areas of the genome that include promoters, resulting in lower levels of transcription [7] (possibly due to loss of transcription factor or other protein binding [8–10]). In this same study, genome-wide patterns of aging-associated gene expression change in one region of the human brain cortex (the frontal pole; Figure 1) were measured using DNA microarrays, and genes that had decreased transcription with age were shown to be the ones that are most susceptible to oxidative damage [7]. Since different regions of the human brain have been shown to accumulate DNA damage at different rates [11,12], it is reasonable to suppose that these different regions may show different gene expression changes with age as a result.

Leave aside for the moment the fact that aging eventually kills us. Leave aside that we get more illnesses and disabilities as we age. The fact that our brains decline is extremely distasteful to me. Do you love the thoughts in your mind? Do you love learn and take in new experiences and see new sights and form new memories? Do you love to recall old memories or solve new puzzles? Your ability to do all those things declines with age. That such a large fraction of proteins in the brain are oxidatively damage strongly suggests that the extent of brain aging is quite far reaching. Aging is not just a process that happens to our arms and legs and skin and hair. It happens to our minds, to the very core of our identities. We learn a lot and then our brains gradually decay and even while we are alive part of us dies and the rest us our identity becomes impaired. How repugnant.

The cerebral cortex regions showed the same pattern of gene expression changes with aging while other (and notably older) regions of the brain did not show this pattern.

Strikingly, all four regions of cerebral cortex for which we had expression data (prefrontal cortex, Broca's area, primary visual cortex, and anterior cingulate cortex) showed excellent agreement with the aging pattern in frontal pole (Figure 2A; r > 0.8 and p < 0.02 for each). We note that the true similarity of aging patterns in these regions is likely to be even stronger than is indicated by the correlations because, as mentioned above, approximately 15% of our genes are expected to be false positives with no true aging-related changes. In sharp contrast to cortex, the cerebellum and caudate nucleus showed far less agreement with frontal pole (Figure 2A; |r| < 0.1 and p > 0.4 for each). These results have several implications. First, the agreement between frontal pole and four regions of cortex indicates that we were able to accurately measure the direction of gene expression changes with age for most genes, even with only three samples from each region; thus the age range, number of samples, etc., are all sufficient to reflect the pattern of gene expression changes previously reported in frontal pole [7]. Second, we can have even greater confidence in the results from frontal pole [7], because they have been independently reproduced (albeit in different brain regions). Third, and most importantly, the human brain appears to have different aging patterns in cerebellum and caudate nucleus than in cortex. The fact that our four cortex samples all show strong correlations with frontal pole is akin to having a positive control, and it allows us to interpret the lack of correlation in cerebellum and caudate nucleus as evidence suggesting a difference in aging patterns, as opposed to several more trivial explanations (e.g., too few samples).

Think about this result from an evolutionary perspective. The frontal lobe has developed most recently. Its development was a big selective advantage. One way to see this result is that our frontal lobes have been "overclocked" because making ourselves think faster allowed us to get more food, defend ourselves, and leave more progeny. I'm speculating here but perhaps our frontal lobes operate faster and wear out more quickly because there was a net selective advantage to turning up the metabolic rate of the frontal lobe because the faster thinking helped us more than the accelerated aging hurt us.

I see the brain as by far the toughest challenge for the development of rejuvenation therapies. For many parts of the body the simplest approach to rejuvenation will be parts replacement. Once tissue engineering and stem cell research advance far enough we'll be able to replace bad parts just as mechanics do with old cars. Got old failing kidneys dodgy lungs ruined by emphysema? Grow new ones. Is your liver shot? If you don't want to get a whole new liver then send in stem cells that programmed to gradually replace the existing cells with new ones. Got liver scar tissue that doesn't want to go away? Send in cells programmed to eat it up to make room for new liver cells made from stem cells. But the brain's three dimensional network of neural connections defines who you are. Put a new brain in place of your own and that body will no longer be you for most practical purposes.

To rejuvenate the brain each cell in the brain must be repaired. But the scope of such a repair job is enormous. While estimates on the number of neurons in a human brain vary the range goes from 10 billion to 100 billion or 100 billion to 200 billion with the number of neuroglial support cells ranging from 5 to 10 times the number of neurons or perhaps 50 to 100 time sthe number of neurons. So we might have a half trillion or even a trillion cells in our brains, all aging and accumulating DNA mutations, intracellular lysosomal junk, and other damage. To develop methods repair all those cells right in the brain is an enormous scientific and engineering challenge.

While stem cell therapy gets a great deal of press (and deservedly so) and while stem cell therapy does have a crucial role to play in brain rejuvenation stem cells can not do most of the brain repair job. Much of brain rejuvenation probably requires highly advanced gene therapy delivery methods and basically DNA programs to send into cells to carry out repair tasks. Future advances in nanotechnology will eventually produce nanobots that can carry out many brain repair tasks. But to repair DNA we need gene therapy to send in corrective sequences to replace mutated sequences and deleted sequences.

If you treasure your ability to think and your mental identity then support a rapid increase in the rate of development of gene therapies and other therapies aimed at brain rejuvenation.

By Randall Parker 2005 August 08 02:17 PM  Aging Studies
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2005 August 05 Friday
Acambis Attempts Universal Flu Vaccine

Acambis thinks they might have a way to build a universal vaccine against the new flu strains that pop up each year.

Cambridge, UK and Cambridge, Massachusetts – 4 August 2005 – Acambis plc (“Acambis") (LSE: ACM, NASDAQ: ACAM) has commenced development of a potentially breakthrough new influenza vaccine that could offer permanent protection against influenza and may also offer protection against influenza pandemics. Influenza vaccines are currently administered annually.

Acambis has entered into a research collaboration and licensing agreement with the Flanders Interuniversity Institute for Biotechnology (“VIB"), a Belgian research institute.

Acambis and VIB will work together to develop a vaccine against both A and B strains of influenza, using Acambis' influenza A vaccine candidate that it acquired from Apovia earlier in the year and additional technology licensed from VIB. Apovia is a US biotechnology company and started development of the influenza A vaccine candidate in 2000, having originally licensed the technology from VIB. Walter Fiers, emeritus professor of Molecular Biology at the University of Ghent, is an inventor of the patent rights licensed from VIB.

The aim of the research collaboration would be to generate a ‘universal' vaccine candidate that would protect against both A and B strains of influenza and, more importantly, would not require annual changes to the formulation. This contrasts with current influenza vaccines that need to be changed, generally each year, to cope with genetic drift, mutations that occur in influenza strains circulating in nature, as well as major genetic shifts that can result in influenza pandemics. The need to change vaccine formulations each year results in delays in initiating vaccine coverage.

Unforunately it sounds like they are not far enough along to offer anything against the H5N1 avian flu strains should avian flu manage to mutate into a form that spreads easily between humans in the next few years.

The appeal here is not just the universality of the vaccine. Their use of baterial fermentation technology addresses the big problem of slow production and poor scaling of today's chicken egg-based influenza vaccine production technology.

The initial vaccine candidate against influenza A is currently in pre-clinical development. It is manufactured using recombinant bacterial fermentation technology, which aims to provide time and cost efficiencies compared with traditional egg-based production methods.

They haven't yet proven their vaccine will be universal but they are hopeful.

Walter Fiers, Professor emeritus, University of Ghent and VIB, said:

“The research and pre-clinical development carried out so far supports the promising potential of a universal, M2e-based influenza vaccine. In view of the conservation of the M2e structure, vaccination against all human influenza virus strains may become possible, even before new epidemics or pandemics have started to spread. Moreover, the vaccine is a recombinant protein with a defined chemical structure which can be rigorously characterised and produced on a large scale. We are pleased to collaborate with Acambis in the further development of this promising vaccine."

Could this vaccine save us from avian flu? If avian flu breaks out into a pandemic could this approach be scaled up rapidly without clinical trials? Even if the vaccine would be risky in an emergency where the alternative is a decent chance of dying from a killer flu a rapid deployment of this vaccine might be worth the risk.

By Randall Parker 2005 August 05 10:05 AM  Dangers Natural Bio
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Harvard Group Lowers DNA Sequencing Cost Order Of Magnitude

Biotechnology increasingly resembles electronics technology as costs fall by multiples.

BOSTON-August 4, 2005-The theoretical price of having one's personal genome sequenced just fell from the prohibitive $20 million dollars to about $2.2 million, and the goal is to reduce the amount further--to about $1,000--to make individualized prevention and treatment realistic.

The sharp drop is due to a new DNA sequencing technology developed by Harvard Medical School (HMS) researchers Jay Shendure, Gregory Porreca, George Church, and their colleagues, reported on August 4 in the online edition of Science. The team sequenced the E. coli bacterial genome at a fraction of the cost of conventional sequencing using off-the-shelf instruments and chemical reagents. Their technology appears to be even more accurate and less costly than a commercial DNA decoding technology reported earlier this week.

The commercial DNA decoding technology they are referring to is from 454 Life Sciences Corporation and you can read about it in my post "New Tool Speeds Up DNA Sequencing By 100 Times". Whether the Harvard or 454 Life Sciences approach can go further in lowering DNA sequencing costs in the long run remains to be seen. But these are not the only two efforts aimed at lowering DNA sequencing costs and another company or academic group might yet bypass both of them.

The Church group built their sequencer using an assembly of existing technologies. How creative.

The Church group's technology is based on converting a widely available and relatively inexpensive microscope with a digital camera for use in a rapid automated sequencing process that does not involve the much slower electrophoresis, a mainstay of the conventional Sanger sequencing method.

"Meeting the challenge of the $1,000 human genome requires a significant paradigm shift in our underlying approach to the DNA polymer," write the Harvard scientists.

The new technique calls for replicating thousands of DNA fragments attached to one-micron beads, allowing for high signal density in a small area that is still large enough to be resolved through inexpensive optics. One of four fluorescent dyes corresponding to the four DNA bases binds at a specific location on the genetic sequence, depending on which DNA base is present. The fragment then shines with one of the four colors, revealing the identity of the base. Recording the color data from multiple passes over the same sequences, a camera documents the results and routes them to computers that reinterpret the data as a linear sequence of base pairs.

In their study, the researchers matched the sequence information against a reference genome, finding genetic variation in the bacterial DNA that had evolved in the lab.

"These developments give the feeling that improvements are coming very quickly," said HMS professor of genetics Church, who also heads the Lipper Center for Computational Genetics, MIT-Harvard DOE Genomes to Life Center, and the National Institutes of Health (NIH) Center for Excellence in Genomic Science.

"The cost of $1,000 for a human genome should allow prioritization of detailed diagnostics and therapeutics, as is already happening with cancer," Church said.

The Church lab is a member of the genome sequencing technology development project of the NIH-National Human Genome Research Institute.

I predict that within 10 years most of us who survive the coming killer flu pandemic will know our primary DNA sequences. Many debates about the degree of heritability of various human characteristics - especially cognitive characteristics - will then be resolved very quicky. The knowledge spawn many uses and not just medical uses (valuable though they will be). Social science as a field will become orders of magnitude more productive as genetics becomes a much better controlled variable in social science studies.

I'm also looking forward to improvements in stem cell therapy development when many genetic sequences that affect longevity are identified. We'll be able to use stem cells not only to build replacement parts but also to build longer lasting replacement parts.

Thanks to Brock Cusick for the heads-up.

By Randall Parker 2005 August 05 09:43 AM  Biotech Advance Rates
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2005 August 04 Thursday
Prompt Response Might Stop Avian Flu Pandemic

We have some bad news and we have some possibly good news.

If Asian bird flu mutates into a form that spreads easily between humans, an outbreak of just 40 infected people would be enough to cause a global pandemic. And within a year half of the world’s population would be infected with a mortality rate of 50%, according to two studies released on Wednesday.

And yet, the models show, if targeted action is taken within a critical three-week window, an outbreak could be limited to fewer than 100 individuals within two months.

This result comes out in a pair of papers published in Nature and Science by teams of British and American researchers.

Neil Ferguson, a professor at the Imperial College in London and lead author of the Nature paper says that if the pandemic happens half the world's population could be infected within a year.

Prof Ferguson said if nothing was done, half the world could be infected within a year. But a stockpile of Tamiflu, along with a policy of closing schools and workplaces, could have more than a 90 per cent chance of stopping a pandemic virus.

Bummer dudes. If I survive I'll probably have a much smaller readership. Could all my readers please plan in advance and buy provisions to allow themselves to flee to isolated cabins for a year? I don't have a big marketing budget to attract new readers. So you guys and gals have got to be careful and stay alive. Oh, and stop smoking, get more exercise, eat better food, lose weight, and don't drink and drive.

During the pandemic using cellular broadband on broadcast towers you'd still be able to read me from your mountain cabins while I hole up in a cabin of my own. Note to self: Buy a cabin with a water well and a bunch of solar panels and batteries and in sight of a cellular internet modem tower. Stock it with lots of pop corn, Total cereal, and other vital necessities.

The American team also found that early intervention with antivirals and quarantines has the potential to stop a pandemic.

Another team from Emory University in Atlanta, the US, led by Dr Ira Longini, simulated an outbreak in a population of 500,000 in rural Thailand, where people mixed in a variety of settings, including households, schools, workplaces and a hospital.

Provided targeted use of antiviral drugs was adopted within 21 days it would be possible to contain an outbreak, they found, as long as each infected person was not likely to infect more than an average of 1.6 people.

If it was more infective than this, household quarantines would also be necessary, they said.

But among the many reasons such a strategy might fail is the possibility that the outbreak strain could develop esistance to the anti-viral drug Tamiflu (chemical name oseltamivir).

Another problem is that the earliest victims must be identified promptly.

Professor Ferguson then considered what would happen if Tamiflu were given rapidly to everybody within a 5km (3.1m) or 10km radius of an infected person, and measures were taken to reduce contact by closing schools and workplaces.

These approaches will contain an outbreak, but only if Tamiflu is given swiftly, preferably within 48 hours of a case being diagnosed. Prevention must begin before more than 30 to 40 people are infected, and 90 per cent must take the drugs they are given.

Well, imagine that the early victims are in Laos or Cambodia or Burma (all quite plausible) and since large areas of those places are pretty primitive what if nobody of importance notices for weeks? Also, to enforce household quarantines and other measures one needs a fully functional government with plenty of public health workers. Well, in some parts of the world government is dysfunction or effectively non-existent.

Even with prompt response we'd still have to get lucky.

"If we end up with a pandemic like [previous catastrophic pandemics], we'll have a lot of people dead," said study team member Elizabeth Halloran, professor of biostatistics at Emory University in Atlanta, Georgia.

Halloran added that the simulations show that it should be possible to contain an outbreak at its source. But the results are unpredictable. "We have shown in these simulations that—even given the same [hypothetical] situation—sometimes when we intervene it's successful and sometimes it's not," Halloran added.

Bottom line: Do not count on this approach working even if the political will and resources are available to execute the containment strategy.

The experts are aware that success of a prompt containment strategy depends on many "ifs".

"The models show that if you combine well-directed, targeted treatment with some social interventions like closing schools, ideally together with some vaccination, it's conceivable you'd be able to stop the epidemic," said Anthony S. Fauci, chief of infectious diseases at the National Institutes of Health, which funded much of the work through its National Institute of General Medical Sciences.

But the odds of success are tempered by many "ifs," Fauci and others warned.

Here's one problem with this strategy: A reluctance to commit resources. They assume a few million doses of Tamiflu available and some panel or person authorized to employ it. Well, as it stands now the WHO is reluctant to raise the warning level for a pandemic because raising the level causes stuff like the use of Tamiflu stocks. They know if they use it prematurely they will basically shoot their guns but without ammo to reload. So there is going to be a bias against committing resources until absolutely certain. Well, how to determine that a strain that has pandemic capability has finally emerged and how to do that very quickly?

Suppose that the WHO and national governments got together 10 million or 20 million Tamiflu doses. Then public health officials could afford to commit resources against each potential outbreak before being absolutely sure. Would this work? Maybe. But then again, maybe widespread use of Tamiflu would help select for Tamiflu-resistant strains.

But there's another problem: The H5N1 strains that are popping around in animal populations could mutate into a human pandemic capable form more than once. We might need to stop it 2, 3, 4, or 5 times. Are we going to get that lucky? Heck if I know. But I'm not optimistic.

I think governments and public health officials ought to consider the rapid development and widescale delivery of vaccines to populations in Southeast Asia right now. Even if the vacines would be only partially effective against some future avian flu strain the ability to slow the spread of a new strain using partial immunity might give the containment strategy a much better chance of working.

My joking aside, this is serious business. Lots of us could die. We ought to be doing orders of magnitude more to avoid getting killed by an avian flu pandemic. Think about it. Complain to your elected representatives. Buy the sorts of supplies you'd need to survive a major societal disruption.

Update: Even a slowing of the pandemic would provide more time for vaccine development and production.

"Our findings indicate that we have reason to be somewhat hopeful. If -- or, more likely, when -- an outbreak occurs in humans, there is a chance of containing it and preventing a pandemic. However, it will require a serious effort, with major planning and coordination, and there is no guarantee of success," said coauthor Elizabeth Halloran of Emory University.

"Early intervention could at least slow the pandemic, helping to reduce morbidity until a well-matched vaccine could be produced," she said.

The danger of avian flu is that the virus could develop into a new strain that could be transmitted among humans. The virus might mutate, or it might jump over to a human already infected with the flu and then mix, or "reassort," with the human flu virus. Because humans would have little or no immune protection against this strain, it could potentially cause a massive pandemic.

"There were three influenza pandemics in the 20th century alone. The threat of another pandemic, related to avian influenza, is real and very serious. Fortunately, as the new study shows, for the first time in human history, we have a chance of stopping the spread of a new influenza strain at the source through good surveillance and aggressive use of public health measures," said Katrina Kelner, Deputy Editor, Life Sciences, at Science.

The effectiveness of containment depends on quick decisions to do targeted antiviral drug use, a fairly low multiplier for how many others each infected person passes the virus on to, a high level of use of antiviral drugs, and effective quarantine measures.

They found that targeted use of antiviral drugs could be effective for containment as long as the intervention occurred within 21 days and the virus' reproductive number (which represents the average number of people within a population someone with the disease is able to infect) had a relatively moderate value of roughly 1.6.

A process of administering antiviral drugs to the people in the same mixing groups as the infected person, called TAP for "targeted antiviral prophylaxis," could contain the outbreak as long as it reached 80 percent of the people targeted. A related strategy, GTAP, for "geographically targeted antiviral prophylaxis," which targets people within a certain geographic range of the initial case, produced similar results as long as it achieved coverage of 90 percent.

Vaccination before the outbreak, even with a vaccine that is poorly matched to the actual virus strain, increased the effectiveness of TAP and GTAP.

For even higher viral reproductive numbers, household quarantines would also be necessary to contain the virus. A combination of TAP, prevaccination and quarantine could contain strains with a reproductive number around 2.4. A value of 2.4 is relatively contagious, though some other viruses such as measles are substantially higher. In all cases, early intervention would be essential.

We can't have a wonderful long future if we die first. Future rejuvenation therapies are useless to anyone who dies from bird flu next year.

Update: Do not expect Western governments to allocate sufficient vaccines and drugs to implement the early preemption strategy to stop an outbreak.

Would the United States, Europe and Japan be willing to donate their precious vaccine supply to mount this long-shot defense? This is perhaps the biggest unanswered question in pandemic flu planning -- and one likely to be answered only at the moment of truth.

Officially, it is a possibility.

"If it was done in consultation with the WHO [World Health Organization] -- and with other governments that would make contributions, as well -- we would be more likely to consider it," said Gellin at HHS. But observers both in and out of the government said, not for quotation, that they doubt the U.S. government would ever send a significant amount of its vaccine stockpile overseas.

Production of a sufficient supply of vaccine could take years. The economic disruption of a pandemic will be enormous. I am expecting an economic depression. The threat of terrorism will seem tiny by comparison.

Also see my previous posts "Yet Another Avian Flu Preparedness Warning Report" and "More Warnings On Avian Flu Danger To Humanity".

By Randall Parker 2005 August 04 05:32 PM  Dangers Natural Bio
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2005 August 03 Wednesday
Average Age Of Cells In Body May Be Below 10 Years

Nicholas Wade of the New York Times reports on how the use of carbon-14 dating of cellular DNA by Jonas Frisen shows that most cells in the body are less than 10 years old. (same article here and here)

But Frisen, a stem cell biologist at the Karolinska Institute in Stockholm, Sweden, has also discovered a fact that explains why people behave their birth age, not the physical age of their cells: A few of the body's cell types endure from birth to death without renewal, and this special minority includes some or all of the cells of the cerebral cortex.

...

Most molecules in a cell are constantly being replaced but the DNA is not. All the carbon 14 in a cell's DNA is acquired on the cell's birth date, the day its parent cell divided. Hence the extent of carbon 14 enrichment could be used to figure out the cell's age, Frisen surmised. In practice, the method has to be performed on tissues, not individual cells, because not enough carbon 14 gets into any single cell to signal its age. Frisen then worked out a scale for converting carbon 14 enrichment into calendar dates by measuring the carbon 14 incorporated into individual tree rings in Swedish pine trees.

Having validated the method with various tests, he and his colleagues reported the results of their first tests with a few body tissues in the July 15 issue of Cell. They say cells from the muscles of the ribs, taken from people in their late 30s, have an average age of 15.1 years.

The epithelial cells that line the surface of the gut have a rough life and are known by other methods to last only five days. Ignoring these surface cells, the average age of those in the main body of the gut is 15.9 years, Frisen found.

Read the full article for more details on the average age of various types of cells. Note that the vast majority of neurons have existed since childhood. The need to rejuvenate existing neural cells makes brain rejuvenation by far the hardest part of the total rejuvenation therapy development puzzle.

While the researchers found that in some parts of the brain the average cell age was less than the age of the person in the visual cortex the brain was about the same age as the person.

They found that all of the samples taken from the visual cortex, the region of the brain responsible for processing sight, were as old as the subjects themselves, supporting the idea that these cells do not regenerate. "The reason these cells live so long is probably that they need to be wired in a very stable way," Frisén speculates.

Keep in mind that just because a cell divided, say, 7 years ago that doesn't make it youthful. The duration of time since a cell was created from mitotic division is not a measure of the cell's functional age. The damage done to parent cell DNA is inherited by the two cells that are produced when a cell divides. Therefore newly created cells in older organisms will function more like old cells. Also, chromosome telomere caps get shorter each time cells divide and this limits how many times cells can divide. A 7 year old stem cell is of no use if it can no longer divide when damage occurs in joints, muscles, blood vessels, or other components of the body.

The fact that on-going cellular division makes most cells chronologically young and that old cells divide less well actually presents an opportunity for the development of rejuvenation therapies. The development of technologies for producing youthful adult stem cells will provide sources of youthful and healthier stem cells cells to replace the older and less healthy cells that accumulate in our bodies as we age. Since older stem cells divide more slowly rejuvenated stem cells introduced into various parts of the body would out-compete and gradually displace the older cells. Then since most cells are, as reported above, not all that old gradually over a period of several years many more specialized cells (again, blood vessel lining, skin cells, gut cells, etc) would get produced from the healthier introduced stem cells. So gradually a larger fraction of our bodies would become young again.

This latest result supports arguments for an acceleration of the development of stem cell therapies. But we still need to develop gene therapies and other therapies aimed at repairing existing aging neurons and glial support cells in situ, meaning right in the brain. Stem cell therapies and gene therapies are probably the two most important Strategies for Engineered Negligible Senescence (SENS).

By Randall Parker 2005 August 03 12:37 PM  Aging Studies
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False Memories Decrease Desire For Food

UC Irvine psychologist Elizabeth Loftus has found that students can be fooled into believing that some foods caused them to get sick as children.

After 204 students completed questionnaires about their food preferences, they received computer-generated analyses – some of which included false feedback indicating they had gotten sick from eating strawberry ice cream as a child. Researchers used two techniques to encourage the participants to process the false information, which resulted in 22 percent and 41 percent of the participants believing they had such a childhood experience.

Participants even provided details of the experience such as “May have gotten sick after eating seven cups of ice cream.” However, both groups showed similar tendency to want to avoid that food now that they “remembered” getting sick from it as a child.

“People do develop aversions to foods; for example, something novel like béarnaise sauce may make someone sick once, and they can develop a real aversion to that food,” said Loftus. “And with alcohol, there’s a medication that actually makes alcoholics sick if they drink, and the idea is to develop an aversion so that the person avoids drinking. It may be possible to do something similar with food, but without the physical experience.”

Loftus points out that further research must be done to show whether the effects are lasting and whether people who believe the false memory actually avoid the food when it is in front of them, as they indicated in the surveys.

People are awfully gullible.

In experimenting with false memories about fattening foods, Loftus’ team looked at both chocolate chip cookies and strawberry ice cream. Because participants were more likely to believe strawberry ice cream had made them ill, the researchers speculate that only novel food items are effective with the false feedback technique – a finding consistent with research showing real taste aversions are more likely to develop with novel foods. How recently participants had eaten the food appeared to have no effect.

Their next challenge is to try to fool people into liking vegetables.

In next study, Loftus and her team will look at whether people can be led to falsely believe that as a child they really liked certain healthful vegetables, like asparagus, and whether that will make them more inclined to eat such foods as adults.

The techniques these researchers employed to implant false memories are too weak. But surely false memory implantation technologies will improve. But also memory erasure technology might work just as well or better. If you had no memory of a particular food's taste you couldn't crave that taste. If you had a bad memory you'd even be averse to eating that food.

Parents are in the best position to use false memories. Start telling a 7 year old that ice cream made his tummy hurt each time he ate it. Probably 5 or 10 years of telling him that lie and encouraging him to repeat it back would leave a lasting effect. But I suspect that obese kids would respond by finding other foods to pork out on. Unless one can create a more general aversion to calorie consumption or at least an aversion to junk food consumption this sort of deception seems pointless.

I can see memory erasure and false memory implantation technologies as useful to treat for the effects of traumatic events and to get over addictions and compulsions. But we really need better technologies for reducing cravings and compulsions. Such technologies will come in the form of neural stem cell therapies targetted to specific regions of the brain.

Using today's technology a constant stream of PDA messages could tell dieters that high fat foods are disgusting and nauseating or tell them how great they are going to look if they avoid snacks would provide some benefit. PDA message streams could be automated to send out an assortment of encouraging messages with all sorts of justifications and praise for sticking to a diet. The messages could include suggestions for low calorie foods to eat or activities to engage in instead of eating. The same could be done with cell phone voice mail.

By Randall Parker 2005 August 03 11:34 AM  Brain Appetite
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2005 August 01 Monday
New Tool Speeds Up DNA Sequencing By 100 Times

DNA sequencing keeps getting faster and cheaper.

454 Life Sciences Corporation, a majority-owned subsidiary of CuraGen Corporation , today announced the publication of a new genome sequencing technique 100 times faster than previous technologies. This is the first new technology for genome sequencing to be developed and commercialized since Sanger-based DNA sequencing. 454's proprietary technology is described in the paper "Genome sequencing in microfabricated high-density picoliter reactors," in the July 31, 2005, online issue of Nature, with the print edition of the paper to follow later in the year. The technique was demonstrated by repeatedly sequencing the bacterial genome Mycoplasma genitalium in four hours, with up to and exceeding 99.99% accuracy. With a 100-fold increase in throughput over current sequencing technology, 454 Life Sciences' instrument system opens up new uses for sequencing, including personalized medicine and diagnostics, oncology research, understanding third world diseases, and providing fast responses to bioterrorism threats and diagnostics.

"It is clear that sequencing technology needs to continue to become smaller, faster and less expensive in order to fulfill the promise of personalized medicine," said Francis S. Collins, M.D., Ph.D., Director of the National Human Genome Research Institute. "We are excited that our support of sequencing technology development is yielding results and we look forward to the applications of such innovative technologies in biomedical research and, ultimately, the clinic."

In May 2004, the NHGRI awarded a grant to 454 Life Sciences to help fund the scale-up of 454 Life Sciences' technique toward the sequencing of larger genomes, starting with bacterial genomes, and to develop the Company's ultraminiaturized technology as a method to sequence routinely individual human genomes. The scalable, highly parallel system described in this article sequenced 25 million base pairs, at 99% or better accuracy, in a single four hour run. The researchers illustrated the technique by sequencing the genome of the Mycoplasma genitalium bacterium.

"Much like the personal computer opened up computing to a larger audience, this work will enable the widespread use of sequencing in a number of fields, and ultimately place machines in your doctor's office," stated Jonathan Rothberg, Ph.D., senior author and 454 Life Sciences' Founder and Chairman of the Board of Directors. "This sequencing technique, leveraging the power of microfabrication, is 100 times faster than standard sequencing methods at the start of its development cycle. We expect, as with computers, for it to get more powerful and cheaper each year, as we continue to advance and miniaturize the technology."

To repeat a frequent FuturePundit theme: Biotechnology is going to advance at the rate of computer technology because biotechnology is shifting toward the use of very small scale devices. The current cost of human DNA sequencing is in the tens of millions of dollars per person. But that high cost won't last for much longer.

The half million dollar sequencing machine uses 1.6 million tiny reaction wells in parallel.

The novel sequencing technique, designed by Jonathan M. Rothberg of 454 Life Sciences Corp. in Branford, Conn., and his colleagues, uses tiny fiber-optic reaction vessels that measure just 55 micrometers deep and 50 micrometers across--a slide containing 1.6 million wells takes up just 60 square millimeters.

The 25 million base pairs that this machine sequenced in 4 hours should be compared to the approximately 3 billion base pairs in the human genome. If the machine's ability to process 25 million base pairs in 4 hours scales up to larger genomes then the human genome would take 480 hours or 20 days on this machine. But there are additional challenges in sequencing a large genome such as breaking it down into doable pieces. Also, the genome has to be read several times to correct for errors.

This article has details on the process used by this sequencing instrument.

The 454 approach involves shearing the starting material DNA using a nebulizer. Rothberg explains: “[We] nebulize the DNA into little fragments, shake it in oil and water, so each DNA fragment goes into a separate water droplet. So instead of bacteria, we separate the DNA into drops. Then we do PCR, so every drop has 10 million copies. Then we put in a bead, drive the DNA to the bead, so instead of the cloning and robots, one person can prepare any genome.”

The DNA-covered beads are loaded into the microscopic hexagonal wells of a fiber-optic slide, which contains about 1.6 million wells. In 454’s benchtop instrument, chemicals and reagents flow over the beads in the wells. Solutions containing each nucleotide are applied in a repetitive cycle, in the order T-C-A-G. Excess reagent is washed away using a nuclease, before a fresh solution is applied. This cycle is repeated dozens of times.

The researchers see their techology following a similar pattern to the development of integrated circuits which have sped up at the rate predicted by Intel co-founder Gordon Moore with his famous Moore's Law.

“Future increases in throughput, and a concomitant reduction in cost per base, may come from the continued miniaturization of the fibre-optic reactors, allowing more sequence to be produced per unit area – a scaling characteristic similar to that which enabled the prediction of significant improvements in the integrated circuit at the start of its development cycle.”

Future iterations of their design will increase the level of parallelization while at the same time keeping costs the same per instrument or even lowering costs per instrument. So these folks have an approach that will drive down DNA sequencing costs by orders of magnitude.

Rothberg expects individual DNA sequencing for medical purposes once DNA sequencing costs fall to $20,000.

Jonathan Rothberg, board chairman of 454 Life Sciences, said the company was already able to decode DNA 400 units at a time in test machines. It was working toward sequencing a human genome for $100,000, and if costs could be further reduced to $20,000 the sequencing of individual genomes would be medically worthwhile, Dr. Rothberg said.

Another very important application of cheap DNA sequencing technology which is rarely mentioned is in social sciences. Cheap DNA sequencing will allow controlling for genetic influences on behavior in social science experiments. Most existing social science research results will be discredited by experiments that control for genetic influences. The excessive assumption of environmental influences on human behaviors and abilities will be discredited. This will lead to the disproof of key assumptions underlying beliefs of factions on both the political Left and the political Right.

By Randall Parker 2005 August 01 10:14 AM  Biotech Advance Rates
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