Sunday, February 22, 2004

Stem-cell research still an embryonic business

Whoever learns to control embryonic stem cells that can morph into healthy human cells could be standing on a gold mine: Four million Americans have damaged brain cells from Alzheimer's, and a million people each year suffer tissue damage from heart attacks.

No one doubts that those people -? and millions more who suffer from Parkinson's, diabetes or stroke - would pay big money to restore their quality of life. But that powerful profit motive hasn't pushed stem-cell research quickly toward to development of new treatments.

Despite the progress ?? earlier this month a team of South Korean researchers showed that they could clone human embryos and harvest their stem cells ?? building a business in the field is tough. Investors in the pharmaceutical and biotechnology industries aren't committing billions of dollars, largely because society hasn't clearly decided whether the research is moral.

With the stem-cell research in its infancy and massive government funding constrained by a policy enacted in August 2001, industry experts say the field is too risky, the business model too vague. Researchers don't know how to control embryonic stem cells, for example, so they will become heart cells instead of cancer cells, and they don't know how do it cheaply, conveniently or consistently enough to make it a viable business.

Some startups have failed, unable to raise cash. To the industry, the efficiency isn't there. The South Koreans' work is a breakthrough, but the group got only one cloned embryo to produce stem cells, out of 240 attempts.

Chuck Murry, a human-embryonic-stem-cell researcher at the University of Washington who has used the cells to grow human heart tissue in rats, believes it could take 20 years before the first stem-cell-based treatment could arrive -?? five to 10 years to get ready for tests in humans and then several years in human testing.

Murry's next step ?? a tricky one, he said ?? is to show that human heart tissue from stem cells can repair the heart's lost functions in animals. He's filing patents on the work but hasn't been bombarded with calls from investors, he said.

"The typical venture capitalist has a horizon of getting a return on investment in about three years, with some exceptions," Murry said. "This kind of stuff, the benefits of it, are much further off."

There are some exceptions -? companies that say the world of stem cells is closer to human testing than many believe.

Geron, a tiny 14-year-old biotech company in Menlo Park, Calif., is the world leader in embryonic stem-cell research. The company believes it will be cleared to start the first stem-cell therapy in human tests next year, possibly for spinal-cord injury.

David Greenwood, Geron's chief financial officer, said the company believes it can build its business by adding a centralized factory to mass-produce standardized embryonic human cells. If a patient's immune system is suppressed, he said, the standardized cells could be transplanted into random patients without being rejected by their immune systems.

The company decided to go that route, Greenwood said, because it would cost too much to take a personalized approach. In that technique, a patient's own skin cells could be scraped off, the nucleus of DNA taken out and cloned in a lab dish to make a "therapeutic clone" that could produce stem cells. Those cells could regenerate, for example, spinal-cord cells that are a patient's identical genetic match, cells that, in theory, wouldn't be rejected by the immune system. But the logistics don't yet make sense, Greenwood said.

"The problem is, you have to have a therapeutic you can deliver at a reasonable cost so we can charge a reasonable cost," Greenwood said. "If you can say to a patient, 'We can help you. Do you have $200,000?', that's not going to be helpful for most people. We believe we have to operate within the current parameters of health insurance."

Investors have not shown a willingness to jump at the idea, either. Geron stock has fallen from a high of $75 to around $10, and the company has laid off many to save money. The tide will turn, Greenwood said, and pharmaceutical investment will flood in once Geron gets approval from the Food and Drug Administration to start human tests.

The debate over ethics is one of the risks scaring away investment. Each year, Congress considers an outright ban on all human cloning, for reproductive or therapeutic research. The FDA has said it will consider allowing stem-cell therapies to be tested on a case-by-case basis, but it hasn't given the green light for a trial.

The National Institutes of Health provides grants for work on about a dozen kinds of embryonic cells, but supplies are not abundant, and scientists say they need more to understand how cells from multiple embryos ?? not just the few approved by the federal government ?? react in experiments to prove their theories.

The obstacles aren't entirely about money or regulation. Science can be difficult.

Tony Blau, a stem-cell researcher at the UW, said it is "extremely laborious" to keep the embryonic cells growing, well-nourished and stable in the lab so they don't die or turn into a cell type with less potential. Researchers need to know how to channel the stem cells to create a specific kind of cell, how to test whether they're pure, and how to develop drugs that could serve as a sort of antidote in case infused stem cells started creating something dangerous, such as cancer.

Big companies, Blau said, want to know that their drugs will be almost completely stable, standard, pure and consistent, because they can behave differently if they aren't. Stem cells never will achieve that kind of standardization, Blau said, because living cells are more complex than chemically synthesized drugs. That fact discourages pharmaceutical companies.

Small biotech companies have more scientific interest, Blau said, but in many cases, "they don't have the money."

Doug Williams, chief scientific officer of Seattle Genetics, said the long-term potential of the stem-cell business is intriguing but is not on the radar screens of most companies. Companies like his are judged by investors on the odds that their experimental products will reach the market - and provide a return on investment ?? within five years.

Before investing serious money, Williams said, companies can't just be wowed by the science but have to think early on about how much it would cost to make the product and how convenient it would be to give to patients. Re-infusing cells is much more complicated than a pill or an injection.

Most shudder at the idea of cloning to reproduce people, but it is conceivable that a few people wealthy enough to afford it could want to be cloned or could want to replace a lost child or loved one with a genetically identical twin. The question is whether market demand could push it ahead despite the objections of scientists and physicians who consider it unethical.

"That's not where the market is ?? the market is in curing diseases with huge populations," said Robert Nelsen, a managing director with Arch Venture Partners in Seattle. His firm hasn't invested in the work and is nervous about doing so until the debates are settled and more-compelling scientific evidence emerges.

Bob Overell, a venture capitalist with Frazier Healthcare Ventures in Seattle, said investors are intrigued by the potential of stem-cell treatments but are reluctant to invest.

"There's a point at which we have to decide as a country if this is something we want to happen," Overell said. "If it is, we'll have to look at how to regulate it appropriately and put a ban on certain kinds of work. Otherwise, it's not worth the risk."

By: Luke Timmerman ~ Seattle Times business reporter
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Thursday, February 19, 2004

Therapeutic Cloning Prompts Call for Ban

First Human Cloning to Obtain Stem Cells Sparks Calls for Ban on All Cloning in United States

The Associated Press

In a clash of politics and science, the first successful cloning of a human embryo and the extraction of stem cells from it has ignited new calls for a ban on all forms of human cloning in the United States.

The cloning announcement by South Korean scientists on Thursday prompted members of Congress and church leaders to ask for immediate legislation.

"Cloning human beings is wrong. It is unethical to tinker with human life," said Rep. Joe Pitts, R-Pa. A ban must be passed, he said, "before this unethical science comes to our shores."

The Bush administration favors such action and referred reporters to a statement by the president calling for "a comprehensive and effective ban."

"Human life is a creation, not a commodity, and should not be used as research material for reckless experiments," Bush said last month.

Sen. Edward Kennedy, D-Mass., who voted against a bill passed last year by the House that called for a ban on human cloning, said there needs to be legislation that would prevent cloning of babies, but permit "lifesaving stem cell research to proceed under strict ethical guidelines."

Two South Korean scientist who announced the landmark achievement here Thursday said they have already been the target of street demonstrations and egg-throwing incidents in Seoul even though their work is directed at treating diseases and not at making cloned babies.

Woo Suk Hwang, lead author of the study, admitted at a news conference that the technique developed in his lab "cannot be separated from reproductive cloning" and called on every country to prevent the use of the technology in that way.

He said the work was controlled and regulated by the Korea Stem Cell Research Center "to prevent the remote possibility of any uncontrolled accidents such as human reproductive cloning."

Shin Yong Moon, a co-author of the study, said the work must continue because of its great promise for treating of diseases such as Parkinson's, Alzheimer's, spinal cord injury and diabetes. But he said a new law passed in Korea will now require his group to get a government license before proceeding with their research.

The medical use of stem cells derived from cloning will require at least another decade of research, he said.

Both Hwang and Moon are researchers at the Seoul National University.

Donald Kennedy, editor of the journal Science, which published the study, said the work is not a recipe for cloning babies.

"It is a recipe (for human cloning) in the sense that 'catch a turtle' is the recipe for turtle soup," said Kennedy at a news conference. "There is much difficulty that would remain for anybody who tried to use this technology as a first step toward reproductive cloning."

Hwang, Moon and their team created the human embryo after collecting 242 eggs from 16 unpaid, anonymous volunteers. They also took from each woman cells from the ovaries. To attempt male embryo cloning, they used cells taken from the ear lobes of adult men.

The researchers extracted the nucleus from each of the eggs and then inserted the nucleus from the other cells.

The eggs were then nurtured into blastocysts, an early stage of embryo development, and the stem cells were extracted.

Hwang said the group had a 43 percent success rate in making cloned embryos, but was successful only in making one colony of stem cells. Only the embryos made using both the nucleus and the egg from the same woman successfully matured enough to make stem cells, he said; eggs that received nuclei from adult male cells or from adult cells of women other than the egg donor failed to produce stem cells.

Hwang, a veterinarian, developed the cloning technique on animals and then teamed with Moon for the human embryo experiment.

Embryonic stem cells are the source of all tissue. Researchers believe they can be coaxed to grow into heart, brain or nerve cells that could be used to renew ailing organs.

In the experiment, Hwang and his team said, the embryonic stem cells in tests that followed the cells for 70 divisions formed muscle, bone and other tissue.

Using cloned embryonic stem cells for therapy would avoid the problem of tissue rejection. Cloned stem cells, in theory, would be an exact genetic match to the cell donor and would not be attacked by the immune system.

Regulations approved by President Bush permit federal funding of stem cell research, but only on cell lines created from embryos destroyed before Aug. 9, 2001. The approved cell lines were not created by cloning, however.

Kennedy said the U.S. restrictions are handicapping American researchers.

"There is no question that the degree of restriction has given other nations some significant advantage," he said.
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New Insights Into Spinal Cord Injuries

People who suffer a spinal injury can still generate leg muscle activity independent of brain signals, says a study in the new issue of Spinal Cord.

Previous research showed locomotor training, such as exercising patients on treadmills, helps people who have suffered a spinal cord injury to learn to walk again. This new study says that adding weight to the limbs during therapy provides an important sensory cue to help those people regain the ability to walk.

The study of four patients with clinically complete spinal cord injury also found that moving one leg during therapy helps activate muscles in the opposite leg.

"Nobody has been able to show that in humans before. It appears there are left-to-right connections in the signal of the spinal cord, not just connections from the brain to the legs," research leader Dan Ferris, an assistant professor of kinesiology at the University of Michigan, says in a statement.

He conducted the study as part of his post-doctorate work at the University of California, Los Angeles David Geffen School of Medicine.

The findings offer information for developing rehabilitation strategies. The study shows that therapists working with people who've suffered spinal cord injury should provide sensory information that simulates walking as closely as possible. Weight loading and movement in one leg can influence what happens in the other leg, the study says.
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Spinal cords fixed in tests

With a genetic tweak, scientists have created an unlimited supply of a type of nerve cells found in the spinal cord and have been able to use the cells to partially repair damaged spinal cords in lab animals.

While application of the discovery to humans is still years away, being able to generate such a limitless supply of the specialized nerve cells has long been a goal toward treating many neurological diseases.

"This work is the culmination of six years of work, and it will be many more years before an approach like this can be tried in human patients. But the promise is extraordinary," said Dr. Steven Goldman, a professor of neurology at the University of Rochester Medical Center in New York.

His team reports online today and in the March issue of Nature Biotechnology that it was able to create the unique cells by introducing a gene called telomerase, which allows stem cells to live indefinitely, into more specialized "progenitor" cells.

In normal development, progenitor cells turn into specific types of spinal cells. But because they lack the ability to continuously divide, they can only form a few generations of the nerve cells. Due to this limitation, scientists have been unable to produce enough of the cells to have an impact on spinal cords damaged by injury or disease.

But with the addition of telomerase just at the point where the progenitors have committed to making a specific type of cell, the spinal progenitor cells were able to churn out new neurons indefinitely.

"The progenitor cells are immortalized at a stage when they only give rise to the type of neuron we want, thus becoming an ongoing source," said Goldman, whose work was supported by Project ALS and the Christopher Reeve Paralysis Foundation.

Goldman's team propagated the cells for more than two years, the longest anyone has ever maintained a line of progenitor cells.

Using some of those neurons, a group of Goldman's colleagues led by Dr. Maiken Nedergaard, a professor of neurosurgery, injected the cells into rats in which small sections of spinal cords had been damaged. The cells replaced the damaged part of the spinal cord with new nerve cells. But after about a month, the cells in the animals stopped proliferating, as neurons in the spinal cord normally do.

The researchers also were pleased to find that the telomerase-enhanced cells did not show any inclination to grow tumors.

Spinal cords are made up of several types of neurons, so the group is now creating and working with other cells that would create the types of neurons needed to completely repair spinal nerves.

Treating some neurological conditions may actually require a steady supply of just one specific type of nerve cell. A patient with Parkinson's disease may only have to replace neurons that manufacture dopamine, for instance, or a patient with multiple sclerosis may only require restoration of cells that produce myelin.

More information is available on the Web site: www.nature.com.

By Lee Bowman - Scripps Howard News Service
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Stem cells found in adults may repair nerves

It used to be considered dogma that a nerve, once injured, could never be repaired. Now, researchers have learned that some nerves, even nerves in parts of the brain, can regenerate or be replaced. By studying the chemical signals that encourage or impede the repair of nerves, researchers at the University of Washington, the Salk Institute, and other institutions may contribute to eventual treatments for injured spines and diseased retinas.

From the University of Washington:

Stem cells found in adults may repair nerves

It used to be considered dogma that a nerve, once injured, could never be repaired. Now, researchers have learned that some nerves, even nerves in parts of the brain, can regenerate or be replaced. By studying the chemical signals that encourage or impede the repair of nerves, researchers at the University of Washington, the Salk Institute, and other institutions may contribute to eventual treatments for injured spines and diseased retinas, according to a presentation at the annual meeting of the American Association for the Advancement of Science (AAAS).

Much of this research focuses on stem cells, one of several types of general cells that can give rise to specialized cells, like neurons. It was once thought that human stem cells were only found in embryos, and in bone marrow, where they produce blood cells. But stem cells are also being found in adults, including the brain and the eye. For example, stems cells steadily replace dead neurons in the olfactory bulb, which transmits scent signals to the brain, and the hippocampal dentate gyrus, an area that organizes short-term memory.

However, the pace of stem-cell repairs in humans is slow. And in some cases, stem cells can even impede healing. Stem cells in an injured spinal cord can create a sticky scar that blocks nerve regeneration, according to Dr. Philip Horner, an assistant professor in the Department of Neurosurgery in the UW School of Medicine.

"We've found that the axons, the parts of the nerves that transmit signals, try to regenerate after an injury but get caught in the scar. It's like they're stuck in the mud," Horner said. "We're studying ways that this process is regulated to see if it can be manipulated to promote healing. In other words, we're looking at ways to get the axons out of the mud. One way is to make the mud less sticky by manipulating stem cells that participate in scar formation. Another is to stimulate the axons to push through the scar by providing the cut nerves with molecules that induce elongation. We're using molecular signals called growth factors to simulate the growth of cultured nerve cells in the laboratory."

Horner and Dr. Thomas Reh, professor in the UW Department of Biological Structure, will join Dr. Fred Gage from the Salk Institute for a 12:30 p.m. session Feb. 16 on "Neural Stem Cells in Health and Disease" at the AAAS's annual meeting in Seattle. Gage will present an overview of neural stem cells, Horner will discuss stem cells and the repair of the spinal cord, and Reh will focus on stem cells in the eye.

The same types of cells that create scar tissue in the spinal column can create new cells in the retina of the eye, especially in young animals of some species, according to Reh. The retina is a delicate light-sensitive membrane that transmits light signals to the brain. Many eyes diseases that cause blindness, such as glaucoma and as age-related-macular-regeneration, damage the retina.

Salamanders don't get glaucoma because they can readily regenerate retinal cells. The same is true of newts, frogs, and some types of fish. "We're trying to understand the remarkable regenerative powers of these lower vertebrates, and through this understanding, develop strategies to stimulate regeneration in the human retina," Reh said.

While salamanders can regenerate retinal cells through their life, many other species lose this ability as they age. "At some point in each species life cycle, the stem cells in the retina make a transition from a regenerative cell to a cell that will make a scar in response to injury, like the cells that cause scars in the spinal cord," Reh said. "Chickens make the transition a few weeks after hatching in most of their retina, though they retain some limited capacity to regenerate retinal cells throughout life. In rats, it's only a matter of a few days after the cells are generated that they lose their ability to regenerate other retinal cells."

Human retinas seemingly can't repair themselves, yet in recent studies human retinal cells have grown new neurons when cultured in the laboratory. "The hope is that many of the molecular and cellular mechanisms necessary for regeneration, that serve amphibians so well, are still in place in humans," Reh said. "Future studies from the nervous system, as well as other organ systems, should enable us to define the roadblocks in the regenerative process, and develop strategies to go around them."
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Key advance reported in regenerating nerve fibers

Researchers have advanced a decades-old quest to get injured nerves to regenerate. By combining two strategies ?? activating nerve cells' natural growth state and using gene therapy to mute the effects of growth-inhibiting factors ?? they achieved about three times more regeneration of nerve fibers than previously attained.

From the Children's Hospital Boston:

Key advance reported in regenerating nerve fibers

Two-pronged approach synergizes growth

Researchers at Children's Hospital Boston and Harvard Medical School have advanced a decades-old quest to get injured nerves to regenerate. By combining two strategies ?? activating nerve cells' natural growth state and using gene therapy to mute the effects of growth-inhibiting factors ?? they achieved about three times more regeneration of nerve fibers than previously attained.

The study involved the optic nerve, which connects nerve cells in the retina with visual centers in the brain, but the Children's team has already begun to extend the approach to nerves damaged by spinal cord injury, stroke, and certain neurodegenerative diseases. Results appear in the February 18th Journal of Neuroscience.

Normally, injured nerve fibers, known as axons, can't regenerate. Axons conduct impulses away from the body of the nerve cell, forming connections with other nerve cells or with muscles. One reason axons can't regenerate has been known for about 15 years: Several proteins in the myelin, an insulating sheath wrapped around the axons, strongly suppress growth. Over the past two years, researchers have developed techniques that disable the inhibitory action of myelin proteins, but this approach by itself has produced relatively little axon growth.

The Children's Hospital team, led by Dr. Larry Benowitz, director of Neuroscience Research, reasoned that blocking inhibition alone would be like trying to drive a car only by taking a foot off the brake. "Our idea was to step on the gas ?? to activate the growth state at the same time," Benowitz said. "Knocking out inhibitory molecules alone is not enough, because the nerve cells themselves are still in a sluggish state."

The researchers injured the optic nerves of rats, then used a two-pronged approach to get the axons to regenerate. To gas up the sluggish nerve cells, Dr. Dietmar Fischer, first author of the study, caused an inflammatory reaction by deliberately injuring the lens of the eye. Though seemingly harmful, this injury actually stimulates immune cells known as macrophages to travel to the site and release growth factors. As Benowitz's lab had found previously, these growth factors activated genes in the retinal nerve cells, causing new axons to grow into the optic nerve.

To try to enhance this growth, the researchers added a gene-therapy technique. Using a modified, non-infectious virus as a carrier, they transferred a gene developed by co-investigator Dr. Zhigang He into retinal nerve cells that effectively removed the "braking" action of the myelin proteins ?? spurring production of a molecule that sopped these inhibitory proteins up before they could block growth.

"When we combined these two therapies ?? activating the growth program in nerve cells and overcoming the inhibitory signaling ?? we got very dramatic regeneration," said Benowitz, who is also an associate professor of neurosurgery at Harvard Medical School and holds a Ph.D. in biology/psychobiology. The amount of axon regeneration wasn't enough to restore sight, but was about triple that achieved by stimulating growth factors alone, he said.

Benowitz's lab will continue working with the optic nerve in hopes of restoring vision. "We have to fine-tune the system, and we have some ideas of how to do it," Benowitz said. "But then we come to another big hurdle." That hurdle is getting the nerve fibers from the eye to hook up to the correct centers in the brain in such a way that visual images do not become scrambled. "It's a mapping problem," Benowitz said. "We have to retain the proper organization of fiber projections to the brain."

Meanwhile, he and his colleagues have begun using a similar two-pronged approach to regrow axons damaged by stroke or spinal-cord injury. They have already found a way to step on the gas ?? using a small molecule known as inosine to switch damaged nerve cells in the cerebral cortex into a growth state. In 2002, they reported that inosine helped stroke-impaired rats to regrow nerve connections between brain and spinal cord and partially recover motor function.
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Sunday, February 15, 2004

Spinal Research Planned for Novi, Michigan

Doctors want to find a cure for spinal cord injury.
Patient advocates also want to help victims deal with the affliction better.

The answer for both might be a Novi outpatient facility planned by the Rehabilitation Institute of Michigan.

The $3.5 million facility would specialize in the treatment of spinal cord injuries and be a leading research center for discovering a cure, institute officials said.

The Detroit Medical Center, which operates the institute, is trying to raise $39.9 million for the facility, for the renovation of the DMC'??s main hospital and for a new outpatient center connected to the hospital. So far, it has raised $26 million, partly through grants.

Saturday night, the DMC raised an additional $1 million at its St. Valentine Ball in Dearborn through contributions and the sale of $250 tickets.

Maurice Jordan, executive director of the Michigan chapter of Paralyzed Veterans of America, was one of 396 people who attended the fund-raiser at the Ritz-Carlton Hotel.

"??We'?re incredibly excited about this,"?? said Jordan, who suffers from a spinal cord injury. "??Anything that gets us closer to the day where you can get up and walk, which is of course what all of us want someday."

Researchers in other nations are making inroads against the disorder, said Dr. Steve Hinderer, specialist-in-chief of physical medicine and rehabilitation at DMC.

"??Our purpose is to literally develop an epicenter of activity that studies worldwide practices,"?? he said.

Advocates for spinal cord victims say the search for a cure should not overshadow the need to help patients deal with their affliction.

Marcie Roth, chief executive of the National Spinal Cord Injury Association in Arlington, Va., said more needs to be done to develop drugs and programs that help patients lead fuller lives, and for insurance companies to pay for those expenses.

"??We want to make sure the message is very clear: There is life after a spinal cord injury,"?? she said. "??It'??s not a fate worse than death. There are many people living enriched lives."
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