Caption: Induced stem cells, adult skin cells that have been genetically reprogrammed to mimic embryonic stem cells, have been made potentially safer by removing the introduced genes and the viral vector used to ferry the genes into the cells. These cells were reprogrammed to an embryonic like state with the aid of a plasmid, a loop of DNA, which prompts the reprogramming but is not integrated into the genome of the cells. The work was accomplished by geneticist Junying Yu in the laboratory of James Thomson, a UW-Madison School of Medicine and Public Health professor and the director of regenerative biology for the Morgridge Institute for Research.
Photo credit: courtesy James Thomson
GoogleNews.com, MinnPost.com, October 12, 2009, by Alex Leff — SAN JOSE, Costa Rica – Dr. Orlando Morales is something of a celebrity at Costa Rica’s University of Medical Science, sauntering through the halls in his white lab coat. On a recent walk, students and faculty greeted him with “Feliz cumpleanos, doctor.” He just turned 68.
With the excitement of a young doctor fresh out of medical school, Morales’ eyes light up when he observes the petri dishes that harvest “celulas madre,” or stem cells, from mice.
“It’s practically science fiction,” Morales said of what he considers the medicine’s new miracle worker. Morales is one of the firmest believers around in the power of stem cell treatments.
“After a heart attack, they can begin to make new tissue. In a gland, which for example has to make insulin, the cells begin to create insulin. Nervous tissue, they regenerate it … It’s a panacea,” he said.
An increasing number of foreigners are undergoing stem cell treatment in Costa Rica for ailments from bone fractures to multiple sclerosis. Costa Rican doctors say they are providing these medical tourists with groundbreaking treatments. But stem cell scientists in the U.S. accuse Costa Rica of offering false hope by pushing techniques that have not been scientifically proven.
Dr. Fabio Solano – who directs the stem cell institute at San Jose’s CIMA Hospital, one of the country’s leading private hospitals – says his team has treated as many as 400 patients with procedures that involve stem cells.
Costa Rica has eschewed the contentious debate around stem cells by prohibiting work with human embryos and instead promoting research on what’s known as “adult” stem cells – derived from tissue including body fat and umbilical blood or tissue. In Costa Rica, where Catholicism is the state religion, working with human embryos is out of the question.
Embryonic stem cells are considered a goldmine that could lead to treatment for any number of ailments. Unlike adult stem cells, embryonic ones can evolve into any of more than 200 cell types.
And yet, Solano said, many “miracle” treatments have been accomlished with adult stem cells. “We have demonstrated that adult stem cells are as good as embryonic.”
Success stories have grabbed media attention, with TV networks running stories like “Paralyzed valley woman holds hope in Costa Rica treatment” and “Glenburn boy returns from Costa Rica after having adult stem cell therapy.”
But the buzz has made doctors in the U.S. nervous.
“The lay press is unfortunately replete with many overstatements and misconceptions about what can be accomplished in the short term by stem cell biology,” said Dr. Jack Kessler, an expert in stem cell research at Northwestern University’s Feinberg School of Medicine in Chicago, Ill.
In March, President Barack Obama issued an executive order that lifted Bush-era restrictions on federal funding for stem cell research, but much of the treatment is still a long way off, experts say.
Meanwhile, Costa Rican legislators are putting the finishing touches on a law to promote and regulate adult stem cell research and treatment across a spectrum of diseases. This could fuel further debate over techniques that U.S. doctors say have only produced anecdotal success – but it certainly won’t stem the flow of stem cell medical tourism.
According to Solano, Americans already make up close to 90 percent of the stem cell patients at CIMA Hospital.
Kessler warned that clinics around the world are exploiting patients’ hopes by offering treatment that he calls a “placebo effect,” and hasn’t been proven to work.
“There’s really little if any evidence at the present time – where we are with the current technology – that stem cell therapies are useful for disorders like spinal cord injury, stroke, Parkinson’s disease, multiple sclerosis and some of the other things that are being treated with stem cells,” Kessler said.
Determined to prove the experts wrong, Jennifer Blankenship, a 49-year-old resident of Denver, Colo., made her second visit to Costa Rica in August to treat MS.
Blankenship had looked around in the U.S. for stem cell treatment but could only find offers from university labs that “wanted to charge $100,000 to $150,000 for me to be a guinea pig,” she said. Last month she underwent two weeks of treatment at CIMA Hospital for about $10,000. A December 2008 study by the journal Cell Stem Cell found that international stem cell treatment hovers around an average of $20,000.
Blankenship said that within hours of her first IV injection, “I started moving my left leg, which I hadn’t moved for years.”
Following her second visit, she said, “I’m so excited,” detailing what she described as further progress toward recovery. Costa Rican doctors conducted liposuction to extract and transplant stem cells from her own fat tissue, as well as transplanted further cells derived from umbilical cords. Blankenship said she was charged up with some 200 million stem cells. “I pictured them like little Pacmen,” she joked.
After the trip, Blankenship says she took five steps, then nine. She said: “In the coming weeks, my physical therapist and I are going to my neurologist’s office to show him how I can walk.” And once she can walk on her own again, she said, “I’d love to come to Costa Rica just for fun.”
By David Brown
Washington Post Staff Writer
Monday, October 12, 2009
GoogleNews.com, WashingtonPost.com — Forgive the question, but have you had a colonoscopy yet?
If the answer is yes, you can thank Charles K. Kao, Willard S. Boyle and George E. Smith, who won the 2009 Nobel Prize in Physics last week.
Four decades ago, the men produced key scientific insights that have led to fiber-optic data transmission and digital photography.
Those two technologies today exist side by side — or more precisely, one in front of the other — in the endoscopes that are ubiquitous in diagnostic medicine and surgery.
Or course, fiber-optic cable is responsible for carrying much of the information, voices and pictures that ceaselessly course around the planet. And “charge-coupled devices,” or the guts of digital cameras, have changed the recording of images from a chemical process into an electronic one.
Rarely has there been a Nobel Prize whose relevance to the ordinary person is as indisputable as this one.
“Taken together, these inventions may have had a greater impact on humanity than any others in the last half-century,” said H. Frederick Dylla, director of the American Institute of Physics.
Although the discoveries involve important theoretical insights, they both arose from serious wrestling matches with practical problems.
In the early 1960s, Kao was a young engineer at Standard Telecommunication Laboratories, the research arm of a British telephone company. His assignment was to see whether light might be an alternative to microwaves as a vehicle for transmitting information over long distances.
The problem was that light beams sent through the atmosphere were not stable. So Kao considered the possibility of using glass as a conduit.
While light normally passes through glass and does not go around corners, Kao’s work — aided by that of many other scientists and engineers — is proof that under the right conditions, those generalities do not hold true. Sometimes light can be kept inside a strand of glass, like water in a pipe.
This is achieved by exploiting light’s tendency to bend when it passes from one transparent medium into another. That phenomenon, called “refraction,” occurs because the velocity of a beam of light slows, and its wavelength shortens when it enters a “slower” (usually denser) substance.
Kao and other physicists realized that if a beam of light was aimed down a glass fiber that had specific optical properties, the angle at which the light was refracted when it hit the glass-to-air boundary would keep at least some of the beam inside the fiber, basically bouncing between the walls.
Some of it . . . but not enough to be useful. Only 1 percent remained after traveling a distance of 50 feet. The rest of the beam had been scattered through the glass or absorbed by the atoms and molecules in the glass itself.
It seemed hopeless until Kao and a theoretician colleague, George A. Hockham, made some measurements and calculations. They determined that if the impurities scattering the light rays could be removed from the glass, and if they used a wavelength that the glass molecules could not absorb, then much, much more light would stay inside the fiber.
“I don’t think people had really thought about this earlier,” said Cherry Murray, dean of engineering and applied science at Harvard University, and president of the American Physical Society. “After the fact now it’s pretty obvious.”
Of course, that tends to be true of most really important scientific discoveries.
Four years after Kao and Hockham’s 1966 paper, Corning Glass Works in the United States produced a strand of glass with the properties the researchers outlined. Today, optical fibers — covered with a coating that prevents a glass-glass interface when they are bundled together — preserve 95 percent of light at the end of a kilometer (0.62 miles).
In an interview in 2004, Kao remarked on the lucky confluence of things.
“The material is very cheap, as I went to the most abundant material on Earth,” he said. Silicon, the main constituent of glass, is 26 percent of the planet’s crust by weight. Kao added: “And it is also that the fiber itself has very, very good durability. It is really the cheapest and strongest material that you can use.”
Willard Boyle and George Smith, the other physics Nobelists, also exploited silicon, although to a different end.
In the late 1960s, at Bell Laboratories in New Jersey, they were working on ways to improve memory devices — a way of storing information acquired over time. The ultimate goal was to eliminate the annoying echo that sometimes occurred in very-long-distance telephone calls.
They used an array of small squares made from silicon-based semiconductor material. “Semiconductors” are capable of generating an electrical charge, although not as readily as metals and other conductors (hence their name). Electrodes placed nearby can then be used to hold the charges in place and keep them from dispersing.
Like a row of dominoes of different face value, a line of small semiconductor squares called “pixels” outfitted with electrodes were able to hold a row of different charges. If a voltage was then applied to the array in the right fashion, the charges could be moved off the pixels and “read out.”
In 1969, Boyle and Smith built a prototype of their device. When they tried it out, however, they noticed it worked much better when the lights were off in the lab.
After some pondering, they realized that light falling onto the semiconductor chips was being transformed into electrical energy. (Explaining that phenomenon, called the “photoelectric effect,” is what won Albert Einstein his own Nobel Prize in Physics in 1921.) With the lab lights off, that interference disappeared.
“They put two and two together and they realized they had made an imaging device,” said J. Anthony Tyson, who was at Bell Labs with the two men and is now a professor of physics at the University California at Davis.
By combining the photoelectric effect — light’s tendency to kick electrons out of atoms, creating a charge — and the ability to hold and move an entire array of charges in an organized fashion, they created the basis for digital photography.
As it turns out, a “charge-coupled device,” as these image sensors are called, is 100 times as sensitive as photographic emulsion in detecting light, which makes it perfect for Tony Tyson’s current project.
He is director of the Large Synoptic Survey Telescope, slated to start construction next year on a mountaintop in Chile. It will contain a 3 billion-pixel digital camera, the largest in the world. Scheduled for completion in 2015, the LSST will eventually produce an ultra-sensitive movie of the sky available for public viewing in real time.
“It will be a completely new window on the universe, enabled by the device that Smith and Boyle invented. Already the CCD has produced advances in many field, from biomedicine to the discovery of cosmic dark energy,” Tyson said last week.
Medical College team reports advance
By Mark Johnson of the Journal Sentinel
October 11, 2009
In a fresh demonstration of science’s newfound ability to alter the basic units of human life, researchers at the Medical College of Wisconsin have turned the cells in human skin into those in the liver, work that opens new avenues for treating diseases of the liver without relying on organ transplants.
Professor and stem cell researcher Stephen A. Duncan and other scientists in his lab reported this week in the journal Hepatology that they have created reprogrammed mouse liver cells that were identical to those grown in nature and were able to integrate and grow alongside those in a mouse liver.
Duncan and his fellow researchers also showed that human liver cells made through reprogramming are virtually the same as those grown from embryonic stem cells, though both appear to differ from adult liver cells in one respect. Those grown with reprogrammed or embryonic stem cells in the lab had fewer of the enzymes that fulfill the liver’s function of filtering out toxins than adult liver cells that have developed in the body.
The Medical College experiments, which represent roughly 2½ years of work, also showed that scientists have a reliable and efficient method of turning primitive cells into liver cells, a finding that could offer pharmaceutical companies opportunities to test drugs and provide researchers with a window that will allow them to observe liver diseases progress at the cellular level.
The cells the scientists made are called hepatocytes and make up about 70% of all the cells in the liver.
“You can now make hepatocytes from (the skin cells of) individuals with a liver disease. Then you can start screening for drugs and molecular approaches to reverse the disease or treat the disease,” Duncan said.
Karim Si-Tayeb, a post-doctoral researcher in Duncan’s lab, said it may still be five to 10 years before liver cells made using reprogramming are “clinical grade” and approved for use in people. He and Duncan, however, envision the possibility that liver cells made in the lab can be injected into an unhealthy liver and replace damaged cells.
Much of the mouse work for the new paper was done by Fallon Noto, a graduate student in Duncan’s lab.
“It’s really very impressive. Only a few elite labs in the world have done what Duncan’s lab has done,” said Kenneth Zaret, associate director of the Institute for Regenerative Medicine at the University of Pennsylvania School of Medicine. Zaret was not involved in the research.
Duncan’s team had hoped to become the first group to provide published evidence that reprogramming could be used to make liver cells, but two other groups have succeeded in making liver cells in this manner. Chinese scientists published their results in late September, and this week a group led by Scottish scientist Ian Wilmut published similar work online.
However, the Medical College work in both human and mouse cells suggests treatment strategies right out of the pages of science fiction. For example, both Duncan and Si-Tayeb talked about the possibility of growing livers in mice that contain mostly human cells.
“I could make a mouse that has your liver. That’s incredibly valuable,” Duncan said.
Such a technique would help doctors solve the problems created by drugs that are generally safe but in a small number of people have devastating side effects.
In theory, here’s how the procedure would work:
Scientists would take a skin biopsy from you and reprogram the cells back to the embryonic state, then coax them into becoming liver cells. They would then inject these liver cells into a mouse’s liver until most of the mouse’s liver was made up of your cells. Before they gave a drug to you they would give it to the mouse, which has a liver very similar to yours. If the drug harmed the mouse’s liver, doctors would know not to use it on you.
Since some drugs have serious side effects in a small percentage of patients, this technique would allow scientists to create a model of your liver in a mouse, then use that specific mouse to determine whether a drug will be safe for you.
Duncan’s team also will be looking to build on the new work by collecting skin cells from patients with liver diseases and reprogramming them into liver cells. Diseases they hope to examine using this method include mature onset diabetes of the young, mutations that affect cholesterol levels and hypercholesterolemia, a metabolic problem.
The Medical College work also could one day help people whose livers have been damaged by hepatitis C, alcohol or large amounts of certain drugs. Such ailments could be addressed by the injection of healthy liver cells to replace those that have been damaged or destroyed.
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Caption: Gabriela “Gabby” Cezar, an assistant professor of animal sciences at the University of Wisconsin-Madison, looks into a microscope in her research lab to study stained samples of undifferentiated human embryonic stem cells. An example of the stem cell imagery is displayed on a computer monitor in the background.
The-Scientist.com, GoogleNews.com, October 12, 2009, by Jef Akst — Stem cell researchers must take more care in identifying true pluripotency in reprogrammed human cells, according to a study published online today in Nature Biotechnology. The paper outlines strict molecular criteria for recognizing pluripotency, and warns that relying on just a single marker will muddle the field.
“All too often people in the human [stem cell] field use the most minimal criteria to call cells pluripotent,” said George Daley, a stem cell biologist at the Harvard Stem Cell Institute and Children’s Hospital Boston who coauthored the study. “[The] colonies, on the surface, look like their reprogrammed, but by stringent criteria are not.”
Scientists are getting better at reprogramming human cells into stem cells with embryonic-like properties — known as induced pluripotent stem (iPS) cells — but identifying those cells that have successfully reached true pluripotency may not be so easy. Researchers who work with mouse cells use molecular reporters integrated into pluripotency genes — such as Fbx15, Oct4, or Nanog — but there are currently no reliable parallels for human reprogramming studies. Simply looking at the cells is certainly not enough, and even common molecular markers of pluripotency can be misleading, Daley said.
Using live cell imaging, Daley and his colleagues tracked various markers of pluripotency through the reprogramming process, and characterized the resulting cell types based on morphology and molecular makeup. Of the tens of thousands of human fibroblast cells in each well at the start of a reprogramming run, the majority of the cells formed colonies that were morphologically indistinguishable from embryonic stem (ES) cells, but only a minority of those cells was truly pluripotent, a series of in vitro and in vivo tests revealed.
Based on the imaging results, the team divided the ES-resembling colonies into three distinct types — dubbed type I, II, and III. The researchers injected each cell type into immunodeficient mice to perform a teratoma assay — one of the “gold standards” of pluripotency in human stem cells, Daley said. They found that type III and most type II cells formed tumors that differentiated into multiple germ-cell layers, albeit to varying degrees — an indication that they had indeed achieved some level of pluripotency. Several epigenetic factors, however, including hypomethylation on the gene promoters of NANOG and OCT4 and histone modifications characteristic of a pluripotent state, were only found in type III cells.
“Our paper is a warning that if you want to be sure you are dealing with pristine iPS cells you need to do a host of things: teratomas, epigenetics, gene expression,” coauthor and stem cell biologist Thorsten Schlaeger of the Children’s Hospital Boston wrote in an email to The Scientist. “That’s cumbersome, but necessary to avoid problems, confusion, and conflicting results down the road.”
“The field is more eager to find the different methods to produce a higher yield of iPS cells,” said molecular biologist Xiangru Xu of Yale University, who was not involved in the research. “This study is emphasizing the quality rather than the quantity of iPS cells. It will eventually lead the field to produce better quality iPS cells, [which] will be very helpful to produce patient-specific cells.”
Despite pointing out the difficulties associated with identifying true iPS cells, the study does provide some tools for doing so, said cell biologist Mahendra Rao of Life Technologies in California, who was not involved in the work. It describes in detail the molecular changes that cells undergo during reprogramming and, in doing so, provides a fairly reliable way to distinguish cells that are on their way to becoming truly reprogrammed. “It’s a step in the right direction,” Rao said. Furthermore, he added, because they are using live cell imaging, “you don’t kill the colony to detect if it’s truly reprogrammed, which means you can do it early in the process and select cells” that are likely to reach true pluripotency.
Based purely on the molecular signature of the different cell types, the researchers were able to identify future iPS cells within just a week or two, which is much sooner (and easier) than conducting the teratoma assays. It is also “vastly superior” to another widely-used assay known as alkaline phosphatase staining, which this study shows can falsely identify cells as pluripotent, Schlaeger said.
“I wouldn’t trust any single marker,” Daley said, “[but] this is a step towards identifying a molecular signature for pluripotency that we can be confident in. One day we’d like to be able to [provide a trustworthy] molecular surrogate” for true pluripotency.
GoogleNews.com, ECNmag.com, October 12, 2009 — This advanced research effort to demonstrate a silicon-based “DNA Transistor” could help pave the way to read human DNA easily and quickly, generating advancements in health condition diagnosis and treatment. The challenge in the effort is to slow and control the motion of the DNA through the hole so the reader can accurately decode what is in the DNA. If successful, the project could improve throughput and reduce cost to achieve the vision of personalized genome analysis at a cost of $100 to $1,000. In comparison, the first sequencing ever done by the Human Genome Project (HGP) cost nearly $3 billion.
Having access to an individual’s personal genetic code could advance personalized medicine by using genomic and molecular data to facilitate the discovery and clinical testing of new products, and help determine a person’s predisposition to a particular disease or condition.
A team of IBM scientists from four fields – nanofabrication, microelectronics, physics and biology — are converging to master the technique that threads a long DNA molecule through a three nanometer wide hole, known as a nanopore, in a silicon chip. A nanometer is one one-billionth of a meter or about 100,000 times smaller than the width of a human hair. As the molecule is passed through the nanopore, it is ratcheted one unit of DNA at a time, as an electrical sensor “reads” the DNA. This sensor that identifies the genetic information is the subject of intense ongoing research. The information gathered from the reader could be used to gain a better understanding of an individual’s medical makeup to help further the pursuit of personalized healthcare.
“The technologies that make reading DNA fast, cheap and widely available have the potential to revolutionize bio-medical research and herald an era of personalized medicine,” said IBM Research Scientist Gustavo Stolovitzky. “Ultimately, it could improve the quality of medical care by identifying patients who will gain the greatest benefit from a particular medicine and those who are most at risk of adverse reaction.”
IBM Research is working to optimize a process for controlling the rate at which a DNA strand moves through a nano-scale aperture on a thin membrane during analysis for DNA sequencing. While scientists around the world have been working on using nanopore technology to read DNA, nobody has been able to figure out how to have complete control of a DNA strand as it travels through the nanopore. Slowing the speed is critical to being able to read the DNA strand. IBM scientists believe they have a unique approach that could tackle this challenge.
To control the speed at which the DNA flows through the microprocessor nanopore, IBM researchers have developed a device consisting of a multilayer metal/dielectric nano-structure that contains the nanopore. Voltage biases between the electrically addressable metal layers will modulate the electric field inside the nanopore. This device utilizes the interaction of discrete charges along the backbone of a DNA molecule with the modulated electric field to trap DNA in the nanopore. By cyclically turning on and off these gate voltages, scientists showed theoretically and computationally, and expect to be able prove experimentally, the plausibility of moving DNA through the nanopore at a rate of one nucleotide per cycle – a rate that IBM scientists believe would make DNA readable.
A human genome sequencing capability affordable for individuals is the ultimate goal of the DNA sequencing and is commonly referred to as “$1,000 genome.”
In the Fall of 2005, IBM revised its corporate privacy and equal opportunity policies to reflect the corporation’s intention to handle information about an employee’s genetics with a high regard for its privacy, and also to refrain from using genetic test information to discriminate against a person in the employment context. At that time, IBM was arguably the first company in the world to restrict genetic data from being used to make employment-related decisions.
On May 21, 2008, the United States signed into law the Genetic Information Nondiscrimination Act (GINA) that protects Americans against discrimination based on their genetic information when it comes to health insurance and employment. The bill passed the Senate unanimously and the House by a vote of 414 to 1. The long-awaited measure, which has been debated in Congress for 13 years, is helping to pave the way for people to take full advantage of the promise of personalized medicine without fear of discrimination.