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Catching Elephant is a theme by Andy Taylor
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How Can a Genetic Mutation Cause Muscle to Turn into Bone?
A rare genetic disease leaves its victims debilitated by transforming soft tissue cells into bone cells, creating a strange second skeleton. A leading researcher explains how the disease works and what we can learn from it
What would happen if some soft tissue cells in your body randomly got the message to transform into stiff bone cells? Patients born with a disease called fibrodysplasia ossificans progressiva (FOP) are locked into this fate, often becoming severely disabled before adulthood. The disease first manifests itself at birth, when a baby appears normal but has bent big toes. By early childhood, however, some of the body’s connective tissues—including muscles, ligaments and tendons—have begun ossifying into skeletal bone, locking the joints and distorting posture and movement. Some bone formation appears to be spontaneous, while some can be brought on by trauma from surgery or even a mild impact. FOP is one of the most rare genetic diseases known, occurring in about one in two million people, but spontaneous bone development is relatively common in the broader population. This bizarre shift of tissue systems, known as heterotopic ossification in most cases, can be brought on with spinal cord injury, amputation and even hip surgery. Eileen Shore, a research associate professor of orthopedic surgery at the University of Pennsylvania, has been studying the disease since 1991. “I always had been interested in development on a cellular level,” she says. “What changes a cell, or what regulates a cell to follow certain cell fate decisions? We usually think about development on an organism level, but it was more a question of what determines the personality of the cell?” When she discovered FOP and the work of Frederick Kaplan, a professor of orthopedic surgery at Penn, she realized she had found a puzzle that was “a disease of misregulated cell differentiation,” she says. Three years ago, she and Kaplan identified the genetic mutation that causes the disease in a paper published in Nature Genetics (Scientific American is part of the Nature Publishing Group). This year, Shore and her team found some of the key biochemical steps that lead soft tissue cells to turn to bone. The results were published in the Journal of Clinical Investigation in November. The progress bodes well for the development of new therapies for people imprisoned by this genetic abnormality, and suggests that “we have a very, very good possibility of being able to treat other types of ossification, as well,” Shore says. [An edited transcript of the interview follows.]Is fibrodysplasia ossificans progressiva (FOP) caused by a genetically inherited mutation or is it random? It can be inherited, but it’s random in the sense [that] it is a random occurrence of a new mutation. The main reason for that is even though the mutation could be inherited, most of the people who have it don’t have children. There have been some instances where people have had children—often at a very young age—and have passed it on to one or more child. When does it start? When someone with FOP is born, we don’t have any evidence that there is any of the extraskeletal bone that has started. Their embryonic development is pretty normal—except for a bent great toe. The bone formation typically starts by the age of five. There have been some cases where it starts in the first month and others where someone is 10 or a little older. Is every case similar? The majority of them are very similar. We’ve analyzed a number of patients’ DNA to look for the mutation in the gene we [found]. The vast majority of them have the same identical nucleotide change. All of these patients are pretty similar in the way their FOP develops—in terms of malformation of the big toe that we see at birth. So far, less than 10 percent of the people we’ve examined have variations of that mutation. All of them still have mutations in the same gene, but mutations occur in different parts of the gene. They have cases that are more severe or less severe. How is the bone formation response triggered? The mutation occurs in the gene ACVR1, and this gene produces a protein that is a receptor that spans the cell membrane—so part of the receptor is outside of the cell, and part is on the inside. Cell receptors will receive a signal from outside, and when it binds, that information is transmitted through the receptor to other proteins within the cell, [creating] a chain of events to change how the gene works in the cell. The pathway that ACVR1 is on is part of the BMP (bone morphogenetic protein) pathway, and that pathway has been known for a long time to stimulate cells to differentiate into cartilage and bone. So is the bone formation just spontaneous? It seems to be spontaneous in that many instances of the bone formation are not associated with any obvious trauma. Or maybe it’s a relatively minor event like a stretched tendon or muscle. It could be something that in most other people wouldn’t elicit any other obvious response—these patients could be more sensitive to something like that.
How does trauma spur bone development? That’s an area that we’re very interested in. We don’t know how it occurs, [but] we suspect that trauma induces a normal tissue repair response. The tissue either perceives the signal incorrectly or overstimulates [the response]. We know that even though this occurs at very low levels, the signaling triggers an event of bone formation. Are there currently any treatments or therapies for those with the disease? The treatments that seem to be effective in most patients with FOP are antinflammatory drugs. We think they’re repressing some of the early events that are associated [with the bone formation]. It’s not an ideal treatment because it doesn’t work in all cases. Clearly better treatments are needed. Are there other diseases or conditions that studying FOP might help us better understand or treat? I think so because it’s a disease that affects cartilage and bone cell differentiation. There are different conditions—osteoporosis is a clear example—where bone formation is no longer happening properly, so there is a possibility this could be applied to understand how to encourage cells to produce bone. We have also been talking with a number of people who are involved in tissue engineering to see: Can stimulating this pathway help heal broken bone? There are more common instances of bone formation called heterotopic ossification. Extraskeletal bone is a relatively common occurrence following hip replacement surgery, head trauma or spinal cord trauma. It’s been a very big issue in soldiers who have had certain types of war-related injuries. In many cases, heterotopic ossification has formed at amputation sites making it difficult to fit prostheses. It actually does affect a lot of people. Presumably the process is the same and has the same cellular process. Your most recent research made use of zebrafish embryos to examine the molecular processes. What are the next steps in studying FOP? The mouse model is going to be very important to understand the disease. We have been using cell culture models and zebrafish as an assay to determine the effects of BMP on signaling, but we also want to be able to understand what the effect of the mutation is in the tissue and organ systems. We need to be able to study this in vivo. We will continue to use the zebrafish to develop transgenic models. With mice, we can do a lot of studies to understand what will initiate heterotopic ossification. We are interested in understanding the impacts of the mutation on tissues other than bone. It is also very important in development in other tissues or organs. It might be that there are other underlying health issues in these patients. It will also give us a better understanding of the process. Being such a rare disease, has FOP been difficult to study? It was difficult. Especially when trauma induces bone formation [so] we weren’t able to take samples. Now that we’ve been able to identify the gene, we can use model systems to gain terrific insights. And we’ll be able to take that information and verify and see that those processes are happening in patients. Identifying the gene mutation gives us tremendously greater opportunities. [By] identifying the specific cells that are important in developing the disease, we can develop more targeted therapies and treatments.](http://24.media.tumblr.com/tumblr_m9e13f86FF1qkssp4o1_250.jpg)
How Can a Genetic Mutation Cause Muscle to Turn into Bone?
A rare genetic disease leaves its victims debilitated by transforming soft tissue cells into bone cells, creating a strange second skeleton. A leading researcher explains how the disease works and what we can learn from it
What would happen if some soft tissue cells in your body randomly got the message to transform into stiff bone cells? Patients born with a disease called fibrodysplasia ossificans progressiva (FOP) are locked into this fate, often becoming severely disabled before adulthood.
The disease first manifests itself at birth, when a baby appears normal but has bent big toes. By early childhood, however, some of the body’s connective tissues—including muscles, ligaments and tendons—have begun ossifying into skeletal bone, locking the joints and distorting posture and movement. Some bone formation appears to be spontaneous, while some can be brought on by trauma from surgery or even a mild impact.
FOP is one of the most rare genetic diseases known, occurring in about one in two million people, but spontaneous bone development is relatively common in the broader population. This bizarre shift of tissue systems, known as heterotopic ossification in most cases, can be brought on with spinal cord injury, amputation and even hip surgery.
Eileen Shore, a research associate professor of orthopedic surgery at the University of Pennsylvania, has been studying the disease since 1991. “I always had been interested in development on a cellular level,” she says. “What changes a cell, or what regulates a cell to follow certain cell fate decisions? We usually think about development on an organism level, but it was more a question of what determines the personality of the cell?”
When she discovered FOP and the work of Frederick Kaplan, a professor of orthopedic surgery at Penn, she realized she had found a puzzle that was “a disease of misregulated cell differentiation,” she says.
Three years ago, she and Kaplan identified the genetic mutation that causes the disease in a paper published in Nature Genetics (Scientific American is part of the Nature Publishing Group). This year, Shore and her team found some of the key biochemical steps that lead soft tissue cells to turn to bone. The results were published in the Journal of Clinical Investigation in November.
The progress bodes well for the development of new therapies for people imprisoned by this genetic abnormality, and suggests that “we have a very, very good possibility of being able to treat other types of ossification, as well,” Shore says.
[An edited transcript of the interview follows.]
Is fibrodysplasia ossificans progressiva (FOP) caused by a genetically inherited mutation or is it random?
It can be inherited, but it’s random in the sense [that] it is a random occurrence of a new mutation. The main reason for that is even though the mutation could be inherited, most of the people who have it don’t have children. There have been some instances where people have had children—often at a very young age—and have passed it on to one or more child.
When does it start?
When someone with FOP is born, we don’t have any evidence that there is any of the extraskeletal bone that has started. Their embryonic development is pretty normal—except for a bent great toe. The bone formation typically starts by the age of five. There have been some cases where it starts in the first month and others where someone is 10 or a little older.
Is every case similar?
The majority of them are very similar. We’ve analyzed a number of patients’ DNA to look for the mutation in the gene we [found]. The vast majority of them have the same identical nucleotide change. All of these patients are pretty similar in the way their FOP develops—in terms of malformation of the big toe that we see at birth. So far, less than 10 percent of the people we’ve examined have variations of that mutation. All of them still have mutations in the same gene, but mutations occur in different parts of the gene. They have cases that are more severe or less severe.
How is the bone formation response triggered?
The mutation occurs in the gene ACVR1, and this gene produces a protein that is a receptor that spans the cell membrane—so part of the receptor is outside of the cell, and part is on the inside. Cell receptors will receive a signal from outside, and when it binds, that information is transmitted through the receptor to other proteins within the cell, [creating] a chain of events to change how the gene works in the cell. The pathway that ACVR1 is on is part of the BMP (bone morphogenetic protein) pathway, and that pathway has been known for a long time to stimulate cells to differentiate into cartilage and bone.
So is the bone formation just spontaneous?
It seems to be spontaneous in that many instances of the bone formation are not associated with any obvious trauma. Or maybe it’s a relatively minor event like a stretched tendon or muscle. It could be something that in most other people wouldn’t elicit any other obvious response—these patients could be more sensitive to something like that.How does trauma spur bone development?
That’s an area that we’re very interested in. We don’t know how it occurs, [but] we suspect that trauma induces a normal tissue repair response. The tissue either perceives the signal incorrectly or overstimulates [the response]. We know that even though this occurs at very low levels, the signaling triggers an event of bone formation.
Are there currently any treatments or therapies for those with the disease?
The treatments that seem to be effective in most patients with FOP are antinflammatory drugs. We think they’re repressing some of the early events that are associated [with the bone formation]. It’s not an ideal treatment because it doesn’t work in all cases. Clearly better treatments are needed.
Are there other diseases or conditions that studying FOP might help us better understand or treat?
I think so because it’s a disease that affects cartilage and bone cell differentiation. There are different conditions—osteoporosis is a clear example—where bone formation is no longer happening properly, so there is a possibility this could be applied to understand how to encourage cells to produce bone. We have also been talking with a number of people who are involved in tissue engineering to see: Can stimulating this pathway help heal broken bone?
There are more common instances of bone formation called heterotopic ossification. Extraskeletal bone is a relatively common occurrence following hip replacement surgery, head trauma or spinal cord trauma. It’s been a very big issue in soldiers who have had certain types of war-related injuries. In many cases, heterotopic ossification has formed at amputation sites making it difficult to fit prostheses. It actually does affect a lot of people. Presumably the process is the same and has the same cellular process.
Your most recent research made use of zebrafish embryos to examine the molecular processes. What are the next steps in studying FOP?
The mouse model is going to be very important to understand the disease. We have been using cell culture models and zebrafish as an assay to determine the effects of BMP on signaling, but we also want to be able to understand what the effect of the mutation is in the tissue and organ systems. We need to be able to study this in vivo. We will continue to use the zebrafish to develop transgenic models. With mice, we can do a lot of studies to understand what will initiate heterotopic ossification.
We are interested in understanding the impacts of the mutation on tissues other than bone. It is also very important in development in other tissues or organs. It might be that there are other underlying health issues in these patients. It will also give us a better understanding of the process.
Being such a rare disease, has FOP been difficult to study?
It was difficult. Especially when trauma induces bone formation [so] we weren’t able to take samples. Now that we’ve been able to identify the gene, we can use model systems to gain terrific insights. And we’ll be able to take that information and verify and see that those processes are happening in patients. Identifying the gene mutation gives us tremendously greater opportunities.
[By] identifying the specific cells that are important in developing the disease, we can develop more targeted therapies and treatments.
Australian Scientists Implant Prototype Bionic Eye: Blind Woman Sees Pulses of Light
In a world first, scientists have successfully implanted a prototype bionic eye that has helped a woman see shapes.
Researchers from the government-funded consortium Bionic Vision Australia made the announcement in a statement yesterday; in it the implantee said she “didn’t know what to expect, but all of a sudden, I could see a little flash—it was amazing.”
The team is hoping they can start to “build” shapes based on what she sees, eventually creating a bionic eye that works like its organic counterpart.
The prototype device is set up in a lab. Electrodes in the implant stimulate nerve cells, and in the controlled environment scientists can get feedback from the user on the “flashes of light.” That could help them adjust until the “flashes of light” reflect the actual environment enough to be helpful.
It’s not full vision, but it’s an early step toward it. The next stage, the scientists say, is incorporating an external camera into a device, and creating versions with more electrodes. With 98, a person could be able to see large objects; with 1,024, they could recognize faces and large print.
Tick Tock, Circadian Clock
Japanese biologists have tracked the levels of over 50 biological molecules over time to produce this high-resolution map of our body’s natural clock.
Our body’s rhythms are far more complicated than just being a “morning person” or “night owl”. We, and other creatures, possess true biological clocks, called circadian rhythms, dependent on things like light/dark cycles, sleep and hormones. Perhaps they aren’t “clocks” in the true sense of a biological “time keeping” device, but we are subject to regular chemical and signaling cycles.
Circadian rhythms are how Monarch butterflies navigate across the globe, how plants respond to the seasons, and even how some bacteria turn their metabolic circuits on and off like oscillators. Humans have them too, of course, just more complicated versions. By decoding where a person is in their cycle with high precision, we can direct things like chemotherapy and neural treatments to precisely when they will be most effective.
(more at ScienceNOW)
Rogue Response: Chemotherapy Undermines Itself
A new study, published in Nature Medicine, has suggested that chemotherapy used to treat metastatic cancers can cause a rogue response in healthy cells, which helps to explain why people become resistant to the treatment. Chemotherapy has been shown to lose effectiveness in a large number of patients (approximately 90%) with secondary cancers - those that started out as solid cancers in areas such as the breast, lung, and colon, and metastasised, or spread to a different area of the body. The new research shows that the cause of this resistance could be hidden in fibroblasts - wound-healing cells around tumours discovered to create a protein that may teach the cancerous cells how to evade the treatment.
Researchers at the Fred Hutchinson Cancer Research Center in Seattle looked at the damage chemotherapy was causing to the fibroblast cells surrounding tumours. Because the radiation caused DNA damage, the fibroblasts produced up to 30 times more of a specific protein, Wnt16B, than they should. The protein fuels cancer cells to invade and attack surrounding tissues and evade chemotherapy treatments.
It was already known that Wnt16B was involved in the development of cancers, but not in treatment resistance. The researchers hope they can put a stop to the protein response, and greatly improve the effectiveness of chemotherapy, especially for those patients with multiple cancers.
Professor Fran Balkwill, a Cancer Research UK expert on the microenvironment around tumours, said: “This work fits with other research showing that cancer treatments don’t just affect cancer cells, but can also target cells in and around tumours. Sometimes this can be good - for instance, chemotherapy can stimulate surrounding, healthy immune cells to attack tumours. But this work confirms that having healthy cells around the tumour can help the tumour become resistant to treatment.
“The next step is to find ways to target these resistance mechanisms to help make chemotherapy more effective.”
Top image: A human fibroblast cell. Bottom image: Mouse fibroblast cells.
The original paper was published in Nature Medicine. A brief synopsis, and link to the full paper, can be found here.
Currently, large doses of chemotherapy are required when treating certain forms of cancer, resulting in toxic side effects. The chemicals enter the body and work to destroy or shrink the tumor, but also harm vital organs and drastically affect bodily functions. Now, University of Missouri scientists have found a more efficient way of targeting prostate tumors by using gold nanoparticles and a compound found in tea leaves. This new treatment would require doses that are thousands of times smaller than chemotherapy and do not travel through the body inflicting damage to healthy areas.
The study is being published in the Proceedings of the National Academy of Science.
The future of humanity - Bioprinting
This is the coolest thing I’ve read in a long time.
After a lot of theorizing, postulating, and non-human trials, it looks like bionic eye implants are finally hitting the market — first in Europe, and hopefully soon in the US. These implants can restore sight to completely blind patients — though only if the blindness is caused by a faulty retina, as in macular degeneration (which millions of old people suffer from), diabetic retinopathy, or other degenerative eye diseases.
Researchers at Sandia National Laboratories have developed a lab-on-a-disk platform that they believe will be faster, less expensive and more versatile than similar medical diagnostic tools. Lab officials are seeking industry partners to license and commercialize the SpinDx technology, which can determine a patient’s white blood cell count, analyze important protein markers, and process up to 64 assays from a single sample, all in a matter of minutes. “Patients have become accustomed to an initial visit, some tests, samples that are sent off to a far-away lab, a wait of a week or more for results, more tests and charges every step of the way,” said Anup Singh, manager of Sandia’s biotechnology and bioengineering department. ”With SpinDx, you can see results before you even leave the office.” (via Speeding up lab testing for medical diagnosis and toxin detection | KurzweilAI)
Slate explains the sweaty details:
“Because our bodies need to disperse heat, and they can’t do that effectively when the air temperature is close to our body temperature. Our muscles and metabolism generate heat continuously. We transfer that heat into our surroundings by sweating, exhaling warm air, and circulating blood near the surface of our skin to cool. When the temperature gradient (or difference) between the body and the air is high, heat flows easily from us into the environment, and we cool down. But when the weather hovers around our internal temperature, our inner swelter lingers, and we feel hot and uncomfortable. Humidity makes things worse by interfering with the vaporization of sweat, one of the human body’s main cooling mechanisms.”
Nano-Material Inspired by Moth’s Eyes Enables Medical Imaging With Less Radiation
If you want a detector to pick up more light, the technique has usually been to increase the intensity of the X-rays. But this obviously has associated health risks.
Yi and his team believed that if they could improve the scintillation material so that it reemitted more light from the same amount of X-rays, then they could create safer medical imaging devices. To do this, the researchers needed to create a new class of materials.
What they came up with is based on a thin film made from cerium-doped lutetium oxyorthosilicate crystals. They were then able to cover these crystals with pyramid-shaped bumps made of silicon nitride. It is these bumps that make the scintillator appear like the moth’s eye and give the structures its ability to extract more light.
The results have been pretty dramatic. Yi and his team measure that adding their moth-eye-inspired thin film to the scintillator of an X-ray mammographic unit increases the amount of reemitted light by 175 percent.
“The moth eye has been considered one of the most exciting bio structures because of its unique nano-optical properties,” Yi says in Nanomagazine article. “Our work further improved upon this fascinating structure and demonstrated its use in medical imaging materials, where it promises to achieve lower patient radiation doses, higher-resolution imaging of human organs, and even smaller-scale medical imaging. And because the film is on the scintillator,” he adds, “the patient would not be aware of it at all.”
(via Nanostructures Modeled on the Moth Eye Reduce Radiation in Medical Imaging - IEEE Spectrum)
Nanotechnology battling cancer
Cancer causes cells to undergo uncontrolled division and invade the surrounding healthy tissue, so it’s vital to detect cancerous cells in their early stages before they spread. They must be specifically targeted so normal cells aren’t killed, but this is tricky. One proposed treatment is the use of carbon nanotubes, which are rolled-up biocompatible sheets of carbon atoms only a few nanometres across. Thousands could fit into a cell, and they’re highly porous—over 99% air. The new treatment injects microscopic multi-walled nanotubes into tumours, where they bind to tumour specific receptors on the surface of cancer cells. They’re then exposed to 30 seconds of laser-generated near-infrared radiation. The tubes absorb the radiation and convert it into heat, and in response the tumor cells shrink and die without harming the healthy cells. Tests of this treatment were able to effectively kill 80 percent of kidney tumours in mice, and according to lead investigator, Suzy Torti, Ph.D, these mice not only survived but also “maintained their weight, didn’t have any noticeable behavioral abnormalities and experienced no obvious problems with internal tissues.” Since it’s a heat therapy rather than a biological therapy, the treatment can work on all tumour types, and researchers are confident that it can eventually be applied to humans.
I’m too fascinated to not to reblog this againA donor heart beating in a mechanical system which keeps it warm, oxygenated, with nutrient enriched blood pumping through.
ok, thats really cool
I’m not sure whether to feel fascinated or a tad disgusted-
Reblogging anyway.
The new technology is remarkable.
This is so wicked cool
(Source: milesian)
A new way to focus light into tissue paves the way for incision-free surgery that leaves skin intact.
The heart of a genetically modified pig has been successfully transplanted into a monkey, according to scientists in South Korea.
It is the first time the country has claimed to have accomplished such an inter-species operation
Known as xenotransplantation, it is seen by some as a way to end the chronic shortage of human organs available for transplants.
Before the controversial procedure, conducted in Seoul, the cloned pig had its genes responsible for immune rejection removed.
The ultimate aim of such experimentation would be to put pig hearts and other swine organs into humans.
And the South Koreans believe this could become a commercially viable reality within five years.
The first known transplant of a genetically engineered pig heart in a primate was performed in 1994.
But the possibility of animal-to-human operations has divided the medical ethics community.
Medical ethicist Associate Professor Nicholas Tonti-Filippini, speaking in 2010, said such transplants had the potential to bring animal diseases into the human population.
‘It is about whether the community is prepared to accept a part human, part animal.’He said the creation of genetically modified pigs was not ethically acceptable, explaining: ‘It is basically a human-pig, a hybrid, or whatever you want to call it.
South Korean scientists first claimed to have cloned a piglet whose organs were genetically modified to make them more suitable for human transplants in 2009.
Lead scientist Lim Gio-Bin said the cloned piglet, born on April 3, had been genetically altered to lack the ‘alpha-gal’ gene which triggers tissue rejection, according to PhysOrg.
He said his government-sponsored team, involving scientists from four universities and two research institutes, used stem cells of smaller-than-normal pigs to clone ‘mini-pigs’ with modified genes.
Immuno-rejection has been a major hurdle in human organ transplants.
Pig organs are well suited for transplantation but are coated with sugar molecules that trigger acute rejection in human bodies.
Human antibodies attach themselves to such molecules and quickly destroy the transplanted pig organ.
In cloning a pig called Xeno, the scientist said his team adopted almost identical technology to that used by U.S. scientists in 2002 to create cloned piglets, in which one copy of the sugar-producing gene was ‘knocked out’.
An organism receives two copies of a gene, one from the mother and one from the father. Scientists have tried to produce pigs lacking both copies, so far unsuccessfully.
‘Through our achievement, South Korea became the second country in the world to clone such piglets after the United States,’ Lim said at the time.
Lim said then that his team would conduct clinical trials on humans in 2012 and he believed genetically modified mini-pigs could be used commercially around 2017.
Two years ago, Australian scientists kept pig lungs alive and functioning with human blood.
The breakthrough came after scientists at Melbourne’s St Vincent’s Hospital were able to remove a section of pig DNA which made the pig organs incompatible with human blood.
Prof Tony D’Apice - who had been breeding pigs for possible transplants since 1989 - said human DNA was added to the engineered animals to control blood clotting and rejection in humans.
Dr Glenn Westall, from the Alfred Hospital in Melbourne, said the world-first discovery meant pig-human lung transplants were a real prospect.
I’m a little bit wary of this claim. I’d like them to explain the steps they took and how they can prove their claim since this would be a pretty big deal.
