Osteoporosis: now and future

Osteoporosis is a very common disease defined by an impairment of bone mass and small architectural defects that result in fractures. It is an ever growing medical concern with our ageing population continually increasing. With research always progressing, therapeutic targets have been found in osteoblast and osteoclasts to inhibit high amounts of bone resorption and increase bone formation. Some of these treatments include denosumab, odanacatib, and antibodies against the proteins sclerostin and dickkopf-1, which are inhibitors of bone formation. Denosumab is a monoclonal antibody designed to attack RANKL, a protein which signals to promote bone removal. Odanacatib is an inhibitor of the osteoclast protease cathepsin K, which is involved in bone resorption.

The excellent thing about these new therapies is that there is a great need for additional and affordable anabolic treatments for patients. Since there are many bone drugs receiving medical approval, treatment for osteoporosis is going to become complex; therefore, integrating these therapies will not be difficult. Many of the current medications taken for osteoporosis have limitations and long-term side effects that could be dangerous. Since osteoporosis is an highly undesirable, unpreventable disease, these therapies could be revolutionary for people that are diagnosed.

URL: http://www.sciencedirect.com.lib-ezproxy.tamu.edu:2048/science/article/pii/S0140673610623495#sec2

Telomerase: the Secret to Reverse Aging

In 2009, Elizabeth Blackburn, Carol Greider, and Jack Szostak were awarded the Nobel Prize in medicine for discovering telomeres along with the enzyme, telomerase, which helps promote the growth of telomeres. Telomeres are located at the ends of a DNA strand in order to protect the crucial parts of the DNA. During DNA replication, the ends of the DNA strand are usually cut off because DNA polymerase III does not replicate them. The reason for this is because during DNA Replication, DNA polymerase III lands on the end of the strand causing replication to fail at that ending strand. Telomeres counter this by serving as “filler” DNA because they do not code for anything in particular which is useful for protecting the coding parts of the DNA. However, as humans age, the lower levels of telomerase contribute to the degradation of telomeres causing the important part of the DNA to not be fully replicated.

In this particular article, scientists, from Harvard Medical School in Boston, engineered mice to completely lack telomerase, which causes the telomeres to run out much quicker. This results in the mice aging much faster than average, eventually resulting in age related diseases.  After allowing the engineered mice to reach adulthood, the scientists stimulate telomerase growth by feeding the mice a chemical called 4-OHT. Within the next month, the mice’s organs were restored to proper health. This also resulted in production of new neurons and supporting brain cells, allowing the reversal of the aging of the brain.

Although these organs were able to regenerate, telomerase has a negative side to it. Since telomerase is what allows DNA to be “endless,” it can often be mutated in human cancers to help tumors grow faster. If a telomere rejuvenation therapy were to occur, it is possible that it can stimulate cancer in a patient. Another possible downside of this discovery is the fact that this reverse aging occurs in accelerated aging mice and not normal aging ones. Consequently, this reveals that there could be other possible factors for aging besides short telomeres.

This article was interesting for multiple reasons. This article shows that if telomerase happens to be harnessed properly, it can be used to restore organ function to aging patients and combat age related diseases, thus allowing humans to live longer. Another reason is that it can be used to eliminate a possible contributing factor in cancer. Since telomerase can promote cancer, then there could possibly be a way to reverse the effects of a mutated telomerase. Overall, the article was intriguing and although telomerase is still being researched, it holds potential to improve the quality of life of aging humans.

http://www.nature.com/news/2010/101128/full/news.2010.635.html

Use of Insect Virus in Safer Stem Cell Therapy

As discussed in class today, stem cells are promising candidates for tapping the human body's own potential to repair itself. Many applications of stem cells in regenerative medicine involves integration of genes into human embryonic stem cells (hESCs) that direct the cells in exhibiting a desired therapeutic function. However, gene integration is not always accurate; it can be random. While integration of these therapeutic genes is important, inaccurate integration can lead to several problems. The gene integration into the hESCs may interfere with the correct sequence of DNA and create undesired sequences that cause the hESCs to reproduce too rapidly, and form a tumor, fail to differentiate into the desired form, fail to exhibit desired functions, or malfunction and die.
Thanks to scientists, driven by the need for a safe method to insert therapeutic cancer-killing genes into hESCs, at the Institute of Bioengineering and Nanotechnology (IBN), these malfunctions may be closer to a thing of the past. Researchers have discovered a method of accurately integrating therapeutic genes into a specific region of DNA--site 1 locus (AAVS1)--that, when altered, exhibits no known adverse effects. AAVS1 has been the target of genetic engineering in the past due to its unharmful post-alteration nature. The two previously discovered methods for integrating into this region, however, were inaccurate in one method, and toxic to humans in the other.

The method discovered by the researchers uses a baculovirus, an insect virus, to insert DNA into the AAVS1 region with 100% accuracy. The researchers demonstrated successful homologous recombination of AAVS1 in hESCs (the DNA can be reproduced without change) and use the insect virus to target and splice DNA into specific regions utilizing the Cre/loxP recombinase system (see http://en.wikipedia.org/wiki/Cre-Lox_recombination). The researchers' method is inherently safer than previous random insertion because baculoviruses are specific to insects and do not insert themselves randomly into human DNA. (Patients won't catch a "bug" from this treatment, ahahaha).
Hopefully this method for integrating therapeutic genes will provide for great improvements in the future of regenerative medicine and cancer treatment.

article: http://insciences.org/article.php?article_id=10253#pics

3-D Environment for Cell Cultures,

There is a major stumbling block to create a 3-D environment for the creation of human organs and the proper analysis of cancer invasiveness. A new approach to the process is being studied by Thomas Killian at Rice University. This new approach is called Magnetic Levitation. The temporary conventional methods used currently are the degradable porous scaffolds, protein matrices, protein-based gels, but Dr. Killian argues that through the use of magnets and magnetic nanoparticles, current obstacles within the 3-D arena will be removed.

His method requires a three dimensional Bio-Assembler that will rely on cellular uptake of a compatible gel containing iron oxide and gold nanoparticles. As most of you'll have already read through various other articles, the potential of magnetic forces is already well recognized. The desire of Dr. Killian is to craete a levitated 3-D cell culture. The presupposition is that magnetic iron oxide nanoparticles are well tolerated by mmmalian cells, a result that is backed up by previous reports. To form the cultures (levitated), they incubate cells with gel that allows neighboring cells to absorb the nanoparticles. Then an external magnet causes the cells to rise to the air-medium interface. Within 12 hours, multicellular structures assemble. This was tested with neural stem cells, and they formed branching configurations consistent with aggregated cell clusters.

This new application of creating 3-D cell environment provides new opportunities for culturing and manipulating mixed populations of cells. This method has an extremely powerful potential for analysis of brain tumor invasiveness in co-culture assays. Recent studies have demonstrated that cancer cells growing in two-dimensional sheets are not the optimal places to study for anticancer agents. Creating this optimal 3-D environment can impact the race for the cure of cancer much quicker.

http://www.genengnews.com/gen-articles/3-d-cell-culture-takes-research-deeper/3810/?kwrd=Regenerative%20Medicine&page=2

New Study Shows Effectiveness of Spina Bifida Treatment

Typically, during the first four weeks of healthy fetal development, the two sides of the backbone join together to cover the spinal cord, nerves and meninges. However, if this development does not occur completely, a defect known as spina bifida can result. This defect, characterized by protrusion of the spinal cord through an opening in the spine, often leads to a fluid-filled sac attachment on the back, and ultimately, permanent nerve damage. Some affected individuals have additional complications, including a buildup of excess fluid around the brain.

There is no cure for spina bifida, as the nerve tissue that is damaged or lost cannot be repaired or replaced. However, there are a number of treatments available to help manage the disease and prevent complications. Perhaps most interesting is a remarkable fetal surgical procedure that can be performed on the fetus prior to the 26^th week of pregnancy. In this procedure, a three-inch-wide incision is first made in the pregnant mother’s uterus. The fetus is then surgically positioned so that the spinal defect is exposed and the spinal cord is carefully repositioned. Finally, the spinal cord is covered with membranes and muscle, and the uterus is carefully closed up.

This remarkable procedure has received much attention recently; the Management of Myelomeningocele Study (MOMS) has just completed a study of 183 pregnancies comparing prenatal and postnatal spinal bifida surgeries, showing much success with prenatal surgery. It was found in many cases that in utero operations reduced or even eliminated paralysis and brain damage. In fact, “More than 80 percent of the children who had the surgery after birth needed shunts, compared to 40 percent among those operated on prenatally” (Knox). Shunts are tubes that carry cerebrospinal fluid from the brain to the abdomen, preventing fluid build up in the brain. Additionally, the study showed that children who had the in utero surgery were twice as likely to eventually walk unaided.

Possibly most novel about this study is that it “is the first time that fetal surgery has ever been attempted and validated for what we think of as a non-fatal birth defect” (Farmer). Typically, fetal surgery is not performed unless it is necessary for the survival of the child because it is highly invasive, exposing both the mother and the baby to health risks. However, these recent findings are likely to change the criteria for prenatal surgery in the future.

Article:

http://www.npr.org/2011/02/09/133619351/a-birth-defect-breakthrough-prenatal-spinal-surgery

In-vivo Test of Visual Prosthetic

A few years, a group of researchers from such institutions as Cornell University and MIT tested the second-generation version of their Boston visual prosthesis (concept drawing shown at right). This device includes a 15-channel stimulator chip inside a hermetic titanium case and secondary data/power receiving coils that surround one’s cornea upon implantation. The idea for this prosthetic came after this and other groups around the world demonstrated that focal electrical stimulation of the retinal ganglion cells in patients with degenerative retinal diseases can yield responses from the cells, which hints at the possibility of one regaining their sight if enough electrical stimulation is applied. However, it soon became apparent that a chronic implantable device was necessary to return a patient’s eyesight.

The second-generation version of this prosthetic improves on the first-generation model in three important ways. First, the second-generation is designed with larger receiver coils to make data and power telemetry easier; the team hoped to minimize the impact of adding volume on to their existing device by having the coils conform to the patient’s eye. Also, a hermetic titanium case to house the circuitry was designed to allow the prosthetic to be viable for years of usage. Finally, the second-generation model was designed with an electrode array extending from the titanium case to the superior-temporal quadrant, which allows for an easier implantation surgery when compared with the first-generation version.

One of the primary purposes of the test was to determine if long-term electrode pulsing was a possibility with the new design. To assess this possibility, the electrodes used for the device were subjected to long-term in vitro pulsing. Additionally, the entire prosthetic system was tested dry on the bench, in a phosphate buffered saline solution, and in vivo inside a Yucatan mini-pig.

The device worked reliably for over three months; however, tension on the conjunctiva as a result of the coils forced the experiment to end early. In response, the researchers redesigned both the coil forming process and the connection between the coils and the titanium case so as to ease the tension. They remain hopeful that this technology can someday be used to help people afflicted by degenerative retinal diseases.

I found this article interesting enough to create a blog about it partly because I did not know the current status of visual prostheses. The primary reason remains that I am fascinated by prostheses in general, and especially by prostheses that affect prominent body parts/functions. I do not think that I am alone in this viewpoint.

http://dspace.mit.edu/handle/1721.1/58563

Brain-Eating Amoebae

Recently, my biology professor discussed the effects of an extremely rare amoebic infection that results in the deterioration of the brain. The amoebae, Naegleria fowleri, cause a disease called Primary Amoebic Meningoencephalitis and reside in warm, usually stagnant freshwater, which is ubiquitous in a southern summer. This particularly interested me, because many of my friends were recently counselors at summer camps at which they played in lakes. I was interested to see what kind of danger they were subjecting themselves to, so I looked up the amoeba online and came across this article.

The amoebae are harmless unless they are inserted into the nose, usually via splashing or horseplay in the infected freshwater. Even when an open wound is exposed to Naegleria fowleri, the amoeba doesn't attack the the wound, because it would rather consume other bacteria found in the water rather than eat human tissue. But when it is forced into the nose, it travels down the olfactory neuroepithelium, feasting on that tissue until it reaches the brain, where it spreads throughout the brain, breaking it down and digesting it. Once the amoebae have reached the brain, there is no current treatment to save the patient's life. They will show fever, headache, nausea, and a stiff neck, and they will die a few days later.

An interesting part of this study is that the number of deaths from Naegleria fowleri is increasing in Karachi, Pakistan. This city has experienced 13 deaths over the past 17 months (in February 2011), an unexpectedly large and increasing number of deaths. As a frame of reference, the United States usually loses 1-8 people a year from primary amebic meningoencephalitis, the disease caused by Naegeria fowleri. Twelve of the 13 deaths were of men, and only one of the deaths reported recent freshwater swimming. So how did the amoeba get inside these victims? All of the victims were Muslim and performed ritual ablution, which involves inserting water into the nose. The city's water supply wasn't properly cleaned, so it was circulating the brain-eating bacteria through the water supply. However, since the amoeba isn't harmful unless inserted into the nose, nobody had showed indication of Naegleria fowleri in the water supply until the patients mentioned in the study started dying.

http://wwwnc.cdc.gov/eid/article/17/2/10-0442_article.htm

Building Organs, Like Houses, Depends on the Foundation

Imagine a world where people aren't suffering and dieing while waiting for an organ that they have to spend the rest of the life protecting from rejection. This is a world that tissue engineers and researchers are determined to make a reality. It seems that the extracellular matrix (ECM), once thought as no more than a 3D structural foundation, might be the key.

One of the main obstacles to growing a transplantable organ is having the proper cell grow, in the proper location, with the proper alignment with its neighbors. The ECM (pictured right) is a nanostructure where morphogenesis, differentiation, proliferation, adhesion and migration of cells are determined. The cells adhere to the ECM and the ECM's topography, mechanical properties, and immobilized growth factors can all deliver important cues to the cell. The natural ECM is made of collagen and elastins, but scientist hope to recreate them by using nanofibers. These nanofibers would be woven to create the 3D structure of the organ, but the important aspect of these fibers would be what was done to them.

The first aspect of the nanofibers to be altered would be their topography. It seems that the surface of the fiber can have an important role in cell differentiation and morphogenesis. Different tissues, be they cardiac or liver, require different types of scaffold with different nanotopography (see below). Scientists have grown a 2 dimensional cardiac muscle using this technique that resulted in cardiac muscle that could produce an aligned contraction. This technique has not been able to be Incorporated into a 3D scaffold as of yet but controlling the alignment of cells is an important step to organ development.

The next aspect of the fibers to be modified allows the ECM to release instructive cues to the cells. The delivery of certain molecules, like cytokines or growth factors, are vital to the viability and functionality of tissue whether they be in the body or an in vitro 3D scaffold. One possible way to give the cells the cues they need is by the use of gold nanowires. These wires can be functionalized with certain biomolecules and maneuvered around the 3D scaffold using electric fields. Once in the proper location this wire would release its contents and the cells in that location would get the desired cues needed to differentiate into the needed cells at that location.

This research shows that the ECM scaffold of an artificially grown organ is a lot more important than just giving the organ it's overall shape. It determines what cells grow were and whether those cells will even be able to function as a tissue. It seems that organs, like buildings, depend a lot on their foundation.

Article: http://www.nature.com/nnano/journal/v6/n1/full/nnano.2010.246.html

Reprogramming Cells to Fight Cancer

Instead of using conventional methods to treat cancer, doctors used an experimental method of engineering T cells to destroy cancer cells in leukaemia patients.

The cells are programmed to recognize CD19, a protein found on cancer and B cells. B cells create antibodies, and to make up for the ones that aren't being produced; doctors give patients infusions of antibodies.

The initial attempts to program the cells were not successful and generally had very little impact on the cancer. However, researchers got to the point that the T cells caused such an impact that a patient was required to be hospitalized due to the amount of dead cancer cells in his body.

I find it interesting how far cancer treatment has come. Instead of exhausting all possible options and still seeing no progress, an alternative has come up that could save that one or however many patients. While this treatment is still at the experimental phase, it is interesting to think how much more this method could develop to the point when it becomes an accepted method of treatment.

http://www.nature.com/news/2011/110810/full/news.2011.472.html

Inject. Mold. Stabalize

The importance of bioengineering materials during surgery is the main focus of so many bioengineers but what about the the need of post-surgical biomaterials? Post surgical scars are traumatic memories that the patient has to carry with them for the rest of their lives, this can cause not only social underdevelopment but can lead to other various psychological hindrances. Replacing soft tissue around the body has been hard because even with tissue implants it is hard to sculpt the tissue to look like its supposed to. This new biomaterial that is being introduced can be injected in liquid form, sculpted while in the body to take any shape, then by green LED light be solidified. This advance in bioengineering will be beneficial in replacing soft skin like lips, cheeks, parts of the back, and stomach. Now, because the material is half biological and half synthetic there has been a problem with this material being absorbed into the body, currently studies show that there are no harmful side effects to this problem but patients will have to get a replacement every 6-12 months.

I was first interested in this article because the term "molding a prosthetic or biomaterial" will be revolutionary in being able to "transform" all different types of bioengineering materials to fit the patient directly and not the "cookie cutter" approach that is used. The idea of a prosthetic being aesthetically appealing has never crossed my mind before. So much of human interaction deals with having to see the person's face therefore being able to make post-surgical facial scars look as normal as possible would be the best way to make physical rehabilitation the importance after surgery and not the scars left behind.


article: http://www.technologyreview.com/biomedicine/38150/page1/

Possible Link Between Sleep and Alzheimer's Disease

I have spent a considerable amount of time volunteering in nursing homes, a place where Alzheimer’s disease is prevalent. Because of this, an article about the possible connection between Alzheimer’s disease and sleep deprivation caught my interest.

Sleep deprivation has already been known to be harmful and can lead to effects similar to those caused by alcohol intoxication. It is also known that sleep deprivation can lead to pathological processes that are related to disease. However, it is only recently being considered that sleep deprivation is related to pathological processes that lie behind Alzheimer’s.

The possible connection is found in amyloid beta, which is a marker for Alzheimer’s. Levels of amyloid beta fluctuate based on sleep patterns. The levels drop to a minimum six hours into sleep and are restored to the highest level six hours after being awake. These changes tend to level out as one ages, and in people with brain plaques, levels of amyloid beta remain constant. This suggests that better sleep could reduce the risk of Alzheimer’s disease later on in life.

http://health.usnews.com/health-news/family-health/sleep/articles/2011/09/28/study-suggests-link-between-sleep-deprivation-alzheimers-risk

The Brain's Silent Majority

Glial cells make up almost 90% of the brain, yet these cells have been a mystery to scientist for many years. Once thought of as just "nerve cement" there is now evidence that glial cells do much more. The new evidence in astrocytes, a certain type of glial cell, is shedding new light on how neurons actually work and how neurodegenerative diseases happen.

This article is very interesting as it concentrates on the 90% of the brain that most people don't know about. As you go up the evoltionary complexity ladder, the more complex the organism, the more glial cells they have. If the scientific community can figure out exactly the role glial cells play in the brain, there may be substantial breakthroughs in treating diseases such as Alzheimers, ALS, glaucoma, MS, and many others.

Link
http://www.stumbleupon.com/su/3ZeMYw/stanmed.stanford.edu/2009fall/article6.html

http://stanmed.stanford.edu/2009fall/article6.html

Controlling a Computer With Thoughts?

It may, in fact, be a possibility. This is a fascinating article about brain-computer interfaced (BCI) technology. Research done at the University of Pittsburgh revealed that it could soon be possible for patients with spinal cord injuries (i.e. specifically quadriplegics, but really anyone with in a paralytic state) to control an external device or machine simply with their thoughts.

The research team(s) have been given two grants for clinical work based on current research done on epilepsy patients who, using the interfaces, moved "cursors and play computer games, as well as in monkeys that through interfaces guided a robotic arm to feed themselves marshmallows and turn a doorknob."

The projects would focus on advance the research in two different aspects. The first would train patients in adapting to and learning how to control devices like computers via thoughts. It uses a type of BCI called electrocorticography (ECoG). The second would expand the research altogether. It utilizes electrodes placed directly on the surface of the brain and can interpret more signals. By doing so scientists on the project hope to see how well it could work for different types of people as well as if the movements simulated could become more complex, allowing for broader and more day-to-day use of the technique in the future.

I find this article fascinating for many reasons: 1) It is relatively new and holds great promise of actually coming to fruition; 2) It could potentially be used in many applications. Even healthy people could start their computer up from far away with just thoughts. But it can also benefit patients in wide variety of physically debilitating conditions. 3) It isn't stopping with current research. At the end of the article it talks about wireless applications. So the research seems to be of continued desire and interest.

Link: http://www.sciencedaily.com/releases/2011/02/110217124913.htm

B-12 and Brain Function

A rather interesting article about how brain function is related to vitamin intake caught my eye the other day and I thought I might share it with the rest of you.

Specifically the article concerns the the effect vitamins B-6, B-12 and folate have on homocysteine levels and in turn how that affects brain size and in turn function. The authors explained that high concentrations of homocysteine are related to vascular endothelial cell death which has been shown to lead to stroke and a general reduction in grey matter volume in the brain. The results of the experiment showed that increased levels of B-6 and B-12 led to greater brain size compared to normal patients, with patients taking over the daily dose benefiting even more and no benefit being gleaned from the folate intake in relation to brain size. The B vitamins did not effect the brain globally, but rather in compartments unique to each vitamin that were spread throughout the brain, so a mix of both vitamins was deemed the most useful. Patients who had this increased grey matter volume showed increased cognitive abilities compared to those without a sufficient intake of the vitamins.

The experiment was conducted by taking 32 community dwelling individuals between the ages of 59 and 79. The researchers measured grey matter volume using MRI's, recorded tissue atrophy using voxel based morphometry (which analyzes the ratios of grey matter, white matter and cerebrospinal fluid), and found B vitamin intake using food journals and comparing the results of the three tests to determine their relationship.

In short, take your vitamins, they will keep your brain from shrinking.

http://www.sciencedirect.com/science/article/pii/S0006899308000218

Deadly Progression of ALS Reversed in an Amazing Stem Cell First

Amyotrophic Lateral Syndrome (ALS) is normally regarded as a terminal disease and most patients diagnosed with it are given a period of three years before their untimely doom befalls them. Those diagnosed with the disease also have progressive symptoms that range from constant weakness of the body to the inability to breathe. Very few survive ALS for more than five years and among the rare is a 39-year old male named Ted Harada.

Ted Harada was diagnosed with ALS on May 2010 and he had been coping with the horrid symptoms until March 9th, 2011 when he volunteered to be the test subject of a particular stem cell research sector regarding nerve cell rejuvenation. The scientists at Emory University conducting the experiment warned him of the experiment resulting in unknown consequences, yet Ted Harada, hoping that the research performed on him would hopefully contribute to science in a positive way, agreed to be tested upon.

The test consisted of injecting one million neural stem cells into 10 separate locations in the spinal cord of the patient hoping that the stem cells differentiate into or regenerate the damaged neurons. Throughout the course of the trial, two out of 12 died due to reasons not affiliated with the stem cell research (one died of a heart attack and the ALS in the other had progressed too much to be quelled), and most of the remaining patients have not experienced any recovery. But, resting alone, Ted Harada actually benefited from the experiment and is now enjoying life to its fullest without being hindered by his cane.

This article was particularily interesting for two reasons. First, it provides reasonable evidence why stem cells should be prioritized higher by the government since the positive results shown was in a human. Most recognized stem cell research involved rats and other animals who's genetic make up was not similar enough to a human's. Second, the stem cells in this experiment were all derived from one aborted and donated embryo. Such a donation did have limitations on the amount of stem cells retrieved, but the scientists duplicated the cells to have enough for 12 people to be tested. In a utilitarian perspective, one embryo for the sake of 12 people is always a justifiable cause. Overall, this article was quite interesting and the research should be properly funded since stem cells could be the next treatment for ALS and several other diseases.

http://gizmodo.com/5844786/deadly-progression-of-als-reversed-in-an-amazing-stem-cell-first