New gene therapy for sickle cell disease

A team of researchers at the Stanford University School of Medicine has used CRISPR to repair the gene that causes sickle cell disease in human stem cells, which they say is a key step toward developing a gene therapy for the disorder. 

The team demonstrated that the modified cells could make a functioning hemoglobin molecule, and then successfully transplanted the stem cells into mice. The researchers say the study represents a demonstration in principle for the repair of blood-borne genetic diseases, such as sickle cell disease and thalassemia.

As many are aware, the sickle mutation causes the red blood cells to make an altered version of the hemoglobin that forces the red cell into a sickle shape. These cells do not flow smoothly through blood vessels; they jumble together and cause blockage. This leads to severe pain and dangerous health consequences. Sickle cell disease affects 70,000 to 100,000 Americans and millions globally.

The research team started with human stem cells from the blood of patients with sickle cell disease, corrected the gene mutation using CRISPR and then concentrated the human stem cells so that 90 percent carried the corrected sickle cell gene. The team injected the concentrated, corrected hematopoietic stem cells into young mice.The corrected red blood cells do not have to replace all of a patient's original sickle cells. If the amount of sickle cells is below 30 percent, patients have no symptoms of disease

Some may question the safety of using gene therapy. According to the article, "the team found that their corrected human hematopoietic stem cells seemed to behave like normal, healthy human hematopoietic stem cells." But there are the possibilities of problems including the alteration of the wrong sequence of DNA or unexpected immune reaction. So the effects of gene editing are really impossible to predict. For now, it looks like CRISPR is the best thing we've got.

Hidden Genetic Mutations in Stem Cells Could Weaken Therapeutic Benefit

A microscopic image of human induced pluripotent stem cells (iPS). 

Mutations in mitochondrial DNA occur more frequently in individual cells as the human body ages. Since there are thousands of mitochondrial mutations and most of them are hidden, researchers have a hard time identifying all of the mutations present in a sample of a blood or piece of skin. However, researchers are able to distinguish the mutations easier if they are in iPS cells. In order to identify these mutations, iPS cells undergo a process where they are cloned in skin or blood cells which results in a iPS cell line that contains the same mitochondrial DNA mutations as the original adult cell. 

In a study conducted by Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University, researchers analyzed mitochondrial DNA mutations in 20 iPS cloned cell lines per patient that were obtained from blood and skin samples from healthy people and people suffering from degenerative diseases. When the iPS cell lines were sequenced, the researchers discovered that there was a significantly high number of mitochondrial mutations in the cells of patients who were over 60 years old. Based off of the results, the researchers observed that the larger the number of mutations in mitochondrial DNA caused a greater compromise to be made in the cells functions. Additionally, any defects in the mitochondria can potentially weaken or diminish the iPS cells ability to repair damaged tissues and organs. From this study the team of researchers discovered that iPS cells, specifically a type of stem cell from blood or skin sample, contain mutated mitochondrial DNA. In order to effectively use iPS cells to their full potential in humans, medical geneticist Taosheng Huang suggests that doctors and researchers need to check first if there are any mutations in the mitochondrial genome (Oregon Health and Science University 2016). 

I think that potential therapies involving the use of iPS stem cells can be used to treat diseases that occur with old- age. In the article, Mitalipov expressed that "pathogenic mutations in our mitochondrial DNA have long been thought to be a driving force in aging and age- onset diseases, though clear evidence was missing. Now with that evidence at hand, we know that we must screen stem cells for mutations or collect them at a younger age to ensure their mitochondrial genes are healthy" (Oregon Health and Science University 2016). In my opinion, I think the background knowledge of how cells are damaged with old age can serve as a basis for future studies to further examine how mutations in the mitochondria play a role in degenerative diseases. 

Creating "Old" Cells from Skin Cells

In the article scientists create 'old' cells  the author discussed how skin cells can now be converted into neurons without losing their "age".  This was done by Prof. Gage and colleagues, who decided to use the direct conversion technique to try (and succeed) in creating neurons out of skin cells, rather than the traditional induced pluripotent stem cell method, which was previously (and currently is) done to do the same conversion.
The problem scientist had with the pluripotent method, although it worked, was that this reset epigenetic signatures of the old cell and made them like that of a younger neuron.  This can become a problem when it is used to look at diseases such as Alzheimer's disease and other age related neurological diseases.  This new technique is and can be very important, because by using the new method of conversion scientists are able to bypass the stem cell precursor state, and as a result create an "induced neuron".

I find this to be an amazing advancement, because as they mentioned in the article this allows researchers to identified age related changes within the brain.  Which with the induced pluripotent stem cell method was more difficult because after going through that process they would end up with young neurons, which did not seem to have the same qualities as older neurons.

Mutation May Cause Early Loss of Sperm Supply

      Biologist at Brown University have been experimenting with the gene that makes the protein TAF4b. Through their research they have discovered how premature exhaustion of fertility in male mice has been the result of the loss of the gene. The discovery in male mice may help us understand the same loss in fertility in men. According to Brown University biologists, "Protein TAF4b causes a deficit in the number of progenitor cells at an embryonic stage of male mouses reproductive development". The problem is that mice struggle to develop stem cell structure to maintain sperm production to the normal age of two years old. Mice lacking the gene have shown loss of fertility by four months old.

     TAF4b protein affects how genes are regulated and transcribed which greatly impacts the reproductive system. Mice with the protein have shown progenitor cells for sperm in male embryos arise normally and have a large variety of spermatogonial stem cells to develop. However, mice lacking the protein have less progenitor cells and stem cells. Although, sperm production occurs at first they cant replenish production. Researchers are still figuring out the reasons why the process fades out rather than continuing at a low rate of production.

     The interesting segment of the article is that last year by coincidence a study was done that showed evidence that matters for sperm count and humans have a gene for TAF4b. The research was done on four Turkish brothers who all carried mutation in the TAF4b gene and all resulted in low sperm counts. Even more interesting is that the region of the gene that was mutated in the Freiman's mice is the same exact region affected in the brothers.

      In my opinion, I found the information a breakthrough for those who are infertile and could potentially detect the mutation as a teenager. Detection would allow teenagers to freeze there sperm before infertility and use the sperm to have children later in life. Unfortunately, for the Turkish brothers it is to late but, if caught sooner those men possibly at one point were able to produce functional sperm. The research at the Brown University also suggests importance of development at the embryonic stage as well as later in life.








 Original Article
http://www.omim.org/entry/601689

Using Genetic 'editing' stem cells to combat HIV/AIDS.

        Harvard Stem Cell Institute researchers are currently developing a new technique to try and fight HIV/AIDS. The technique is genetically editing a persons cells to block HIV from entering and destroying a persons immune system. This is the first group to publish a report using CRISPR Cas technology to "edit relevant genes out of cells collected directly from people. The people behind this research are Chad Cowan and Derrick Rossi associate professors in Harvard's Department of Stem Cell and Regenerative Biology.

       HIV targets T cells in the blood based immune system. It enters the system through a gene receptor called CCR5. Once the HIV has entered the system it kills and replicates all of the host cells. Leaving the immune system prey to a host of infectious virus and diseases. Cowan and Rossi are using the CRISPR gene-editing technology "Cowan and Rossi teams knocked the CCR5 receptor out of blood stem cells that they showed give rise to differentiated blood cells that did not have CCR5. In theory, such gene-edited stem cells could be introduced into HIV patients via bone marrow transplantation, the procedure used to transplant blood stem cells into leukemia patients, to give rise to HIV-resistant immune systems."
      The reason why this research has arrived is because it is relatively close to the technique that cured Timothy Ray Brown of HIV. Brown is considered to be the only person who has been cured from HIV. Brown got a bone marrow transplant from someone with a rare genetic defect that left the person free of the CCR5 receptor. After six years of these transplants he is considered to be cured of HIV. The technique that Cowan and Rossi are using is close to this technique except it uses the persons own cells, instead of trying to find a rare bone marrow donator who does not have the CCR5 receptor.
      Although the researchers think this technique could be used on humans in less then five years, they realize the battle they still face. They have listed three cautions of the research. The first the researchers realize they could run into unexpected complications. The also know that the HIV/AIDS community is flooded with "cures" that don't actually cure anything. The third the researchers know that there could be an issue trying to make this applicable in areas where the epidemic has hit the hardest. Overall, I think this technique could be the first step to eventually help fight or possibly cure HIV/AIDS.

Original Article
http://www.medicalnewstoday.com/releases/285077.php 
Related Article
http://news.sciencemag.org/health/2014/09/how-did-berlin-patient-rid-himself-hiv

Human stem cell-derived neuron transplants reduce seizures in mice

     The Harvard Stem Cell Institute has been working to find ways to treat disease with stem cells. A recent study by Harvard has shown that stem cell transplantation could be a useful way to help epileptics who don't respond well to the current anti-seizure drugs. What they have successfully transplanted in mice are seizure-inhibiting human embryonic stem cell-derived neurons into the brains of mice. The results show that half of the mice no longer had seizures and the other half showed significant drops in frequency of seizures. More research from this project can be viewed in this paper, where the methods are more in depth and results are displayed.

   

     This picture above shows one of the stem cell-derived neurons integrating itself into an affected epileptic brain. I find it interesting how valuable stem cells are to researching new ways to treat disease. I believe they have endless possibilities once we establish ways to mass produce them. The brain is always a touchy subject when it comes to treatments of disease because of all the complications that can come with it, but reading articles like this gives me hope about the future.

Main Article
Additional Reading

reprogramming stem cells to make blood

 



 

 

the blood of young and old people differs. In an article published recently in the scientific journal Blood, a research group at Lund University in Sweden explain how they have succeeded in rejuvenating the blood of mice by reversing, or re-programming, the stem cells that produce blood.

Stem cells form the origin of all the cells in the body and can divide an unlimited number of times. When stem cells divide, one cell remains a stem cell and the other matures into the type of cell needed by the body, for example a blood cell.*

“Our ageing process is a consequence of changes in our stem cells over time,” explained Martin Wahlestedt, a doctoral student in stem cell biology at the Faculty of Medicine at Lund University, and principal author of the article.

“Some of the changes are irreversible, for example damage to the stem cells’ DNA, and some could be gradual changes, known as epigenetic changes, that are not necessarily irreversible, even if they are maintained through multiple cell divisions. When the stem cells are re-programmed, as we have done, the epigenetic changes are cancelled.”

The discovery that forms the basis for the research group’s method was awarded the Nobel Prize in Medicine last year.

Source: sciencedaily.com

 

Disease's in a Dish

Prior to 2006, stem cell research was an ethically challenging field of study. The only known obtainable undifferentiated cells were human embryos. To obtain a stem cell, meant aborting a life.  This all changed however when a Japanese scientist, Shinya Yamanaka discovered a new type of stem cell called the IPS or induced pluripotent stem cell. It is formed by injecting programmed genes into fibroblast skin cells.

Wendy Chung, a geneticist from NY, sampled skin from elderly women infected with ALS syndrome or Lou Gehrig's disease. Wendy then created IPS cells from the skin of the women. Using a pitri dish, she grew ALS infected motor neurons from the IPS cells! The next step is comparing the ALS motor neurons to  healthy ones in hopes of finding a cure.

This is a very exciting field of science. The discovery of IPS cells has opened endless possibilities in biology. It is interesting to think if one day they could grow entire organs outside the body using IPS cells and then transplant them.

 

 

Scar Tissue Turned Into Heart Muscle Without Using Stem Cells

Scientists have recently found a way to turn scar tissue that forms on a heart after a heart attack into heart muscle, in a rat subject. This discovery eliminates the need for a stem cell transplant of the heart. The scientists found a way to use a molecule called microRNAs, molecules that serve as master regulators that control the activity of many genes, to activate the cardiac tissue conversion. This creates a simpler way for tissue regeneration. The microRNAs, in a specific combination, were delivered in fibroblasts. Fibroblasts are developed in the heart after a heart attack and impair the heart from pumping blood. The microRNA reprograms the fibroblasts to resemble the cardiomyocytes that make up the heart muscle. MicroRNA has many advantages over transplants of stem cells, such as the microRNA process eliminates the technical problems of surgery such as genetic alternations, and avoiding the ethical dilemma posed by stem cells. Even though this is a big step towards a better way to cure scar tissue in the heart, the procedure is still too risky to try in humans. This is just an early stage of trial, and it shows that the procedure is doable. This discovery has the potential to treat the twenty-three million people worldwide who suffer from heart failure and heart disease.

Engineered Stem Cells Seek out and Kill HIV in Living Mice

A team of researchers at UCLA, led by Scott G. Kitchen, who is an assistant professor of medicine in the division of hematology and oncology at the David Geffen School of Medicine at UCLA, have demonstrated that human stem cells that have been genetically altered into HIV-fighting cells can actually be used in living organisms to attack HIV-infected cells.  The research team at UCLA, knowing that CD8 cytotoxic T lymphocytes of the “killer” T cells are able to destroy the HIV-infected cells but are not sufficient enough in numbers to destroy all of the HIV-infect cells to clear the body, have discovered a way to clone the receptor cells which has allowed them to genetically engineer human blood stem cells.  They made this discovery by implanting human thymus tissue, which they have injected with the human stem cells, into mice.  This allowed the research team to study the reaction that the human stem cells had inside of a living organism.  They discovered that the human stem cells developed into HIV-specific CD8 cells that could attack the cells that contained the HIV proteins, but in doing so realized that the T cell receptors need to be matched to an individual.  The mice were tested two and six weeks after being introduced to the engineered human stem cells and concluded that the steam cells were capable of developing and fighting the infections.  The research showed that during these tests the CD4 “helper” T cells had increased and the HIV infected cells had decreased.  They concluded with a potential weakness that HIV- infected cells may be less likely to attack mice cells as quickly as humans so this could be one way to account for a possibly higher mutation rate of the HIV cells in humans.This is still a great first step in correcting the defects of the human T cell with regards to HIV infected humans.

New Hope for Huntington’s disease

A story posted in the Medical News Today Janurary 14, 2012, states that new hope has been discovered for Huntington’s disease. Last year a research study conducted by Jan A. Nolta (UC Davis stem cell program and UC Davis Institute for Regenerative Cures) was published in the journal Molecular and Cellular Neuroscience that they may be able to provide gene therapy for individuals affected with Huntington's Disease by using inhibitory RNA sequences to reduce the amount of the mutant huntingtin protein. Huntington’s disease is a neurological degenerative genetic disorder that is caused by the mutation of the huntingtin gene, comprised of the abnormal repeating of the building block of DNA that appears on the fourth chromosome. The accumulation of the huntingtin protein in the brain of an individual leads to progressive uncontrolled movements, dementia and death.

In the study conducted by using a mouse model, the research team genetically created mesenchymal stem cells that were made from the bone marrow of the individuals that were unaffected with the disease to transfer the inhibitory RNA sequences from donor cells to the target cells. From this transfer, the amount of the huntingin protein present dropped significantly by over 50 %. The research team has hopes of transferring the RNA inference technology over to humans in a “sustained, safe and effective manner”.

It is intriguing to find that researchers have found a way to reduce the Huntingtin protein and even possibly eliminating the disease all together.  Huntington’s disease usually does not appear in individuals until they reach middle age, so individuals who have not developed the signs and symptoms the chance to stop the progression of the disease for it begins; also help the individuals already suffering from the disease before it progresses further.

Intestinal Stem Cells

In a recent article, researchers from the University of California, Berkeley found that intestinal stem cells may lead to understand certain intestinal diseases, like diabetes and obesity. Working with fruit flies, the scientists at Berkeley found that when the flies eat their gut becomes enlarged. This is due to the intestinal stem cells expanding the intestines so the food can flow through gracefully. This was a new discovery in itself because scientists initially thought that stem cells just replaced tissues when an accident or injury happened, but other than that they did relatively nothing else, until now. These intestinal stem cells enlarge the gut for about four day and then go back to normal size once all the food is digested. The insulin secreted from the intestines is what causes the intestinal stem cells to expand and enlarge the intestines. This phenomenon may give insight to the therapeutic use of stem cells in gastrointestinal diseases and metabolic diseases, like diabetes.  I found this article very interesting because diabetes is a serious condition that should not be taken lightly. The fact that researchers are still trying to find ways to treat this disease is enlightened

  

Skin cells saving lives!!!

I never would have thought that our skin cells could be lifesaving?  Although a recent article has revealed that scientists have recently discovered the benefits of converting our skin cells into functioning liver cells.  This new study occurs by undergoing a new stem cell technique in which liver cells can be grown from our skin cells.  British scientists believe that this researched study may be the solution of liver transplant patients with many rewarding benefits.  During this procedure, scientists from the University of Cambridge, use a technique known as the zinc finger nuclease which allows scientists to snips the genome to correct it.   This new process creates these functioning liver cells without any evidence of gene correction that had occurred.   I definitely find this article to be extremely interesting.  It's amazing how scientists can find such ways to cure an issue so rapidly by undergoing a few scientific tests.  Even though this procedure will take about ten years to take affect, I feel that many lives will be saved and this will become beneficial to many throughout.

Mutations Found in Human Induced Pluripotent Stem Cells

In this article  induced pluripotent stem cells (hiPSCs) need to go under further research before becoming used clinically. "A national team of researchers examined 22 different hiPSC lines obtained from seven research groups that employed different methods to reprogram skin cells into pluripotent stem cells. In all of these cell lines, the researchers found protein-coding point mutations, an estimated six mutations per exome. The exome is the part of the genome that contains the genetic instructions for making proteins and other gene products." They found that some mutations seem to be silent and others chaged a specific function in the protein. Even though these stem cells are new and exciting to bring into a clinic to use, researchers are still testing them to make sure they are safe to use. An assay was used to find any mutations in the strating cells of a cell line at a low frequency. They found that about half of the mutations were found in the stem cell lines. Some starting cells had rare mutations that could not be detected which could indicate that this happened after the reprogramming. Also,they found that  there were genetic damages that can occur, such as nucleotides or base pairs that can alter the protein when it under goes reprogramming.

Scientists Grow Key Memory Cells in Lab Dish

In this article  it states that researchers say that a person with Alzheimer's disease have stem cells that die early. To help restore a person's memory who were affected by this disease, there is technology that can provide a ready supply of stem cells for new drugs or transplants. This new way will help researchers find the disease in human cells rather than the genetically modified mice. These stem cells created neurons which are the parts that get lost in the disease process. "When Kessler and Bissonnette implanted the newly grown nerve cells into the brains of mice, they functioned normally, producing nerve fibers called axons and making the brain chemical acetylcholine, used to retrieve memories from other parts of the brain." Researchers are now finding ways to see the differences between healthy and diseased cells with induced pluripotent stem cells to hopfully be able to create memory cells to place in people with the disease. But for now, unfortunately there is no drug to stop the disease from progressing.

Growing Too Old, Too Soon

This article discusses the genes which cause progeria and how scientists have recently created a model to understand this disease. This disease causes premature aging by affecting the gene for coding protein lamin A. This results in mishaped cell nuclei and causes those with Progeria to die in their teens from a heart attack or stroke. While in the past scientists had only mouse models for this disease, now with the use of stem cell research there are human models. These scientists located in Hong Kong and Singapore now have groundbreaking research to undertake with this new model that will hopefully take steps toward ending progeria.

It is really great that already stem cell research is showing up to be substantial to possibly curing various disease. I fully support the research because it has proven itself helpful and after understanding a disease you can counter it.