Outline of Our Project

Introduction: 45 seconds

  • How many people are affected by autoimmune diseases:
    • Approximately 50 million Americans, 20 percent of the population or one in five people, suffer from autoimmune diseases
    • Women are more likely than men to be affected; some estimates say that 75 percent of those affected–some 30 million people–are women.
  • How many people are affected by multiple sclerosis:
    • 947,000 people in the US and 2.3 million people worldwide

Healthcare costs:

  • “The average annual cost per patient for the country was $29,339 (2010), $20,956 (2011), $23,892 (2012), $24,148 (2013), and $22,688 (2014). Drug therapy represented 86.1% of the total cost.” https://www.ncbi.nlm.nih.gov/pubmed/29605798 (link provided, new information gained for this post)

Other background information:

  • affects the nervous system
    • Brain
    • demyelination of nerves
    • immune system attacks the Myelin sheath and oligodendrocyte cells surrounding/protecting your peripheral and central nervous system
    • cognitive and physical impairments

Current Technology/Treatment: 75 seconds

Current Technology:

  • Gene Therapy: MS itself is not genetic; but there are genetic risk factors involved in the disease. Researchers currently have found 159 variants of genes that are potentially linked to MS
  • modified microglia: adapted the microglia to become anti-inflammatory, creating an environment where remyelination was possible
  • t-cell therapy: certain vaccines containing certain antigens have been tested in mice
  • ability to convert astrocytes within the CNS into oligodendroglia in vivo in order to combat the myelin destruction associated with this disease by forcing the expression of the miR-302/367 cluster in astrocytes

Why isn’t it good enough?

  • Many of the current treatments are not necessarily focused on treating MS but instead are adapted versions of treatments for other diseases
  • The current gene therapy has not gotten beyond identifying certain variations of genes that amplify the risk factor of getting the disease. There has not been further action or study as to how these could be edited out.
  • Modifying microglia as well as converting oligodendroglia into astrocytes only helped create better conditions; did not solve/eliminate the disease
  • Current t-cell therapy including vaccines caused allergic reactions

Your Technology: 3 minutes

How it works:

  • Gene therapy and gene editing could remove the genes causing MS directly from the cells while giving the cells regenerative properties that could help safeguard them from developing MS in the future.
  • Gene editing could also be used to modify the cells in the body that are responsible for t-cell production to stop them from producing t-cells that attack the body/carry MS?
  • Also possibly research into the Deinococcus radiodurans bacterium and applying genes that allow it to repair itself to neurons

Why it’s better:

  • It is specific to MS, but also has potential applications to other autoimmune diseases
  • Potentially less expensive: The main cost of treating MS comes from lifelong expenses for drugs and medications. Gene editing may reduce these costs by offering a one-time or short-term treatment.

Other:

  • Possible information on T-cell therapy from Dr. Susan Koegel and her research with T-cell development and function (still waiting on email response)

Things that are an issue:

  • There is not any work being done on adults for cell-therapy (CRISPR/Cas9, Car T-cells) as it would be very difficult to alter the genome in every single adult cell. In addition, cells in which the genome has not been altered would replicate alongside the altered cells. The CRISPR/Cas9 enzyme most probably wouldn’t be able to infiltrate all the cells targeted with one patient session, and therefore it is unknown how many gene therapy treatments would be needed which could be expensive and exhaustive.
  • Some ideas to fix this: We could only focus on a few specific type of cells such as the myelin sheath cells, oligodendrocyte cells, bone marrow cells that make T-cells, and the T-cells that attack the nervous system. We could then identify the specific genes that produce a negative immune response and change only the genomes in those types of cells.

Research in MS

Our group has discovered that autoimmune disorders in general are severely under researched.  Before we start taking steps towards curing these disorders, we should focus more on researching the workings of specific autoimmune disorders.

We think that a possible way to study MS could be using the silk scaffolding. Silk scaffolding is already being used to study human axons and conditions like Parkinson’s, so why not use it to study MS and its effects on the human nervous system?

Not only would further research in autoimmune diseases, and MS, deepen our understanding of them and how they work, but it would also make finding effective treatments easier. How can you hope to treat the underlying causes of a disorder to try to cure it without knowing exactly what causes it?

Furthermore, our hope is that using the silk scaffolding could also allow us to study possible treatments before they reach human trials to determine whether or not they are effective, and what possible side effects they may have.

Post 4: Synthetic Bio, CRISPR/Cas9, and infecting the body with a healthy immune response

To move forward with the project, the team has decided to focus on Multiple Sclerosis only and to research 5 different solutions that can all work together to cure the disease. Since we have a group of 5, we decided that each person can work on one specific version of a cure that focuses on one step of the autoimmune response that causes the body to attack itself, thus everyone has individualized and important job in the project. The idea behind 5 solutions is that there are so many steps in an immune response, and only focusing on one step to try to stop the attack has failed over and over again in the field. Either the treatment doesn’t work well enough, it only helps a little, or it doesn’t work at all. However, since the field is under researched and the treatments are under developed, creating five different solutions and pairing them together can greatly widen the scope of knowledge with MS and create a series of backup protection if any one of the five steps were to fail.

For my specific step, I will be focusing on the aftermath of an MS autoimmune attack, which is the last defense in our cure idea. Our idea for this step is using the technology developed like CRISPR/Cas9 that genetically modifies a genome in a bacteria or virus. If we were to gene edit a virus, and properly identify the genes in the human genome that remyelinate oligendrocytes and the myelin sheath, then we could edit out all the genes in a specific carrier virus that causes its own immune response and edit in the genes that causes myelination. Therefore, in theory, the virus would infect the human body with the “disease” of remyelination. We would have to pick a virus that focuses solely on the nervous system, and stays with you for life. It also has to have a long enough genome to accommodate human genes. A virus that fits that criteria for example would be the herpes simplex virus, and other than the problem that the idea of giving someone herpes to cure MS by nature has a pretty negative ring to it, it would theoretically be a feasible carrier virus.

https://www.cell.com/cell/pdf/0092-8674(79)90023-0.pdf

 

Post 4: CAR T-Cell Therapy for Autoimmune Diseases

We are looking into CAR T-cell therapy as a means to treat autoimmune diseases like MS. CAR T-Cell therapy currently is used to treat cancer, and works by changing a patient’s T-cells in a lab so they attack cancer cells. Then, a special receptor called a chimeric antigen receptor (CAR) that binds to cancer cells is added to the T-cells. (cancer.gov)  If we apply this technology to autoimmune diseases, but have a receptor that protects the cell instead of attacking, we could make great strides in treatment and quality of life for those with autoimmune diseases.

 

CAR T-cell therapy is more ideal than other treatments for MS as it is a targeted treatment, meaning it won’t kill off the entire immune system. It is an extension of biologics, which are currently being researched. It could be better than other treatments for autoimmune diseases because it can aim directly at the source instead of hoping the side effects of cancer drugs will treat the disease. However, autoimmune diseases are severely under-researched, and in order to apply this treatment you would need to know the root cause of the disease.

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy

Post 4: Applying genetic modification and the D. radiodurans bacteria to MS

Our group is taking multiple approaches to cure multiple sclerosis including the genetic approach, interface approach, and applied cancer research approach to provide multiple paths of intervention and prevention of the symptoms and development of MS in all of its stages. Each person in our group is separately researching one of these topics in order to “fight” multiple sclerosis in different ways. I am focusing on curing multiple sclerosis on the genetic level using the Deinococcus radiodurans bacterium as a model for cell self-reparation. The D. radiodurans bacteria can withstand high amounts of radiation, destroying both its cellular components and its genome, and can fully self repair itself afterwards using extended synthesis-dependent strand annealing (ESDSA) which includes DNA polymerase I (Pol I)-dependent DNA synthesis and RecA-dependent recombination processes (Slade, 2009). These self repairing functions of the D. radiodurans bacterium is encoded in its genome specifically on chromosome II (2009). By studying what genes on the D. radiodurans’ chromosome II lead to the expression of self-reparation and using current gene editing methods such as CRISPR, it may be possible to genetically modify the human genome to promote remyelination and neuron self-reparation for cells affected by MS.

Current treatment of multiple sclerosis today includes gene therapy, modification of microglia, and t-cell therapy, all of which prove partially beneficial to treating MS but cannot fully cure it nor fully reverse the damage to cells caused by the disease. By using gene modification to edit the human genome to contain sequences that code for self-reparation of neurons and oligodendrocyte cells surrounding the peripheral and central nervous system based off of the genes on chromosome II of the D. radiodurans bacteria that code for self-reparation, full cell reparation would inhibit the progression of MS. Remyelination rates decrease as MS progresses (Podbielska, 2013). Therefore having genes that promote self-reparation would increase rates of remyelination, rebuilding the myelin sheath, and lessening the symptoms of cognitive and physical impairments associated with MS. MS could be cured without knowing the full set of genes and gene markers that cause the disease using CRISPR to edit the human genome to contain genes that promote cell reparation modeled after the ESDSA process that D. radiodurans use. Even when the immune system would cause the destruction of the myelin sheath and destruction of oligodendrocyte cells, the edited human genome would contain instructions to self-repair these cells and neurons. One gap that creates difficulties for this approach is that several of the processes that the D. radiodurans bacterium uses to repair its genome are still unknown and not fully understood. Another challenge includes that the ESDSA process of genomic reparation would need modification for application in the use of reparation for other cellular components such as the myelin sheath of the neurons. A problem that results from using CRISPR is the limited current knowledge of how using the genome of a bacteria as a model for self-repairing genes could be directly applied to editing specific genes on the human genome. Even with these challenges, gene modification to promote self-reparation of cells destroyed by MS using the D. radiodurans bacteria’s genome self-reparation as a model could lead to a direct cure of the disease and several other autoimmune diseases.

Podbielska, M., Banik, N. L., Kurowska, E., & Hogan, E. L. (2013). Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination. Brain Sciences, 3(3), 1282–1324. http://doi.org/10.3390/brainsci3031282

Slade, D., Lindner, A. B., Paul, G., & Radman, M. (2009, March 19). Recombination and Replication in DNA Repair of Heavily Irradiated Deinococcus radiodurans. Retrieved September 28, 2018, from https://www.sciencedirect.com/science/article/pii/S009286740900066X

Post #4: Future Idea for Treating MS

This week, our group discussed how adapting new science and engineering principles/research could take MS treatment/prevention to the next level; we came up with ideas on how current engineering principles could be adapted to change the outlook of MS for individuals. Currently, our idea is to take a multi-targeted approach to treating MS; this includes a variety of different concepts at different stages of the disease that could overall be combined and individualized for each person with MS. Each group member has one of our ideas, and we plan on combining these ideas to make a comprehensive plan for the future of MS research.

One of these ideas is to interface neurons with technology in order to replace or bypass the damaged neurons that come about in the disease progression of MS. The concept of interfacing/combining technology with the body is a growing source of research in the biomedical engineering field, and there have been many advancements for how technology could be adapted to be compatible with the body. However, there has been limited to no research as to how technology could be used to either interface with the nervous system (outside of the brain) or even through creating artificial technological neurons themselves.

This would be effective because MS damages/destroys neurons, and sometimes once the disease progresses to a certain point, even with new processes to repair the myelin sheaths it may not be enough to allow a person to become just as they were before getting MS. This is because once a certain level of damage is done, the damage can become unrepairable. However, if a way to replace or interface these neurons with technology were to be developed, then rather than trying to repair damage, a person could just be given new artificial neurons that could allow their nervous system to work in a manner that would not be hindered by past demyelination. This makes this idea better than the engineering principles already established, as it gives the body a new system rather than trying to fix a damaged one.

This could be done by finding a technology that can communicate just like neurons, and then integrating this technology with the body using biocompatible materials that would allow the body to use the new technology without rejecting it. This is a very complicated problem, as neurons are extremely delicate and would be extremely difficult to interface technology with. However, the possibility of adapting the same technology that allows artificial limbs to be connected to and controlled by neurons could be used in this situation, and this could be a promising avenue to investigate. However, the difficulty here would be the fact that this idea would be leading from neurons to neurons/the brain, not from neurons to artificial technology. This difference makes the process more complicated, but many of the same principles can likely be adapted to make the idea plausible.

Overall, this idea is a promising avenue to investigate, and while much more research is needed to figure out materials/interfacing issues this could be a very plausible and effective approach to treating advanced MS. While there are a few gaps in knowledge outlined above, these can likely be overcome by adapting past principles to new situations.

Post #3: isolating and suppressing a specific immune response

In my very first post, I discussed how many autoimmune disorders are treated through immune suppressant drugs which can leave a patient susceptible to many other infectious diseases and infections. It is certainly not a perfect system, and scientists are now looking at ways in which to suppress only the sector of the immune system that is generating the autoimmune response. Researchers supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) are looking at the natural methods the body uses to suppress inappropriate immune responses. Normally, when a cell dies through apoptosis, it releases chemicals that initiate a response from a type of cell called macrophages that absorb and deposit the dead cells’ antigens in the spleen into a pool of T-cells- some of the cells responsible for an immune response. Then the macrophages suppress any T-cells with the ability to bind to self-antigens to not have a negative autoimmune attack. Currently, the method being tested in mice is coupling myelin cells in subjects with multiple sclerosis (in which myelin cells cause an autoimmune response) with self-antigens that do not bind with T-cells. So far this treatment has proven to be extremely effective in halting the progression of the multiple sclerosis in mice, and the next step is clinical trials. However, cellular therapy is apparently very costly, time-consuming, and needs to be done in a high-tech facility, and thus progress with this research is going to be difficult. Still, this method of treatment is not specific to multiple sclerosis and is projected to be effective in many other autoimmune disorders and diseases like allergies, type I diabetes, and maybe even Rheumatoid arthritis

 

https://www.nibib.nih.gov/news-events/newsroom/research-breakthrough-selectively-represses-immune-system

https://study.com/academy/lesson/non-self-antigens-self-antigens-allergens.html

Post #3: The genetic heritability and make-up of MS

In order to find a method for self repairing neurons affected by the degenerative effects of multiple sclerosis, it is necessary to understand from where multiple sclerosis originates. There is limited knowledge regarding the development of multiple sclerosis specifically in terms of genetic heritability. Family based-linkage analyses have shown MS is related to genes that encode for the human leucocyte antigen (Lin, Charlesworth, Mei, & Taylor, 2012). Furthermore genome-wide association studies have identified over 60 loci related to MS in regions of the chromosome corresponding to T-cells and the immune system (Lin, 2012). These two linkage and association studies only explain 18-24% of the heritability of MS (Lin, 2012). Many theories have been created in order to make up for the lack of knowledge about the genetic heritability of MS. The first theory includes that rare and common variants of allele frequencies related to MS that account for most of its heritability have still not been found (Lin, 2012). The second theory of epigenetics suggests that environmental factors may trigger certain gene expressions related to MS (Lin, 2012). The third theory of gene-gene interactions explains how genes of the same phenotype may have an effect on how that phenotype is expressed (Lin, 2012). The fourth theory suggests structural variants in DNA that have not been thoroughly research may hold an association between the genes and complex traits related to MS (Lin, 2012). The last theory describes how pathway involvement of congregated variants of genes may lead to susceptibility of MS and other diseases (Lin, 2012). Genetic studies still lack the methods to understand the complexity of the genes associated with MS (Lin, 2012). Without knowing the exact genes associated with MS it will be difficult to create ways to modify the cell genome in order for the myelin sheath to undergo a self-reparation process. Other ways of treating MS may need to be explored since modeling the self-reparation process of the Deinococcus radiodurans bacteria maybe difficult without knowledge of the genetic makeup of MS.

Lin, R., Charlesworth, J., Mei, I. V., & Taylor, B. V. (2012, October). The Genetics of Multiple Sclerosis. Retrieved October 11, 2018, from https://pn.bmj.com/content/12/5/279.info

Post 3: Microglia and mCSF in Remyelination

This week I decided to look deeper into remyelination. As mentioned in last week’s post, patients with MS experience demyelination. Their immune system attacks the myelin sheaths on their nerve fibers, which are needed to transmit signals from the brain. Other than the death of oligodendrocytes, a cause of demyelination is the “robust immune responses mediated by microglia, which are the resident immune cells of the central nervous system.” (multiplesclerosisnewstoday) Recent studies show that microglia may actually be beneficial in promoting remyelination by promoting regeneration and clearing myelin debris.

 

“Aiming to better understand the role of microglia in MS, scientists at Université Laval, in Canada, administered a molecule called macrophage colony-stimulating factor (mCSF) to mice receiving dietary cuprizone.” (multiplesclerosisnewstoday) The mCSF shifted the microglia to become anti-inflammatory, promoting remyelination. This research suggests that “mCSF would be an ideal target for a clinical trial in individuals diagnosed with primary and secondary progressive MS.”

https://www.frontiersin.org/articles/10.3389/fncel.2018.00178/full

Immune Response Promotes Remyelination in MS Mouse Model

Biomarkers for Rheumatoid Arthritis

The traditional means of diagnosing rheumatoid arthritis (RA) has largely relied on the manifestation of symptoms and joint damage. Furthermore, the treatment of RA generally relies on a trial and error method with different medications because many different treatments don’t work for a lot of different patients. However, a recent study from the United Kingdom has identified four biomarkers that may help diagnose RA as well as predict the effectiveness of methotrexate as a treatment method for patients (Shervington, et al 2018). Because methotrexate was original designed as a cancer treatments and essentially kills parts of the immune system in hopes that it grows back healthy, the possibility of predicting whether or not it will be an effective treatment for a patient without them having to take it is an important advancement in the RA field. Personally, the use of methotrexate and other cancer drugs as treatments for RA is something that I would like to see dissipate in the coming years and I hope that this study will be an important step in the right direction.

Shervington, L., Darekar, A., Shakh, M., Mathews, R., Shervington, A. (2018) Identifying Reliable Daignostic/Predictive Biomarkers for Rheumatoid Arthritis. Biomark Insight. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30262983