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.

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: Investigating Neurofilaments and Their Role in Identifying MS Disease Progression

Recently, a research journal entitled “Neurofilaments as Biomarkers in Neurological Disorders” published in Nature Reviews Neurology earlier this year by Michael Khalil et al. investigated neurofilaments and their role in identifying MS in patients. Included in this study was the purpose of neurofilaments, how neurofilament light chains can be used as a biomarker to identify disease progression in MS patients, and how the techniques can be used to help in the identification of effective treatments for MS and other neurological disorders.

To begin, neurofilaments, a part of the neurons, are thought to be important components in providing radial growth and overall stability in axons throughout the body. Therefore, when MS causes disease progression and axonal injuries, these neurofilaments are released into the body. Certain techniques using four different generations of immunoassays (a biochemical test that can help identify these neurofilaments) can identify the levels of these neurofilaments in both the cerebral spinal fluid (CSF) and the blood. If this is done, the concentration of these neurofilaments can be an important indicator in determining the level of disease progression for MS. The first two generations of immunoassays work for identification in CSF, although identification in blood is only reliable in the third and fourth generation immunoassays identified in the study (these immunoassays are more sensitive).

This process is an important landmark in not only identifying how severe a patient has MS, but it can also be an effective tool in future MS research. This process can be used in future clinical trials to help determine how well a MS treatment works by comparing the number of neurofilaments that are in the blood before and after treatment. This process is also much more reliable than using MRI scans which are only reliable in showing damage in white matter, while MS causes damage in both white matter and gray matter. While the first and second generation immunoassays have limitations based on low sensitivity (and therefore rely on CSF sampling), the newer third and fourth generation immunoassays have opened up opportunities in future testing and research. While not perfect, these immunoassays could help find a future treatment, if not a future cure, for MS.

As said before, the information in the above paragraphs was located in an article published in Nature Reviews Neurology entitled “Neurofilaments as Biomarkers in Neurological Disorders” by Michael Khalil et al.. The link to the article is listed below.

https://www.nature.com/articles/s41582-018-0058-z#Sec5

Post #2: Converting Astrocytes into Myelinating Cells In Vivo for Possible MS Treatment

Multiple sclerosis, or MS, is a disease that is characterized by the degradation of the myelin sheaths in the central nervous system (CNS). As one of the autoimmune diseases that our group has chosen to focus on, this autoimmune disease results in the interruption of nerve signals in the body, creating many cognitive and physical impairments upon the individual affected. This disease currently is very difficult to combat, and many patients lose a lot of their function over the course of many years. A recent study done by Maryam Ghasemi-Kasman, Leila Zare, Hossein Baharvand, and Mohammad Javan explored the ability to convert astrocytes within the CNS into oligodendroglia in vivo in order to combat the myelin destruction associated with this disease.

According to the study, when the degradation of myelin occurs, astrocytes appear in higher numbers at the injury site. These astrocytes change the inflammatory response in the body, creating a situation where the myelin cannot repair itself and therefore helps in the progression of nerve damage. The study completed by the four researchers above found that forcing the expression of the miR-302/367 cluster in astrocytes can create a situation where the astrocytes will turn into oligodendroglia, or nerve cells that naturally repair the myelin within the CNS. This study was completed using mice subjects, and after the above process was completed the study found an increase in neurological function within the mice and saw increased myelination via staining techniques. This conclusion shows a possibility for remyelination within the human body, which eventually could lead to the slowing if not the reversal of MS and other neurogenerative diseases.

The above information was found on the SCOPUS database. This study was published in the Journal of Tissue Engineering and Regenerative Medicine in 2018. The DOI for the scientific journal is below.

10.1002/term.2276

Brooke Smiley: Autoimmune Disease Introduction Post

Autoimmune diseases, or diseases in which a person’s own immune system attacks their body’s cells, are a prevalent form of disease in the world today. Every year, there are many people worldwide that are diagnosed with autoimmune diseases, and each disease varies greatly. Not only does each disease attack a different bodily organ, but  each one can also range in severity from mildly noticeable to severely debilitating. Some diseases, such as multiple sclerosis (MS) or rheumatoid arthritis (RA), can end up creating much hardship on the patient in terms of life quality and length as well as financial difficulties for repeated hospital visits and treatments. Therefore, many researchers worldwide are trying to find the cause of these diseases in order to prevent, treat, and hopefully even cure these diseases. Researchers are trying to find ways to use scientific, engineering, and biological principles in order to achieve these ends.

My group for EN1 is investigating some of these autoimmune diseases and how the field of biomedical engineering is progressing towards the outcomes outlined in the above paragraph. For me, I want to investigate this topic further because I feel that autoimmune diseases, especially ones like MS and RA, can be extremely detrimental to the lives of those who suffer from them. I want to learn about the current research on the topic to find out what the possibilities are in terms of treatments or possible cures in the future related to the field of biomedical engineering.

Therefore, I took the first steps in my path of research by obtaining an article written by Hugh McDevitt from the Department of Microbiology and Immunology and Department of Medicine at the Stanford University School of Medicine. Called “Specific Antigen Vaccination to Treat Autoimmune Disease” (published on October 5 of 2004), it is one of the first articles that extrapolated upon research into T cells to find a possible cause of autoimmune disease and the use of vaccines containing antigens to treat the T cell problems by altering certain mechanisms within the body. Having been cited many times since then, this article expresses many of the founding principles of the research done for autoimmune diseases and how vaccines were first shown to have some effects in mice for treating the problems associated with autoimmune diseases and T cells. While the article expresses that many of the symptoms were prevented, stopped, or reversed in many of the mice to which the vaccines were given, the article also expressed danger in the use of these vaccines. In the studies cited in the article, many mice formed hypersensitivity to the vaccine, creating a problem where repeated doses of the vaccine would cause anaphylaxis to the point where death resulted for a majority of the mice. While human tests for similar vaccines only created small local reactions, the severe outcome of the various mice studies creates a need for further studies to be completed before any vaccine research and findings become viable.

Overall, I need to investigate further this broad outlook of the use of vaccines and other treatments to help the T cell issues present in autoimmune diseases. I will likely look at some of the more recently written articles that cited this early piece. However I also want to investigate other modes of treatment and study, as I feel that T cells, while important to this topic, may only be one key to engineering a treatment or cure for these diseases.

The links below are to the resources I used to begin the above research. The first link is to the National Institute of Allergy and Infectious Diseases website where I located the basic information for the description of autoimmune diseases, while the second link is to the article published by Hugh McDevitt.

https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases

https://doi.org/10.1073/pnas.0405235101