Team:Freiburg/Motivation
Our Motivation
On our journey to find a topic for the iGEM competition, we knew, we wanted to lay our focus on a medical issue. Something everyone could relate to. So we chose to revolutionize the targeted drug delivery with regard to the sickness ulcerative colitis.
To gain more information about the disease we’ve conducted a survey that we shared with ulcerative colitis patients. In our survey more than half of the patients stated that they were diagnosed with ulcerative colitic between the ages of 16-30 years. This common onset occurring in young adults personally affected us , however ulcerative colitis is a disease which can be found in every age. (Figure 1)
To gain more information about the disease we’ve conducted a survey that we shared with ulcerative colitis patients. In our survey more than half of the patients stated that they were diagnosed with ulcerative colitic between the ages of 16-30 years. This common onset occurring in young adults personally affected us , however ulcerative colitis is a disease which can be found in every age. (Figure 1)
Ulcerative colitis belongs to the inflammatory bowel diseases (IBD). In industrial countries, the incidence of ulcerative colitis is between 5-10/100,000 people each year4 and with some cases the diagnosis can take up to 20 years, since the symptoms are not very specific.3 Patients suffer from diarrhea, abdominal pain, rectal bleeding, fatigue, ulcers and fever. Ulcerative colitis is represented in every age and limits the time management, since you end up planning your whole life depending on your gut. At the moment, there is no cure for ulcerative colitis, in contrast, patients need to take daily medication that cause systemic side effects like tiredness in more than 60% of the cases or joint pain, skin rashes headaches, depressions or nausea. In our survey, only 10% stated that they had no side effects at all.
When we heard about this disease, we felt the improvement of the therapy is long overdue. By enhancing current strategies we aim for bringing back the quality of lives and ease it for patients. While we looked into today's treatment protocol, we learned about the high amount of negative side effects that medications most often have. Most of us had experienced that ourselves. You take some drugs that intend to make you feel better, but in the end the negative side effects are sometimes even worse than the sickness itself. Sure, you could refuse medication, but unfortunately that is not a serious option for most patients. So what would be an alternative? We thought about this particular topic for a long time and finally decided to focus our project on improving the targeted drug delivery. From the beginning, we were fascinated by bacterial spores which are very stable under various extreme conditions such as high temperature, strong chemical reagents and dehydration. Since spores can easily be (genetically) modified we aim for changing spores to our needs so they are able to express certain proteins. Spores behold great potential because they can be used as a tool for delivering enzymes, antibodies or other proteins in an organism. Another advantage (compared to conventional targeted drug deliveries) lies in the short doubling-time of Bacillus subtilis, therefore, the spores can be easily produced in high quantities within hours. Spores are able to express various components on their surface ,which makes them a perfect tool for targeting. It increases the overall multivalency and therefore the affinity. This advantage can be used for the targeted drug delivery.
So, the idea of targeted therapy with spores was born!
There are several reasons, why targeted therapy with spores will revolutionize the treatment of ulcerative colitis: In contrast to Crohn’s disease which also belongs to the IBD, ulcerative colitis affects the colon and the rectume while Crohn’s disease affects the entire bowel.1 Therefore, the site of target is very clear and limited. It is a place in the human body you can easily reach orally and rectally to apply drugs.
At the current state, there is neither a cause nor cure for this disease, and most importantly, ulcerative colitis is a high risk factor for colon cancer.2 The pathogenesis of ulcerative colitis is not yet well elucidated, it seems that unknown factors on colon epithelial cells attract T-lymphocytes, which cause a local inflammatory reaction. Consequently, epithelial cells undergo ulceration, and due to strong inflammatory signals, they die.5 Since ulcerative colitis has a strong likelihood to become a lifelong disease the patients rely on therapeutic options. The therapy of ulcerative colitis consists of steroids and long-term use of immune system suppressing or modelling drugs like azathioprine, therapeutic monoclonal antibodies such as infliximab ® or at late stage, surgery to remove the colon.7,8,9 Both steroids and immune modelling drugs can cause severe systemic side effects like cytopenia (low count of blood cells), resulting in higher risk for infection, bleeding disorders or anemia.10 Side effects and discomfort are major reasons why patients stop their treatment.10,11 Minimizing these side effects might lead to more compliance and acceptance of patients.
Therefore, our vision was to design the first targeted drug delivery system with spores!
Realistically spoken this is possible within half a year, so we set our goal to demonstrate with proof-of-principle experiments, that a nanobody with a defined specificity can be displayed on the surface of spores. Another motivation for some of us was to contribute to the scientific community with a number of useful, new biobricks.
So, the idea of targeted therapy with spores was born!
There are several reasons, why targeted therapy with spores will revolutionize the treatment of ulcerative colitis: In contrast to Crohn’s disease which also belongs to the IBD, ulcerative colitis affects the colon and the rectume while Crohn’s disease affects the entire bowel.1 Therefore, the site of target is very clear and limited. It is a place in the human body you can easily reach orally and rectally to apply drugs.
At the current state, there is neither a cause nor cure for this disease, and most importantly, ulcerative colitis is a high risk factor for colon cancer.2 The pathogenesis of ulcerative colitis is not yet well elucidated, it seems that unknown factors on colon epithelial cells attract T-lymphocytes, which cause a local inflammatory reaction. Consequently, epithelial cells undergo ulceration, and due to strong inflammatory signals, they die.5 Since ulcerative colitis has a strong likelihood to become a lifelong disease the patients rely on therapeutic options. The therapy of ulcerative colitis consists of steroids and long-term use of immune system suppressing or modelling drugs like azathioprine, therapeutic monoclonal antibodies such as infliximab ® or at late stage, surgery to remove the colon.7,8,9 Both steroids and immune modelling drugs can cause severe systemic side effects like cytopenia (low count of blood cells), resulting in higher risk for infection, bleeding disorders or anemia.10 Side effects and discomfort are major reasons why patients stop their treatment.10,11 Minimizing these side effects might lead to more compliance and acceptance of patients.
Therefore, our vision was to design the first targeted drug delivery system with spores!
Realistically spoken this is possible within half a year, so we set our goal to demonstrate with proof-of-principle experiments, that a nanobody with a defined specificity can be displayed on the surface of spores. Another motivation for some of us was to contribute to the scientific community with a number of useful, new biobricks.
1. http://www.ccfa.org/what-are-crohns-and-colitis/what-is-ulcerative-colitis/ (Crohn’s & Colitis Foundation of America)
2.Popp, C., et al., Expression Profile of p53 and p21 in Large Bowel Mucosa as Biomarkers of Inflammatory-Related Carcinogenesis in Ulcerative Colitis. Dis Markers, 2016. 2016: p. 3625279.
3. Zimmerman, J., D. Gavish, and D. Rachmilewitz, Early and late onset ulcerative colitis: distinct clinical features. J Clin Gastroenterol, 1985. 7(6): p. 492-8.
4. Da Silva, B.C., et al., Epidemiology, demographic characteristics and prognostic predictors of ulcerative colitis. World J Gastroenterol, 2014. 20(28): p. 9458-67.
5.Kryczek, I., et al., Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma. Oncoimmunology, 2016. 5(8): p. E1105430.
6. Larsson, K., L. Loof, and K. Nordin, Stress, coping and support needs of patients with ulcerative colitis or Crohn's disease: A qualitative descriptive study. J Clin Nurs, 2016.
7. Luan, Z.J., et al., Treatment efficacy and safety of low-dose azathioprine in chronic active ulcerative colitis patients: A meta-analysis and systemic review. J Dig Dis, 2016.
8. Wlodarczyk, M., J. Fichna, and A. Sobolewska-Wlodarczyk, Pharmacology and metabolism of infliximab biosimilars - A new treatment option in inflammatory bowel diseases. Pharmacol Rep, 2016. 68(4): p. 797-801.
9. Shen, B., The Evaluation of Postoperative Patients with Ulcerative Colitis. Gastrointest Endosc Clin N Am, 2016. 26(4): p. 669-77.
10. Connell, W.R., et al., Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut, 1993. 34(8): p. 1081-5.
11. Timmer, A., et al., Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev, 2016(5): p. CD000478.
2.Popp, C., et al., Expression Profile of p53 and p21 in Large Bowel Mucosa as Biomarkers of Inflammatory-Related Carcinogenesis in Ulcerative Colitis. Dis Markers, 2016. 2016: p. 3625279.
3. Zimmerman, J., D. Gavish, and D. Rachmilewitz, Early and late onset ulcerative colitis: distinct clinical features. J Clin Gastroenterol, 1985. 7(6): p. 492-8.
4. Da Silva, B.C., et al., Epidemiology, demographic characteristics and prognostic predictors of ulcerative colitis. World J Gastroenterol, 2014. 20(28): p. 9458-67.
5.Kryczek, I., et al., Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma. Oncoimmunology, 2016. 5(8): p. E1105430.
6. Larsson, K., L. Loof, and K. Nordin, Stress, coping and support needs of patients with ulcerative colitis or Crohn's disease: A qualitative descriptive study. J Clin Nurs, 2016.
7. Luan, Z.J., et al., Treatment efficacy and safety of low-dose azathioprine in chronic active ulcerative colitis patients: A meta-analysis and systemic review. J Dig Dis, 2016.
8. Wlodarczyk, M., J. Fichna, and A. Sobolewska-Wlodarczyk, Pharmacology and metabolism of infliximab biosimilars - A new treatment option in inflammatory bowel diseases. Pharmacol Rep, 2016. 68(4): p. 797-801.
9. Shen, B., The Evaluation of Postoperative Patients with Ulcerative Colitis. Gastrointest Endosc Clin N Am, 2016. 26(4): p. 669-77.
10. Connell, W.R., et al., Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut, 1993. 34(8): p. 1081-5.
11. Timmer, A., et al., Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev, 2016(5): p. CD000478.
