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Our Motivation
On our journey to decide on a project for the iGEM competition, we knew, we wanted to lay our focus on a medical issues. 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, made the issue more relatable for us. However, ulcerative colitis is a disease which can be found in every age. (figure 1)

At what age were you diagnosed with UC?

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 year1. In some cases the diagnosis can take up to 20 years, since the symptoms are not very unspecific.2 Patients suffer from diarrhea, abdominal pain, rectal bleeding, fatigue, ulcers and fever. Ulcerative colitis is represented in every age and limits the patient's everyday life, since you end up planning you whole life depending on your gut.
At the moment, there is no cure for ulcerative colitis.
Patients need to take daily medication that cause systemic side effects like tiredness in more than 60% of the cases and also joint pain, skin rashes headaches, depressions or nausea. In our survey, only 10% stated that they had no side effects at all.

What side effects occurred when taking your medication?

When we heard about this disease, we felt than an improvement of the therapy is long overdue. By enhancing current strategies we aim to enhance the quality of patients lives.
While looking into current treatments, we learned about the high amount of negative side effects of most medications. A nuisance, that most of us had already experienced when taking medication. You take some drugs that intend to make you feel better, but in the end, the negative side effects can be even worse than the disease 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 issue for a long time and finally decided to focus our project on improving the targeted drug delivery systems.
From the beginning, we were fascinated with 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 to modify the spores, so they are able to express specific proteins. Spores offer 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, high quantities of spores can be easily produced 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 . This advantage can be used to improve targeted drug delivery.

This is how the idea of targeted therapy with spores was born!

There are several reasons, why targeted therapy with spores can 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 rectum while Crohn’s disease affects the entire bowel.3 Therefore, the target is very clear, limited.and can easily be reached orally and rectally.
Currently,neither a cause nor cure for this disease are known, even though ulcerative colitis is a high risk factor for colon cancer4.The pathogenesis of ulcerative colitis is not yet well understood, 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, go into apoptosis5.

Since there are strong implications of ulcerative colitis becoming a lifelong condition, patients heavily rely on therapeutic options. Current therapies consist of steroids and long-term use of immune suppressing or modeling drugs like azathioprine, therapeutic monoclonal antibodies such as infliximab ® or at late stage, colon removal surgery6,7,8.Both steroids and immune modeling drugs can cause severe systemic side effects like cytopenia (low blood cell counts), resulting in higher risk for infection, bleeding disorders or anemia9. Side effects and discomfort are major reasons why patients decide to stop treatment10,11.Minimizing these side effects might lead to more consent and acceptance by the patients.

Therefore, our vision was to design the first targeted drug delivery system with spores!

Realistically spoken this is not 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 us was to contribute to the scientific community with a number of new, useful biobricks.
1. Da Silva, B.C., et al., Epidemiology, demographic characteristics and prognostic predictors of ulcerative colitis. World J Gastroenterol, 2014. 20(28): p. 9458-67.
2. 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.
3. (Crohn’s & Colitis Foundation of America)
4.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.
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.