To enable XP patients to live safely under sunlight like normal individuals, this project has developed a
<strong>UV-driven gene switch</strong> and synthetic biology toolset that modulates the expression of the XPC protein in response to UV light, alleviating the symptoms of XP. The project started by <strong>simulating key protein complexes' motions</strong> involved in metabolic processes and gradually traced upstream, designing <strong>a sequence optimization tool</strong> for relevant mRNA sequences.
<strong>UV-driven genetic switch</strong> and synthetic biology toolset that modulates the expression of the XPC protein in response to UV light, alleviating the symptoms of XP. The project started by <strong>simulating key protein complexes' motions</strong> involved in metabolic processes and gradually traced upstream, designing <strong>a sequence optimization tool</strong> for relevant mRNA sequences.
</p>
<p>
Additionally, we <strong>mathematically modeled the gene circuit</strong> to depict the complete metabolic process within cells.
...
...
@@ -116,7 +115,7 @@
<listyle="font-size:22px">
<strong>Dynamic Simulations of Intracellular Gene Circuits:</strong></li>
<p>
After conducting a detailed analysis of the gene circuits in the project, we mathematically abstracted the circuits and solved ordinary differential equations to model the dynamics of each step in the UVB-induced gene switch signaling process. By integrating experimental data, this approach offers
After conducting a detailed analysis of the gene circuits in the project, we mathematically abstracted the circuits and solved ordinary differential equations to model the dynamics of each step in the UVB-induced genetic switch signaling process. By integrating experimental data, this approach offers
<strong>rapid numerical simulations with low cost and high adjustability</strong>, providing theoretical insights into the key dynamic behaviors of the system and offering efficient guidance for parameter tuning and optimization.
On this page, we show how XPCures is good and responsible for the world. We identified the problem with the support of a <B>Patient Journey Timeline</B>. All relevant stakeholders are identified, and we engage with all stakeholders to gather their needs, perspectives, and suggestions for our project. A comprehensive <B>Stakeholder Identification Map </B>was created, illustrating the relationships between various stakeholders. Besides, a <B>Power-Interest Matrix</B> is positioned to illustrate the relative level of interest and power of stakeholders regarding XPCures. Then we applied <B>Value-sensitive analysis</B> as iGEM TU Eindhoven 2022 employed, analyzing the design requirements based on the values, interests, and ethical considerations of each stakeholder to ensure that our project aligns with their needs and expectations. At last, we reflected on the potentials and challenges of XPCurs from six aspects.
</p>
</div>
<divclass="title"id="Identifying the problem">
Identifying the problem
</div>
<divclass="block">
<p>
Whilst brainstorming for a topic of our research, a name none of us has ever heard of popped up on the screen. Xeroderma Pigmentosum, or XP, is an extremely rare genetic skin disease, with a global incidence of only 0.004%. As we dig deeper into the illness, a horrendous truth striked all the team members: XP patients may possibly die from simply walking under the sun. Their particular biological mutation, a defect in one of the XPC gene for XPC (a subtype of XP)<sup>[1]</sup> patients, for example, causes them to be significantly susceptible to UV light. That is, no sunshine, no outdoor activities, no regular socializing, no freedom. Through close interviews with XP patients and their family (since most patients are underaged), we learned that people diagnosed with XP will suffer a life-time of more than simply departure from sunlight. Imagine being fully “armed” with a heavy UV-proof face mask and a one-piece UV-proof clothing that covers you from head to toe whenever you are outside, especially during torrid summers when UV rays are the strongest on earth. The sweltering heat is not the worst. People on the street will be judging, not only for the peculiar outfit, but also for the dark brown spots on your face. You are always known as the weirdo; kids in school would never speak to you, and colleagues at work never take you seriously. <b>Imagine never being able to live like a normal person does</b>. Even worse, with a 100% risk of getting skin cancer, two-thirds of XP patients die before the age of 20, according to National Center of Biotechnology Information.
</p>
<p>
Currently, there is no cure for XP. During one interview, the patient describes that she is practically waiting for death, as the symptoms only get worse and worse without any way to inhibit its growth. The huge tragedy behind this situation is that the National Medical Products Administration of the People's Republic of China has not yet included XP in the official list of rare diseases. Due to the very few lack of awareness, there are not enough expertise research on this particular disease to make it considered an important area of focus. Since there are only around 6,000 diagnosed patients in China, the potential market is too limited for any large pharmaceutical company to even consider putting effort into developing medications for XP.
</p>
<p>
Luckily, gene therapy can be a potential cure for XP. Inspired by the gene therapy for Epidermolysis Bullosa (EB) in the United States that has recently been approved by the FDA, we wanted to design a gene therapy specifically aimed to alleviate the symptoms of XPC, which can also be altered slightly to aim at other subtypes of XP. By inserting XPC gene directly into the epidermal stem cells through microneedles, XPCures allows XP patients to finally dance under the sun. Though our method may not radically eliminate the illness embedded in the genes of XP patients, it provides an alternative solution to the longstanding issues that they encounter.
</p>
<p>
The simplified timeline below illustrates the general journey an XP patient must undergo throughout the course of development of the disease. With the innovative gene therapy, XPCures, iGEM SJTU-BioX Shanghai also aims to call attention to the often neglected disease, and by doing so eliminate the obstacles a patient would encounter during diagnosis and therapy to our greatest extent.
</p>
<pstyle="font-size: 10%; text-align: left;">
<strong>[1]:</strong> XP is classified into 8 categories according to current researches: XPA, XPB, XPC, XPD, XPE, XPF, XPG, and XP-variant.
<figcaption><b>Fig.1 Patient Journey Timeline</b> The Regular Journey of XP Patients.</figcaption>
</div>
<p>
In order to validate the practicability of our project, our HP team interviewed several stakeholders, including individuals and organizations, to investigate the perception of our project amongst the society. After interacting with various stakeholders relevant to our field of research, we classified them into six distinct categories, shown and briefly described in the following section. The <b>interactive stakeholder identification map</b> below specifically indicates the correlations among different stakeholders by illustrating the flow of influence.
</p>
<divclass="title3"><i>Academia</i></div>
<p>
Acadamia consists of organizations of research expertise on XP and genetic diseases in general, such as renowned university research institutes.
</p>
<divclass="title3"><i>Healthcare</i></div>
<p>
Healthcare consists of hospitals and hospital workers. We interviewed dermatologists and geneticists from various hospitals across few cities in China.
Public Organizations consists of authorized organizations concerned with public health and well-being.
</p>
<divclass="title3"><i>Government</i></div>
<p>
Government consists of the government itself as well as relevant organizations and advising bodies.
</p>
<divclass="title3"><i>Industry</i></div>
<p>
Industry consists of pharmaceutical companies that direct researches along the path of XP medications.
</p>
<divclass="title3"><i>Patients</i></div>
<p>
Patients consists of patients diagnosed with various subtypes of xeroderma pigmentosum (XP) and parents or guardians of those patients. We interviewed one patient diagnosed with XPA, one patient diagnosed with XPC, and the parent of two underaged patients diagnosed with XPC.
</p>
<divclass="title3"><i>Local Community</i></div>
<p>
Local Community consists of local organizations and the general public and society.
<figcaption><b>Fig.2</b> Stakeholder Identification Map. The diagram displays all the stakeholders that are correlated with XPCures, some of which we have interacted closely with, as well as the flows between the sectors.</figcaption>
<divclass="title2"id="Management"> 2. Management
</div>
<divclass="block">
<p>
Figure 3 below shows a power-interest matrix<sup>[2]</sup> for all the stakeholders, arranging them according to their interest in XPCures and their impact on the design. The matrix effectively helps us identify the most relevant stakeholders. That is, the most interested and most powerful/impactful ones. We developed distinct strategies upon interacting with stakeholders in each of the four quadrants.
</p>
<divclass="title3"><i>High interest, high power</i></div>
<p>
The stakeholders in this quadrant are the ones most relevant to XPCures, and thus deserve the most attention when building up our product. We have interacted with all of the stakeholders here which we have the access to, asked for suggestions about our project, and improved upon our design after close conversations with them. As mentioned previously, it is crucial to meet the expectations of these stakeholders in order to make XPCures a product well-suited for the general society.
The stakeholders in this quadrant are the primary consumers of XPCures, and they are the major reason XPCures exists. Thus, it is important to satisfy the needs of these stakeholders despite their limited power. We went into thorough conversations with members of these stakeholders and encouraged them to keep in contact with us by following our official account to ensure that they will be informed upon any updates in our progress.
</p>
<divclass="title3"><i>Low interest, high power</i></div>
<p>
The stakeholders in this quadrant are generally the ones that are harder to gain access to. These global health organizations are crucial for the promotion of XPCures and raising awareness for rare diseases and orphan drugs. However, since they would have little interest in XPCures, the connection with them is relatively low and mainly single-sided. We aim to simply satisfy certain laws passed by these organizations.
The stakeholders in this quadrant are the least relevant to XPCures, so there will be limited focus on them. We do, in occasions, reach out to them for needs of expertise advice.
</p>
<pstyle="font-size: 10%; text-align: left;">
<strong>[2]:</strong> Also known as the Mendelow's Matrix
<figcaption><b>Fig.3</b> Power-Interest Matrix. The matrix visualizes the relative level of interest and power of stakeholders regarding XPCures.</figcaption>
Iyer SS, Cheng G. Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease. Crit Rev Immunol. 2012;32(1):23. doi:10.1615/CRITREVIMMUNOL.V32.I1.30
</li>
<li>
Tough DF, Sprent J. Life span of naive and memory t cells. Stem Cells. 1995;13(3):242-249. doi:10.1002/STEM.5530130305
</li>
<li>
Kojima R, Aubel D, Fussenegger M. Building sophisticated sensors of extracellular cues that enable mammalian cells to work as “doctors” in the body. Cellular and Molecular Life Sciences. 2020;77(18):3567-3581. doi:10.1007/s00018-020-03486-y
</li>
<li>
<ahref="https://www.who.int/zh/news-room/fact-sheets/detail/patient-safety">World Health Organization. Patient Safety</a>
</li>
<listyle="word-break: break-all">
Hruskova Z, Rihova Z, Mareckova H, et al. Intracellular Cytokine Production in ANCA-associated Vasculitis: Low Levels of Interleukin-10 in Remission Are Associated with a Higher Relapse Rate in the Long-term Follow-up. Arch Med Res. 2009;40(4):276-284. doi:10.1016/j.arcmed.2009.04.001
