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<h2 align="center">INTEGRATED HUMAN PRACTICES</h2>
<p align="center" style="font-size:27px"><strong>Overview</strong></p>
<p class="pl-20 pr-20">Amidst the first wave of the Covid-19 pandemic in India, a group of undergraduate students from IISER Thiruvananthapuram came across iGEM. Being extremely keen on synthetic biology and recognizing the potential iGEM had to develop their interest in synbio, they decided to give it a shot.
</p>
<p class="pl-20 pr-20">Our search for a plausible iGEM project led us to scour through numerous wikis of erstwhile iGEM teams. Catechewing coli- an eco-friendly enzyme to remove paan stains from walls by iGEM Ruia Mumbai 2018 grabbed our attention. Taking inspiration from their project, we explored many different issues, primarily prioritizing environmental concerns.
</p>
<p class="pl-20 pr-20">We also observed black patches on walls, later identified as a collection of several mold species. We decided to develop an antifungal enzyme in the form of recombinant chitinases to eradicate black mold thriving on walls of buildings because they were nasty to look at. We started working along this line and identified a few fungal species growing on our campus’ walls. Our interactions with protein biologists helped us design gene sequences that would later produce our recombinant chitinases.
</p>
<p class="pl-20 pr-20"> Dr. Binod Parameswaran pointed out the difficulties of manufacturing an enzyme for application in external settings due to concerns over its stability and the high cost-benefit ratio. He suggested that we could make a more significant impact through our project by showing us the plight caused by fungi in mainly two domains: health and agriculture.
</p>
<p class="pl-20 pr-20"> Prevention is better than cure. Developing an enzyme that would remove molds from walls would substantially prevent the diseases they caused. This belief of ours largely met with dissent from many medical experts whom we consulted to assess the impact of our project. Regardless of medical experts not being our direct stakeholders, our correspondence with them helped us realize that removing molds from walls would not significantly reduce the fungal spore contamination in the atmosphere. The persistent fungal spores can still lead to severe complications in people. Additionally, our parallel dialogue with local farmers (Farmer) pointed at agricultural losses due to fungal infestation, especially in rubber plantations.
</p>
<p class="pl-20 pr-20">Consequently, we were open to two choices:</p>
<ol class="ordered-list"><li><p> An antifungal therapeutic solution to fungal infections in humans.</p>
</li>
<li><p> An antifungal solution to the havoc wreaked by losses in agriculture due to fungal infestation.
</li></ol>
<p class="pl-20 pr-20">During this time, India witnessed an enormous soar in the number of Mucormycosis cases as a post covid complication. This essentially helped us in resolving the dilemma and chose to work on the former option, ergo <b>‘Moldemort’</b>- a class of antifungal therapeutics to invasive fungal infections. In addition to the recombinant genes we had already designed, our team developed a new gene from two bacterial species, mainly to target <i>Rhizopus spp.</i>, which is one of the main causative agents of Mucormycosis.</p>
<p class="pl-20 pr-20">We also indulged in interactions with our stakeholders through surveys and awareness programmes to educate the public about fungi and their menace. Their feedback and suggestions, along with a discussion with Dr. Rachit Agarwal, were instrumental in designing our drug-delivery system. Dr. Ravindra Ghooi’s guidance helped us devise a plan for implementing the future aspects, including commercialization and clinical trials.
</p>
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<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
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</div>
<div class="timeline-label">
<blockquote>Prof. M. R. N. Murty</blockquote>
<h2>Distinguished Professor and AstraZeneca Chair, IIBAB Bengaluru.</h2> </div>
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<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
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</div>
<div class="timeline-label">
<blockquote>Prof. J.N.Moorthy</blockquote>
<h2>Director,IISER Thiruvananthapuram</h2> </div>
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<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
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</div>
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<blockquote>Dr. Binod Parameswaran</blockquote>
<h2>Principal Scientist, NIIST, Thiruvananthapuram</h2> </div>
</div>
</article>
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<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
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<blockquote>Medical doctors</blockquote>
<h2>Dermatologist, Paediatrician, General physician,Pulmonologist</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
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</div>
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<blockquote>Gigi Kurian</blockquote>
<h2>.Farmer</h2> </div>
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</article>
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<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
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<blockquote>Dr.Robin Allshire</blockquote>
<h2>Professor of Chromosome Biology, University of Edinburgh.</h2> </div>
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<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
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<blockquote>Patients</blockquote>
<h2>Literature survey</h2> </div>
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<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
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</div>
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<blockquote>Dr.Hariprasad.P</blockquote>
<h2>Associate Professor,IIT Delhi</h2> </div>
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<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
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<blockquote>General Public</blockquote>
<h2>For high schoolers:Reading Day</h2> </div>
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<blockquote>Dr. Harilal Madhavan
</blockquote>
<h2>Ad-hoc Faculty (Humanities)
IISER, Thiruvananthapuram.</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote> General Public
</blockquote>
<h2>Survey on the incidence of fungal infections among people residing in Kerala
</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote>General Public</blockquote>
<h2>Dark Side of Fungi</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-syringe"></i>
</div>
<div class="timeline-label">
<blockquote>Dr. Rachit Agarwal
</blockquote>
<h2>Assistant Professor
IISc, Bengaluru</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote>Fr. Jeejo</blockquote>
<h2>MKMRRC, Thrissur, Kerala</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-book-open"></i>
</div>
<div class="timeline-label">
<blockquote> Dr. Subha C. C.
</blockquote>
<h2>Assistant Professor, School of Arts and Humanities, Christ University,</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote>Dr. Chintu Ravishankar</blockquote>
<h2>Associate Professor, College of Veterinary and Animal Sciences, Wayanad, Kerala..</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote>Dr. David Denning</blockquote>
<h2>Chief Executive,
Global Action Fund for Fungal Infections-an NGO</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-syringe"></i>
</div>
<div class="timeline-label">
<blockquote> Dr. Ravindra Ghooi
</blockquote>
<h2>Director,
Scientia Clinical Services</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholder</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote> General Public
</blockquote>
<h2>Survey on Drug preferences of the public
</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Expert</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-book-open"></i>
</div>
<div class="timeline-label">
<blockquote> Ms. Parvathy Suresh
</blockquote>
<h2>Graduate student
National Law School</h2> </div>
</div>
</article>
<article class="timeline-entry">
<div class="timeline-entry-inner">
<time class="timeline-time" datetime=""><span>Stakeholders</span> <span></span></time>
<div class="timeline-icon bg-primary">
<i class="fas fa-user-alt"></i>
</div>
<div class="timeline-label">
<blockquote> General public
</blockquote>
<h2>Book for kids:The World Of Fungi</h2> </div>
</div>
</article>
</div>
</div>
</div>
</body>
<p align="center" style="font-size:35px"><strong>Understanding the problem</strong></p><br>
<p class="pl-20 pr-20">Fungal diseases have been on a rise with over 1 billion cases of fungal infections every year. <b>Invasive fungal infections (IFIs)</b> result in approximately <b>1.7 billion deaths per year</b> making it one of the most vicious diseases in the current scenario<sup>[1]</sup>. During the <b>Covid-19 pandemic</b>, there was a rapid increase in the IFI cases worldwide, especially in our country, India. IFIs also carry a 60-90% mortality rate among all ICU patients<sup>[2]</sup>. Although fungal infections have been on the rise, it wasn't until the wake of Covid-19 that this issue was brought to the limelight. Even before the pandemic, fungal infections had have been on a rise due to <b>increasing usage of medical devices such as catheters<sup>[3]</sup> or cardiac valves (formation of biofilms),immunosuppressants and organ transplants.</b>There are currently five classes of antifungal drugs such as Azoles, Polyenes, Echinocandins<sup>[4]</sup> etc. Most of these antifungal drugs target similar pathways involving ergosterol biosynthesis. Tackling these infections has proven difficult due to a limited repertoire of antifungal drugs, their costs, drug interactions, the routes of administration, and side effects like nephrotoxicity <sup>[5],[6]</sup>. Furthermore, the rampant use of these limited drugs raises the alarming possibility of developing drug-resistant fungal strains.
<sup>[7]</sup>. </p>
<p class="pl-20 pr-20">Aware of this issue, our team at IISER-TVM set out to develop a solution to alleviate the suffering of millions of people across the world. We embarked on a journey to understand the underlying principles of fungal infections and tried to address the root cause of the issue. Almost immediately, the stark inadequacy of existing antifungal drugs was glaringly apparent. <b>Existing therapeutics</b> not only foreshadow the emergence of <b>drug-resistant fungal strains</b>, as proven by many studies but may also have significant <b>cytotoxic and nephrotoxic effects<sup>[8]</sup>.</b></p>
<p class="pl-20 pr-20" style="font-size:20px" style="font-family:'Garamond'"><strong><i>Our efforts culminated in the development of "Moldemort," a novel antifungal agent, which we believe holds the potential to reduce the global burden of invasive fungal infections significantly.</i></strong> </p><br>
<p align="center" style="font-size:35px"><strong>Designing the Solution</strong></p><br>
<p class="pl-20 pr-20">Once we understood our problem, we conducted in-depth literature studies to formulate recombinant chitinases. We laid out the experimental plans planned out through intensive brainstorming sessions. To better understand and assess the problem, the team met various experts from diverse fields and significant stakeholders. </p>
<p class="pl-20 pr-20">The expert interactions we conducted greatly influenced our experimental plan. Our parallel interaction with stakeholders gave us insights into the potential broader impact of our project and methods to address the gaps between what society wanted and what we had. Furthermore, we shifted the project’s initial goal of tackling fungal infestation on walls to develop a novel antifungal therapeutic solution solely based on our stakeholders’ inputs. Additionally, we added BC2-our fourth recombinant chitinase combo, to our initial list of three. This gene was purely designed against <i>Rhizopus spp.</i>, which is the causative agent of Mucormycosis.
</p>
<p class="pl-20 pr-20">Further studies on this matter led us to realize that India has a relatively higher load of invasive fungal infections among the affected Asian population. The need for affordable and effective antifungal drugs with minimum side effects dramatically increased the relevance of our project, particularly in the Indian scenario.
</p>
<br>
<p class="text-center" style="font-size:33px"><strong>Expert Interactions</strong></p>
<br>
<div class="image-block, text-center">
<img src="assets/img/hp/ihp/Expert_Interactions.png" alt="sample image" class="png-fluid" width="800"
height="450" /></div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>1. Prof. M. R. N. Murthy and Prof. H. S. Savitri </b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Wetlab</strong></a></div>
<p class="pl-20 pr-20">Prof. M. R. N. Murthy (Photograph)<br>
Distinguished Professor and AstraZeneca Chair<br>
Indian Institute of Bioinformatics and Applied Biotechnology, Bengaluru<br><br>
Prof. H. S. Savithri (Photograph)<br>
Faculty<br>
Department of Biochemistry<br>
Indian Institute of Science, Bengaluru<br>
<p class="pl-20 pr-20"><i><b>It is not only bacteria that produce chitinases, certain plants naturally produce chitinases too.
</b></i></p>
<p class="pl-20 pr-20">Prof. M.R.N. Murthy is a renowned crystallographer who retired as a professor of molecular biophysics at the Indian Institute of Science, Bangalore. He is currently the Distinguished Professor and AstraZeneca Chair at the Institute of Bioinformatics and Applied Biotechnology. His research interests include protein structure and functions, X-ray crystallography and virus structure and assembly. Prof H. S. Savithri is a member of the biochemistry faculty at the Indian Institute of Science, Bangalore. She works on plant virology, enzymology and protein chemistry.
We had an opportunity to interact with them during the initial phase of our project. </p>
<p class="pl-20 pr-20">They were inevitable during the initial stages of the project. They advised us to work with recombinant plant chitinases along with the bacterial recombinant chitinase genes we had already designed. They also enlightened us about the advantage of using endochitinases over exochitinases as the former can lyse the substrate at several locations unlike the latter. They also stressed the importance of choosing an enzyme that would work at room temperature in a neutral pH range.</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list"><li><p>We chose bacterial chitinase based on our literature review/studies. </p>
</li>
<li><p>We were confused regarding the choice of exo and endo chitinases. </p>
</li>
<li><p>Domains were not connected using linkers.</p>
</li>
<li><p>The focus of the project was solely on black mould on walls. </p>
</li></ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong>
</p>
<ol class="ordered-list">
<li><p>Domains could be connected using linkers to preserve the activity of individual domains. </p>
</li>
<li><p>Check about plant chitinases also.[Many plants use their own chitinases to resist fungal infections.]</p>
</li>
<li><p>Consider temperature and pH-dependent activity of chitinases</p>
</li>
<li><p>The cutoff weight of the protein constructs should be taken into account because larger proteins are difficult to fold and express.</p>
</li>
<li><p>Choice of endo-chitinases over exo-chitinases would be better as the former attack the substrate at several locations and hence can provide better antifungal proteins </p>
</li>
<li><p>The project could be expanded to prevent fungal contamination in laboratory settings.</p>
</li></ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong>
</p>
<ol class="ordered-list">
<li><p>Domains were connected using linkers.</p>
</li>
<li><p>Shifted the attention from bacterial chitinases to both bacterial and plant chitinases.</p>
</li>
<li><p>The temperature and pH activity of enzymes were reviewed and chosen in such a way that they are active at room temperature and within a neutral pH range.</p>
</li>
<li><p>The cutoff size was decided to be at 100kDa.</p>
</li>
<li><p>Endo-chitinases chosen over exo-chitinases</p></li>
</ol>
</div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>2. Prof. J. N. Moorthy </b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Project Design</strong></a></div>
<p><strong></strong>
<br> Director
<br> Indian Institute of Science Education and Research, Thiruvananthapuram</p>
<br>
<p class="pl-20 pr-20"><b><i> How broad is ‘broad-spectrum’? </b></i>
</p>
<p class="pl-20 pr-20">Initially, our project aimed to develop an antifungal in the form of a broad-spectrum chitinase. We hypothesized that our recombinant chitinases would have the ability to be effective against a broad range of fungal species, considering that chitin is an essential component of fungal cell walls. However, we did not have any strict definition of the species we would be targeting.
</p>
<p class="pl-20 pr-20">Our interaction with Prof. Moorthy made us rethink our goals. We then decided to streamline our project to a more specific target. Therefore, we focused on obtaining a recombinant chitinase with a higher chitinolytic activity than the wildtypes.
</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>Wanted to make a master chitinase, effective against all fungi i.e, target species of our master chitinase was vague.</li></ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>What advantages does our chitinase have to offer over the currently available chemical antifungals/fungicides?
</li>
<li>How broad is “broad-spectrum”? </li>
</ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong></p>
<ol class="ordered-list">
<li>Master chitinase to the broad spectrum</li>
<li>Defined “broad” in broad-spectrum i.e., specified what all species our chitinase will target. Species:<i> Penicillium, Aspergillus niger, Aspergillus flavus, Fusarium, Rhizopus, Cladosporium</i>. </li>
<li>Decided to analyze the side effects and mode of action of current antifungals available in the market.</li>
</ol>
</div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>3. Dr. Binod Parameswaran </b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Wetlab,
Project Design</strong></a></div>
<p class="pl-20 pr-20">
Principal Scientist <br>
National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram</p>
<br>
<p class="pl-20 pr-20"><b><i> Your project can have a greater impact on the community. Why not try a different track? </b></i>
</p>
<p class="pl-20 pr-20"> Dr Binod Parameswaran is a Principal Scientist at the National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala. His lab primarily focuses on various industrial applications of microbial enzymes such as biocatalysts, biofuels, production of biopolymers etc. He had also worked extensively on chitinases during his Master’s Degree. The team had numerous interactions with him regarding the project and its applications in the real world. He has also helped us in troubleshooting various experimental aspects of our chitinases.
</p>
<p class="pl-20 pr-20"> Initially, our project aimed to remove the black mould thriving on walls using our recombinant chitinases. However, Dr Binod briefed us about the challenges we could face during the external application of our recombinant chitinases, out of which the enzyme stability in an external environment seemed to be of great concern. He had also suggested looking at the therapeutic or agriculture applications for our project.
</p>
<p class="pl-20 pr-20">His expertise in working with chitinases helped us in choosing <i>E.coli</i> as our chassis and was instrumental in designing the experimental setup for antifungal assays.
</p><br>
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<h3>A. 1st Interaction (22-05-2021)</h3>
<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>The team had designed 4 different recombinant chitinases that include domains from various plants and bacteria.</li>
<li>The primary application of our chitinase was to remove moulds from walls. There were some ideas of using it as a therapeutic drug or as a biocontrol agent in Agriculture. </li>
<li>If a therapeutic drug was the choice, we planned on using nanoparticles as a drug delivery vehicle.</li>
</ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>Using only enzymes on walls had several challenges like:
<br>
a. Enzyme optimum temperature and pH might not be maintained. <br>
b. Enzyme loses stability quickly. <br>
c. The cost of production would be very high. <br>
d. The protein solution might induce the growth of some other microbes. <br>
e. The enzyme solution might have non-specific activity (affect insects).</ul>
<li> Some types of stabilizers (polysaccharides) could be added like sorbitol or starch to increase the shelf life of our protein. </li>
<li>Could look into further applications like:<br>
a. Therapeutic Drug with the proper delivery mechanism. <br>
b. Biocontrol agent in Agriculture. <br>
c. As an ointment or anti-dandruff product. </li>
<li> If planning on a therapeutic drug, we need to account for the immune response, the localization of the product and the cost of developing it.
<br>
a. Using magnetic nanoparticles to allow localization of a drug to the target site.<br>
b. Using a cocktail of enzymes to make it more effective. </li> </ul>
<li> If the idea is still to be used on walls, then we can think about using the engineered organism to produce our enzyme upon induction.
<br>
a. The organism can be incorporated into bricks or paints.</li>
<li>For expressing bacterial chitinases, <i>E.coli</i> is a good choice whereas Eukaryotic chitinases are best produced in Eukaryotic cell lines like <i>Pichia pastoris.</i> </li>
</ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong></p>
<ol class="ordered-list">
<li>We decided to focus more on the interior walls of hospitals to protect the enzyme from the extreme conditions outside.</li>
<li>Began looking further into the idea of using chitinase as a therapeutic drug and its delivery using nanoparticles.</li> </ol>
<br>
<h3>B. 2nd Interaction (8-07-2021)</h3>
<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>The team had made progress on successfully cloning one of the proposed recombinant proteins.</li>
<li>A crude design of the upcoming experimental assay was made but a lot of doubts regarding the method to be used arose. Hence a second meeting was required with Dr. Binod to clarify the doubts.
</li> </ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>Suggested to use DNS (3,5-Dinitrosalicylic acid) assay which was a common and conventional method to measure chitinase activity.</li>
<li>While conducting temperature and pH assay of the enzyme, it is important to note that,<br>
a. The optimum pH of most bacterial and plant chitinases are within 5-9.<br>
b. The optimum temperature of most bacterial and plant chitinases are within 30°C-60 °C </li>
<li>While performing the Zone of inhibition, temperature and pH assay, the crude enzyme could also be used instead of purified protein.</li>
<li>Explained in detail how to perform a Zone of inhibition assay.</li></ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong></p>
<ol class="ordered-list">
<li>The DNS method was chosen to measure the chitinase activity of our enzyme.</li>
<li>A zone of inhibition assay was carried out with crude enzyme first.</li> </ol>
<br>
<h3>C. 3rd Interaction (4-09-2021)</h3>
<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>The team was facing difficulties carrying out the assays with the crude enzyme. </li>
<li>Could not estimate activity using DNS assay.</li>
<li>Colloidal chitin solution was precipitating.</li> </ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li> Dr. Binod reviewed our method of experiment and asked us to change the preparation of colloidal chitin.</li>
<li> A water bath should be used instead of an incubator as the heating would be uniform.</li>
<li> The moisture content of Colloidal chitin could be determined without drying the entire product.</li>
<li> Zone of inhibition to be conducted with spore suspension instead of inoculum.</li>
<li> Adding stabilizers (like sorbitol, starch) to increase the stability of our enzyme.</li>
<li> Provided us with a formula to calculate Enzyme units from OD540 absorbance data.</li> </ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong></p>
<ol class="ordered-list">
<li>Colloidal chitin was prepared again using the modified method.</li>
<li>Water baths were used instead of incubators to heat the solutions.</li>
<li>A zone of inhibition was performed with spore suspensions as well.</li>
<li>Calculated Enzyme Activity in units from the OD540 absorbance data.</li> </ol>
</div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>4. Dr. Robin Allshire </b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Project design</strong></a></div>
<p class="pl-20 pr-20">
Wellcome Principal Research Fellow and Professor of Chromosome Biology<br>
University of Edinburgh</p>
<p class="pl-20 pr-20"><b><i> Targeting multiple molecules in the fungal cell wall at the same time would be a more efficient way to solve the issue of antifungal resistance.</b></i>
<br>
<p class="pl-20 pr-20">Robin Allshire is a Wellcome Principal Research Fellow and Professor of Chromosome Biology at the University of Edinburgh. His research focuses on epigenetic inheritance: establishment and transmission of specialized chromatin domains. He discovered an epigenetic mechanism that allows fungi to develop resistance to antifungal drugs without alterations to their DNA, which helps understand how pathogenic fungi become resistant to the limited number of available antifungals agents in clinical and agricultural areas. </p>
<p class="pl-20 pr-20">Dr. Allshire enlightened us with the emergence of antifungal resistance and the consequent need for new antifungal agents. As a result, we wanted to ensure that our recombinant chitinases would help resolve this issue. An exact solution cannot be designed without rigorous laboratory experiments; however, we could conduct studies on antifungal resistance in 96-well plates. Moreover, targeting multiple molecules in the fungal cell wall (glucan and chitin) simultaneously can increase the success percentage of the antifungal activity of the drug.</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>We aimed to target only chitin in the fungal cell wall.</li>
<li>We didn’t know how to check for antifungal resistance.</li></ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>Targeting multiple molecules in the fungal cell wall such as glucan and chitin at the same time can decrease the chances of antifungal resistance.</li>
<li>We can check for antifungal resistance using 96-well plates.</li></ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions::</strong></p>
<ol class="ordered-list">
<li>We planned to make a cocktail of glucanases along with chitinases in a later stage of our project.</li></ol>
</div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>5. Dr. Hariprasad P.</b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Safety</strong></a></div>
<p class="pl-20 pr-20">
Associate Professor<br>
Centre for Rural Development and Technology<br>
Indian Institute of Technology, Delhi
</p>
<p class="pl-20 pr-20"> </p>
<br>
<p class="pl-20 pr-20">
<b><i> Why prepare your fungal culture media in petri plates? Make the media slant by preparing them in test tubes.</b></i>
</p>
<p class="pl-20 pr-20">Dr. Hariprasad P is an Associate Professor, at the Centre for Rural Development and Technology, Indian Institute of Technology, Delhi. He had worked on fungal samples as a part of his research career. We got his expert advice on how to handle fungus safely derived from environmental origin.</p>
<p class="pl-20 pr-20">Dr. Hariprasad’s experience in working with fungal samples proved to be of great help to us. It was after his suggestion that we started preparing fungal cultures in a slant medium of Potato Dextrose Agar. Additionally, he was able to provide us with authoritative resources, which was a great succour to identify and classify fungal species under different risk groups.</p>
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<class="pl-20 pr-20"><strong>Status of project before the discussion with them:</strong></p>
<ol class="ordered-list">
<li>Fungal samples were mostly cultured on Petri dishes.</li>
<li>Confusion regarding Biosafety Cabinet to handle fungal samples</li>
<li>
Confusion regarding the procedure for inducing the wheat chitinase secretion in plants, using fungi.
</li></ol>
<class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>Using slant Potato Dextrose Agar (PDA) prevents the spreading of spores even while working in a biosafety cabinet.</li>
<li>The biosafety cabinet of class II type A2 equipped with a HEPA filter is good enough to work with fungi belonging to risk groups 1 and 2.</li>
<li>Suggested some sources to look upon the risk group of fungi found on the wall.</li>
<li>He suggested spraying the spore suspension to induce wheat Chitinase secretion and also explained the protocol for making spore suspension.</li></ol>
<class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong></p>
<ol class="ordered-list">
<li>Fungal cultures are made in slant PDA for identification and assays.</li>
<li>The wheat sample induced with spore suspension showed high chitinase secretion.
</li></ol></div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>6. Dr. Rachit Agarwal</b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Proposed Implementation</strong></a></div>
<p class="pl-20 pr-20">
Assistant Professor<br>
Indian Institute of Science, Bengaluru
</p>
<p class="pl-20 pr-20">
<b><i> Considering the difficulty in manufacturing capsules, why don’t you try nanoencapsulation?</b></i>
</p>
<p class="pl-20 pr-20">Dr Rachit Agarwal is an assistant professor at the Centre for Biosystems Science and Engineering, IISc Bangalore. His lab focuses on using a wide range of tools and concepts such as nano and micro particles, hydrogels, scaffolds and 3D organoids to generate treatment for diseases like tuberculosis and osteoarthritis. His insights were highly valuable to design an efficient drug-delivery system for the therapeutic we were developing.
</p>
<p class="pl-20 pr-20">Our project would be successful only if it happens to be of any use to the common man. Our initial idea was to engineer a hollow capsule that would carry our recombinant chitinase to the human body. Dr. Agarwal’s expertise in nano-particle drug-delivery systems proved to be of great help to us. He stated that nano-encapsulation of our recombinant chitinase would be an easier and efficient technique than a capsule. His advice of using Poly Lactic-co-Glycolic Acid (PLGA) as the nano-polymer was incorporated into our project as it would elicit a very minimal immune response. Furthermore, he also stressed the importance of using stabilizers like Trehalose for increased shelf-life of the drug.
</p>
<p class="pl-20 pr-20">Moreover, if we would want to expand our project to the realm of dermatological fungal infections, hydrogels would be a better approach than ointments and have an added benefit of not requiring stabilizers.
</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong>
</p>
<ol class="ordered-list">
<li>Initial idea was to engineer a hollow capsule for the delivery of our recombinant chitinase inside the human body.</li>
<li>If our recombinant chitinase is effective we thought to formulate an ointment for superficial skin infections in the future.</li>
<li>We planned on using NIR [near infrared] light triggered drug delivery.</li></ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong>
</p>
<ol class="ordered-list">
<li>Hollow capsules are difficult to manufacture.</li>
<li>It would be better to formulate hydrogels than ointments because they don’t require stabilisers.</li>
<li>Unsterilised nano vectors can host pathogens that can lead to infections and other associated problems in our body upon its administration.</li>
<li>If the drug is designed to target lung tissue then NIR will not be of much use as the depth of penetration of NIR will be less compared to the thickness of lung tissue.</li>
<li>Even though most of the drugs do not take into account active targeting during their manufacture, it is still a better option to use it. Active targeting is able to significantly increase the quantity of drug delivered to the target site compared to free drug or passively targeted nanosystems. This is achieved through the decoration of the nanocarrier surfaces with receptors (in our case dectin-1) binding to the beta-glucans found on fungal cell walls.
</li></ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong>
</p>
<ol class="ordered-list">
<li>We decided to use PLGA as the potential polymer for our nano-particle based drug delivery due to its ability to elicit a minimal immune response.</li>
<li>We read more about active targeting and decided to include Dectin-1, a mammalian innate immune receptor on the surface of our nanocarrier. </li>
<li>We plan to use hydrogels instead of ointments once our project expands.</li>
<li>We dropped the idea of using NIR light triggered drug delivery.</li></ol></div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>7. Dr. Ravindra Ghooi</b></h3></a>
<a class="text-body ml-auto"><strong>Expert: Proposed Implementation</strong></a></div>
<p class="pl-20 pr-20">
Director<br>
Scientia Clinical Services</p>
<p class="pl-20 pr-20">
<b><i> You can independently commercialize the antifungal drug you are developing; need not approach a pharmaceutical company.
</b></i>
</p>
<p class="pl-20 pr-20">Dr. Ravindra Ghooi was the Director of Scientia Clinical Services for the past 14 years. He was a professor at the Symbiosis School of Medical Sciences teaching and guiding students in Drug Development and Clinical Research. He has also worked as the DEAN of Bilcare Research Academy, an academy dedicated to Clinical Research Education. He was also the Vice President of CliniRx Research Pvt. Ltd. Having worked as a Medical Advisor in different Pharmaceuticals, his extensive knowledge in Clinical Research Education helped the team gain insights on marketing our product.</p>
<p class="pl-20 pr-20">Our interaction with Dr. Ghooi was primarily for us to learn about the procedures to commercialize the antifungal drug we were developing. His expertise in this area of clinical trials, market policies, and the explicit presentation of facts turned out to be really helpful for us. His suggestions were instrumental in devising a plan for implementing our project.
</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>The aim of our project is to produce a novel, safe, and effective antifungal drug for therapeutic use.
</li>
<li>With the team’s background in research, our focus was primarily on the design, cloning, expression, purification, and in vitro characterisation of the antifungal molecules, leveraging synthetic Biology techniques.
</li>
<li>We lacked a comprehensive understanding of the drug discovery process beyond the first steps; having a hypothesis and generating a new drug molecule.
</li>
<li>We had only a preliminary understanding about the classification of drug molecules, the definition of a new drug, various regulatory committees and bodies involved, different stages of preclinical and clinical trials, the regulatory and ethical approval required at each of these stages, regulations on the price of new drugs, timeline and cost of the drug discovery process, tie-ups with pharmaceutical companies etc.
</li></ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>The interaction with Dr Ghooi opened our eyes to the practical side of drug development beyond the laboratory. He broadened our understanding on various topics, such as the ones mentioned earlier.
</li>
<li>We appreciated that most drugs take 12-15 years to reach the market, and millions of dollars are spent on their development.</li>
<li>Thus, it becomes imperative to “see ahead of the curve” so to speak, and assess whether the drug is likely to be valuable in the future, more so than in the present.</li>
<li>Dr. Ghooi outlined a rough strategy for us to follow: a) decide which specific fungal species we are targeting,b) Identify incidences of infection by that particular species from medical literature to determine its prevalence, c) Identify existing drugs in the market and determine their annual sales from the IMS database; pay special attention to the rate at which the sales are going up/declining, d) Make a realistic comparison of our compound to the existing drugs on the market based on factors such as efficacy, safety, and price.</li>
<li>He also suggested that we pay close attention to the nature of clinical trials which we need to follow: they are likely to differ from conventional drugs since we are targeting invasive fungal infections in immunocompromised patients.
</li>
<li>Dr Ghooi also directed us to explore the possibility of patenting our drug, and register our clinical trials on the clinical trials registry of India whenever applicable.
</li></ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong>
</p>
<ol class="ordered-list">
<li>Our project has become much more focused after interacting with Dr Ghooi. Now aware of the regulations in place for the development of new drugs, we have started working towards ensuring they will be met.
</li>
<li>Based on the activity of our recombinant enzymes, we have chosen species of Rhizopus, Aspergillus, and Candida to target.
</li>
<li>The antifungal activity of our recombinant enzymes will be contrasted against that of a commercial antifungal, Nipagin.
</li>
<li>vA detailed literature review on the procedures to be followed for preclinical and clinical trials has been conducted; these have subsequently been included in our long term plans.</li>
</ol></div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>8. Dr. Harilal Madhavan</b></h3></a>
<a class="text-body ml-auto"><strong> Expert: Survey and Handbook design</strong></a></div>
<p class="pl-20 pr-20">
Ad-hoc Faculty (Humanities)<br>
Indian Institute of Science Education and Research, Thiruvananthapuram</p>
<p class="pl-20 pr-20">
<b><i> People prefer short surveys, with more open-ended questions.
</b></i>
</p>
<p class="pl-20 pr-20">Harilal Madhavan is a development economist specialized in economic and interdisciplinary research on Asian indigenous medicines, health and pharmaceutical policies and intellectual property rights. Dr. Harilal helped us with numerous aspects of the project, especially the Human Practices department.
</p>
<p class="pl-20 pr-20">Being a faculty of the Humanities department, he was able to guide us in framing the questions for the survey. He also helped us form the template that we followed for making all the surveys we released. As the world is becoming busier by every passing day, not everyone would find time to take part in surveys. Hence, it is important to include more objective questions, where the respondent wouldn’t have to think much before answering the questions. He also stressed on the importance of obtaining consent from the respondents before submitting the survey. He also helped us with structuring the handbook we made on the legal scenario of biotechnology in India.
</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>Our surveys contained more subjective questions than objective ones.</li>
<li>Handbook lacked a proper framework.</li>
</ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>Include more objective and less time-consuming questions in the survey.</li>
<li>He gave us insights about restructuring the handbook.</li>
</ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong>
</p>
<ol class="ordered-list">
<li>We included objective questions in the survey than the earlier draft.</li>
<li>We restructured the handbook by incorporating his suggestions.</li>
</ol></div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>9. Dr. Subha C. C.</b></h3></a>
<a class="text-body ml-auto"><strong> Expert: Handbook design</strong></a></div>
<p class="pl-20 pr-20">Assistant Professor,<br>
School of Law<br>
Christ University, Delhi NCR Campus</p>
<p class="pl-20 pr-20">
<b><i> 'Act' is not synonymous with 'policy' and 'rule.'
</b></i>
</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>We used the words 'act', 'rule', 'policy', 'bill', synonymously. </li></ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>There is a difference between 'act', 'rule', 'policy' ,and 'bill'.</li></ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong>
</p>
<ol class="ordered-list">
<li>We understood the proper usage of those words and rectified them in our handbook. </li></ol>
</div>
<br>
<div class="d-flex">
<a class="text-body"><h3><b>10. Ms. Parvathy Suresh</b></h3></a>
<a class="text-body ml-auto"><strong> Expert: Handbook design</strong></a></div>
<p class="pl-20 pr-20">
Graduate student<br>
National Law School of India University,Bengaluru</p>
<p class="pl-20 pr-20">
<b><i> 'Giving sections of actual legal provisions will not serve your purpose. Write about them in your own words.
</b></i>
<p class="pl-20 pr-20">Parvathy was the first person to review the draft of our handbook on Indian biotechnological legal scenario. Back then, the content was redundant and we had given relevant sections of laws also in the handbook, which made the book unwantedly long and complex, which did not fulfill the purpose of our handbook. She also offered to connect us with various legal experts who could help us in this regard.
</p>
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<p class="pl-20 pr-20"><strong>Status of project before the discussion:</strong></p>
<ol class="ordered-list">
<li>The handbook was unwantedly long.</li>
<li>The book contained sections from laws and policies.</li>
<li>It did not have a special section for iGEM teams.</li>
</ol>
<p class="pl-20 pr-20"><strong>Suggestions:</strong></p>
<ol class="ordered-list">
<li>Stick to a word limit, and reduce the length of each section.</li>
<li>Remove the actual sections from laws, and briefly summarize them. You can provide links to the particular law if required.</li>
<li>Add a special section for iGEM teams, so that more people can find it relatable.</li>
</ol>
<p class="pl-20 pr-20"><strong>Status of the project after incorporation of suggestions:</strong>
</p>
<ol class="ordered-list">
<li>We consistently reduced the length of each section.</li>
<li>We removed redundant content, especially when a particular legal provision came about in two chapters.</li>
<li>We briefly summarized each legal provision</li>
<li>We also added a special section - "What should you take care of as an iGEM team?" at the end of each chapter.</li>
</ol></div>
<br>
<p class="text-center" style="font-size:33px"><strong>Stakeholder Interactions</strong></p>
<div class="image-block, text-center">
<img src="assets/img/hp/ihp/Stakeholder_interaction.png" alt="sample image" class="png-fluid" width="800"
height="450" /></div><br>
<p class="pl-20 pr-20" style="font-size:27px" align="center"><strong>Interaction with Medical Doctors</strong></p>
<br>
<p class="pl-20 pr-20"><b>1. Dr. Rashmi Mary Philip</b><br>
Dermatologist, Amala Institute of Medical Sciences, Thrissur, Kerala
</p>
<p class="pl-20 pr-20">Dr. Rashmi Mary Philip is a consultant dermatologist and a Senior Resident in dermatology at Amala Institute of Medical Sciences, Thrissur. Dr. Rashmi’s proficiency and experience in dermatology became really useful to us. She was able to give us common names of the fungal infections seen so that it would become easier for us to understand if we had to talk to affected patients in the future.
</p>
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<p class="pl-20 pr-20">She discussed in detail about dermatophytes, and how they cause superficial fungal infections. Dermatophytes have the ability to invade keratinized tissues, such as the skin, hair, and nails. Classified on the site of infection, dermatophyte infections include tinea corporis (ringworm), tinea unguium (nail infection), tinea capitis (scalp ringworm), and tinea pedis (athlete's foot), among others. She also briefed us about different other fungal species affecting humans.
</p>
<p class="pl-20 pr-20">She was genuinely impressed with our project idea but also suggested expanding it as a therapeutic because pathogenic fungal spores would persist in the environment even after removing fungi thriving on walls.
</p>
</div>
<br>
<p class="pl-20 pr-20"><b>
2. Dr. Kiran N.</b><br>
Paediatrician, Government Medical College, Thiruvananthapuram, Kerala</p>
<p class="pl-20 pr-20"> Children are an important group of individuals affected by fungal infections. As a paediatrician, Dr. Kiran provided us with an overview of common fungal diseases affecting children.
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<p class="pl-20 pr-20">His department comes across children with topical fungal infections regularly. They are caused by dermatophytes. Immunocompromised children, especially those who have undergone solid or liquid organ transplants, are prone to life-threatening fungal infections. They are commonly infected by Candida spp., Aspergillus spp., and Mucorales. He discussed in detail the different types of infections caused by them, covering the following pointers:
</p>
<ol class="ordered-list">
<li>Source of infection</li>
<li>Site of infection</li>
<li>The defense mechanism of the immune system</li>
<li>Prevalence in children and high-risk groups</li>
<li>Current antifungal treatment regimen and their side-effects</li>
<li>Antifungal resistance to existing drugs</li></ol>
<p class="pl-20 pr-20">He also highlighted the prevalence of Candida infections in neonates and the prophylactic treatment given for its prevention. Also, fungal contamination in hospital settings, especially on ICU walls, can lead to severe infections in critical-care patients. Our team had identified Penicillium spp., Aspergillus spp., Cladosporium spp., and Fusarium spp. from the walls of our institute. He mentioned that other than Aspergillus spp., the other genera are not clinically significant and do not cause severe infections in the Indian Population.
</p>
<p class="pl-20 pr-20">Dr. Kiran appreciated our idea of removing fungal infestations from walls, thereby reducing the concentration of harmful fungal spores in the atmosphere. However, he also stressed that fungal spores from other habitats of fungi would persist in the environment.
</p>
<p class="pl-20 pr-20">The narrow range of antifungals available for the treatment compared to a wide range of antibiotics often leave doctors like him left with very few options to treat patients; ergo, the successful completion of our project would be helpful in the treatment of fungal infections.
</p></div>