Event Timeline

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  Harry Adamson

  5/17/2023
  
  Harry Adamson is a PhD Student working in Dr. Howard Salis’s Laboratory. He is well versed in synthetic biology and its relation to commercialization.
  
  PURPOSE
  We spent the first weeks as new members of the synthetic biology and iGEM community learning more about the field and competition. From this learning period, we began to understand the intricacies of synthetic biology and how it branches into other scientific fields than just biotechnology and pharmaceuticals. Based on Harry’s understanding of our project, he taught us essential protocols and encouraged different topics to research. After reading papers based on different types of glucometers, we concluded to use Glucose Oxidase (GOx) production as an indicator of biomarker presence. Harry discussed the possibilities of riboswitches with the team and the limitations of. He also encouraged the team to use a commercial viewpoint when deciding which aptamers to use.
  
  CONTRIBUTION
  Based on the fundamentals given to us from Harry, we designed our first riboswitches. As a team we discussed a variety of potential aptamers before deciding on the five (Basic Fibroblast Growth Factor, Thyroxine, mCRP, Bovine Thrombin, and IL-32y) we will be optimizing. We reflected on Harry’s suggestion and found a medical purpose for each aptamer.
  
  IMPLEMENTATION
  The next step is to fully create an operational computational model of our riboswitches. We decided to break off into teams to complete efficient creation and literature studies of each aptamer success. During the modeling portion, we will keep several objectives in mind. To perfect the switches, we need to ensure operational success with our decided promoter (J23100), no random stop codons present, and pre/post aptamer sequences that will not interfere with the plasmid.
  Helped us identify potential issues with producing glucose dehydrogenase
  

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• 

  Merck

  Trevor Wiley & Craig McKelvey

  5/22/2023
  
  Trevor Wiley is an Associate Principal Scientist with Merck Bioprocess Drug Substance Commercialization. He has 14 years experience in Biologics and Vaccine purification process development and has been lucky enough to have supported several early phase and commercial projects. He is passionate about people management and building on technical knowledge through a mindset of being a student for life. Trevor attributes most of his early career opportunities to my Chemical Engineering undergraduate degree from Penn State and 2008 iGEM team membership.
  Craig McKelvey is a Distinguished Scientist in Vaccine Drug Product Development. He has 22 years of experience in new drug product design and development at Merck including multiple commercial products. He also has previous experience developing small molecule products for oral administration, high concentration mAbs, drug eluting implants, respiratory products, and drug-device combination products. Craig is passionate about designing products and developing people to positively impact human health. He earned his B.S. in ChE at Penn State and his PhD in ChE from the University of Delaware.
  
  PURPOSE
  With the intention of making a plan for the future of our product, we sought out industry stakeholders who could upscale and market our product one day. As a biopharmaceutical giant, Merck was the perfect candidate to consult.
  
  CONTRIBUTION
  While the process of manufacturing drugs and therapeutics differs from devices and diagnostics, Trevor and Craig helped familiarize the team with scale-up practices that we would need to consider if we wanted to mass produce our product. They introduced us to Gantt charts, target product profiles, biomanufacturing readiness levels, and relevant industry terminology.
  
  IMPLEMENTATION
  We used what we learned about commercialization to help develop our Proposed Implementation Plan. The team developed a target product profile to help gauge acceptable and ideal performance of our theoretical product, as this would be helpful to reference as we work toward our goals and consider the future applications of our project.
  

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  Dr. Benjamin Steil

  6/23/2023
  
  Dr. Benjamin Steil is a Senior Product Development Scientist at Daicel Arbor Biosciences with over 15 years of experience in the molecular biology field.
  
  PURPOSE
  We decided to use Daicel Arbor Biosciences’ myTXTL cell-free protein expression systems for our tests, but since we intended to use it for point-of-care testing, we had concerns about its shelf life. We planned to lyophilize the cell-free system on a paper strip to produce glucose oxidase or dehydrogenase directly on the strip itself. As our supplier, Ben had previously answered our inquiries about myTXTL, so we wanted to know his thoughts on freeze-dying the myTXTL system.
  
  CONTRIBUTION
  While Ben did could not find too much on specific methods of lyophilizing myTXTL, he was able to provide a successful example of lyophlizing the kit as well as some general guidance. Regarding lyophilizing myTXTL on paper, he warned us that it had been done before, but there was a significant loss in enzymatic activity.
  
  IMPLEMENTATION
  Ben’s advice led us to rethink lyophilizing the CFS on the strip and begin considering alternatives. We conducted a literature search on lyophilizing cell-free systems on paper, and our findings only reinforced our growing skepticism. We began brainstorming workarounds to freeze-drying on a strip, and we raised other questions to further test the feasability of our inital idea.
  
  
  7/5/2023
  
  PURPOSE
  We had changed course from our original idea in favor of a reworking the idea from the Pardee paper that Ben had initially sent to us. Naturally, we would ask Ben about the feasibility of our new plan. We were considering producing lactase or trehalase to convert lactose or trahalose into glucose and read the relative increase, or we would produce glucose dehydrogenase and measure the decrease in glucose. Since glucose dehydrogenase is a complicated heterodimer, we had concerns about producing this with myTXTL and sought out Ben’s assistance. Additionally, we were considering reducing the volume of each reaction to half of the instructed myTXTL volume to save materials.
  
  CONTRIBUTION
  While Ben was unsure of the glucose dehydrogenase issue, he did mention the presence of glucose-6-phosphate dehydrogenase for the system’s active glycolysis. Because of this, he recommended that we test the glucose changes without the added enzymes to test for background variabliltiy. He also said that halving the reaction would be fine, and he gave us some recommendations for our initial fluorescence tests.
  
  IMPLEMENTATION
  With lowered hopes for glucose dehydrogenase, we then made the decision to move forward with producing lactase or trehalase. We were previously unaware of the glycolysis present, which would interfere with our measurements as glycolysis will lower the glucose as we are attempting to increase it. Now knowing this, we designed an extra control in which the system would still produce trehalase, but no there will be no glucose increase since we will exclude trehalose. Ben’s input on the reaction volume also gave us more confidence to optimize our resources and decrease the volume for our fluorescence tests.
  

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  Dr. Aida Ebrahimi

  6/26/2023
  
  Dr. Aida Ebrahimi is an associate professor in Electrical Engineering and Computer Science at the Pennsylvania State University.
  
  PURPOSE
  We met with Dr. Ebrahimi to obtain feedback on feasibility on the project concept and design of our modified glucometer. Dr. Ebrahimi focuses on medical devices and more specifically biosensors. A majority of her research consists of electrochemical monitoring and/or customizable machinery. As we were designing our own glucometer testing strips and devices, we sought to understand the limitations of doing so.
  
  CONTRIBUTION
  In the beginning, the team explained our idea of creating a new glucometer strip with our riboswitch including the production of Glucose Oxidase (GOx) in the presence of a biomarker. Dr. Embrahimi discussed the specifics of designing our own testing strip including the presence of an electrode, selection of a conductive carbon material, and freeze drying the riboswitch on the paper. Our team had minimal knowledge on glucometers, so Dr. Ebrahimi stressed the importance of conductive materials and an electrode. She gave us multiple papers comparing differing materials to find the best fit for our project. She brainstormed with us the potentiality of creating our own strip material using GOx and chitosan. She also described how a glucometer with a hydrogen peroxide sensor would be the best option for our testing purposes. In the creation of a stable matrix in our strip, we need to consider parameters such as concentrations, ratios, and viscosity, all of which she defined as essential for our design. She suggested commercial GOx as a control to test our created GOx via the riboswitch under the presence of a biomarker. She advised us to further research strip creations and H2O4 sensors.
  
  IMPLEMENTATION
  After meeting with Dr. Ebrahimi the team delved into researching hydrogen peroxide sensors combined with a glucometer. After several team discussions, it was decided that we would not be able to accurately create our own glucometer strips. Our next step was to create a new riboswitch system that would allow us to utilize commercial glucometer strips. It was decided that the future team will explore the creation of customized strips with Dr. Ebrahimi’s aid.

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  Dr. Michael Snyder

  7/9/2023
  
  Dr. Michael Snyder is board certified by the American Board of Obstetrics and Gynecology and is the Chairman of the Department of Gynecology at Virtua Willingboro Hospital.
  
  PURPOSE
  As we sought to make a point-of-care diagnostic test, we needed to hear from the doctors who would use the system with their patients. In literature, we read that VEGF could potentially serve as a marker for ovarian cancer. We believed Dr. Snyder’s clinical experience in gynecology would give us a more realistic view on the controversial biomarker.
  
  CONTRIBUTION
  Upon hearing the general synapsis of our device and the aptamers we will be using, Dr. Snyder explained VEGF cannot be used as an early-detection marker. He discussed the importance of both sensitivity and specificity, and VEGF tests simply lack the specificity to identify any cancer with full confidence. He believes an unspecific marker like VEGF would not pass the rigor of the American Board of Obstetrics and Gynecology’s standards. Fortunately, Dr. Snyder introduced us to CA125, which is commonly tested to monitor the progression of ovarian cancer. He explained that it can be quantified in a routine blood test that would be sent off to the lab and would return in about a week.
  
  IMPLEMENTATION
  Dr. Synder’s input led us to do a literature review on the use of CA125 in the search for a compatible RNA aptamer, which would allow us to create a riboswitch. Sure enough, we discovered a high-affinity CA125 RNA aptamer existed, and we used it to design another riboswitch! While we did not have the time to order this riboswitch and characterize it, we still were able to design multiple candidates that are ready to be ordered in the future.
  

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  Dr. Edwin Empaynado

  7/13/2023
  
  Dr. Edwin Empaynado specializes in Colon and Rectal Surgery at Advocare. He is board certified by the American Board of Surgeons and the American Board of Colon and Rectal Surgeons. Ed is also a Penn State alum!
  
  PURPOSE
  While Dr. Snyder explained how VEGF would be a poor marker for ovarian cancer, we wanted to explore its potential relevance to other cancers before we completely ruled out the use of VEGF as an early detection method. We previously discovered literature evidence of VEGF having a significant correlation to the size of cancerous colorectal tumors in a relatively small sample size, so we went to Dr. Empaynado for his professional opinion.
  
  CONTRIBUTION
  Dr. Empaynado was able to provide a more in-depth explanation on how VEGF plays into tumorigenesis. He explained how sometimes, tumors grow too fast for VEGF to catch up. While tumors need new new blood vessels to form, sometimes they are able to continue growing on the outside while necrosis sets in on the inside. This further affects the specificity of VEGF and discredits its role as an early detection tool. Even so, Dr. Empaynado helped us identify another marker: CEA. He explained how CEA is produced naturally in colon cells but is expressed in high amounts when cancer is present. Still, he warned that aggressive colon cancers may only produce normal amounts of CEA, so it is not always reliable. This serum test would occur every six months and helps determine if patients will benefit from chemotherapy.
  
  IMPLEMENTATION
  Dr. Empaynado helped us direct our focus away from VEGF, as it continued to be problematic in yet another type of cancer in which literature claimed it would be “promising.” On the other hand, Dr. Empaynado led us to reconsider CEA as a marker. We had previously discovered a CEA RNA aptamer, but we disregarded it as some literature expressed its issues as a marker. Dr. Empaynado made us aware that it is still a useful test that is common in clinical practice, so we went ahead and designed a riboswitch for CEA. While we did not have the resources to pursue testing with the CEA riboswitch, we still designed candidates for a CEA riboswitch that we implemented into our proposed application.
  

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  Abbey Fisher & Shaweta Gupta Singla

  7/19/2023
  
  Abbey Fisher is the vice chair for research for the Depart of Medicine at the Pennsylvania State University. In addition to providing operational support for clinical trials, she is the Research Project Manager for the Opioid Use Disorder (MOUD) ECHO project.
  Shaweta Gupta Singla is the Program Manager for the Penn State Clinical and Translational Science Institute.
  
  PURPOSE
  If we were to commence with clinical trials after further developing our proof of concept, we would need to work with the Clinical and Translational Science Institute at Penn State. To learn more about clinical trials for our proposed future application, we reached out to the CTSI and were connect with Abbey and Shaweta.
  
  CONTRIBUTION
  Abbey and Shaweta gave us the full breakdown of what to expect from a typical clinical trial. Abbey walked us through how the CRC operates, detailing what they would provide and the steps we would need to take to prepare, including the proper forms to fill out and people to contact. She walked us through the logistical aspects to consider and offered to connect us with other resources to help us better design our proposed trials. They discussed common flaws in clinical trials, which mostly included underestimating budgets and working with humans.
  
  IMPLEMENTATION
  We began the meeting with very little knowledge about clinical trials, but Abbey and Shaweta helped us understand the process and prepared us to begin planning the our proposed future applications. If we were to ever take this project past the conceptual testing stage, the clinical trials stage would follow. This new information structured our plan to engage in human testing through Penn State resources.
  

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  Dr. Beata Clapp

  7/20/2023
  
  Dr. Beata Clapp is a senior biosafety officer at the Pennsylvania State University through the Office of Environmental Health and Safety (EHS). She oversees the University’s biological safety programs through academic, research, and service areas. Before Penn State, she oversaw biosafety programs for the Texas Biomedical Research Institute.
  
  PURPOSE
  This year, our work is restricted to a BSL-1 lab, so our biosafety considerations are relatively minimal; however, much of the work in our proposed future applications would involve testing with human cells and blood samples. We would have to work with EHS to proceed with this at Penn State, so we reached out to Beata Clapp.
  
  CONTRIBUTION
  We discussed how our project currently would not involve human testing, and it would only involve the use of E. coli and E. coli-based cell-free systems. Beata reassured us that our current safety considerations were minimal and up to standard. We discussed the possibility of testing with human cells in the future, and she explained all of the necessary steps and paperwork required to advance our testing to a BSL-2 lab. We also discussed the biosafety concerns of scaling up our product for our proposed future commercialization applications, and she overviewed the general safety concerns and how there was not much worry since human cells would still not be involved. We then asked her about common misconceptions in biosafety. Beata has worked in BSL-3 and BSL-4 labs, which she says are safe due to the high standards of training. She says that BSL-1 labs are not too dangerous, but the danger lies in BSL-2 labs. There is not enough training and caution taken as BSL-2 concerns are often underestimated, and extra care must be taken to ensure optimal safety. Finally, Beata mentioned that EHS was planning on preparing a training lab on campus that would be ready by the end of the fall semester.
  
  IMPLEMENTATION
  Beata’s input provided great considerations to make when discussing our future applications. Testing on human cells would be the next step, and Beata helped flesh out the details of expanding our research. If we plan to continue, we now know to start planning ahead to collaborate with a BSL-2 lab on campus and develop our training earlier and more thoroughly with the help of EHS’ new training lab. Beata also helped us address the safety requirements for our proposed commercialization.

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  Tania Lange

  7/20/2023
  
  Tania Lange is the Clinical Director of ABA Results who has 7 years of experience with autistic children.
  
  PURPOSE
  To verify our device’s success in the medical field, our team was given the suggestion to look into individuals who possess impediments to typical blood draws. Our team met with the Clinical Director of ABA Results to discuss how our device would transform a medical visit for children with autism. Children with autism are uncomfortable with changes to the environment, routine, and people. She explained that depending on where a child lies on the spectrum, the more extreme behaviors can be. A child who is rated slow on the spectrum will rock back and forth, stim, or flap causing people around them to grow uncomfortable furthering their behaviors. On a higher level, children can elope and/or engage in self injurious behaviors (SIB) to themselves or others. The change in daily routine, driving to the doctors office, waiting in the waiting room, and even a different doctor can cause these behaviors. As we are looking into implementing our device into doctor’s examinations, we wanted to possess insight on how our device can improve a typical doctor’s visit.
  
  CONTRIBUTION
  When we explained that our test will be using a finger prick rather than drawing blood, Tania said she saw “so many benefits.” With a finger prick, we eliminate a long drawn out process that can create a sensory overload. One suggestion she gave to us was creating a mock toy of our project. If we create this toy, an autistic child would be able to explore the device before it's used. Being able to explore our device, without the needle, would make the child more comfortable in the new environment. She mentioned that doctor visits can take weeks of preparation by both the parents and therapists, but those weeks are nothing compared to the actual visit. Instead of sitting for a prolonged period of time, typically leading to restraining by the doctors when blood is drawn, it would take a few minutes.
  
  IMPLEMENTATION
  After meeting with Tania, our team began to brainstorm a potential toy design. We also held a reflection as many of us did not consider potential adversities in the doctor's office. We are now more inspired to make our device a success to potentially change the outcome of medical examinations for autistic children.

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  Dr. Ronny Drapkin

  7/21/2023
  
  Dr. Ronny Drapkin is the Director of Gynecologic Cancer Research and the Penn Ovarian Cancer Research Center at the University of Pennsylvania. He is also an astounding member of the cancer research community, holding several leadership positions in other programs at the University of Pennsylvania and the Department of Defense Ovarian Cancer Academy.
  
  PURPOSE
  After our meeting with Dr. Snyder, who has more of a clinical focus, we wanted to know more about ovarian cancer and specific biomarkers from a research standpoint. Seeking someone with a strong, cancer-specific research background, we scheduled a meeting with Dr. Drapkin. Dr. Drapkin’s work at Penn Medicine with gynecological cancers made him the perfect consultant.
  
  CONTRIBUTION
  Dr. Drapkin explained that there are currently two FDA approved markers for ovarian cancer: CA125 and HE4. He discussed how these were used for monitoring ovarian cancer after it has been diagnosed, and that these were poor early detection markers. He also mentioned a study where it was found that early detection of ovarian cancer still did not improve prognosis, which he believes is due to the cancer originating in the fallopian tubes. He reasserted that low specificity markers would generally be unhelpful in early detection. In addition to these markers, Dr. Drapkin discussed newer cancer markers in the field that are growing in interest and may be better for early detection, with an emphasis on LINE-1 ORF1p. He also discussed research on Claudin-6 and CRABP2 as cancer markers and possibly exploring composite tests.
  
  IMPLEMENTATION
  Dr. Drapkin helped us gain more insight on the CA125 marker. He clearly stated its limitations in clinical use, leading us to adjust our proposed application of the CA125 riboswitch. He also helped us shift our focus away from the unspecific markers and better explained the origin of ovarian cancer, further pushing us to emphasize our system’s modularity rather than its applications in early detection. He also led us to do a literature search on LINE-1 ORF1p and consider future tests on binary biomarkers.

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  Dr. Kuruppumullage

  Associate Research Professor
  Assistant Director of Online Programs
  Department of Statistics
  

  The team convened with Dr. Kuruppumullage, an expert biostatistician specializing in clinical trials. This meeting aimed to identify the necessary quantity and quality of data, providing valuable insights for our upcoming steps. Dr. Kuruppumullage's expertise guided us in determining the specific data requirements essential for creating a comprehensive and reliable dataset for our study results. We were specifically asked not to include the specifics of our meeting but wanted to mention how Dr. Kuruppumullage aided in the project’s next steps.

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  Penn State Clinical Trials Office

  Dr. Kevin Gardner & Dr. Andrea Stevens

  7/24/2023
  
  Kevin Gardner is the Director of the College of Medicine Clinical Trials Office at Penn State College of Medicine. He is responsible for the oversight and budgeting of the 8 Penn State Hospitals and works closely with Hershey Medical as the Clinical Director. Dr. Andrea Stevens is the Undergraduate Clinical Research Training Program Coordinator at Penn State in addition to being both a Science Lab Coordinator and Assistant Biology Teaching Professor.
  
  PURPOSE
  After our meeting with Dr. McCormick, who explained the basis of research ethics, we discovered our lack of knowledge surrounding the requirements of starting a clinical trial and common misconceptions. Kevin and Dr. Stevens are responsible for leading and maintaining a variety of clinical trials and as such were the best individuals to connect with.
  
  CONTRIBUTION
  Kevin and Dr. Stevens explained the general start up process of clinical trials. They discussed the initial paperwork and how medical devices are seen as niche in the field. Dr. Stevens laid out the groundwork for obtaining human samples from Hershey Medical and the types of questions an IRB team would ask before testing. After hearing more about the project, Kevin confirmed that we would not need to use animal testing in our trials. They discussed how to maintain patient confidentiality and follow HIPAA guidelines during the experimentation process. In addition to general guides, they reflected on common mistakes during a trial and how as a team we could prevent such occurrences.
  
  IMPLEMENTATION
  Kevin and Dr. Stevens highlighted the importance of documenting and seeking approval during the entirety of the process. They helped us shift our focus to specific medical devices trials rather than the broad trials we were looking into previously. The two encouraged us to delve deeper into the medical research field and information the IRB would ask before our project could continue.

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  Research Quality Office - Courtney Karmelita

  7/29/23
  
  Courtney Karmelita is the Director of Research Integrity and Quality for the Office of Research Protections at Penn State. She is responsible for quality management and research misconduct throughout the University Park Campus. She serves as the institution’s Research Integrity Officer and educational initiatives related to research misconduct and quality management.
  
  PURPOSE
  Meeting with Dr. Stevens and Kevin Gardner sparked our interest in what the FDA and/or IRB looks at for clinical trial approval. Courtney Karmelita provides feedback and protocol alterations before a trial submits their documentation to the IRB or FDA. In order to receive approval, our team met with Courtney who is extremely knowledgeable on the research compliance side of clinical research.
  
  CONTRIBUTION
  Courtney broke down what the FDA and IRB views as the definition of device, drug, and a clinical trial. The extent of approval we need depends on the risk our device will be associated with. Courtney discussed how our project will be the lowest risk given we are not insertining the device into a human being. She also confirmed that in order to have a clinical trial for a modular device, we would need to submit for IRB approval for each biomaker. Each trial would need a seperate testing population and protocol.
  
  IMPLEMENTATION
  Courtney Karmelita gave us several links to expand our research into general clinical definitions, FDA resources, and consultation aids. Under her suggestion, the team sat down and discussed how we would reply to the generic IRB questions each clinical trial must answer in detail before approval of a project.

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  Jennifer McCormick

  Associate Professor
  Department of Humanities
  Faculty, Biomedical Sciences Program
  Penn State College of Medicine
  Lead, Research Ethics Core
  Director, Research Ethics Consultation Service
  Penn State CTSI
  

  
  PURPOSE
  Following our discussion with the CTSI consultants, we sought a deeper understanding of clinical trial and research ethics. Abbey Fisher introduced us to Dr. McCormick, an expert in the field, whose wealth of experience made her the ideal person to consult on this matter.
  
  CONTRIBUTION
  Dr. McCormick provided us with a comprehensive introduction to Ethics 101, offering a glimpse into the clinical research process. She elaborated on the Common Rule, Nuremberg Code, and highlighted past trials condemned for ethical violations. Emphasizing the significance of informed consent, she guided us on what specifics our project should include. Additionally, we explored the intricacies of data collection, security measures, and analysis methods.
  
  IMPLEMENTATION
  Under Dr. McCormick's guidance, we pondered the appropriate course for the clinical trial and the subsequent project steps. Drawing from her expertise, we formulated a concise list of questions and concerns we anticipated subjects might have. Our discussion covered a range of angles and severity levels to ensure we addressed all crucial details comprehensively.

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