For our Integrated Human Practices (iHP), we conducted a series of interviews with experts in various fields to gather insights and recommendations that would shape our project. We also engaged with the wider scientific community, attending events to share our advances, receive constant feedback and actively learn from other perspectives.
Interviews with Industry Professionals
Our discussions spanned across dry and wet lab research, as well as entrepreneurship and patient advocacy.
Each expert provided valuable feedback on different aspects of our project, from data analysis and
computational modeling to designing therapeutic strategies and patient-centered approaches.
Through these conversations, we sought to refine our project approach, improve model accuracy,
and ensure the relevance of our work to the needs of patients, particularly those affected by
FSHD. The insights gained also helped us better understand the broader context of FSHD research,
therapeutic development, and how to engage various stakeholders, including young patients,
in the scientific process.
Below, we summarize the key outcomes from each of these interviews, noting the experts' positive
feedback, areas to improve, and actionable recommendations. These engagements have been instrumental
in refining our project and aligning our goals with both scientific rigor and real-world impact.
Dry Lab
Cyrus K.
Ph.D. Candidate @ Stanford, iGEM Team Mentor
Area: Dry Lab
Date: June 22nd, 2024
Being one of our dry lab mentors, Cyrus helped us establish our general dry lab approach
and expectations: find available data and think about what questions we can answer with
these, highlighting a positive mindset toward utilizing existing resources effectively.
A piece of advice that resonated with us is "make the category fit the project rather
than trying to fit the project into predefined categories", as it reflects a strong
focus on tailoring the approach to the unique needs of the research.
After the meeting, we decided to first analyze RNA-seq and methyl-seq as an exploratory pathway, and after
getting acquainted with the data, think about ways to compute the amount of DUX4-DBD
needed to avoid the aberrant expression of DUX4.
He also recommended us areas to improve: As we had our ODE Model finalized,
we realized there is no way to validate the model with the available data,
since the model considered the number of copies, which is not found in any dataset.
We had the idea to further develop this aspect to ensure the model's accuracy and
reliability as a backburner. We also considered MRI images as interesting biomarker
to dive into.
Takeaway: Helped us restructure our approach to utilize available RNA-seq and methyl-seq data for exploring treatment, advising that we tailor the research to the project's needs rather than predefined categories, and highlighted the need to refine our ODE model while considering MRI images as potential biomarkers for further investigation.
Sohaib Hassan
Ph.D. Candidate in Biomedical Informatics @ Stanford, Researcher at the Department of of Biomedical Data Science
Area: Dry Lab
Date: July 3rd, 2024
Sohaib found the use of methyl-seq, RNA-seq, and genome data intriguing.
He acknowledged these data types as valuable for understanding patient variance,
especially in relation to gene deletions encoding TAD variants. He also suggested
to look for concordance between RNA-seq and methyl-seq data was a valuable strategy,
as combining these datasets could reveal important patterns and relationships which
lead to new insights into FSHD.
For next steps, he encouraged us to use k-means clustering when finding patterns
in RNA-seq and then check concordance with methyl-seq. However, he pointed out that
RNA-seq alone as a predictor is not completely reliable. RNA-seq data alone may be
insufficient for predictive modeling due to sample variability. Sohaib advised against
using RNA-seq as the sole predictor in models, suggesting that it be combined with other
data types in an ensemble method to improve reliability. Additionally, he pointed out
that predictive models, especially with rare diseases like FSHD, have not yet reached
a level of accuracy that allows for confident predictions across multiple datasets.
Hence, we then found the challenge of joining multiple datasets for analysis
(multicohort analysis).
Takeaway: Sohaib emphasized the importance of combining RNA-seq and methyl-seq data for multicohort analysis, advising against using RNA-seq alone as a predictor due to variability, and suggesting ensemble methods with other data types to improve model reliability for FSHD insights.
Dr. Purvesh Khatri Ph.D.
Associate Professor (Research) of Medicine (Biomedical Informatics - Research Institute for Immunity, Transplantation and Infection)
Area: Dry Lab
Date: July 10th, 2024
Dr. Khatri concurred with the importance of data curation over running analyses, since it reinforces the critical role of quality data in research. For future steps, he introduced us to his lab software and stressed the importance of normalizing data correctly before analysis. At the end of the day, it would be incorrect to treat different datasets as if they were from the same cohort.
Takeaway: Dr. Khatri emphasized the importance of data curation and proper normalization, highlighting that treating different datasets as if they were from the same cohort would lead to incorrect analyses.
Dr. Jeffrey Statland M.D.
Professor of Neurology @ University of Kansas Medical Center in Kansas City, Kansas.
Area: Dry Lab
Date: July 22nd, 2024
As we fleshed out the MRI model, Dr. Statland mentioned that MRI analysis is a very
new area of analysis in the FSHD space. He also brought up the new work with full-body
MRI scans, which would be an interesting pathway to consider.
Dr. Statland also pushed us to write down the expectations of our “ideal dataset”:
compare expected results with longitudinal vs. short-term data, patient characteristics
and image format. To do so, we wrote a one-pager with specific aims and expectations of
the dataset, to then further discuss it with Dr. Seth Friedman led by his referral.
He also recommended reaching out to Stanford Medicine to collect the data we needed.
Takeaway: Dr. Statland highlighted the novelty of MRI analysis in FSHD research, encouraged defining expectations for an "ideal dataset" comparing longitudinal and short-term data, and recommended connecting with Stanford Medicine and Dr. Seth Friedman to advance the project.
Dr. Seth Friedman Ph.D.
Manager, Innovation Imaging and Simulation Modeling @ Seattle Children's
Area: Dry Lab
Date: August 7th, 2024
On our meeting, Dr. Friedman endorsed the approach of using prediction models,
but mentioned a significant challenge of doing so with MRI: Sometimes,
the muscle degrades but keeps it volume. Other times, the muscle shrinks
and the rest of the space becomes fat. This is an important point to consider
in the space, and it is challenging to account for that to predict disease progression
solely with MRIs.
It was also noted that it’s very difficult to convert data into numerical units
that can be used to analyze and parcel up the muscles under the iGEM timeline.
An upcoming progression model (pending publication from their end) will analyze
changes in muscle fat infiltration over time. Hence, their recommendation was
made to focus on progression rather than segmentation. The Wong paper was highlighted
for its supplemental data, which includes RNA-seq and MRI values from biopsied muscle,
suggesting these could be used to help predict disease progression.
Takeaway: Supported the use of prediction models but emphasized the challenge of accounting for muscle degradation vs. fat infiltration in MRI data, recommending a focus on progression over segmentation, and highlighted the Wong paper's RNA-seq and MRI data as useful for predicting disease progression.
Dr. Doris Leung M.D., Ph.D.
Director, Center for Genetic Muscle Disorders @ Kennedy Krieger
Area: Dry Lab
Date: August 7th, 2024
Dr. Leung was present in our meeting with Dr. Friedman, emphasizing the learning curve
of converting data into numerical units.
Dr. Tina Duong MPT, Ph.D.
Senior Clinical Research Scientist and Director of Clinical Outcomes and Research Development @ Stanford University
Area: Dry Lab
Date: August 6th, 2024
Our meeting with Dr. Duong was focused on our MRI research pipeline. She mentioned how MRIs as biomarkers is a very new area of research in the muscular dystrophy space, and one worth diving into. However, robust prediction would require a large dataset, so it would be more of a longer term project. Even though we could have access to a more limited dataset at Stanford, it would not be as efficient. This meeting led us to develop an initial MRI pipeline for future opportunities in the space.
Takeaway: Emphasized that using MRIs as biomarkers is a new but promising area in muscular dystrophy research, noting that reliable prediction requires a large dataset, and the limited dataset at Stanford may not be sufficient for efficient analysis in the short term.
Dr. Matthew Cowley Ph.D.
Associate Vice Provost for Career and Professional Development @ Virginia Tech
Area: Dry Lab
Date: August 16th, 2024
Our meeting with Dr. Cowley, Dr. Zammit and Dr. Banerji was one we were particularly excited for.
Especially since their paper inspired a big portion of our ODE model. We discussed their recent paper about
Markov Chains for cell state predicition, and talked about insights gained from both our Markov Models.
They showed the importance and effect of the diffusion rate - understanding DUX4 diffusion is vital for
developing effective treatments for FSHD, as diffusion-mediated import of DUX4 into myonuclei can lead
to significant cell death. There a potentially significant differences in susceptibility between muscle
fiber type. Talked about my (chris xu's) model and how it provides an alternative approach gives potentially
more nuanced parameters and prediciton. Talked about both versions of my model: a parameter optimiztion model
based on the set transition variables and previous version with less rigity and estimating each transition
probability independently. The later model model gave computation proof of the research hypothesis that
DUX4 has a built in regulatory degradation rate that is higher than infected cells. We then talked about
how future avenues of research and how we could build of my bayesian approach. Proffessor Zammit proposed
that we colloborate on a followup paper if I would like and I agreed. Then I explained a bit about what
iGEM was and Professor Zammit recommended I apply for a research grant with @friendsofFSHD.
They validated our application of Markov Models for a more robust prediction model, stating that
both models could provide new and impactful insights in DUX4 progression. They also mentioned
room for further research and a possible future collaboration. Even though the model simplifies cell processes and relies
on key assumptions, they stressed the strong potential of these models for aiding in and deisgning specialized
treatments for FHSD patients.
Takeaway: The application of Markov Models was validated, offering impactful insights into DUX4 progression and potential for designing specialized treatments for FSHD, though limited clinical data and key assumptions simplify the model, leaving room for further research and collaboration.
Dr. Peter Zammit Ph.D.
Professor of Cell Biology @ King's College London
Area: Dry Lab
Date: August 16th, 2024
Present at meeting with Dr. Cowley (description above).
Dr. Christopher Banerji M.D., Ph.D.
Interdisciplinary clinician-scientist with an interest in mathematical and computational approaches to big biomedical data analysis
Area: Dry Lab
Date: August 16th, 2024
Present at meeting with Dr. Cowley (description above).
To summarize, the flow of the interviews and their relationships are summarized in the following flow chart.
Wet Lab
Dr. Helen Blau Ph.D.
Donald E. and Delia B. Baxter Foundation Professor, Director, Baxter Laboratory for Stem Cell Biology and Professor, by courtesy, of Psychiatry and Behavioral Sciences
Area: Wet Lab
Date: Ongoing
Dr. Blau served as a project mentor for the duration of our research. As an expert in the muscle biology and physiology space, Dr. Blau consistently provided feedback on the feasibility, validity, and implementations of our experiments. She contributed to team meetings by helping our team interpret data, design future experimental conditions, and troubleshoot inconsistencies with our muscle cell-based projects. Dr. Blau also helped us think through the complete packaging and delivery of our drug. We also thank the Blau lab for generously donating C2C12 cells for use in our cell-based experiments. Dr. Blau also advised our team on the use of nuclear localization and export signals, suggesting that these might not be of relevant use in the context of a truncated transcription factor given the migratory nature of these proteins. Additionally, she provided recommendations for assessing potential off-target effects of our therapy.
Takeaway: Dr. Blau, as a project mentor, provided valuable feedback on the feasibility and design of our muscle cell-based experiments, guided drug packaging and delivery, donated C2C12 cells, and advised against using nuclear localization and export signals due to the migratory nature of truncated transcription factors, while recommending strategies for assessing off-target effects.
Dr. Silvère M. van der Maarel Ph.D.
Professor of Medical Epigenetics and Chair of the department of human genetics @ Leiden University
Area: Wet Lab
Date: August 1st, 2024
Our discussion with Dr. van der Maarel highlighted the importance of integrating personalized medicine approaches in FSHD treatment development, especially given the variability in disease progression. Dr. van der Maarel also expressed the value of incorporating patient feedback into research. He talked about the approach he saw at the Netherlands, where patient input significantly influences study direction, supports your efforts to consider patient experiences in your project. There were concerns about the risks of competitive inhibition and controlling DBD expression, including potential off-target effects. Also, the variability in DUX4 expression across different nuclei and the challenge of sporadic DUX4-fl expression were mentioned as factors that could complicate your model. This highlights the need to account for this heterogeneity in your predictions and models.
Takeaway: Dr. van der Maarel emphasized the importance of integrating personalized medicine and patient feedback in FSHD treatment development, while raising concerns about the risks of competitive inhibition, DBD expression control, and variability in DUX4 expression, which should be accounted for in your predictive models.
Dr. Peter Jones Ph.D.
Mick Hitchcock, PhD, Endowed Chair in Medical Biochemistry at University of Nevada, Reno School of Medicine
Area: Wet Lab
Date: July 11th, 2024
Considered one of the pioneers in FSHD research, Dr. Jones was a crucial resource in validating the usefulness and therapeutic potential for our research. We discussed the advantages of a "dominant negative" therapy compared to existing and other possible approaches. Additionally, Dr. Jones helped us imagine creative optimization techniques for the delivery and activation of our cargo. In our discussion, we also explored the potential for personalized medicine according to each patient's unique progression as a next step for our therapy. Additionally, Dr. Jones helped our team ideate the challenges associated with drug delivery and troubleshoot such concerns using innovative drug expression techniques.
Takeaway: Dr. Jones, a pioneer in FSHD research, validated the therapeutic potential of our work, discussed the advantages of "dominant negative" therapy, and helped us explore personalized medicine approaches, while also offering innovative solutions to optimize drug delivery and troubleshoot related challenges.
Entrepreneurship
Dr. Mark Smith Ph.D.
Head of Medicinal Chemistry @ Stanford Chem-H, Director of Stanford Innovative Medicines Accelerator, Co-Founder of Riboscience LLC
Area: Entrepreneurship
Date: Ongoing
In our first meeting, Dr. Smith provided initial IP advice, delineating the difference between a method vs product patent. The discussions around patenting, particularly the idea of filing a patent before the Jamboree and making the inventive step clear, were appreciated. It was noted that having a clear IP strategy is crucial for the project’s long-term success. After being mindful with this and drafting our first pitch, he recommended being more mindful of our logo's color scheme (e.g. color blind people, asesthetics), as well as restructuring the flow of our pitch to make the content more digestible. He also emphasized the importance of considering the versatility of our logo depending on the context (for example, printing it in black and white).
Takeaway: Dr. Smith provided crucial IP advice on method vs. product patents and emphasized the importance of filing a patent before the Jamboree, while also recommending improvements to our logo's color scheme for accessibility, its versatility, and restructuring our pitch for better clarity and flow.
Dr. Bruce M Wentworth, Ph.D.
Senior Advisor @ Dyne Therapeutics
Area: Entrepreneurship
Date: July 1st, 2024
The goal was to get a general overview of the solutions in the field. Dr. Wentworth explained the biggest challenges in the field, including toxicity of treatment and lack of funding. The use of modeling to understand drug dosage, dosing regimes, and drug delivery was acknowledged as valuable. Dr. Wentworth highlighted that sophisticated programs are being developed for predicting drug structures and optimizing dosing, which aligns with the project's focus on computational approaches. He also mentioned that the focus on drug delivery, particularly in getting a higher percentage of the drug into muscle at a lower dose, is crucial for therapeutic success. This area was highlighted as a significant challenge, indicating that the project is addressing an important need in FSHD treatment.
Takeaway: Dr. Wentworth outlined the major challenges in FSHD treatment, including toxicity and lack of funding, while emphasizing the value of computational modeling for drug dosage and delivery, noting that improving delivery efficiency to muscles at lower doses is crucial for therapeutic success and aligns with the project's focus on addressing key challenges in FSHD research.
Dr. Huijun Ring Ph.D.
Adjunct Professor @ Stanford, Primary Care and Population Health
Area: Entrepreneurship
Date: Ongoing
Dr. Ring is an experienced biotech entrepreneur and executive.
Previously she worked at Incyte Pharmaceuticals and DNA Direct in Silicon Valley.
She was the founder and CEO of iDNA Inc, a precision medicine company.
iDNA Inc. was named as one of the fastest growing technology companies in China by
Deloitte and was acquired by a public company. She has also cofounded and advised several
biotech startups in Silicon Valley and mentored many first-time entrepreneurs. Currently,
Dr. Ring is an Adjunct Professor in the Department of Medicine at Stanford University,
specializing in genomic medicine, AI and longevity research.
Dr. Ring helped educate the team on what the process of creating a biotech start up looks like.
This included showing us the general timeline, helping us to understand the scale of the commitment
if we were to pursue this further. As well, she generously shared with us useful guidebooks on
entrepreneurship. With her years of industy knowledge, she was able to instill a practical
understanding of what founding a biotech company is like. She recommended us to consider the scale of
work it is to bring a therapy from benchside to bedside.
Takeaway: Dr. Ring provided valuable insights into the biotech startup process, outlining the timeline, scale of commitment, and sharing entrepreneurship guidebooks, while emphasizing the significant effort required to bring a therapy from benchside to bedside.
Dr. Glenn Foulds Ph.D.
Associate @ Fenwick & West
Area: Entrepreneurship
Date: August 6th, 2024
Glenn contributed valuable insights on the patenting process. He outlined the steps for filing a new patent. As well, since there are prior research on this topic, he told us about how claims can be infringed and gave us advice about navigating these patents. He also emphasized the importance of obtaining orphan indication status, which provides regulatory exclusivity from the FDA, separate from patent protection. He recommended that we file a preliminary patent, which requires very little compared to a full patent. This also gives us a year of buffer time before having to submit the full patent. In line with our plan, he suggested taking advantage of the organ designation.
Takeaway:Glenn provided valuable insights into the patenting process, outlining the steps for filing and advising on navigating existing patents. He emphasized the importance of obtaining orphan indication status for regulatory exclusivity and recommended filing a preliminary patent to gain a year of buffer time before submitting a full patent, aligning with our plan to leverage orphan designation.
Outreach
Dr. Ria de Haas Ph.D.
Project Manager @ FSHD Europe
Area: Outreach
Date: August 5th, 2024
Ria previously worked at Spierziekten Netherlands and is now based at Radboud
university medical centre working with the European Trial Network chair, Nicol Voermans. During
our meeting, Ria generously explained FSHD Europe's vision, as well as the initiatives
they are involved in. One of this is Project Mercury, a global initiative aimed at
accelerating drug development and improving trial readiness, currently involving six
EU countries with plans to expand. They are conducting a large survey across Europe
to understand the needs of FSHD patients and involve them more in the research process.
While FSHD Europe is not yet working directly with research, they are gathering patient
input to develop a research agenda based on survey results and patient experiences. This
agenda is intended to identify research topics that patients find interesting and relevant.
After the meeting, we agreed to develop an initial draft for a workshop tailored to early onset FSHD
patients, as they are the ones left out from most of the conversations in comparison to
other age groups. Making an activity to empower them through research and incite interest
in scientific research from a young age was a collaboration they were interested in.
Takeaway: Ria explained FSHD Europe's vision and their involvement in Project Mercury, a global initiative to accelerate drug development and improve trial readiness, while gathering patient input through a large survey to develop a research agenda based on patient needs. We agreed to collaborate on a workshop for early onset FSHD patients to empower and inspire their interest in scientific research, addressing a gap in conversations for this age group.
June Kinoshita
Senior Director of Research & Education @ FSHD Society
Area: Outreach
Date: August 13th, 2024
June is the senior director of the largest organization for FSHD patients in the world. During our meeting, she agreed that there is a need of more young adults engagement in the society. There is a need of more activities specifically tailored to younger FSHD patients, and having a workshop would be something of interest for both the patienst and parents. Moving forward, we accorded to collaborate with the young adults group to help coordinating their virtual conference at the end of the year, and also deliver a workshop along with their help.
Takeaway: June acknowledged the need for more engagement and activities tailored to younger FSHD patients and expressed interest in hosting a workshop for both patients and parents. We agreed to collaborate with the young adults group to coordinate their virtual conference at the end of the year and deliver a workshop with their assistance.
Ariam Mogos
Emerging Tech + Education Lead @ Hasso Plattner Institute of Design at Stanford (d.school)
Area: Outreach
Date: August 15th, 2024
Being experienced with Human-Centered Design and being a lecturer at the Stanford d.school, Ariam was of immense help when developing our iHP Handbook. She mentioned that having a Human-Centered Design (HCD) approach to synthetic biology is a very interesting angle, and agreed to review our initial plan to provide feedback. She directed us to specific resources from the d.school to approach the HCD definition section, and mentioned other faculty and people she thought would be helpful to flesh out the specific synthetic biology applications of HCD.
Takeaway: Ariam found the Human-Centered Design (HCD) approach to synthetic biology intriguing, agreed to review our initial plan, and directed us to d.school resources while recommending other faculty and individuals to help refine the specific applications of HCD in synthetic biology.
Bay Area Bioengineering Symposium (BABS)
In collaboration with iGEM Teams, we attended and presented our initial idea to the wider iGEM community in the Bay Area. Our team had no initial expectations of the gathering, but we left with incredibly rewarding friendships, feedback from both students and faculty of the different universities present and inspiration from other team's problem solving approaches. One of our favorite talks was Dr. Adam Arkin's "From elements to technologies: Challenges for engineering biology for earth and beyond"
Check out the poster we presented!
We want to thank iGEM at Berkeley for organizing such an amazing event and for inviting us!
FSHD Society Early Onset Roundtable
The FSHD Society is the world's largest grassroots network of individuals with FSHD,
their families, and research activists. They are at the forefront of FSHD activism,
and count with a network of thousands of families awaiting for a cure.
As one of our
team members had strong ties with the organization, we wanted to present our team, get to
know some of the patients, and listen to their questions, comments or concerns regarding
the project. We found this crucial as we finished designing our project before getting into
the lab, since we wanted to gather user input into our planned therapeutic.
When developing a new therapeutic, it is imperative to consider its effect on those it is being developed for.
However, interaction with patients themselves is often something of a neglected or forgotten
element in scientific research. There is a systemic disconnect that exists between researchers
and patients. We wanted to bridge this gap as we were in initial stages of developing dux., to
develop a technology that will be genuinely beneficial to the user, created with patients realities
and context at the forefront of our design. We had very positive feedback from the guests.
Our team had the opportunity to give a face to the disease at a large scale.
Listening to
Heloise's story, as well as the other patient's specific problems, pushed to think in a
different way: How can we further integrate the user's realities into our product?
Check out our talk and slides here!
SB. Talk - Meet the iGEM Team
Stanford iGEM has historically been constantly engaged with the wider synthetic biology community. As such, we wanted to continue sharing our yearly project with the community at Stanford. We pitched the proposal to around 20 people from both students and faculty, followed by a Q&A. This was the first time our team presented our idea to a larger public. Having the support of the wider synthetic biology community and receiving their initial feedback was very enlightening.
10x Genomics Workshop
After using the 10x Genomics Cloud Analysis tools for bulk RNA-seq analysis, we were
sure that the workshop would deepen our understanding of this tool in another type of
dataset: scRNA-seq. We found useful to know the gene markers in different cell populations
and to accurately identify cell types to have a more precise view of future pathways for
the project, and other questions we can solve with available data.
The workshop provided
comprehensive training on the entire data analysis flow, from processing FASTQ files to more
advanced techniques like clustering, visualization, and differential gene expression analysis.
The tools covered, such as Cell Ranger and Loupe, are crucial for our project, particularly for
processing and visualizing single-cell data, while community-developed tools like Seurat and
Scanpy offer additional flexibility. The workshop also covers essential topics like cell type
annotation, trajectory analysis, and handling data noise.
iHP Handbook
The iHP Handbook is a resource we wanted to develop to shed light onto the myriad of possibilities of applying Human-Centered Design in synthetic biology. With the help of CityU iGEM and iGEM IISER-TVM, we could develop an open-ended guide to provide a new perspective into solution-making.
The guide is friendly for those with no background with human-centered design, and it is intended to be adaptable to a variety of situations. Accept or reject the feedback you find valuable and fit, and adapt it to the needs and objectives of your project. The handbook is, by no means, exhaustive. In fact, it encourages the reader to think about their specific project and either accept or reject the feedback depending on the situation.
