No project is complete without taking inputs from experts in the field. Hence, for Coca Coli, we talked to several experts from fields ranging from product development to oncology and got their suggestions on the project. We are grateful for the insights we received from them since these helped shape our project.
While our interactions with all the experts we talked to furthered our understanding in several ways, there were some interactions that we were able to directly integrate into our project and make it better. These Integrated Human Practices are given below, highlighted in gold!
Conducted by Uttara Khatri and Deevitha Balasubramanian
We sought to approach an expert in modelling biological systems in our institute itself to better understand the approach that we should take for modelling (and to be able to bug them anytime!). Being relatively inexperienced in this part, we needed to know what the step-wise approach to construct and solve ordinary differential equations; and who better than an expert on non-linear dynamic systems - Professor Ambika herself!
Our questions were focused on the correct approach required to efficiently replicate a complex biological system via mathematical equations.
After we explained our design and the aspects we wanted to model, she guided us through:
1. The common techniques used to simultaneously solve ODEs; and the variations that are necessary given particular conditions
2. The use of time-sensitive delays as a better estimation of biological systems, which are commonly left out in models for simplicity
3. The refinement of the function that gave us a time-dependent dosage of IL12 in the module: Coca coli vs. cancer How did we use this information?
Prof. Ambika’s inputs were crucial in building up a firm basis for modelling, and making sure that we weren’t too far from biological scenarios.
The construction and solution of the ODEs in the The Lactate Module and the CoCa coli vs Cancer, and their simultaneous solving have been greatly influenced by the inputs we got from her, especially the terms involving the correlation between the variables.
Following her suggestion, we conducted an in-depth research into the parameter values, specifically for the case of colon cancer patients, and incorporated these into our model. We’ve also tried to get as close to the actual biologically observed values for cell populations as possible, characteristic to each stage of colon cancer.
Laboratory of Self-Assembled Biomaterials and Translational Research, InStem
Conducted by Dibya Saha
The first phase of our Integrated Human Practices began with an interview with Dr. Praveen Vemula from InStem. Our main aim from the interview was to get an expert's opinion on the current state of scientific product development in our country, to see what challenges Coca coli might face if it comes to the market.
How did this help CoCa coli?
The inputs from Dr. Praveen were extremely crucial and these directed us to do an in-depth literature survey on the probiotic delivery systems, and the constraints that they face in biological ...systems. We also realised that we are at the earliest stage of development, and other large-scale problems like drug production and industrial work comes much later on in the story. However, setting up a firm base in the first step, considering all scenarios, will help us sketch a success story for CoCa coli.
Transcript:
What are some essential things to keep in mind when developing translational products?
It all depends on the unmet need. What is the bigger need that is being addressed. For developing such products, a deep knowledge of the existing tools, the stuff that has already been done and things which do not work are essential.
How is the translational research landscape in India different from that abroad? Are there any challenges specific to India?
In India, a lot more infrastructure is needed to meet the needs. However, it has increased tremendously over the past decade and the ecosystem to promote translational science has developed. At the end of the day, it comes down to individual effort and determination to build the team to take these efforts forward. The path of translational research is challenging everywhere, but with proper commitment, it is always possible.
When embarking on a project, how important is it to involve regulatory rules in project planning?
It is critical to consider regulatory rules. There is no point in developing a working product which cannot be delivered due to regulatory constraints. Keeping these rules in mind will not negatively impact the project, but it will allow one to think more innovatively.
How essential are industrial collaborations when it comes to translational research?
Industrial collaborations are helpful as it is always good to bring in varied expertise. The experimentation stage of a project happens in the lab while the industry comes in at the development stage, which is the later part of the project.
If there are problems which are more significant than what one is addressing, how does one ensure proper funding?
The priority of problems is a myth. The priority of a problem is not determined by the number of people it affects, but by the need of the hour. For example, consider a headache. Almost everyone has suffered from it, and there are medications available. If one creates a new medicine for headache, it will not be that impactful because there are already alternative drugs. On the other hand, consider sepsis, a condition which has no medications available for its cure, so developing a therapy for that will be paradigm-changing. When it comes to funding, there is a niche funding for all problems. It is wise to choose the proper sources, depending on the problem you are trying to solve.
Most of the translational work is innovative, and the public is often unaware of the science behind it. In this regard, how important is science communication?
Before embarking on it, the idea should be clear to the researchers themselves. The work done should be communicated to everyone, be it the experts community or the general public. Communication to the people working for the development of the project is equally important as they might not be motivated to work otherwise. Translational projects require a lot of time and money.
As undergraduates motivated to address real-world problems with science, do you have any advice for us?
For any research, strong fundamentals are necessary. A firm base will be helpful throughout the scientific career, especially in translational sciences, which involve a long path. Doing a project and then trying to use it a real-world problem is not recommended. Instead, from day zero have a definite aim that you want to achieve. You can have many starting points, but finally, they should converge towards the final goal.
Head of Cell line Development, Pfizer, Chennai, Tamil Nadu
Conducted by Namita Chutani and Mayur Bajaj
We talked to Dr. Ambrish Saxena from Pfizer, to get inputs from someone working in the industry. We discussed our project with him and got inputs the possible flaws in our plan, and how we could overcome them. Furthermore, we wanted to know the possible methods of drug delivery.
The first important input that we received from the interaction was that IL-12 administration often has a dosage limit upto which the tumor-reduction effects can be seen; after this limit, cancer promoting symptoms start to reappear. This input validated the need for the constructs we created to fine tune the concentration of protein secreted. Check out our parts here!
Secondly, we talked about RPMrel which is our protein that binds specifically to colon cancer cells. He suggested us to investigate the binding kinetics of RPMrel to its receptor: integrin α5β1. We integrated this input in our Modelling module of Fluid Dynamics of the Colon, check it out here!
Lastly, while talking about how our drug could possibly be delivered, he suggested the use of pH based capsule method.
Conducted by Bhabesh Kumar Tripathy, Uttara Khatri and Namita Chutani
Discussion with Dr. Venkita Subbulakshmi was very fruitful as she validated several aspects of our design, and greatly appreciated the idea of lactate sensors, which she suggested to study both in wet lab and through modelling, Further, she supported the idea of using... a bacterial vehicle, as compared to a viral vehicle for oncotherapy as it is less harmful.
She told us about what makes a drug good: patient-friendly, non-invasive method that gives an instantaneous result and can detect even early onset of the disease in consideration.
How did this help CoCa coli?
We approached Dr. Venkita after most of the design phase of the project was done, in order to gain an in-depth insight into the specific-system that we shall be using; and went ahead with our project with high confidence after the green signal from her.
Professor of Surgical Oncology specializing in GI Oncology
and
Dr. Mani Kandan
Associate professor of Medical Oncology
Conducted by Bhabesh Kumar Tripathy At what stage of cancer do patients mostly approach you for treatment?
They mostly approach us when cancer has ...already reached the third stage.
Why is it that they approach only after the third stage has been reached? Is it something to do with the lack of adequate diagnostic tools or just the ignorance of early symptoms?
We do get patients at earlier stages but we don’t have any screening program in India to detect cancer at its earlier stages. Most patients do approach us once they develop symptoms.
Are patients willing to accept experimental treatments that are coming up now or they prefer tried and tested conventional treatments?
Experimental treatments have to be conducted in the context of clinical trials. It can’t just be given to a patient. Once it is approved and recommended by the governing bodies, it can be made available as a treatment.
How long does it take for an experimental trial to become a treatment, especially in India?
It’s not just in India. Normally, for a newly developed product or drug to come into clinical practice as an approved treatment takes somewhere around twelve to fifteen years.
How effective do you think IL-12 can be as a therapeutic agent?
There have been extensive studies on IL-12 as an immunotherapeutic agent, both in preclinical and Phase I and phase II. Most of the studies have been negative. It has been found that IL-12 has a small therapeutic window. It causes autoimmune side-effects like autoimmune thrombocytopenia and autoimmune hepatitis. That’s a major limitation why IL-12 didn’t make it to Phase III studies.
How effective can a combination of chemotherapy and immunotherapy be?
Immunotherapies don’t have common side effects like nausea, vomiting and hair loss that chemotherapies can cause. But they sometimes can cause autoimmune side-effects. Currently, extensive studies are being conducted to study the effectiveness of combinatorial therapy, especially in lung cancer.
What does your project focus on- immunotherapy or to design an efficient vehicle to carry your immunotherapeutic agent?
The vehicle we have chosen is E. coli. But we want to see how efficiently it can respond to lactate levels and release our target molecule in the colon cancer environment. We are using several combinations of lactate level regulators to sensitize our vehicle to different lactate thresholds.
Our vehicle is designed to release IL-12 only when there is a high level of lactate in the gut. But the gut microbiota can be affected by the entry of a foreign microbe. What characteristics do you think our vehicle should have such that it has minimal effect on the microflora of the gut?
It’s going to be a difficult task. Any probiotic you give will disturb the gut microbiome. You need to know all the possible interactions between your vehicle and the gut microbiome. You can refer to “The earth microbiome project’ which includes identifying the various types of microbiomes in different types of cancer including colon cancer. This might help you mimic the conditions that exist in the gut when you conducting experiments ex-vivo.
Would you recommend probiotics to your patients?
Once the treatments are approved by regulatory agencies after they have gone through extensive research and trials and proven to have benefits, they become part of the guideline. Then there is no problem in recommending it to patients. Currently, probiotics are administered only to patients who suffer from a mild disease like diarrhea or antibiotic-induced diarrhea to reestablish the gut microflora. If your treatment is found to be effective and works then it will surely be recommended.
Will the general public readily accept such treatments?
Most of the times people don’t have choices. If the doctors recommend some treatment then the patients generally accept it. In case multiple treatments with similar efficacies exist, then it’s up to the patients to choose.
Do you see any drawbacks in our project or any general suggestions that you would like to make about our project?
Your project is in a preliminary stage. You should read about already published articles on the therapeutic efficiencies of IL-12 and its side-effects. You can look into the work of researchers working on probiotics and have immunotherapy experience. They can guide you better.
Conducted by Mrugank Dake, Kartikeya Avadhani, Megha Maria Jacob and Neelima K.
This interview gave us insights into things to consider if we intend to release our product into the market. Dr. Viswanadham D., the chief manager (innovation) from IKP Knowledge Park, visited IISER Tirupati, our parent institute. We grabbed the opportunity to interview him and get insights into the ethical ...concerns underlying marketing of synthetic biology products. He told us the importance on the way to present ideas when we want to pitch in for good market value. The way we deliver the ideas to industrialists and the public is one of the major players in determining the success. He also informed us that the method of delivering the probiotic is crucial in choosing the appropriate pharmaceutical to approach. Being a probiotic for human subjects, there will be a lot of screening required to decide on the actual importance as well as to rule out any toxic or hazardous effects of these on humans. This has to follow getting FDA Approval which itself will take some time before we go for human trials. This gave us insights into things we need to consider before we put our product into the market.
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