The Systems Biology of COVID-19 and the SARS-CoV-2 virus. The class will build a foundation that includes the emergence of complexity, simple biological subsystems, their reductionist and equivalent toy and organ-chip models, and the measurements required to specify model architecture and parameters. Applications to biology, physiology, medicine, chemical and biological defense, pharmacology, drug discovery, and toxicology. UGrad: PHYS 240 01 and BME 290B; Grad: PHYS 326 and BME 395C.
Juan Gnecco
ReplyDeleteAsgn_2A/Article 1
0. Knew: Fundamentals and potential of organ-on-chips as a new model for integrating engineering and biology to better represent whole organs in a systems biology perspective.
1. The concept of hermeneutic circle of biology and microphyisiological systems. Also I learned about many of the issues, difficulties and challenges in current biological research and those that come with fabricating these devices. Also learned briefly about the concepts behind the logistics that have to be considered to make it physiologically relevant i.e dimensions, flow, pressure, etc.
2. People always ask me "how much does a chip cost?" and I can't really ever answer the question in numbers but rather man power and opportunity costs. Also, what are some end-point validations techniques to define an organ (depends on the organ I suppose).
3.Introduction to the OoC as a presentation of the current issues, conceptualization of biology, and projected goals along with the challenges that come with it.
4. We need more integration of biologists, biophysicists, M.D.s, etc to accomplish these goals and better ways of communicate between these different worlds.
James Pino
ReplyDeleteAsgn_2A_Article_01
0:Knew- Basics of OoC. Knew that multiple OoC could be connected to provide better understanding of model systems of humans. Hermeneutic circle and biology.
1:Learned: The difficulties and problems of MPS. The vast list of remaining questions and challenges that exist.
2:Pressing: Does scaling of volumes stay linear for biological systems? I understand the logic, but is there justification in this? By scaling a single cell by reducing all its components by 1/10, would it function as 1/10 of a cell? At which scaling does the stochastic effects provide unrealistic effects compared to the actual system? What kind of data is obtained from MPS as of today? Is is possible to monitor flow into and out of particular OoCs? What are some examples of how MPS have provided more insight than cell culture and animal models? What is the computational modelling state? Are they agent based models of each organ with inputs and outputs connections?
3:Presentation: An introduction to a special issues in Experimental Biology and Medicine that provides overview about the biology and medicine of MPS.
4:Thoughts: As a modeler I am very hopeful that MPS will provides more valuable information about biological processes. I have a tough time understanding a lot of assumptions taken from most experimental methods and I view them as a major source of error when attempting to model processes. I understand why John based his career on obtaining the data to fit the mole of parameters rather than constructing the models first.
Cameron Togrye
ReplyDeleteAsgn_2A_Article_01
0:Knew-MPS's offered an additional asset when it came to testing the affects of toxins and drugs on the human body by enabling users to see drug-drug, organ-drug, and drug-organ-organ interactions.
1:Learned: The difficulties and problems of MPS. The vast list of remaining questions and challenges that exist.
2:Pressing: It is mentioned that targeted searches present a major bioinformatics problem with MPS's because of the small volumes and risk of "toxifying" by trying to look for too many things. Seeing as part of the purpose of MPS's is to look for unforseen interactions between organs as the result of a drug, how does this detract from the viability of MPS's? Also, as mentioned in the article, how do we assess the responses of said MPS's, ie is the MPS reacting this way because of the drug? Or some deficiency in the MPS?
3:Presentation: Various instrumentation which may prove useful in attaining useful bioinformatics from the MPS
4:Thoughts: When reading about milli and microhumans, the biggest thing that strikes me is the sheer magnitude of the project. As has been mentioned in class, biological complexity is immense, and it seems practically impossible to model the human body in all its nuances. This obviously leads to some simplifications being made (as in tissue cultures), but at what cost? Are we potentially creating more unknowns than we are solving?
0. Knew: The limitations that come with using one-dimensional cell culture to model the human body, as well as the general structure of OoC systems and the exciting benefits they offer compared to cell culture and animal models.
ReplyDelete1. Learned: About the hermeneutic circle of biology, it is very interesting how over time, the field of biology has taken a bottom up approach to engineering the human body, culminating today in OoC technology. OoC systems also have media to cell ratios much closer to the human body than the ratios in a culture flask, which helps maintain appropriate concentrations of signaling molecules in the OoC.
2. Pressing ?: Does the missing-organ formulator in a MPS output a constant stream of hormones, nutrients and metabolites or does it vary these quantities over time, mimicking normal body function? If so, how is normal body function defined?
3. Presentation: Components of a MPS, as well as the benefits and challenges this technology presents.
4. Thoughts: How long is it likely going to take before OoC systems will be integrated into the FDA required drug approval process? How expensive are these chips and will their use significantly lower the costs of drug development?
Kate Jones
ReplyDeleteAssignment 2A
0. Knew: I knew of the recurring theme of the hermeneutic rule in reference to biology and parts of the body. I also knew the primary reasons for creating a model that better anticipates the drug-drug, organ-organ, drug-organ, and drug-organ-organ interactions that take place in the body.
1. Learned: I learned that the cells used in an MPS are from immortalized cell lines, embryonic stem cells, iPSCs, or primary cells. I also learned of the many challenges researchers developing organs on a chip face in designing the model.
2. Pressing ?: In the section on accounting for missing organs, the author poses many questions but only really addresses the question on accounting for metabolic activity by limiting nutrients and oxygen. However, how do you account for an unknown or undiscovered action of another organ?
3. Presentation: Because there are so many different obstacles in creating the ideal model, experts in many different fields are likely to need to collaborate on the project. It might be worthwhile to discuss how each field is involved, especially given the wide educational background in the class.
4: Thoughts: Though the OoC system ideally could be used by an average person as a form of personalized medicine, is it likely to be that far reaching? Also, what could some of the negative consequences be? It seems that if these systems can be used to detect toxins and biological warfare agents, they could also be used to develop them and ensure their method of action.
Nate Braman
ReplyDeleteAssignment 2A/The relevance and potential roles of microphysiological systems in biology and medicine
0. Knew: Some of the general obstacles of OoCs, OoC applications as drug development platforms and personalized care tools, how OoCs address current flaws in cellular monolayer and animal models.
1. Learned: Specific challenges of OoCs, such as: delivering drugs to the OoC model, precisely controlling minute volumes, and developing a suitable O2-carrying blood surrogate. The history of isolated organ research.
2. Pressing ?: To what extent can simplification of the human system in a milli or microhuman be standardized? How might the assumptions of the model need to be changed for different applications? How can OoC components and the platform that connects them be made versatile enough for mass production?
3. Presentation: A brief history and overview of microphysiological systems/organs-on-a-chip, covering their advantages and applications, as well as current obstacles to their realization.
4.Thoughts: I think MPS could have significant benefits, especially within drug development for currently problematic targets like the central nervous systems. I was very interested in the section on RTA, and am looking forward to gaining a better understanding of the subject in the weeks to come. How will RTA data be interpreted? Will a RTA device require a significant software component to assess the mechanisms of chemical agents?
Mark Vander Roest
ReplyDeleteAssignment 2A
0. Knew: The concept of the hermeneutic circle and some of the approaches for individual organs on chips.
1. Learned: A few more of the technical challenges associated with combining multiple OoCs.
2. Pressing ?: How closely do OoCs mimic native organs? Are there multiple iterations of a single organ that have differences to test different things? ie. would you use the same OoC to test pharmacologic agents as to study various pathologies?
3. Presentations: An overview of MPS, OoCs, some of the challenges faced in creating these devices, and current progress in the field.
4. Thoughts:I'm starting to get a better feel for how OoCs might work and why those working on them are so optimistic about their future, but I still wonder if there might be some crucial stuff lost in the simplification of organs.
Kendra Oliver A01/ The relevance and potential roles of microphysiological systems in biology and medicine
ReplyDelete0. Knew: Biology is reliant on both the timing and the conditions in which the biological phenomenon, where is be a pathology or an endogenous system, is being studied. When we consider the whole organism, such as a human in this context, it is clear that there is a vast amount of complexity within the system. This includes intracellular signaling events, to paracrine signaling, to alteration in cellular function, to whole tissues responses, and intrer-organ communication that develop the resulting pathology, biological phenomenon or behavior. Major emphasis has been put on the reductionist approach to science, allowing us to know in great detail about the signaling systems. Using in vtiro cellular system we are able to understand intracellular processes well (within a given context) however this fails to tell us of the extracellular conditions that may arise (cell-cell interaction, cell-matrix interactions, whole tissue response, organism response). Furthermore, it fails to put into perspective the microenvironment in which the cells are situated bringing into question the accuracy of the intracellular findings. Finally, in pharmacology temporal issues that lead to dynamic detection problem when studying metabolites is a major issue. Metabolites may be toxic and lead to unforeseen consequences in vivo. Furthermore, because the body is in constant flux the production of these metabolites can be rapid leading to issues of detection.
1. Learned: The main idea of a microphysiological system is a integrated system of cellular constructs. The idea would be to re-create a multi-organ system that allows for holistic view of drug action. These constructed can be made with immortalized cell lines, primary cells, or derived stem cells. Discussed in this article are some of the remaining issues with developing this system including the volume the fluidic constitution, and sample size/detection issues. These systems are commonly referred to as organs-on-chips or in-vitro organ constructs.
2. Pressing ?: To test if MPS will be useful the main questions are the how accurately they represent and mimic the in vivo system. There are additional questions that are related to development including easy of manufacturing, functionality, and reproducibility of findings. Could MPS be able to model drug delivery in a physiologically realistic manner? Based on the size scaling on system-on-a-chip how would this relate to the accuracy of the model when examine diffusion across larger tissues? Reference 18, 23.
3. Presentation:
4. Thoughts: Along with reinforcing an appreciation for regulatory biology, the multidimensional aspects of physiological complexity that is seen with biological phenomena and pathologies are indeed challenging, exciting, and intimidating. Based on the idea that “we can’t understand the part until we understand the whole and that you can’t understand the whole until you understand the parts”, an issue that I can foresee arising in the application of MPS is that the readouts that we would be assessing (toxicology and drug efficacy) are based on our current contextual set of knowledge. Therefore it is important to keep and open lenses when assessing the accuracy of the MPS systems.
Additionally, because of epigenetics differences within individuals, what is the practicality of constructing personalized organs-on-chips? Would we need to acquire primary cells from the individual and, once again are we not altering the cells function by removing it from its endogenous environment? If we reconstruct the cells based on genetics, is this a true mimic for whole human environment or would the system need to arise to its own equilibrium before being an accurate model of the individual?
0. Knew: The basics on how Ooc might be useful and revolutionary.
ReplyDelete1. Learned: The many challenges that stand in the way of this revolution.
2. Pressing ?: Would a better approach be to talk about the how Ooc might currently contribute to the medical science, instead of boosting its promises?
3. Presentation: About the promise and challenges of Ooc and micro-physiological systems.
4. Thoughts: Given the many challenges facing a complete MPS or small scale human model, is there a realistic timeline before appreciable contributions will be felt throughout the community?
Arman Chowdhury
ReplyDeleteAssignment 2A
0. Knew: An MPS is an interconnected set of two or three dimensional cellular constructs that are frequently referred to as organs-on-chips or in-vitro organ constructs. The initial motivation for creating MPS was to increase the speed, efficiency and safety of pharmaceutical development and testing, paying particular regard to the fact that neither monolayer monocultures of immortal or primary cell lines nor animal studies can adequately recapitulate the dynamics of drug-organ, drug-drug, and drug-organ-organ interactions on humans. There are pressing ethical concerns regarding experiments on both animals and people.
1. Learned: The process of discovery in biology is governed by the universal hermeneutic rule “that we must understand the whole in terms of the detail and the detail in terms of the whole.” Biology distinguishes itself from the physical sciences by the breadth and depth of the spatial and temporal scales over which biological systems are connected. Biology spans multiple dimensions of complexity (molecular, structural, temporal and algorithmic, etc). One of the great advantages of microfluidic systems is that they can support media-to-cell ratios that are much closer to physiological values than can be achieved in a culture flash, Petri dish, or well plate, thereby avoiding a thousand-fold dilution of paracrine, autocrine and other signaling molecules and metabolites. However, there is a tradeoff between sampling frequency, sampling volume, and the number of analytes that can be quantified in the sample, whether with optical interrogation or analytical chemistry. An MPS should be viewed as an approximation of reality, not as an accurate reconstruction.
2. Pressing ?: As stated in the journal itself, the effectiveness of microphysiological systems will be determined in part by how easy the constructs are to use, how well they function, how accurately they recapitulate and report human pharmacology and toxicology, whether they can be generated in large numbers to enable parallel studies, and if there use can be standardized consistent with the practices of regulatory science. What are the criteria for delivering soluble effector molecules, such as morphogens, growth factors, hormones, metabolites, and cytokines, that would be produced by organs not included in the MPS?
3. Presentation: The article introduces microphysiological systems, explains the biology and medicine of MPS, talks about addressing various challenges of MPS, and concludes with future opportunities with MPS. Figures and diagrams make the content easier to understand.
4. Thoughts: Although the prospect of microphysiological systems seem promising in the field of drug development and personalized medicine, at the moment the model seems too simplistic. Iterative improvements need to be made to make the physiological approximations more realistic.
Tim Lee
ReplyDeleteAsgn_2A/Article 1
0. Knew: General concepts of the Organs on a Chip project and the potential for clinical use.
1. Learned: The specific details on the cost of the project, the complications that arise from handling such minute volumes and distributing the drug throughout the chip, and the concerns for numerically modeling the homunculus and all of its biological oscillations to account for.
2. Pressing: How complicated will the transition be to move from a general model to a personalized model for drug screening? It seems that there are a lot of factors to consider that will multiply once we start modeling for individuals.
3. Presentation: The challenges and potential of the Organs on a Chip project and applications of micro-physiological systems.
4. Thoughts: It was interesting to read up on the complications that arose from working on a microscale level. Some of these issues definitely seem solvable but I am concerned about a new wave of complications that can surface once drugs are tested for personalized chips.
Cami Johnson
ReplyDeleteAssignment 2A/Article 1
0. Knew: MPS could prove to be more accurate models for drug testing than currently used plate culture and animal models, but the complexity of the organ system is difficult to match in an organ- or human-on-a-chip.
1. Learned: Although I understood superficially how difficult recreating something as complex as the interconnectivity of organs, some of the specific challenges facing the research hadn't occurred to me, such as the issue of drawing quantifiable conclusions from the devices. Due to the small volumes involved, traditional methods may not be useful and an analytical instrument with scaled sensing volumes might be necessary. I now understand much better the specific problems that need to be addressed.
2. Pressing ?: The organ system is so intricate, even the paper states that if the MPS were 100% accurate, it may be too complicated to understand, so where is the threshold for accuracy? Exactly how close does the system need to be in order to provide useful information? Is accounting for missing organs sufficient/possible, or do more organs need to be connected?
3. Presentation: The article discusses the potential uses and the importance of microphysiological systems, while also addressing a few of the biggest challenges facing their development.
4. Thoughts: Although I knew that developing humans-on-a-chip wasn't easy, it now seems more daunting than ever. The article seemed to present so many challenges and questions with very few solutions and answers.
Shuaipeng "Jimmy" Zhang
ReplyDeleteAssignment 2A/Article 1
0. Knew: The challenges of OoCs in accurately representing a physiological environment.
1. Learned: The finer details of the challenges that MPS currently faces, such as accounting for missing organs, delivering the drugs, and the volume problem.
2. Pressing: A more complex OoC would result in a more accurate representation of a physiological condition. Are we at the point in biology where we have accrued enough knowledge to build MPS that can accurately reflect biological conditions? Perhaps a better way to phrase the above question is, when do we know that we have achieved the desired complexity to build a MPS which can accurately predict physiological interactions and produce emergent behavior?
3. Presentation: The challenges that OoCs and MPS current face in research, and their immense potential to advance biological innovations.
4. Thoughts: This article really placed the complexity of developing an accurate MPS into perspective. Even with two thousand years of research, there are still so many unknowns present.
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