Read Article 04: John Wikswo, Erica L. Curtis,
Zachary E. Eagleton, Brian C. Evans, Ayeeshik Kole, L. H. Hofmeister,
and William J. Matloff. Scaling and systems biology for integrating
multiple organs-on-a-chip. Lab Chip In press, doi: 10.1039/C3LC50243K,
2013.
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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.
0. I understood that scaling is critical for application of OoC but did not know the current status of scaling and how it varies between organs.
ReplyDelete1. I learned about the scaling factors which enables to comparison of OoC experiments to large scales which would enable therapeutic development and other potentials.
2. A pressing question that I have deals with the cell lines used in the OoC. I did not see it addressed in the article but how are the cells affected in the OoC. Typical in vitro cultures use immortalized cell lines so are the same cell lines used? And how does the OoC effect the cell lines in terms of behavior such as adhesion to the vessel and other stresses? Also is there a difference in comparing OoC to an adult as to a child?
3. The article highlights large organ systems so is it possible to mimic some of the smaller organs and perhaps some critical micro environments such as hypoxic areas around tumors.
4. I believe the scaling is extremely important for the application of OoC and understanding the complexity and issues involved in scaling is critical to accurately determine the scaling factors.
For your last question, it seems to me that an adult milli organ would simply be a child ~2milli organ and that dosing ratios would be inverted for testing drugs on "child" OoCs. I think that, for a system of OoCs, the differences between relative adult and child scaling (factors of 1 to 2) are insignificant in relation to the differences in scaling intrinsic to building a system of OoCs (organs re-scaled 3 to 6 orders of magnitude). In other words, I doubt those differences would be within the resolution of OoC systems.
DeleteThe idea that I envisioned is that certain organs are not fully developed as a child. The requirements for certain hormones and is different between adults and children. Consequently if you want to study drug interactions for example the outcome in an OoC using a cell line from an adult would be different from using a cell line from a child.
DeleteCameron Stewart
ReplyDelete0. I already knew that OoCs should be scaled according to desired function.
1. I learned about the functions of primary interest of the brain, heart, kindney, liver, blood and lung, and what should be scaled in order to properly scale those functions.
2. Why microOoCs? Would there be a significant price difference between a MicroOoC and a milliOoC? What is the most costly component of an OoC, the supporting hardware or the cells? On a different note, from pg 9, wouldn’t a single celled alveolus make the lung/capillary surface area unrealistically small and how will that problem be approached?
3. Topic: This is paper is all about what compromises must be made in order to properly scale the functions of interest in the corresponding organs of interest.
4. Thoughts: Page 9 has a typo (it should be 1^.95 rather than 1.^95). Otherwise, I found this article to be intriguing and to concisely propose solutions to a broad range of issues. After reading about vague ideas, it is nice to get into the meat of it.
0. Knew: Proper scaling would be important to creating a relevant OoC
ReplyDelete1. Learned: I learned about the different types of scaling organs (allometric and functional) and the challenges of scaling various organs.
2. Pressing ?'s: What are the effects of different growth rates of cells? Can this be overcome/controlled in an effective manner? This is important to consider when looking at heterogeneous populations found in organs.
3. Presentation: Thoughts on how to effectively scale different organs so that they maintain their physiological function.
4. Thoughts: Something that stuck out is the use of "histological sections." This can be really helpful in isolating certain functions which would certainly aid in clarifying the mechanism of action. A simple system with less variables is easier to understand, as long as it's not too simple.
Frank "Edad" Block, Jr.
ReplyDeleteAsgn_3A_Class_03_Article_04_2013_08_29
0 Knew: General problem of scaling
1 Learned: Wikswo’s 3 approaches to scaling
2 Pressing:
--This topic is a critical problem!
--The issue of diffusion distances is also critical (O2, CO2, nutrients, waste)
3 Presentation: There could be other approaches / other solutions
4 Thoughts:
--Why are we starting with a Human on a Chip? Why don’t we start with something simple, such as a Snail on a Chip? You could even make it 1:1 in size (like the map problem).
--ERRORS in paper: Mouse heart rate is NOT 100x human. It’s about 500-600 / minute. Likewise human cerebral blood flow is NOT 7 L / minute. It’s about 800 cc / minute.
--A related and relevant issue is the growth and development of the organism. All of us started out < 1 mm in size. (Exception: egg-laying animals) Fetal organ proportions – and function – are not the same as the adult. Fetal circulation (i.e., in utero) is different. Studying embryology could be useful: How do you get from A to B? Under the right circumstances, if our OoC is “immature,” could it grow and “develop” itself so the organs are the right size?
--Microformulator: Human blood contains thousands of chemicals / compounds / proteins / etc. Most of these cannot be easily identified / detected / measured.
--Aquarium model: If you circulate fresh perfusate and never recirculate, you can keep everything alive but never study drugs etc.
--Can you study one organ at a time? And see what it makes? And use the microformulator to add that to the blood – in various quantities – for the whole OoC? And then see what the other organs do with it (in various quantities)? Now this is almost a computer simulation. This then becomes a slow-motion OoC!
--Missing organs: A functional human being is dependent upon a NERVOUS SYSTEM. People who are brain-dead ALWAYS die within a few days! You CANNOT keep them alive very long if the brain is dead! Also need sympathetic and parasympathetic nervous system, adrenals, thyroid, pituitary, insulin, etc. These are where the major feedback loops are located and how can you model them if you don’t have those organs?
0 Knew: From the other papers I was aware of the general issues surrounding the process of determining appropriate scaling techniques.
ReplyDelete1 Learned: I learned that allometric scaling isn't sufficient and more about what functional scaling means and the specific parameters that must be considered for each organ.
2 Pressing questions: I know we discussed this some in class... but what are the specific drawbacks to using real blood as the perfusive fluid?
The article discussed allometric coefficents and functional scaling... where should we begin when scaling organs? Are allometric coefficients useful at all or do we need an entirely new method? How were allometric scaling coefficients determined?
... side question: How do we culture different cell types together on an Ooc? For instance, the brain contains many different cell types. How do we make sure these are growing in the appropriate amounts and spatially relative to each other?
3 Presentation: Overall Scaling Process for OoCs/HoCs
4 Thoughts: Still trying to piece this OoC idea together in my head. Still difficult for me to believe such a small amount of cells can mimic an entire organ. How do we characterize the OoCs to determine they are physically and functionally accurate?
Jie Zhao
ReplyDeleteAsgn_3A_Class_03_Article_04_2013_08_29
1. a. brain tissue is very diverse across species.
b. the constant trade-off between realism and simplicity.
2. a. the chemical reaction involved in the brain metabolism is actually simple. should the functional scaling related to metabolism consider less important for the purpose of drug test?
3. plumbing of the human body.
4. because of the constant trade-off between realism and simpliciy, the HoC for various kinds of drugs should also vary. it'll be interesting address the design principle for specific drugs.
Asgn_3A_Class_03_Article_04_2013_08_29
ReplyDelete0. Knew: Scaling that results in close to physiological states is key to making OoC successful. There is a fine line between healthy and diseased states; this will be the large hurdle to overcome in OoC.
1. Learned: Key ideas behind the thought process of non-allometric scaling for a handful of specific organs.
2. Questions: Would keeping heterogeneity in the OoC not be extremely helpful if not necessary in representing the physiological state? I would think that eliminating some of the cell types in the tissue would have a large affect on the other cells, mechanisms, feedback, etc. If we are wanting to possibly personalize these chips in the future anyways, could we not start trying to use cells from us humans now - with heterogeneity already present?
3. The scale at which the technologies for gathering data are currently working. Could we not decide on a scale for "organs" that meets this half way instead of moving directly to an extremely small scale?
4. Seems like the community is trying to solve too many issues at once. Need to be sure to keep big picture in mind but work on smaller pieces of the puzzle.
David Wooten
ReplyDeleteAsgn_3A_Class_03_Article_04_2013_08_29
0. Knew: The general concept of organs on a chip, and the desire to integrate them. West, Enquist, and Brown's allometric scaling.
1. Learned: Allometric scaling won't work well because different organs scale at different rates, and at some point, the brain will be bigger than the whole organism (including the brain) which is an obvious contradiction. The most promising way seems to be functional scaling.
2. Pressing ?: Since scaling problems seem to get more dramatic at smaller scales, what is the benefit of going so small? Also, if we can trust Geoff West's assertion that an organisms entire physiology is based upon its mass and metabolic network, along with the observation that more massive organisms have more effecient energy requirement / cell, how can we guarantee that a milli-human (approximately the mass of 1 mouse) won't physiologically respond like an actual mouse does?
3. Presentation: Allometric scaling
4. Thoughts: The idea of compensating for missing organs with additional compartments worries me. While it's important to maintain homeostasis, how can you make sure that these external controls aren't artificially imposing adherence to the "predicted" outcome?
Andrew Nelson
ReplyDeleteAsgn_3A_Class_03_Article_04_2013_08_29
0. Knew: Scaling down organs includes consideration of myriad processes.
1. Learned: The merits of three scaling approaches and issues concerning scaling down specific organs.
2. Pressing: When fine-tuning the details of these organs on chips compromises inevitably must be made so how does one decide which liberties are okay to take in order to achieve the best human relevance?
3. Presentation: Thoughts on streamlining advances in OoC, with this being a relatively new field can previous work be synthesized into creating even greater knowledge gains.
4. Thoughts: In determining relevance even physiologically inaccurate systems can assuredly give more insight into the dynamics of the organ relationships. There have to be larger feedback loops in the body across different systems that cannot be accounted for in these OoC’s, so how can “out of left field” mechanisms be intercepted before clinical trials.
0. I knew that scaling would be critical in building humans on chips.
ReplyDelete1. I learned that there are several methods of producing such scaling. I had not considered the pros and cons of allometric and physiological scaling.
2. Question: How can methods of physiological scaling be evaluated to determine their correlation to actual organisms?
3. Presentation: Math behind allometric scaling.
4. Thoughts: Surface area of many organs (e.g. respiratory and G.I. tracts) is critical to proper function. However, ratio of surface are to organ volume is also important. We are constrained by the size of a cell: We can't make them smaller. This may make it difficult to achieve proper balance between surface area and organ volume.
Rui Wang
ReplyDelete0. Knew: A system with multiple organs in mHu and uHu can simulate similar functions in Hu, which provides rich information in drug testing and guidance in the industrial.
1. Learned: The functional or physiological scaling focuses on the critical part on each organ. The functional parameters help people design the device and the functional readouts of an entire system on chips. For example, metabolism is critical to the scaling of the brain; composition, biochemical and oxygenation factors are important for the balance of maintaining cardiac pump function.
2. Questions: Allometric scaling produces every linear relation among the parameters. Multi-organ systems together present a non-linear system. How to adjust each parameter to allow the entire system to be the best condition? The critical parameters in mHu and uHu are the same?
3. Presentation: different scaling for there models: Hu, mHu, uHu
4. Thoughts: Since every model of organs has critical functioning factors, which also implies that every model is good at simulating one or more functions. We might combine each pros and cons of every model together and build a large non-linear system like choosing an appropriate model for each organ to handle different situations.
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ReplyDeleteJPW