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.
Will Matloff
ReplyDelete10B / Blood Progress
I/O: Blood exchanges components with many different organs. Gases such as Oxygen and Carbon Dioxide are exchanged at the lung. These gases are also exchanged with cells. The liver produces the majority of plasma proteins, and the kidney filters small molecules and ions from the blood. Many blood components originate from food and water intake, which enter the blood mainly through the small intestine.
Feedback/Control: Except for hemostasis, which is not very important for organs on a chip, the blood does not have many internal controls. The components of the blood are controlled by other cells and organs, primarily through input and output, as outlines above. It is important to understand how the blood levels of various components are maintained at relatively constant levels, and the importance this has on physiologic function. I am currently looking for literature which discusses this.
Plan: The plan is to create a blood substitute that is largely similar to a serum-free media, although with the addition of an oxygen carrier. The biggest challenge is to maintain blood levels during recirculation. Since cells use up serum components, it will be necessary to replenish them. Also it will be important to make sure that none of the component levels change drastically.
Zach Eagleton
ReplyDelete10B/ Lung progress
Inputs: Alveolar macrophages are the main defense mechanism for the respiratory system. inputs to the system would be inhaled particles,chemicals, or foreign body. IgG immune complex activates macrophage activity as well a variety of chemokines.\
Outputs: paracrine growth factor signaling to nearby cells,enzymes that promote fibroblast remodeling, neutrophil chemoattractants, and various chemokines
Feedback/Control: Im still digging into exactly how macrophages are contolled, although one paper suggests that gamma-delta T cells play some role in macrophage population control. Macrophages originate from blood lymphocytes but also have to capability to self replicate. They are removed though migration though the interstitial space and into the lympatic system or by the mucociliary escalator.
Plan: The plan is to do a presentation on the systems biology of the alveolar macrophage, possibly focusing on interactions with Type 1 and 2 alveolar cells. Since the macrophage is critically important to defense against pathogens/chemical agents it fits in nicely with the organ on a chip proposal to test versus harmful substances.
Erica Curtis
ReplyDelete10B/Loop of Henle
Input/Output - The filtrate entering and leaving the loop of Henle is isotonic in both cases. The two necessary primary components of the filtrate are water and NaCl. The measurable outputs include analysis of the filtrate leaving the model and measurement of the osmotic gradient produced.
Mechanisms and Internal Controls - The different properties of the descending and ascending limb of the Loop of Henle are mediated by varying permeabilities and active transporters. The descending limb is highly permeable to water yet does not extrude Na. The ascending limb is impermeable to water and the renal tubule cells express pumps that actively extrude Na. These properties can be mediated by differential shear stresses (due to a difference in the radius of the hollow fibers) or perhaps even artificial hormonal control.
The Plan - I propose a bioreactor with hollow fibers that loop through the device to simulate the loop of Henle. The fibers will be suspended in stationary interstitial fluid. Manipulation of the radius of the fibers can alter the shear stress experienced by the cells and influence their transport properties. I have run into trouble though determining how the cells will respond to increased shear stresses.
Lucas Hofmeister
ReplyDelete10B/Brain on a Chip
Input/output - I have clarified my inputs/outputs to include endocrine/hormonal regulation and neurotransmitters. I am starting to think that these will be some of my more useful inputs because i could control connectivity with fluid lines, and i could use will's pet device to introduce perturbations. I am also considering adding external electrical stimulation as a means of control...it seems foolish to totally throw away the idea of patch clamping and exogenous depolarization.
Feedback/Control -- I consider this the most important part of my brain plan. I am hypothesizing that if you put all of these pieces together in the correct way (scaling, architecture, barriers), much of this internal regulation will build itself. This is very convenient for a system as complex as the brain.
The Plan -- Im still basing my plan on a modular system. I will proceed with the engineering plan of how to build this and get it to work...digging into the specifics of what architecture i want to use and details such as cell growth rates, common medium, proper cell seeding and preparation. As an offshoot of my central nervous system brain on a chip, i am considering developing modules which represent the basal ganglia. these could be interfaced with other organ modules to provide an additional layer of connectivity.
1. Inputs:
ReplyDeleteCardiomyocytes - autocrine signaling
Endothelial cells (2 sub populations) - paracrine signaling
Neurons - sympathetic, parasympathetic, muscular
Fibroblasts - support cells
Electrical - Intrinsic automaticity, [ions]
Environmental - Pressure, oxygenation, pH
2. Outputs: Blood flow, contractility, blood pressure modulation, auto/juxta/paracrine factors
3: Feedback: Feedback arises from the complex signaling pathways that exist between cardiomyocytes, endothelial cells, and cardiac neurons. These types of feedback are analagous to those we have been studying in the biochemical networks and biochemical oscillators that we have been studying.
4. Plan: Cells will be grown as a co-culture of cardiomyocytes, endothelial cells, cardiac neurons, and fibroblasts in physiological ratios. A decellularized guinea pig heart will be helically wound around a hemispherical mold to provide a matrix for heart growth. An endocardium will be seeded on a mixture of collage, cardiomyocytes, and cardiac ganglia. Coronary blood flow will be provided by a plexus of arching fiber loops protruding from a membrane adjacent to the endocardial surface and synchronized with the automaticity of the tissue. Electrodes will be used to stimulate and record electrical activity. The pericardial space will contain media to support cardiac cell growth, as well has provide inlet and outlet ports for biochemical infusion and sampling. Force/contractility will be monitored with a froce transducer attached to a pendulum on the endocardial surface. One way inlet and outlet valves in the endocardial compartment will allow for tissue-mediated blood flow through the microfluidic.
Ayeeshik Kole
ReplyDelete10B/Liver Lobule
Input/Output - The input will be the hepatic portal artery. This will also contain the gases from the system circulation. The mixture of nutrients will be through an upstream microformulator that can adjust the nutrient content. Output will be bile to a separate bile duct (hollow fiber). Additionally, outflow from the hollow fiber will be considered the venous return, which will have waste products, plasma proteins, metabolites, and reduced nutrient content (measured via MS).
Mechanisms and Internal Controls - The liver responds to changes in the nutrient content delivered via hepatocyte chemical processes. It is very good at maintaining organ integrity mainly because it can vary its detoxification process based on enzymatic activity (need to look further into the key enzymes, cytochrome p450 is most important).
The Plan - I will construct a hollow fiber bioreactor where two outer fibers will represent the vasculature and another fiber will represent the bile collecting duct. Liver sinusoidal endothelial cells (LSEC) will be seeded in the inner layer of the fiber (along with other non-parenchymal cells). The outer layer of the hollow fiber will contain the hepatocytes. This will be place in a constant perfusion microfluidic bed (necessary to maintain LSEC differentiation). Hepatocytes produce bile on the side opposing the LSECs, it will be very interesting to see if this can be recreated. Main concerns are SA:V, the shear stress from flow rates, and being able to create the "space of Disse" observed in vivo. Best option to address SA:V will most likely be flattening the hollow fiber.