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.
Saturday, November 12, 2016
SysBio16 Asgn_24C_Class_24_Article_21_2016_11_17
CN-Bio Liver: Read-Scan
Article 21 TJ Long et al., Modeling therapeutic antibody-small molecule
drug-drug interactions using a 3D perfusable human liver co-culture
platform, DMD-FF (2016). Reading team - read carefully; Class - read
abstract, captions, conclusions so you know what's going on and can ask
questions of our guests. Post a PCRC on the blog.
Subscribe to:
Post Comments (Atom)
Ben Terrones
ReplyDeleteSysBio16 Asgn_24C_Class_24_Article_21_2016_11_17
0. KNEW:
I knew that liver on a chip existed and that the liver is very important in drug metabolism.
1. LEARNED:
This paper discussed a specific experiment in which they modeled drug-drug interactions using a 3D perfusable human liver co-culture platform (liver on a chip). They did this by measuring the effect of IL-6, an inflammatory cytokine, on CYP3A4 activity, which is important in drug metabolism, and how suppressing IL-6 using the drug tocilizumab affects the metabolism of another drug, simvastatin. The results for the IL-6 stimulation studies were as expected: an increase in IL-6 exposure decreases the activity of CYP3A4. To test the effect of tocilizumab on CYP3A4 activity, they used six samples that went through two testing periods. The results show that IL-6 suppresses CYP3A4 and tocilizumab de-suppresses CYP3A4 when the suppression is caused by IL-6. De-suppression occurred with any combination of IL-6 and tocilizumab. Tocilizumab had an opposite effect on CRP, a marker of inflammation. They then showed that administration of tocilizumab after initial treatment of IL-6 increased the metabolism of SVA as compared to only IL-6 treatment. The point of this paper was to show that the LiverChip™ is a much better platform than 2D cultures because of its long-term capability.
2. PRESSING ?:
Has this liver on a chip had any effect on the drug development process yet or is it too soon for anything noticeable? Has anyone connected a liver on a chip to other organs on chips to see how drug metabolites affect other organs?
3. PRESENTATION:
A presentation on another proof of concept paper for a different organ on a chip would be interesting.
4. THOUGHTS:
This was a very interesting paper that made me realize how fast technology like this is advancing.
0.Knew: I knew that hepatocytes were liver cells. I learned that the prediction of drug safety was a big issue.
ReplyDelete1.Learned: I learned what cytochrome P450 (CYP) enzymes are. I learned that IL-6 is a cytochrome that suppresses the CYP enzyme through down-regulation. I learned that the presence of CRP is an indicator of IL-6 because hepatocytes express it in response to IL-6. I learned that Kupffer cells secret IL-6 locally, in response to inflammatory stimuli. I learned about tocilizumab and simvastatin, and I learned that statins are primarily metabolized by CYP3A4. I learned what a liver sinusoid is, and I learned that albumin synthesis is a marker of hepatocyte activity. I learned that the effect of tocilizumab in the presence of IL-6 is specific to inflammatory cytokine inhibition, as witnessed by experimental results.
2.Pressing Questions: Why are the plates coated with collagen specifically? P4
How is the “shed-soluble” form of Il-6 different from the regular IL-6 (what does it mean for something to be shed-soluble?)? p5
What is a trypan blue exclusion assay? P8
3.Presentation: The methodology got pretty dense to me. Though the figures did help with the explanation, it would be helpful if we could review what happened here.
4.Thoughts: This paper was flooded with measurements and new terms, but I actually found it interesting. I appreciated that there were several figures. I think the experiment was performed well, and the results were consisted with information already known about the molecules under observation.
Asgn 24C, Article 21: Modeling therapeutic antibody-small molecule drug-drug interactions using a 3D perfusable human liver co-culture platform
ReplyDelete0. KNEW
Based on my work in the xenobiotic metabolism project, I knew the basics of how the liver participates in all three phases of drug metabolism. I knew that CYP is often involved in phase I metabolism. I knew that organ on a chip technologies existed and were often focused on being perfusable and mimicking in vivo environments.
1. LEARNED
I learned that IL-6 is an inflammatory cytokine that leads to inflammation vie the IL-6 receptor (which can be membrane-bound or soluble). I learned a lot about different ways to measure inflammation including a decrease in CYP activity, an increase in CRP, and a decrease in soluble IL-6 receptors. I didn't know that traditional hepatic cell cultures were ineffective after a few days, since the cells lost their metabolic functions. I learned that the drug tocilizumab can block the IL-6 signaling in the liver cells, leading to a decrease in markers of inflammation. I also learned that tocilizumab can affect the pharmokinetics of another drug simvastatin hydroxy acid.
2. MOST PRESSING QUESTIONS
What part of the typical cell culture causes the liver cells to lose their metabolic functionality?
What are the underlying genotypes that lead to donor-dependent levels of CYP activity, receptor function, etc? What is a time and cost effective way to explore these different genotypes with liver on a chip technologies in order to explore the full range of bodily responses to drugs?
How economically viable are these LiverChip platforms? Is it possible to mass-manufacture them for drug trials?
3. PRESENTATION TOPIC
Present on the IL-6 signaling pathway that leads to a decrease in CYP, increase in CRP, and decrease in IL-6 soluble receptors. How does inflammation arise in the body and how does it affect the function of proteins in cells, specifically the function of enzymes related to xenobiotic metabolism?
4. THOUGHTS
It's exciting to see how organs on a chip actually can restore the functionality of cell types due to the structure and parameters of the device. It was also interesting to see that the cells returned to normal living conditions in the device after only a week (normal albumin production and very low IL-6 production). I thought their experimental procedure was very well designed and provided a very convincing proof of concept for involving these devices in drug development.
0. Knew: I am familiar with co-culture systems and the benefits of moving in vitro assays to 3D/bioreactor systems. Have some background on physiology of the liver and some cells involved.
ReplyDelete1. Learned: Learned about the interaction of IL-6 with CYP3A4 and the downstream effects of this interaction with drug metabolism. CYP3A4 is important in drug metabolism. Different culturing methods and assays to measure for inflammation and drug metabolism. Enjoyed learning about the design of the LiverChip.
2. Pressing ?: New information learned using this co-culture system in the LiverChip? This paper was a proof-of-concept study for improving in vitro systems to more closely match in vivo. Now I'm curious what new information they have learned so far.
3. Presentation topic: 3D bioreactors. (not organs on a chip specifically), but commercially available bioreactors and their benefits
4. Thoughts: I liked how succinct this paper was - the logical layout of the methods made it very easy to follow. Definitely made me want to read more about the advancements made using bioreactors like the LiverChip.