Archives: April 2015

Learning Journal #5 – My undergrad has taught me that I have a lot to learn!

A. Three main things in BIOL463

Please describe, briefly, the three things that you learned in BIOL463 and that you consider to be the “most important” ones.

     One of the things that I learned in this course and that really stuck with me is X chromosome inactivation and the mechanism behind it. Every time there’s a question that requires to me to think up a mechanism involving silencing, I think non-coding RNA-mediated silencing and specifically Xist inactivating a X chromosome.

            It’s also interesting for me to have learned all the mechanisms behind chromatin remodelling. It’s pretty cool to know that there are regions of the chromosome which are considered transcriptionally active or inert, and they can be identified by epigenetic marks which are commonly associated with activation or inertness. What’s even more interesting is how cells will change their epigenetic profile the further they go down their differentiation pathway.

            Genomic imprinting is something I had a lot of difficulty with in this course but I think it’s one of the most important things we learned in the course. The example with Air RNA and how it silences paternal Slc22a3 particularly stuck with me. Genomic imprinting is so complex and can regulate development in a lot of cases and we probably haven’t even scratched the surface of understanding it yet.

 

 B. Identify types of knowledge

For each of your three “things”, please try to identify what type of knowledge it represents (Factual, Conceptual, Procedural/Skills, Metacognitive).

Xist-mediated X chromosome inactivation and Air RNA silencing Slc22a3 is factual knowledge since there is evidence and research to support these facts. Chromatin remodelling is more conceptual because it deals with theories and models than the other two topics I mentioned. There isn’t anything specific about chromatin remodelling that struck me other than just the general concept, which is why I would classify it as conceptual knowledge.

 

 C.  What makes “things” stand out for you

For each of your three “things”, please indicate what made it stand out for you.

  I think all of these three topics stood out to me for the same reason: they are examples for why science is so captivating. It’s amazing to think that the three topics I mentioned have so much impact on human development when they seem like just inconsequential concepts on their own. Development is so fickle and my mind is blown every time I try to think about the fine-tuned regulation and just how much regulation is required so we can develop into who we are now. There is so much complexity and we haven’t even come close to describing all of it. I think that’s one of the reasons why it’s so intriguing for me: these concepts make me realize that I know very little and there’s still a lot to discover so I will never be short of questions. There’s a lot of knowledge waiting for me and I just have to go out there and ask testable questions. This is why topics like the ones I mentioned stand out for me.  

 D.  Relevance/use

Please describe, briefly, what you expect each of these three “things” to be useful or relevant for.

   I don’t know if this is an applicable analogy but I always think of scientific breakthroughs as comparable water droplets falling onto stone. After years and years, water will eventually break through the stone and erode it. Breakthroughs are similar: you have to keep going and pushing until finally you make that breakthrough. But science is also unique because discoveries are often made because a scientist somewhere makes a tiny, seemingly inconsequential discovery but that can often be the catalyst for something much bigger later on. Discoveries in science are founded by the work of many people together. The topics I mentioned are small steps for greater discoveries down the road and that’s why they are so relevant.

 

E.  Three main things in your undergraduate education

Please describe, briefly, the three things that you learned during your undergraduate education and that you consider to be the “most important” ones. Why do you find them so important?

I have learned that I basically know very little of what there is to know in this world. In high school that might’ve scared me but my undergrad education taught me that this is something to be embraced. I really love the fact that there’s always something unknown in science; it makes life a lot more interesting. Another thing I’ve learned is to always be analytical in terms of the information that is presented to us. We are taught to take everything as it is when we are young but there’s a huge shift of mentality when we start university. It’s a difficult change to make but it’s absolutely worth it. One final thing I’ve learned is that science is a struggle. Sometimes you just want to rip your hair out or destroy things but the sweet release and reward when you overcome that struggle is just so satisfying. When I first started my undergrad I never understood why people with graduate degrees were so proud of one figure they made in their paper, even if it took a year to make that figure. Now I understand that feeling of pride; there’s nothing else like it.

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Final project note

I decided to focus my BIOL 463 Final Project on asthma and the possibility of epigenetic mechanisms regulating it. I initially started the project thinking that i would look at the methylation/acetylation profile of the entire genome and any histone modifications that may arise; Now, the project looks at exclusively DNA methylation. It’s a good example of really focussing on one aspect rather than making things really general.

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Informal post #6 – How science is taught

The discussion we had in our last class of the term, in which we talked about how science articles are perceived and how science is taught in high school, it really made me think about the education that I received prior to coming to UBC. Like a lot of people in class reiterated, I felt like I knew everything there was to know about science when I was in high school. I mastered the material that was presented to me in school and there was never a notion that I needed to know more than that. I never felt like I only knew a small portion of what there is to know in the world. Maybe the education board sets it up this way so that students don’t feel too overwhelmed with their studies when they are so young. But I really think it would be more beneficial if starting in grade 10, that students are taught that there is so much unknown in science and that this unknown should really be embraced. Students should learn from a earlier point to look at information critically, rather than the memorize and regurgitate information sort of education I remember from high school. I think this would go a long way to address the pure shock that some university students like me go though when starting university for the first time. It was a shift in thinking and it took me a long time to change my habits. I think it’s something that the Vancouver School Board really needs to look at in order to provide a more complete education for students. I think it would be much more captivating for students as well. Maybe we would have more researchers if we change our ideas about how to teach science from an early age.

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Assignments

I chose the in-class assignments to be a part of this file because they were really interesting cases to discuss with my group mates and it really forced me to learn but also defend my position to my groupmates  if I thought I was right. So because of this I liked the in-class assignments and they are included. I chose the “If I were a developmental biologist/geneticist”  as the fourth assignment because it forced me to think as well but also because I can’t think of any other assignment we did. I wasn’t there when the January 19th assignment took place in class so I couldn’t include it.

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BIOL 463 N&V presentation

BIOL 463 NandV presentation – Anik

Please click the link to see the slide I used to do my New and Views presentation. It was really difficult and apparently I was way above the time alloted 🙁

 

The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies

 

Increased activation of the RAF-MEK-ERK signaling pathway (also known as the MAPK signaling pathway) is a common hallmark of many human cancers. This is usually due to activating mutations in the RAF (serine-threonine protein kinase) or RAS (small GTPase) genes. MAPK-pathway targeted therapies such as BRAF and MEK inhibitors have been developed to counteract these cancers. However, these therapies are only transiently effective due to resistance. Thus, there is a need to identify the molecular targets which provide resistance to BRAF and MEK inhibitors within cancer cells. This will lead to the development of new therapeutic strategies which can enhance the treatment response.

To determine the molecular targets which regulate the response against RAF and MEK inhibitors, the authors devised a short hair-pin RNA (shRNA) screen in human non-small cell lung carcinoma (NSCLC) cells. These cells express an endogenous BRAF V600E (valine to glutamate substitution at position 600) allele. Their aim was to identify genes which, when inhibited, would display an enhanced response to the BRAF inhibitor Vermurafenib; this would indicate that the gene’s normal function is to provide resistance against the BRAF inhibitor. The best candidate from the shRNA screen was the Hippo signaling pathway effector YAP1. Based on this result, the authors hypothesized that YAP inhibition may increase the efficacy of RAF-targeted therapy.

Independent shRNA knockdown of YAP1 in HCC364 (NSCLC cell line with BRAF V600E allele) cells resulted in increased sensitivity of these cells to both Vermurafenib and the MEK inhibitor Trametinib. Stable overexpression of YAP1 in HCC364 cells resulted in substantially decreased sensitivity to both Vermurafenib and Trametinib, which confirmed the initial screening results.

To determine whether the YAP suppression effect was only limited to BRAF V600E forms of cancer, the authors silenced the YAP1 gene in Cal-12T human NSCLC cells which have normal MEK-ERK activation but encodes a BRAF with a G466V (glycine to valine) substitution. This cell line also displayed enhanced efficacy to Vermurafenib and Trametinib, which shows that YAP1 suppression can be a target to counteract RAF and MEK inhibitor resistance in human NSCLC.

Next, the authors wanted to investigate whether YAP1 regulates the response against inhibition of BRAF signaling in BRAF in other BRAF mutation-driven cancers such as human melanoma, colon, and thyroid cancer. YAP1 suppression increased the efficacy of both Vermurafenib and Trametinib in A2058/WM793 human melanoma cell lines, HT29/WiDr colon cancer cell lines, and KHM-5M and HTC-C3 thyroid cancer cell lines. This indicates that YAP1 suppression can be broadly used as a target in a wide spectrum of BRAF mutant cancers.

RAS mutant cancers work partly through MEK-ERK signalling. There is no effective therapy against this type of cancer, with MEK inhibitors providing variable results. The authors determined that YAP1 suppression also enhanced the sensitivity of multiple KRAS and NRAS mutant human NSCLC, melanoma, and pancreatic adenocarcinoma cell lines to Trametinib. This indicates that YAP1 suppression in conjunction with MEK inhibitors could be an effective therapeutic strategy in patients with mutant RAS.

The authors then wanted to determine the mechanism by which YAP regulates the response against RAF- and MEK-targeted therapy. Previous work had indicated that YAP regulates apoptosis; the authors postulated that YAP might regulate the expression of an anti-apoptotic factor such as BCL-xL to provide resistance against RAF and MEK inhibitors. YAP1 suppression indeed led to a decrease in BCL-xL levels; overexpression of BCL-xL rescued the effect of YAP1 silencing on the response to RAF and MEK inhibitors in HCC364 cells. Pharmacological BCL-xL inhibition using the drug Navitoclax and Tw37 led to increased efficacy of treatment with RAF and MEK inhibitors in several NSCLC, melanoma, and colon cancer models. Overall, these data indicate that YAP, via BCL-xL, acts as a signaling mechanism alongside the MAPK signaling pathway to promote resistance to RAF and MEK inhibitors. This research may lead to a new therapeutic strategy to enhance the efficacy of RAF and MEK inhibitors for patients suffering from a broad range of BRAF-and RAS-mutant cancers.

 

Lin, L., Sabnis, A.J, Chan, E… Bivona, T.G. (2015). The Hippo effector YAP promotes resistance to RAF-and MEK-targeted cancer therapies. Nature Genetics, 47, 250-256. doi:10.1038/ng.3218

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