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the-redeemed-anon · 3 years

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Welp, since we got Wilbur back, let’s take a look at Eight

As a disclaimer, I’ll talk about the character, and if I mention the CC, I will label his name accordingly.

Okay, since the pog thing that happened on the 29th of April, and a couple of bad takes have already started to pop up Jesus Christ guys why do you want the dude that just got back to life after being trapped in limbo for over a decade to get beaten up violently- I think it’s appropriate to bring attention to the thing that gave me my pseudonym and my belief that we may get a redemption/healing arc for Wilbur: the song Eight, by Sleeping at Last.

Why this song matters, you may wonder. Well, it’s a song that we have confirmation to have been CC!Wilbur’s personal inspiration for his character, as said by CC!Wilbur himself. Not only does that give us insight into how and why Wilbur acted in certain ways in Season 1, but it also gives us the opportunity to see the inner turmoil he went through and still will.

Now keep in mind that this is just my interpretation of the song, other people may see the song differently, but overall looking at this song and looking for meaning into it I think is very useful if you plan to analyse Wilbur or even write about him. It truly gives you a lot of insight and context for how he was. Here is a link to it for you to listen to it, before I dive into the analysis.

First, let’s see what Eight is about, as a song. The song is about Type Eight of the Enneagram of Personality, which is basically a system that defines 9 different personality types. Sleeping at Last made a song for each Enneagram, actually, but we’re here to talk about Type 8 (also bear in mind I am not an expert in psychology, so I am not here to comment on the validity of this system. I’m here just to analyze a song lol).

What is Type 8 (aka a bit of analysis on Wilbur outside of the song)

Type 8 is often called the Challenger or the Protector. This type is characterized by a want to not show vulnerability, to have power. Their deepest fear is to not be in control of themselves, to be harmed, to be vulnerable, and their desire is to be in control of themselves, their life/destiny. They want respect over status, value loyalty and they want to make an impact on the world. You can start to see some core characteristics of Wilbur in this description.

We also have levels, from healthy to unhealthy, with which we can see what a Type 8 person can behave like.

Healthy Type 8 people act like a protector for others, they are the strong leaders, the challengers of oppression, the people who don’t stand for injustice in their communities. You can say they are the natural leader type, and I think you can start to see inklings of Wilbur’s personality from early Season 1 here. He started L’Manberg to challenge what he saw as tyranny. When Wilbur described the reasons he cared about L’Manberg, we can also notice that the values he lists align with the core desires of a Type 8: the desire to have control over their life, and not allow others to control them. By making L’Manberg to “stick it to the man“, Wilbur is very stereotypically a Type 8.

Average Type 8 people aren’t as open as someone on the healthy level is. Showing weakness is unacceptable. They may see relationships as the next challenge they need to surpass, and can come easily off as intimidating and ambitious to peers. To me, this sounds a bit like Wilbur after the War, before the announcement of the Festival. He was more closed off around that time, and you could argue that the Elections were a part of his ambition to prove that people respect him, that he can do this, rule a country. The new revelation that Wilbur was lying in his letters to Phil, about the Elections and the formation of Pogtopia also shows that he didn’t want to show weakness, to disappoint or worry his father.

Unhealthy Type 8 people become so closed off that they are intimidating and can appear tyrannical from the outside, often disregarding the feelings of others. They pursue power, and when someone stands in their way, they are cold and become quite antagonistic. They may issue empty threats in their pursuit for power, and their already existing relationships are turned into tests, where the only option is to pass or to fail, with no in-between. This can result in them being abandoned, and them accepting this as being better this way, to be alone. They can force themselves into loneliness.

If this sounds terribly familiar and recent, well... Wilbur, ever since the “Then let’s be the bad guys“ speech, has exhibited the traits of an unhealthy Type 8. Even now, post-resurrection, while he is trying to improve on himself, a lot of his traits remain or have worsened, due to staying in limbo for 13 years. He still has a persona under which he hides his issues, and as I have said in another post, he’s the emotional equivalent of a snail, you poke him gently and he completely retreats in his shell. Wilbur has actively driven people away from him for being so confrontational, and this can be seen again with Ranboo. All in all, Wilbur is definitely cozy in that section of the Type for now.

I also want to talk separately about three things:

1. The Pit

I won’t lie, the Pit is probably the most extreme thing Wilbur did to this date. It’s Wilbur at his lowest point morally and mentally, reveling in his brother figure fighting a much tougher opponent and losing. I won’t sit here and say he was right, nor am I gonna condemn you for your opinion on the Pit, but, when you look at Wilbur’s enneagram, the Pit and why it happened makes sense. What happened right before? The Festival. The Festival was meant to be the time Wilbur either blew up Manberg or left it be, based on Tubbo’s call. Wilbur prepared for those two scenarios, and felt in control of the situation... then it all went horribly wrong. The situation spiraled wildly out of Wilbur’s grasp and it ended with the death of Tubbo and the possibility of Techno being on Schlatt’s side.

This started a breakdown fueled by paranoia that led to the Pit, to Wilbur goading Techno and Tommy to fight. The question is, why? Why do that?

To regain control. Wilbur, in my opinion, did that in an attempt to regain control, after the Festival slipped so hard from his grasp, no matter his effort to keep control of it. That was his urge, that was his need in the moment, no matter how messed up it was, he may have felt like this was necessary. Remember, the core fear of Eights is to not be in control of their own life and destiny, to be puppeteered by someone else. This is why the Pit happened, when you acknowledge the fact that Wilbur was unstable mentally, and he is the type of person to want control.

2. The want to protect others

This is a quality of healthy Eights that still shines through with Wilbur, but it’s sadly overshadowed by his more antagonistic or morally darker actions and quotes.

Wilbur was naturally a protective person. Because Eights challenge authority, this makes them see the world as being inhabited by those who are strong and those who are weak, and not in a bad way. Eights consider themselves part of the strong ones, because they stand up for themselves, but because they see the world also inhabited by the weak, they have the urge to protect them. They also stand up for whom they think can’t stand up for themselves on their own, they think they are responsible for the protection of others.

And when you look at Wilbur, this shines through. He made himself President, and while no one protested, he did it because he felt he was the one fit for the role. Even at the time this scene happened, you can see why Wilbur would have perceived Tommy, Tubbo and Fundy as weaker than him: Fundy was his son, and Tommy and Tubbo, no matter the age intended at the time, were always viewed as younger than him, not to say, Tommy had just lost 2 lives back-to-back. Therefore, Wilbur put himself in charge and with the duty to protect the nation and its people, as the President.

Wilbur even says this in the flashback from Quackity’s stream:

[“What has made you do everything you’ve done up to this point?” (Quackity)

“That’s a- That’s a big question. Um. I guess it’s just protection for my people. I mean, I- I- I just want to see them thrive, and I want to see them safe.” (Alivebur) - (Quackity’s Killing My Enemies: 1:03:02, 12th Apr)]

It’s clear, Wilbur has a desire to protect his nation, and, by extension, his people, his friends, especially with the following quote once Quackity replies: [“Your aspirations of optimism are not going to be subject to my nation’s security I’m afraid. I- I completely disagree with everything you’ve said.” - (Quackity’s Killing My Enemies: 1:05:18, 12th Apr)] He keeps hammering in the idea that he did what he did to protect and offer safety to his friends. That’s why he needed power: [“If you want to really help people, you’re gonna need power, Quackity.” - (Quackity’s Killing My Enemies: 1:05:42, 12th Apr)]

And again, this happens even after the “Then let’s be the bad guys“ speech. Even though he initially says he wants to kill everyone at the Festival, when confronted with this on the day of the event, he second-guesses himself. He doesn’t want to hurt his friends, he doesn’t want to hurt people weaker than him. He distrusts Tubbo, but the moment Techno fires the first rocket, he’s shocked, appalled and moves to go to the button, while urging Tommy to act. When Schlatt wants to kill Niki, he steps out and offers himself to be killed and no one else be harmed.

Even the act of pushing the button himself, there are Wilbur analysts who have pointed out that Wilbur may have wanted to be stopped. And even then, the explosion created no casualties, thanks to all of them wearing armor.

In the Void, Wilbur talks about how he’s evil, how the server is better off without him. He recognizes himself as a hazard, and while that is a part of his self-loathing and hatred, you can also see his care for others shine through: he didn’t want to come back at the time, because he thought he would bring back conflict, suffering [“Here’s the thing, I genuinely think, if it weren’t for me and you dying right, the server would be in shambles. I know for a fact that if I come back, or if I’m brought back to life in some way it’s definitely gonna just go [shit again]” “I know what I’m like, that’s the issue.” - (Tommy’s am i dead?: 10:29, 4th March)]. By staying dead, at this point, he was continuing to prevent weaker people from being harmed.

Even now, post-resurrection, we can see this, but, well...

3. Opinion on Dream

I have looked at this before, from the angle of Wilbur’s mentality. We all know his opinion on Dream so far, that he would have killed him on the spot for what happened to Tommy in the Exile, but Wilbur still considers him his hero. While I said at the time that it may be a subtle way for Wilbur to cloak his self-loathing and self-hatred, but now I want to look at the first part again, from the perspective of Type 8:

Wilbur, by having the urge to kill Dream on the spot, for what he did to Tommy in Exile (and, keep in mind, Ghostbur wasn’t there for all of it, so Wilbur did not see the destruction of Logsted and why it happened, or how Tommy was completely isolated from everyone after the party, and Tommy referred to Dream as his owner to Mexican Dream), no matter what he says after about Dream, proves that he still has the quality to want to protect the weak.

Dream, as always, is one of the strong people of the server. He’s the owner, he has a lot of items and good gear, and in general, everyone recognizes him with a level of danger he presents, and power. Tommy, on the other hand, is one of the weaker ones.

While Tommy has valuable traits, like his loyalty, his fierce determination and the will to keep moving despite how low life kicks him at times, one can’t deny that, in general, Tommy is viewed as one of the weak. He doesn’t have that many powerful items, he isn’t physically that strong, people constantly pick on him, and he is one of the minors of the server, the youngest of them, in fact. Add to that the humiliation of Exile and the treatment he was put through, Tommy was not only at his weakest then, but also at his most vulnerable.

Why would it be a surprise then for Wilbur to want to gut Dream, considering the above? Tommy and Wilbur were very close. As Wilbur acknowledged in the latest stream: [“We were a family, Tommy. We were…” - (Wilbur’s resurrected gentleman of L'manburg: 27:26, 5th May)], they were once so close they could have been brothers. Tommy stuck with Wilbur as a right hand man, he was the only one who didn’t give up on him in Pogtopia, no matter if he thought his choices were right or wrong, and Wilbur confided in Tommy a lot. Now take this little brother figure he had in Tommy, and put him through Exile.

Of course Wilbur would want to gut Dream, Tommy may as well be part of his family, and Wilbur doesn’t strike me as the kind to want his loved ones in pain, genuinely. He may dismiss the feelings Tommy has sometimes, but his reaction to Exile shows that he isn’t blind to suffering. He saw it and recognized as harmful and damaging to Tommy, unprompted by anyone else.

He even makes a comment that I think may be important in the future: [“Tommy, I’m not, I’m not- I wasn’t blind, I saw what he was doing to you, Tommy. I saw. I saw what he was doing to Tubbo. I saw what he did to me.” - (Wilbur’s resurrected gentleman of L'manburg: 21:08, 5th May)]. Remember, Wilbur right now is deeply conflicted, I don’t think he’s properly sorted his feelings on Dream yet. He, in this quote, recognizes he saw how Dream treated Tommy, Tubbo and himself. While Eights want to protect the weak, their core fear is being controlled or harmed by others. I am very curious what will happen if, or, when, Wilbur will decide that Dream is also a hazard to himself, or if Dream will try to use Wilbur for his own plans. But, this is starting to deviate from the purpose of this post so, with that out of the way...

The lyrics:

I remember the minute It was like a switch was flipped I was just a kid who grew up strong enough To pick this armor up And suddenly it fit

Here, Wilbur’s arc and story begins. The lyric recount the moment Wilbur’s spiral began: the Final Control Room. He remembers that betrayal up to his death, still calling Eret a traitor and quoting him, with the same quote he used: “It was never meant to be”. This moment is what will define and shape Wilbur throughout Season 1, and even now. The switch mentioned is the button pressed, the moment everything changed. “I was just a kid” is Wilbur recognizing that he was not ready for the role of President, sentiment reflected by the rest of the lyrics: “who grew up strong enough/To pick this armor up”. Wilbur forced himself to bear the title of president, like a suit of armor, something that protects you, and helps you to fight for others, until “suddenly it fit”.

God, that was so long ago, long ago, long ago I was little, I was weak and perfectly naive And I grew up too quick

Here Wilbur internally recognizes that time passed, his ideology changed, as evident the quotes from Quackity’s stream: [“You say, you say everyone has a good side, Quackity. And you’re right, you’re right, everyone has a good side, but that good side is only there to help themselves. If you want to really help people, you’re gonna need power, Quackity. You can make a movement, you can make a resistance, right, you can go out and you can come back, and they’ll give you a ticker tape parade. They’ll cheer for you in the streets, but you will change nothing. If you have a revolution, everyone will hate you, you will sacrifice everything, and you will lose everything you’ve ever had, but you’ll come back and everything will be changed. And Quackity, if you want to change things, you’re gonna need power. That’s what you want, really, isn’t it? Look at me. And power isn’t gaining from diplomacy, and bureaucracy, and giant courthouses suspended in the sky, blah blah blah. It’s gained from swords, Quackity. It’s gained from blades, it’s gained from steel, iron. Even if everyone has this good side that you’re talking about, then anyone who wants to prove it, has to show their dark side first. You’re going to have to kill, you’re going to have to torture, you’re going to have to maim.” - (Quackity’s Killing My Enemies: 1:06:34, 12th Apr)]. Yet, even if this happened so “long ago, long ago, long ago”, he “grew up too quick”, because the change was too sudden, and it didn’t occur naturally.

Now you won't see all that I have to lose And all I've lost in the fight to protect it I won't let you in, I swore never again I can't afford, no, I refuse to be rejected

I think this verse refers to the Election and its fallout. He quite literally loses a lot on that day, not only his country and his second life, but seemingly, his son, because Fundy takes down the walls. Wilbur also lost a lot in the Independence War, as he lost his first life in there, his son and allies lost their lives too, and this created the perfect environment for paranoia around trust to form. Wilbur, at this point, swears to not let himself be vulnerable with anyone again, or to fully trust people, because of what happened in the Final Control Room and at the Elections. The last line is Wilbur deciding to go ahead and start Pogtopia, to reclaim his nation. As you may remember, the Election was held so that Wilbur could legitimize his presidency, because he felt people started to not listen to him anymore, and an election, in his mind, would have fixed that. Due to his paranoia, and depression, Wilbur couldn’t afford to lose, because the presidency was one of the things that gave him happiness and helped him function. Once he lost and was banished, he decided to strike back and take back the country, or, as the lyrics say, “I refuse to be rejected”.

I want to break these bones 'til they're better I want to break them right and feel alive You were wrong, you were wrong, you were wrong My healing needed more than time

People who’ve broken a bone before may be familiar with this, but there is a possibility for a broken bone to heal incorrectly, so, when that happens, the bone is broken again and you try again. What that lyric means is that Wilbur was not healing properly, and he was constantly damaging himself again, to restart the process, to make his bones stronger, to make himself better. The “feel alive“ part, in my opinion, goes hand in hand with the fact that Wilbur was... not in the best place mentally in that time. We all know how he died, and, to be honest, a lot of the morally bad things Wilbur did could be argued to have been done to give him something to live, be it thrill or satisfaction. The last two lyrics, I feel, are directed to Tommy; Wilbur needed more than just time to “come back around“, and we know how Season 1 ended.

Now, this may be a controversial take, but... This is the end of Wilbur’s Season 1 arc. I think this is as far as Wilbur’s parallel to Eight went in Season 1, it’s the Pogtopia Era, up to November 16th. You may say that it’s his unfinished son- *gunshots*

Okay, okay, but what does that mean for the rest of the song? Well... It could be that either CC!Wilbur will stop with the Eight parallels here, or, the version I like, it means that the rest of the song is a hint for insight into how Wilbur feels and how his character will change in the future.

When I see fragile things, helpless things, broken things I see the familiar I was little, I was weak, I was perfect, too Now I'm a broken mirror

This is Wilbur recognizing that he is not okay, internally, which we know is a thing in canon, because of this quote from the Resurrection stream: [”Are you trying to- Are you trying to make me- Tommy, are you trying to make me- You remember that time in the cave? Are you trying- Are you trying do- Are you trying to make me feel like I did back then, in Pogtopia? Are you trying to- Are you trying to make me feel as bad as I did back then? ‘Cause it’s not gonna work!” - (Tommy’s Breaking Into Prison To Kill Dream: 59:06, 29th Apr)] It’s a great step for Wilbur, afterall, healing starts when you recognize you have a problem, so you can begin fixing it, but, as we know...

But I can't let you see all that I have to lose All I've lost in the fight to protect it I can't let you in, I swore never again I can't afford to let myself be blindsided

Wilbur is the emotional equivalent of a snail. Here we see “Snailbur” doing a reprise of the third paragraph, which I linked to him in the Election Era and its fallout. From the way the lyrics are worded, we can see the how similar they are, but there is a difference: reluctance. Wilbur knows he’s not okay, but he can’t reach out for help, because then, he’ll be showing weakness, but he wants to open up. “Now” becomes “but”, “I won’t let you in” becomes “I can’t let you in”. Now he’s not afraid of rejection, he doesn’t want to be blindsided, which I didn’t know at first what it meant, because my native language is not English, but when I looked it up I came across this definition: “to surprise someone, usually with harmful results”. This shows us something important: Wilbur is hiding his true feelings because he’s afraid to not be hurt again. He doesn’t want another Final Control Room or Election to happen to him.

I'm standing guard, I'm falling apart And all I want is to trust you Show me how to lay my sword down For long enough to let you through

This set confirms it, Wilbur is on the defense now, he’s defending from potential hurt, and the second part of the first lyric is hinting at what a lot of Wilbur analysts have pointed out and we are prepping for: Wilbur having a big crash from the high he’s experiencing from getting resurrected, he’ll be “falling apart“, he’ll be vulnerable, and open to hurt, or... Redemption. This is it. This is the section that made me insist and theorize about a redemption/healing arc: that second lyric, continuing with the rest: Wilbur is reaching out to someone or some people, that he can put his trust to. Wilbur doesn’t just need someone willing to redeem him, because we had that in Pogtopia, with Tommy, no, Wilbur also needs himself to open up, trust people and ask for help. And that is exactly what happens in the last two lyrics: Wilbur is asking for help to open up and let people help him.

Here I am, pry me open What do you want to know? I'm just a kid who grew up scared enough To hold the door shut And bury my innocence But here's a map, here's a shovel Here's my Achilles' heel

And here we have it. Wilbur opening up. Wilbur finally letting someone in, admitting he’s scared, he’s scared of hurting again, comparing himself to a kid. This one I find very symbolic, because if he, at the beginning, was a kid, then by admitting he is a kid at this stage, he’s the same person he was at the beginning, with the good he had, with the flaws he had, what he did and the trauma he gained will never erase that. The innocence in this part of the song, I think is Ghostbur. People forget, but while Ghostbur seems to be a separate entity, he’s still very much a version of Wilbur. He has a lot of his memories, his happy ones. Wilbur and Ghostbur are the two sides of the same coin, different, yet so much alike. You need both to understand the other. Wilbur has the capacity to be innocent, to be kind, good, he just... buried these qualities, and someone has to help him dig them up, when he is ready to open up. I don’t think I need to explain the meaning of someone showing you their Achilles’ heel, beside the fact that it means they trust you with their life. Wilbur needs to find someone to trust.

I'm all in, palms out I'm at your mercy now and I'm ready to begin I am strong, I am strong, I am strong enough to let you in

Here, I think we see Wilbur accepting the consequences of his actions, of the hurt he caused, because, while he’s not irredeemable, he did hurt people, and he needs to be open to them not forgiving them, but, as the song says, just then he’ll be “ready to begin” his healing and redemption. And right at the end there, “I am strong” is repeated thrice, he’s ready to heal, to be vulnerable with someone. It’s the redemption in full swing from here to the end.

I'ma shake the ground with all my might And I will pull my whole heart up to the surface For the innocent, for the vulnerable And I'll show up on the front lines with a purpose

Remember what I said, about healthy Eights? Champions of the people, natural leaders, challengers of oppression and protectors of the weak? This is what Wilbur should become at the end of the redemption, if we are to follow the song. He’s gonna put all of his strength into fighting for what’s right, and he’ll open up, he will heal. We’ll be back to fighting for “the innocent, for the vulnerable”, he’ll have a purpose to fulfill. L’Manberg was deeply tied to both Wilbur and Ghostbur, and Wilbur himself admitted to caring about L’Manberg because what it stood for. Now, L’Manberg is gone, but those ideals aren’t. Maybe, just maybe, he’ll fight in the future to protect those ideals.

And, finally:

And I'll give all I have, I'll give my blood, give my sweat An ocean of tears will spill for what is broken I'm shattered porcelain, glued back together again Invincible like I've never been

I really like the end here. Because, it’s not only reinforcing the idea that Wilbur will be redeemed, but that penultimate lyric always stood out for me: “I'm shattered porcelain, glued back together again”. Porcelain is, while very fragile, a beautiful material. When I think of the word, I think of beautiful vases, handcrafted with skill and care. It’s a shame when a porcelain vase breaks. But, just because something is broken, it doesn’t mean it can’t be repaired. And when I think of repaired porcelain, I think of the Japanese art of kintsugi - a technique with which broken pottery is glued in such a way that the cracks aren’t hidden, but celebrated as a part of the object’s history, by filling them in with gold. I like to think that at the end of his healing arc, Wilbur will be similar, he was broken, he healed, but the scars are still there, and, even then, he’ll be thriving again. It’ll be an experience that, overall, helped him become better. And the final lyric: “Invincible like I've never been“, I like to think that this will be him at his peak: healed, happy, ready to take life by the horns, like he wasn’t before. It’s a hopeful, happy note to finish the song and his story on.

And that is my analysis on the song and the enneagram, I guess (Jesus this got waaay longer than I expected). I really hope Wilbur will get a redemption arc, it’s already wonderful that we have him back AND he wants to live (it’s honestly the first time I see, in any media, a suicide victim that not only is brought back to life, but they are happy to be back). Hopefully this is useful to people, and, as always, thanks to @kateis-cakeis for compiling Wilbur’s/Ghostbur’s quotes in a masterlist with timestamps and anything you’d want to know about them. It’s a goldmine of analyzing Wilbur and I highly encourage you to check it out.

#dream smp #dsmp #wilbur soot #dsmp wilbur #dream smp analysis #dmp analysis #dream smp character analysis #dsmp character analysis #finally... after 3000 years... the Eight analysis is complete #this took so long I am sorry lmao #now I can go focus on schoolwork #and before someone says it I'll say it #snailbur effervescent

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fiamh · 5 years

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SESSION 4: TRANSLATION AND CLINICAL APPLICATION

Drugging the cancer interactome: rational target selection for drug discovery

Presentation from Bissan Al-Lazikani (The Institute of Cancer Research, London, UK) starts with a quick intro of CRUK’s efforts in drug discovery and hurdles in drug discovery (target selection, biological validation, tracability for drugging, clinical efficacy). It’s an exciting time given the availability of large scale data for cancer gene identification (see previous talks), but every study identifies new/non-overlapping lists of cancer drivers resulting in a rather large target space. Try to assess targets through all stages of discovery, i.e., balancing risks (technical and biological); find targets with solid initial rational, also make sure it’s likely to be druggable, non-redundant, etc. Precedence, 3D-structure evaluation, chemistry assessment, network position as a multifaceted target assessment workflow, all depend on large contextual database (available as canSAR).

Quick survey of different steps, e.g., cavitiy assessment in 3D structures and how well ligands could bind (including decision trees from positive/negative examples), identifying viable sites (such as novel allosteric sites). Global approach to look at multiple structures, every protein family member to build evidence profiles (see recent paper for a good summary showing 123 out of 489 putative targets with direct evidence for chemical tractability, including 46 with no prior work — some of which have now been successfully targeted such as BRG1 and IDH1; BRG1 is a tumor suppressor with two druggable domains).

Switch to case study on Rhabdomyosarcoma, a rare childhood cancer without a targeted therapy (hence neglected), limited to surgery and radiotherapy. Collated data from ~100 patients: gene expression, survival, came up with list of potential target list, scored interaction network and identified best chemical tractability scores to enrich for biologically relevant targets that are hopefully druggable. 41 targets with 44% hit rate which is very high indeed; drug screens in cell lines and xenografts now starting. Interesting network approach: the usual hairball but colored by druggabiity, pinpointing cancer drug targets, the targets of non-cancer drugs, and predicted druggable targets currently not covered. Find communities that are not well covered by existing drugs (the social network approach); cancer drug targets tend to occupy distinct subgraphs within the network. Try to find drug combinations hitting complementary areas of the network to reduce resistance development.

Genomic medicine – transforming cancer research and care

Lynda Chin (MD Anderson Cancer Center) is next; she switched talking slots with Michael Speicher who now talks in the next session. We should have a fairly complete catalogue of relevant genes within the next year or two; still away from complete functional validation, much less an understanding of the genome. Even further away when looking at epigenomic alterations. Quick sample case of a chromatin-mark differences between responding and non-responding lesions from a patient drove the decision for a global chromatin mark survey. ChIP-Seq of 36 different marks, but the challenge then is to define chromatin states for different phenotypes (normal, tumor, metastasis), and this is more difficult when only looking at one or two individual states on their own.

Started with isogenic melanocyte cell model systems (HMEL-BRAF, PMEL-BRAF) with different states (non-tumorigenic, tumorigenic, metastatic) to explore the function of the epigenome integratively: test for 35 marks, run RNA-Seq, total of ~4 billion reads. Usual genome segmentation approach via ChromHMM, condensing all data into 18 states (highly acetylated promoter, transcribed enhancer, poised TSS, etc.). Verified by lining up state predictions with known, annotated genomic regions. Check for changes in state transition between different phenotypic conditions, e.g., NT vs T across all promoters characterized by a loss of acetylation marks, H3K4 methylation marks. Link to acetylation change to RNA-Seq expression changes show no significant correlation (which is a bit surprising): deactylation changes are unidirecton, but gene expression changes are bidirectional. Deactylated and downregulated genes are enriched in cancer pathways. Response likely not dictated by a single chromatin signal.

Use the same model system to generate loss of function and gain of function libraries (475 shRNA contructs of 95 epigenetic enzymes), inject in non-tumorigenic cells to identify which can cause a change towards tumorigenicity. Knockdown of just two histone acetyl transferases and four H3K4 modifiers induce the tumorigenic phenotype. Check whether inhibition of these targets recapitulate the epigenetic landscape? MLL2 and Taf1 knockdown seems to recapitulate the acetylation changes seen in tumorigenic cells.

Ideal experiment is to go in with a tumor sample and do all marks. Only been able to do this with 8 TCGA samples so far giving them a complete epigenome and genome map. Still sequencing, at 6 billion reads not reached saturation yet. Other interesting questions can be asked.. what is the higher order of DNA structure? How does the epigenomic change map to those mapped in the NIH Roadmap program (adult vs fetal vs ES cells).

Good final pitch on complexity of cancer. We just look at one mutation rather than the whole tumor system, the microenvironment, genetic background and social/environmental aspects. Need to integrate the research in context of clinical care — the Apollo project.

Lessons from the study of extraordinary responders

Final full talk of the session by David Solit](http://www.mskcc.org/research/lab/david-solit) (Memorial Sloan-Kettering Cancer Center) around speeding up drug discovery. Genotype to Phenotype (G2P) to define targets. Started working on BRAF / melanoma in 2002, but the identification takes a large cohort. How to work with existing data? Test retrospectively, first applied to the response to everolimus in a blader cancer patient which did not work (2 out of 45 patients responded). One patient still alive after 5 years, question to ask then is: why did this patient responded extremely well to mTORC1 inhibition? Could not figure out with targeted sequencing, but WGS showed 17,000 somatic mutations (!), 140 NS coding mutations (paper here). Perfect patient for the drug due to TSC1/2 mutations.

Since gone on and repeated this in other unusual cases (ovarian cancer patient on AZD6244, mutation missed initial due to low cellularity, complexity of the MAP2K1 mutation; other rare and quite extraordinaty cases) [and I’ll skip the details as most are in press / published and I am way out of my depth here]. In brief, use WGS outlier analysis to salvage drugs with low response rates; profile patients with TCGA pipeline and see if those cases can be solved.

Can this be done prospectively instead? Usually based on genotyping patients with a typical disease and allocate patients to clinical trials. Problem is drugs spread across multiple companies, negotiations take ages, drugs often not best in class but just what is available. Ethical problem of randomizing patients when you see response rates in other trials. Finally, number of patients is low (states that 200 patients is ambituous) making it difficult to assess low frequency subtypes.

Alternative approach: basket study. Different cancer patients in same trial, what percentage of lung / breast / ovarian cancer responds to a given drug (see summary)? Challenge of getting multiple disease teams to work together, and identifying patients remains a challenge. IMPACT approach at MSKCC to tackle this. Primary goal to identify molecular drier in every patient beginning with 12,000 patients/year (!). Beyond Foundation Medicine testing to ensure tumor/normal testing. Fun summary of discrepancies between Foundation, their studies, Myriad profiles depending on how germline mutations are handled (Myriad does not report mutations >1% frequency in population).

Bioinformatic analyses approaches for personalized oncogenomics

Katayoon Kasaian (British Columbia Cancer Agency Genome Sciences Centre, Canada) closes the session with a selected short talk. Leads with overview of British Columbia and the patient network. Personalized Oncogenomics (POG) program since 2012 to augment therapeutic decision making in incurable malignancies. Genome/transcriptome analysis, WGS of blood, same for archival samples, sugest therapeutics based on identified cancer drivers and aberrant pathways. Track clinical data and response.

123 patients enrolled in first two years of the program, 81 finished. ~40 days from biopsy to final report on average (goal to shorten this). Lessons learned include that genomic approaches (whole genome) are superior to standard / current clinical tests (Katayoon provides a few examples that I’ll skip here, mostly revolving around mutations missed in other assays such as FiSH). Found WTS necessary and complementary to WGS, particularly for pathway aberration analysis. Useful to correlate copy number change and expression. Case of colorectal cancer patients with KRAS G12V mutant, but WTS found no expression of KRAS (neither wildtype nor mutated) which would have changed the treatment plan. Also found high heterogeneity between tumors from different sites and over time, at times resulting in different treatment options against different tumor locations (rather than one global treatment).

Survey found POG to be informative for 87% of cases, treatment offered to 55% (but since these are end stage patients about 20% die before they get to this point). Future directions for POG 2.0: approval for 5000 cases over 5 years, increase speed and accuracy of prediction, xenograft validation, etc.

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