PATIENT ZERO

December 6, 2013 7:37 PM

There's A Whole New Way Of Killing Cancer: Stephanie Lee Is The Test Case

Adventures In Extreme Science

From Crick and Watson through J. Craig Venter, we had all our eggs in one basket — molecular biology, gene mapping, whatever you want to call it. It failed. And now we're counting on this guy.

posted by the man of twists and turns (45 comments total)

Apparently, autoplaying audio.
posted by JHarris at 7:41 PM on December 6, 2013

Moving story; but they haven't actually tested this approach in treatment yet, all they've done is some in silico and fly models, right?

Also, there isn't a whole new way of killing cancer; it's using existing antitumor drugs for tumors they weren't designed to treat because of some variation in succeptibility shown by these computer and fly models.
posted by lalochezia at 8:09 PM on December 6, 2013 [1 favorite]

While I'm all for some new form of curing cancer, I'm also all for booting in the head every psuedo-scientific quack who comes along taking advantage of desperate people. And a boot to the head would be about the kindest thing I'd do.

From page 5 of the article:

I'm so happy! she wrote to me, heedless of any danger. Stephanie didn't care. She had seen her tumors and she had met a man who might be able to cut them out of her. He gave me HOPE!!!

Schadt was not a doctor.

Excuse me while I go lace up my Doc Martens.
posted by Catblack at 8:34 PM on December 6, 2013 [17 favorites]

Also, there isn't a whole new way of killing cancer; it's using existing antitumor drugs for tumors they weren't designed to treat because of some variation in succeptibility shown by these computer and fly models.

They also briefly discuss a vaccine approach in this update, which sounds interesting but very difficult to ramp up as widely used treatment. Each patient would presumably need a custom-tailored vaccine, which doesn't really lend itself to economies of scale.

But this is a great article, and if anyone is put off by it being six pages long I really recommend it.
posted by figurant at 8:56 PM on December 6, 2013

Just to offer another data point of how computer modeling in cancer drug design has been around for a while, I give you Gleevec. Gleevec (imatinib) was originally designed in the early 90s first by computer modeling a compound that would specifically target and inhibit tyrosine kinase to shut down chronic myelogenous leukemia via a mechanism elucidated by the very gene mapping this article seems to disparage.

Expressing a tumor in a fly is pretty cool, though.

(As for the article, it could have benefited from a good editor. Definitely borders on rambling tl;dr territory.)
posted by darkstar at 8:58 PM on December 6, 2013 [4 favorites]

The important point isn't that a single drug or single treatment is going to cure cancer or any type of disease. The important point is the way that the analysis described in the article was able to not only uncover the genetic network causing the tumors in the patient, but that it was also able to suggest a drug therapy that would target the unique genetic signature of the patient's tumor. Two things allow this to happen: 1) the realization that genes don't work in isolation, but instead in networks and 2) the ability to detect these networks using powerful computers to analyze massive amounts of data aggregated over networks.

It is indeed a very big deal. I suspect the statistical techniques used aren't even that new or complicated. Even the idea of genes working in networks probably was not unknown. The limiting factor was probably the availability of the computing power and data to uncover how the genes worked together. As a result, scientists were left with trying to analyze individual genes, but apparently that wasn't yielding as much progress as hoped.

What changed was the availability of computing technology to aggregate and analyze the data needed to understand how genes interact with each to produce a particular trait. Apparently the scientist profiled in the article is at the forefront of applying the new technology to the task. Oftentimes in science, new technology precedes discovery because it expands our powers of observation.
posted by eagles123 at 9:14 PM on December 6, 2013 [6 favorites]

I'm sorry, in going to ask a tl;dr question: which page to they talk about the science on? Because I would just like to skip the human interest and get a sense of that. I promise I'm not trying to be a total jerk, but I'm not crazy about reading this guy's resume about how mol bio is so much easier than math. I'm not even saying he's wrong. It's just grating to read.
posted by maryr at 9:54 PM on December 6, 2013 [15 favorites]

Read the second article first. The first article doesn't really go into the science much at all. Even the second one isn't as in depth as it could be to be honest.

I do think there is too much melodrama inserted into what is really a story about how new ideas and methods are being introduced, but that seems to come from the author and not the scientists or even the doctors in the first article.
posted by eagles123 at 9:58 PM on December 6, 2013 [1 favorite]

Excuse me while I go lace up my Doc Martens.

"He gave me HOPE" refers to the doctor who performed the traditional surgery.

Many medical researchers are not doctors. Most clinicians do not do medical research.

I am not particularly qualified to judge this science, but if the article can be believed he has drawn the interest of a reputable hospital institutionally and, among others, ~30 individual doctors intimately involved in deciding the course of cancer treatments.

They are giving flies analogous glow-in-the-dark cancers to test treatments suggested for a specific individual from sophisticated automatic mathematical analyses of the raw information of life. Boot to the head.

Moving story; but they haven't actually tested this approach in treatment yet, all they've done is some in silico and fly models, right?

They talk about 19 earlier participants, of which 4 were treated with 1 death, 1 "home run" success, 2 left unmentioned.

I am somewhat of a medical fuckup and a study is being done on me, only instead of a tumor I guess they're doing my DNA, RNA, & gene expression and then some kind of mass microbiome analysis. Somewhere in Manhattan a locked & guarded freezer holds a number of my turds, which are being kept for 20 years. The risks section of the consent form made sure to cover the dangers of taking a shit.
posted by save alive nothing that breatheth at 10:14 PM on December 6, 2013 [8 favorites]

Also, Stephanie Lee in the Facebook comments.
posted by save alive nothing that breatheth at 10:18 PM on December 6, 2013

Metafilter: Somewhere in Manhattan a locked & guarded freezer holds a number of my turds, which are being kept for 20 years.
posted by lalochezia at 10:27 PM on December 6, 2013 [2 favorites]

Wow, this is one of the most overblown pieces of scientific puffery I've seen in a while. First, this is not anywhere close to a "new way of killing cancer," though it may very well be a new way of giving false hope considering how far from clinical application it still is. Even for Stephanie, Schadt himself is quoted as saying (in the pull-quote on pg 1), "But it's a real long shot. I'd say one in a thousand." Second, those flies are not expressing her tumor; the flies are engineered to have mutations to the subset of d. melanogaster genes that are orthologous to the h. sapiens genes that are mutated in her tumor, which may or may not produce an effect in the fly's eye that is at all comparable to human colon cancer cells. It's a personalized model, which is cool, but still very much a model -- one in a different tissue of a different species with a different set of environmental stimuli. And finally, while I appreciate the positive attention paid to network biology (being a network theorist myself), the way they've painted Schadt as some lone-wolf pioneer is ridiculous. There's a large (and growing!) community of computational systems biologists who have produced an exciting body of work over the past couple decades, ranging from network inference techniques to graph-theoretic statistical analyses to dynamical simulation models to network control theory. (In fact, I just returned from a great conference on exactly these topics!) I wish we were as close to a translatable breakthrough as the article would have us believe -- by Schadt or by anyone else -- but the sad reality is that we're still struggling to find ways to change the attractor landscape of some very complex dynamical systems.

& eagles123, you're not wrong that computational advances now enable analyzing genomic data at the systems-level in a way that was previously impossible, but it's not the case that the statistical techniques being used aren't new -- there's PLENTY of new math! In fact, I'd argue that key piece (and currently limiting factor) for network biology is the theoretical development of mathematical/statistical methods that can meaningfully address the underlying complexity. But I definitely agree with you about technology changing our perspective.... hell, none of us complex-systems theory types gave molecular biology a second thought until microarrays revolutionized it.
posted by Westringia F. at 10:41 PM on December 6, 2013 [10 favorites]

Somewhere in Manhattan a locked & guarded freezer holds a number of my turds, which are being kept for 20 years.

I want this to be the final clue in the Cicada ARG.
posted by jason_steakums at 10:47 PM on December 6, 2013 [2 favorites]

...but they haven't actually tested this approach in treatment yet...

...there isn't a whole new way of killing cancer; it's using existing antitumor drugs...

It's not like these people are talking about laetrile and lavender extract or some other woo de jour here. Suggesting that this is non-innovative AND unproven is kind of a stretch, particularly when the current best standard of treatment is "Your oncologist guesses. Hope he guesses right."

I once had a ring side seat for a phase one clinical study where a surprising number of people with refractory melanoma, people who were basically told, "Get your affairs in order"were, a year later, asking for their old jobs back. And then, coming off that high, we had a phase II study that was ended prematurely as "futile". Obviously there was something about the patient population in Phase I that differed from Phase II, but what? Even with hindsight being 20/20 and all, nobody could figure it out. Maybe we just chose unusually lucky people for Phase I. Or maybe we sewered a drug that would save a bunch of peoples lives if we only knew who. But we don't. If only we had some sort of rapid modeling system and some method by which to analyze its output.
posted by Kid Charlemagne at 11:34 PM on December 6, 2013 [6 favorites]

Previously on Metafilter: Kid Charlemagne was a little disillusioned with how medical technology was plodding along then too!
posted by Kid Charlemagne at 11:39 PM on December 6, 2013

I hate articles that are supposed to be about some scientific development and force you to read thousands of words of human interest.

HIGGS BOSON DISCOVERED

Jerzey T Kovacs could see his breath that frosty Maine morning as he repeated his shopping list in his head and prayed that the battered old Chevy would start without jump leads for once. Blue-eyed, athletically built, and standing six feet three in his favourite Doc Martens, Jerzey could almost hear the voice of his eighty-year-old Momma.... (Continue for three chapters, allude once at the very end to the Large Hadron Collider).
posted by Segundus at 1:12 AM on December 7, 2013 [14 favorites]

I thought it was a good article and moving. Then I read the comments on Metafilter and discovered that's not important and a waste of time.

Yay internet.
posted by Brandon Blatcher at 1:21 AM on December 7, 2013 [3 favorites]

Thirty four medical studies showing cannabis helps cures cancer
posted by jeffburdges at 1:48 AM on December 7, 2013 [2 favorites]

These articles are both senselessly long, but at least the second article reveals we're talking about the work of Eric Schadt. And Schadt wikipedia page has the goods :

Demonstrating the ability to infer causal relationships among features in high dimensional data using DNA variation information, Schadt and his colleagues at Merck began reconstructing predictive networks that were shown to be causally associated with disease,[13] [14] [15] [16] [17] leading to the idea of targeting networks, not single genes, to effectively treat common disorders such as Alzheimer’s disease, obesity, and most forms of cancer.[18]

posted by jeffburdges at 1:57 AM on December 7, 2013 [3 favorites]

As for the article, it could have benefited from a good editor. Definitely borders on rambling tl;dr territory.

I made it to page two and starting skimming for parts about the treatment; I came back here from the middle of page three and WHEN ARE THEY GOING TO GET TO THE FIREWORKS FACTORY?
posted by Mayor Curley at 3:03 AM on December 7, 2013 [1 favorite]

Thirty four medical studies showing cannabis helps cures cancer

Yeah, I thought this was gonna be another of those articles too.

I loves me some pot, but:

Cannabis has been shown to kill cancer cells in the laboratory and to affect the immune system. However, there is no evidence that Cannabis' effects on the immune system help the body fight cancer.
posted by PeterMcDermott at 3:06 AM on December 7, 2013

For those who don't want to wade through the pages and pages of human interest stuff to get to the science, there is precious little there. In the end Schadt's connections get Lee a higher level of standard care, while his data guides someone else in putting their oncogenic mutations into the gut of a recombinant fruit fly, with which that colleague finds an unnamed drug that appears effective in recombinant fruit flies. It looks like Lee is on that treatment but it is only a month later, and she is an N of 1 any way. The piece also mentions whole genome sequencing and RNA-Seq being done on the tumor.

I've never met him, but everything written about this dude in the popular press makes him look like a pompous asshole sneering at the hand that feeds him, and I'm starting to consider the thing they have in common.

"What data had taught him was that the underlying faith of molecular biology—of all biology, since Watson and Crick had elucidated the structure of the DNA molecule—was false. Untold billions had been spent in the hope that we could understand disease one gene at a time, or one genetic pathway at a time; by targeting the gene or the pathway "for" Alzheimer's disease, say, we could target Alzheimer's disease itself. Schadt told Merck that this was a strategy doomed to fail, because disease arose not from single genes or pathways but rather out of vast networks of genes and pathways whose interactions could be understood only by supercomputers guided by abstruse algorithms. Evangelical still, though now evangelical on behalf of irreducible complexity, he asked Merck to remake itself in the image of the network model he was determined to pioneer. Merck declined and Schadt headed to Silicon Valley, to the land of data."

Back in the late 90s he and a few other people founded Rosetta Inpharmatics, a company that used a custom built massive supercomputer and a lot of talent to do some really awesome bio-informatics. The tiny startup ended up being so promising that Merck was willing to pay $620 million for it. However, it ended up not having the commercial potential that he promised it did in the way that they were hoping and they ended up disbanding it, donating most of the division to Sage Bionetworks, the non-profit mentioned that was built to keep the research alive. For Merck to just throw him and his company away really was idiotic, they hoped that with the Rosetta platform they could make their current drug discovery process more efficient, and it did but not $620 million more efficient. However, Merck wasn't able to grasp the power that really well done bio-informatics can add to genetics. I'm not sure I can really blame them though because that power is rife with bullshit and arrogance.

Anything involving a gene that hasn't been backed up by solid evidence of the gene's function with time consuming things like activity assays, co-localizations, DNA foot-printing analysis, and some figuring out of what regulates expression, or doesn't have an irrefutably high similarity to something that has, is bound to be bullshit. You can't figure out how the parts of an unknown system work together if you don't know what the parts are. For example Monod back in the day figured out the lac operon, a tiny aspect of the minutiae of E. coli fermentation and through it discovered a hell of a lot. The Systems genetics that this fool champions as being somehow the one true replacement for molecular genetics only has the tools that Monod, and the hundreds that have followed him, have given it.

Fuck this dude, "the difference between medieval alchemy and chemistry," my ass. You can't figure out how the parts of an unknown system work together if you don't know what the parts are. Besides, the minutiae doesn't seem so small when you consider how connected life really is and how we now have the tools to really show it. When you sweat the small stuff and you end up characterizing a gene and then putting it into gene bank you could make hundreds of genomes make that much more sense, instantly, much less the exponentially growing number that will be put into it in the future.
posted by Blasdelb at 4:06 AM on December 7, 2013 [9 favorites]

Well, to be fair, Esquire didn't include any up-shorts shots this time. At least we've got that to be thankful for.
posted by Blasdelb at 4:08 AM on December 7, 2013 [1 favorite]

Just so charming having people angry that someone bothered talking about a person's life and fears, thus interrupting their science download. I suspect it is not co-incidental that person is black and kinda poor.
posted by tavella at 6:06 AM on December 7, 2013 [2 favorites]

> I suspect it is not co-incidental that person is black and kinda poor.

You suspect wrong, ok?
posted by Artful Codger at 6:19 AM on December 7, 2013 [4 favorites]

Tavella: I think lots of people here aren't happy with the articles because they promise to describe an amazing medical advance, then don't. Probably not because we're all racist and/or classist.
posted by Jacob Knitig at 6:29 AM on December 7, 2013 [5 favorites]

But Blasdelb delivers! Hooray Blasdelb.
posted by Jacob Knitig at 6:29 AM on December 7, 2013

Just so charming having people angry that someone bothered talking about a person's life and fears, thus interrupting their science download. I suspect it is not co-incidental that person is black and kinda poor.

tavella, I'm one of the people complaining. Is that really how you want to operate when you disagree on a matter of taste-- accuse the dissenting people of racism? That's ill-considered and crass. In the future, when you're going to make an accusation of that severity, please do it when you have evidence instead of suspicion.

PS-- I'm not accusing you of being a bad person, I'm accusing you of making a remark that you did not fully consider the implications of, which we have all done. You can right this with a simple, earnest apology. I do it when I'm wrong here, and it's absolutely liberating.
posted by Mayor Curley at 6:36 AM on December 7, 2013 [2 favorites]

This week I've been told on Facebook that Grape Seed Extract and Bitter Mellon fight cancer. I can propose Walking on ones hands as a new way to fight cancer.

The fact that the person being treated has hopes and fears does not distinguish her from either a pioneer, or another sad story of a terminally ill person being preyed on by a quack.
posted by wotsac at 7:45 AM on December 7, 2013 [1 favorite]

Just so charming having people angry that someone bothered talking about a person's life and fears, thus interrupting their science download. I suspect it is not co-incidental that person is black and kinda poor.

"Angry that someone bothered talking about a person's life and fears" is unfair. Disinterested is a better word. And your suspicions about Stephanie Lee are unfounded and incorrect. For example, I am also disinterested in Eric Schadt's life and fears and he is white and affluent. The article promised me a new way of killing cancer and then said nothing about it for pages.
posted by maryr at 8:24 AM on December 7, 2013 [2 favorites]

Reading through the article a bit more now that it's not 1 am and I know I can just skip the first page:

• "He still drives fast enough to terrify his colleagues, though instead of going to work in California on a motorcycle at a hundred miles per hour, he now runs two miles to catch a train to New York City, where he then runs another mile and a half to his office." Whelp, sounds like he's still an asshole, but at least he's not endangering other people this time. And there aren't any picture of his shorts.
• The bit with Lee's daughter Marchelle in the car is heart breaking.
• It's sweet that the author offered to try to help to move the case along by talking to Keesler's pathology dept (which I imagine would basically be a kind of blackmail threat - the media know about this!).
• "The healthy cells were as pink as a little girl's room." Well that's a disturbing comparison. But his description of the order of healthy tissue giving way to the explosion of out of control cell division is really good.

In fact, now that I'm to the science, I'm appreciating the writing more, but I have to head out of the house now, I'll finish later. I'm posting this comment anyway because otherwise I'll lose it.
posted by maryr at 8:37 AM on December 7, 2013 [1 favorite]

Despite my eager support of Eric Schadt's work in the thread Kid Charlemagne linked above, he's a complete follower here, not a leader. University of Michigan has been putting cancer sequence into clinical practice years before Mount Sinai, and leading the way with what to do in the clinic. I liked his systems biology work in the 2000s. I do not like his cancer genomics work in the 2010s.

Also, their genome sequence analysis team is extremely new to cancer analysis, and that's a field where arrogance = wrong answers. There are so many ways to mess up in the analysis, and hard won answers to tricky problems that have been sorted out over the past few years, that when you approach it with arrogance you're going to get tripped up by everything that screwed up everybody else and not even know that you're spouting complete bullshit. As this field gets more popular, you see it with all the new guys. This is a field where you want a second or third opinion, even the things that seem basic, like somatic mutation calling, can result in divergent answers.
posted by Llama-Lime at 8:43 AM on December 7, 2013

What a piss poor way to deal with a serious and important subject! on and on and where is the meaqt? Here, though, a seemingly potentially big breakthrough in cancer treatment with, so far, very fine result

TREAT CANCER LIKE A COLD
posted by Postroad at 9:09 AM on December 7, 2013

Are they using genomic sequencing in the same way, Llama-llama? Ie, put the individuals's DNA sequences involved in the cancer mutations into test flies (or other animals), and then hitting them with all the currently available drug combos to see what might knock it out? Someone upthread mentioned Gleevec, and my impression from the story is that they are essentially trying to change that kind of discovery (Gleevec against a particular kind of stomach cancer) into a production line function; instead of discovering via large-population patient trials what drugs are specially effective against which mutations, being able to take an individual and say "the normal first line chemo drugs for this are X and Y, but your unusual mutation was knocked out by drugs A and B which we would normally never get to, let's put them up first or at least early in the batting order of chemo rounds"
posted by tavella at 9:11 AM on December 7, 2013

Well, the fruitfly is definitely unique, most people do xenografts in mouse of the actual tumor, with varying degrees of success. I really hope it works out, but have not seen their data or papers from the fruitfly approach, and look forward to the clinical trial. I am not enamored with their analysis pre-fruitfly, however, which is requisite for the fruitfly phase to be correct.
posted by Llama-Lime at 9:19 AM on December 7, 2013

I'd think that the fruit-fly approach is key to making it function for individuals, right? You can take the leftovers from a biopsy, sequence them, and then churn out infinite numbers of fruitflies to experiment on, with their extremely quick life cycle. With xenograft, presumably you have to successfully get living matter from the tumor for every round of experiments.

But yeah, if you don't identify the right sequences involved in the cancer, then testing them in flies won't do you much good. I assume that is what you mean by the pre-fruitfly analysis?
posted by tavella at 9:30 AM on December 7, 2013

Well, to be fair, Esquire didn't include any up-shorts shots this time. At least we've got that to be thankful for.
posted by Blasdelb

Take another look at the photo of Schadt toward the bottom of the first page, Blasdelb.

He's sitting on the edge of his desk in a polo shirt and a pair of wrinkled shorts, with his legs spread wide in full lavaball mode, with the picture centered on-- and the angle of light arranged to emphasize-- the bulge of his apparently quite substantial package.

And that's the problem with his science, too; it seems driven by the demands of a tumescent ego rather than a desire for understanding or a concern for the lives of victims of cancer.
posted by jamjam at 9:32 AM on December 7, 2013

Science doesn't care whether it is done by people for ego, for selflessness, or for understanding; great results have been produced by both saints and sinners. Unless you have reason to believe that his ego is causing him to produce cooked results, trying to denigrate his scientific analysis for ego is rather pointless.
posted by tavella at 9:40 AM on December 7, 2013 [2 favorites]

You can't figure out how the parts of an unknown system work together if you don't know what the parts are.

Uh, doesn't that strike you as a bit reductionistic? I mean I'm willing to bet that if you divided the number of people commenting on YouTube by the number of people who can build a XOR gate out of transistors you'd get a very big number. And yet, somehow, the YouTube comments keep coming.
posted by Kid Charlemagne at 10:38 AM on December 7, 2013

If only there was some kind of company doing fruit fly to cancer research for the last ten years.

Seriously, couldn't the reporter find a single Exelixis employee from the early days on LinkedIn?
posted by benzenedream at 11:04 AM on December 7, 2013 [1 favorite]

For a clearer perspective on how DNA how sequencing will change medicine, check out this recent editorial from Francis Collins in the NEJM.
posted by euphorb at 11:50 AM on December 7, 2013

Everybody saw that this was from Esquire before they clicked on it, right?

Right?
posted by hobo gitano de queretaro at 11:52 AM on December 7, 2013 [1 favorite]

Thirty four medical studies showing cannabis helps cures cancer

I don't know from cure, but damn if cannabis doesn't help nausea and affect mood in cancer patients.

Oh, wait. We can't have that, because... War on Druuuuugs.
posted by BlueHorse at 4:54 PM on December 7, 2013 [2 favorites]

tavella, "put[ting] the individuals's DNA sequences involved in the cancer mutations into test flies (or other animals)" is NOT what they are doing; see my previous comment. What Cagan does (nb: not Schadt! his work is purely computational, and the article said exactly nothing about it; the fly thing is Cagan's part of the collaboration) is to take a subset of orthologous fly genes and attempt to mutate them in the same way as the patient's human genes. Here's a SciAm blog write-up that explains it a bit:

So back to those 200 or so mutated genes that pop up in a profile of a human cancer patient. Cagan and his colleagues compare those genes to the genes that are found in fruit flies. On average, they find 180 matching genes in the flies. Then they go to a computer and order up 180 fruit fly lines—each one of which is specifically bred to have [known oncogenes plus] one rare variant based on the genetic profile of the human patient’s tumor.... The mutations are designed to show up in the tissues of the fly’s eye because changes there are easy to spot and analyze.... Once the flies become adults, the scientists check how each of those 180 groups of flies are doing—whether or not they develop abnormal growths, how quickly the growths emerge. Eventually they whittle the number of genes down to about ten that seem to matter.

"Matter" meaning inducing tumor growth in a fly's eye given a fly's genes and transcription factors and physiology and environment. As a model, it is very far-removed from a xenograft in a mouse, let alone the patient's tumor. Might it still be a useful model? Perhaps; we should be so lucky. But let's be very clear about what the model actually is. Those aren't the patient's genes, and -- possibly even more critically -- they're not being controlled by the patient's gene regulatory networks.
posted by Westringia F. at 12:37 AM on December 8, 2013 [1 favorite]

Oh, and since we've managed to touch on both transistors and scientists driving recklessly in this thread, let's close the triangle by remembering that bravado behind the wheel caused physics Nobel laureate Bob Schrieffer, the "S" of the BCS Theory explaining superconductivity, to kill a person and injure seven others in a high-speed collision, for which he was later sentenced to two years in prison.

Arguably, driving >100MPH down the 101 is perhaps not the best of Schrieffer's talents for Schadt to emulate, but I suppose one does what one can.
posted by Westringia F. at 1:06 AM on December 8, 2013 [2 favorites]