Life is too easy for comic artists

They don’t even have to write their own jokes any more!

Doonesbury: Well, I want to just start by saying hopefully they’re going to have to fear nothing, ultimately. Right now there is a fear and there are problems, certainly problems, but ultimately I hope there won’t be a fear and won’t be problems and the world can get along. That would be the ideal situation. It’s crazy what’s going on, whether it’s the Middle East or you look at no matter where, the Ukraine, you look at — whatever you look at, it’s got problems. So many problems. And ultimately, I believe that we are going to get rid of most of those problems and there won’t be fear of anybody. That’s the way it should be.

Those word balloons contain obvious bullshit from a bullshit artist — they sound exactly how a kid who hasn’t done their homework sounds when called on in class. It’s ridiculous. It’s meaningless noise. It’s not even good or entertaining bullshit.

But there’s that little note in the third panel: “verbatim from press conf., 4/12/17”. I know, it’s Trump, so of course it’s possible that such crap dribbled out of his mouth, but I had to check. Here’s a partial transcript of his answer, and if that’s not good enough, there’s video of the press conference — skip ahead to about 25:50 to hear the reporter’s question and his ludicrously stupid reply.

I think Garry Trudeau would agree that his ease and comfort in generating text for his cartoons is not adequate compensation for having to live with that boob in charge of the government.

Davies and Lineweaver are back on the atavisms bandwagon

I’ve been complaining about the cancer nonsense peddled by Paul Davies and Charles Lineweaver for years. I imagine nothing will stop them. They’ve got this weird idea that cancers are atavisms — that what they are is a reactivation of an ancestral program that was constructed a billion years ago by free-living single-celled organisms, that was then shackled and constrained by the evolution of multicellularity, but which can then re-emerge when the old program is liberated by mutations in the multicellularity genes that are its jailers. Cancers are your protistan ancestors, yearning to break free.

It’s nonsense. Davies and Lineweaver are physicists with no comprehension of how evolution works. There are no ‘genetic programs’ that can linger for a billion years in a suppressed state to functionally rebound with the accidental removal of a metazoan control program. When you add that Davies justifies his model by invoking Haeckelian recapitulation, a theory that’s been dead and wrong for over a century, you’ve got a recipe for raging crackpotterism from a sober, respected physicist.

Yet they still get published. They still manage to sucker in scientists who ought to know better. They’ve published again in PLoSOne, in a paper titled “Ancient genes establish stress-induced mutation as a hallmark of cancer”. Here’s the abstract.

Cancer is sometimes depicted as a reversion to single cell behavior in cells adapted to live in a multicellular assembly. If this is the case, one would expect that mutation in cancer disrupts functional mechanisms that suppress cell-level traits detrimental to multicellularity. Such mechanisms should have evolved with or after the emergence of multicellularity. This leads to two related, but distinct hypotheses: 1) Somatic mutations in cancer will occur in genes that are younger than the emergence of multicellularity (1000 million years [MY]); and 2) genes that are frequently mutated in cancer and whose mutations are functionally important for the emergence of the cancer phenotype evolved within the past 1000 million years, and thus would exhibit an age distribution that is skewed to younger genes. In order to investigate these hypotheses we estimated the evolutionary ages of all human genes and then studied the probability of mutation and their biological function in relation to their age and genomic location for both normal germline and cancer contexts. We observed that under a model of uniform random mutation across the genome, controlled for gene size, genes less than 500 MY were more frequently mutated in both cases. Paradoxically, causal genes, defined in the COSMIC Cancer Gene Census, were depleted in this age group. When we used functional enrichment analysis to explain this unexpected result we discovered that COSMIC genes with recessive disease phenotypes were enriched for DNA repair and cell cycle control. The non-mutated genes in these pathways are orthologous to those underlying stress-induced mutation in bacteria, which results in the clustering of single nucleotide variations. COSMIC genes were less common in regions where the probability of observing mutational clusters is high, although they are approximately 2-fold more likely to harbor mutational clusters compared to other human genes. Our results suggest this ancient mutational response to stress that evolved among prokaryotes was co-opted to maintain diversity in the germline and immune system, while the original phenotype is restored in cancer. Reversion to a stress-induced mutational response is a hallmark of cancer that allows for effectively searching “protected” genome space where genes causally implicated in cancer are located and underlies the high adaptive potential and concomitant therapeutic resistance that is characteristic of cancer.

A translation:

  • Some have said that cancer is a reversion to the single-celled state. The “some” just happens to be us.

  • We naively predict that the genes involved in a disease of multicellularity, cancer, would be genes that have evolved after the emergence of multicellularity. We helpfully defined a colossal window of one billion years to assay.

  • We compared the distribution of cancer-causing mutations to a uniform, random distribution of mutations. Surprise: some mutations cause cancer, others don’t, so it doesn’t fit a random distribution. There are lots of genes that are less than 500 million years old that are implicated in cancer.

  • But wait! When we looked in a database of cancer-causing gene mutations, COSMIC, we find that the database is enriched for old genes. This is contrary to our hypothesis, therefore we need to find a new rationalization, rather than rejecting our hypothesis.

  • The genes that are commonly broken in cancer are involved in DNA repair and cell cycle control, which are truly primitive, ancient functions — prokaryotes have genes for this. What possible “ancient program” could be reactivated to fit our story?

  • I know! Stress-induced hypermutation! Cancer cells are invoking multi-billion year old processes; it can’t be that breaking genes produces a loss of specificity and efficiency in repair, they are switching on genes to cause mutations. They’re doing it on purpose! Yeah, that’s the ticket!

It’s a truly awful mess of a paper, in which the authors juggle lots of data to make it fit their preconceptions, and in which apparently no result can possibly cause them to reject their hypothesis. And their conclusions are strange.

Here we present evidence demonstrating that cancer manifests as an atavistic recapitulation of pre-metazoan mechanisms of stress-induced mutation in somatic cells, explaining its capacity to evolve resistance to therapy. The mechanistic roots of this behavior are retained over evolutionary time scales because they are critical to the successful function of the germline and immune system. In addition to generating base-line diversity in both the innate and adaptive immune system, normal germline mutational patterns maintain diversity in recently evolved gene families governing functions such as toxin detection and detoxification. In cancer the controlled restriction of this phenomenon to the germline and immune system is disrupted, allowing somatic cells to effectively search ancient genome space for solutions to the stress-induced pressures they are experiencing. We propose stressed-induced mutation as a hallmark of cancer reflected by genomic instability.

There is a phenomenon in the immune system where, for instance, the immunoglobulin genes are prone to greater mutation rates during cell proliferation — it is a way to increase the diversity of antibody types. So yes, there are mechanisms to increase the rate of errors. What Davies and Lineweaver are proposing is that cancer cells are actively and purposefully switching on these mutation-generating processes to “search ancient genome space”, whatever the hell that is and however the hell inducing a greater frequency of random mutations would find and restore these imaginary “ancient genes”. Note also that they’re babbling about “atavistic recapitulation of pre-metazoan mechanisms” while discussing properties of the adaptive immune system. This makes no sense.

Genomic instability is one of the hallmarks of cancer. It’s not necessarily a planned sort of thing. If you disrupt DNA repair mechanisms with a mutation, you’ll get more mutations in other genes. If you mutate the gatekeeping proteins that act to ensure that cell division does not proceed if you have gross chromosomal errors, you will have more gross chromosomal errors. The fact that populations of cancer cells routinely accumulate new mutations as they progress is not an observation that supports the idea that cancers are a reversion to an ancestral healthy, single-celled state.

If you need to cleanse your palate after that dog’s breakfast of bad science, here’s a much more interesting paper on cancer: Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer. The investigators took advantage of a tragic series of events in a cancer patient: an initial biopsy initiated needle track seeding. That is, a few cells trickled out of the biopsy needle, which acted as the mechanism of metastasis, and started new tumors, so they knew precisely when these tumors were initiated. This allowed them to use standard phylogenetic methods on sequences from samples of the cancer as it progressed, and put together a history of mutations for the diversifying cells of the cancer.

Chronology of the patient’s CRC evolution. (A) Whole-genome sequencing of multiple lesions from the patient’s malignancy allowed phylogenetic reconstruction of the tumour tree. In the phylogenetic tree, dates within brackets indicate the time of clinical diagnosis whereas dates in italic highlight the estimated times of the different lesions. (B) Illustrative cartoon of the patient disease progression and samples taken. At time tc the first colorectal cancer cell arose, giving rise to the primary tumour. At time tl the first metastatic clone emerged, giving rise to the lung metastasis, quickly followed by a second metastasis to the thyroid emerging at time tt . At time tcR the sample from the primary tumour was collected (resection) and analysed. During the lung biopsy, the needle tract seeding event spread cancer cells in the chest wall at time tcw. A few weeks later, at time tcR the lung metastasis was resected and profiled. Finally at time tcwR the chest wall metastasis was also sampled.

I know this excerpt from the paper is rather dense, but all you need to take away from it is that the different branches of the cancer pedigree have some common mutations, and also a constellation of unique mutations. Look, TP53, often called the “guardian of the genome”, is completely taken out with a missense mutation, and whole chromosomes show LOH (loss of heterozygosity) — that is, the cancer cells have lost entire copies chromosome 5, and in one subset, chromosomes 2, 9, and 22. This kind of wholesale chaos would not have been an adaptive response by a protistan ancestor.

Targeted sequencing of 409 cancer-related genes in both the primary CRC and all metastatic sites (lung, thyroid, chest wall and urinary tract) of our case revealed the presence of clonal non-sense mutations in APC (Gln1367*), as well as missense mutations in CTNNB1 (Leu156Gln), KRAS (Gly12Asp) and TP53 (Ser215Ile). The same mutations were not detected in the normal tissue or in the Hurthle adenoma. Two genes included in our panel showed discordance between primary and metastatic cancer: ADAMTS20, a metalloproteinase involved with cancer invasion and migration, and AKAP9 an A-kinase anchor protein which binds to the regulatory subunit of protein kinase A. The ADAMTS20 missense mutation Arg1885Thr was observed in the primary cancer but was not detected in either the lung, thyroid or chest wall metastases. Conversely, the AKAP9 missense mutation Ala3077Pro was found in all the metastatic sites but was not detected in the primary cancer. All these mutations were also found using WGS [Whole Genome Sequencing], furthermore ADAMTS20 and AKAP9 were validated by Sanger Sequencing. All lesions were microsatellite stable (MSS). Copy number analysis based on WGS data revealed a relative low level of chromosomal instability (CIN), with LOH of chromosome (chr) 5, gain of chr7, and a focal amplification on chr13q12.2-12.3, encompassing the VEGFR1 and CDX2 genes. These aberrations were clonal in all the CRC lesions, whereas the Hurthle adenoma showed a distinct profile characterized only by loss of chr2, chr9, and chr22. Primary tumour and metastatic sites displayed the same dominant, age related, mutational signature 1 which has previously observed in CRC as well as other cancer types.

Now that’s interesting stuff. Unfortunately, one of the lessons learned from analysis of other cancers is that every cancer is different — there are common modalities, such as the loss of certain checkpoint proteins, but there are multiple ways to achieve certain outcomes, and they don’t have to appear in any particular order. It definitely looks far less like a reactivation of a specific ancestral state and more like a derangement of regulatory functions.

Davies’ approach is kind of silly, too, a test designed to give whatever results the researchers want, with a set of observations that were basically a given with their parameters. For example, a lot of cancers mess up cell signaling to trigger uncontrolled growth. The signaling molecules are often factors like receptor tyrosine kinases (RTKs), which are only found in multicellular animals and one group of protists. So yes, it’s inevitable that you’ll find a lot of “young” (less than a billion years old) genes among your cancer-causing candidates. That observation does not support the idea of cancers being atavisms.

The Trump voter

And here we have the perfect apotheosis of the Trump voter, a small resentful man finding satisfaction by berating a Muslim family and thinking himself bigger because of his religion and his president.

In the viral video, Downing is seen with a clear plastic cup while shouting Donald Trump is my president! and You can try to act like you’re innocent. You can try to fuck with me, but guess what? You will never, ever, ever stop me. My Christianity will rise above your Sharia law. Your Sharia law … don’t mean shit to me!

And here is the next stage in the development of the Trump voter: crying in jail.

You know, since Jeff Sessions wants to keep those for-profit prisons full, maybe he should start jailing more Republicans.

Friday Cephalopod: that’s the weirdest octopus I’ve ever seen

This is the Octoprof. Do not be shocked at its frightful appearance.

The Octoprof is a Lesser Blue-Ringed Octopus (Hapalochlaena maculosa), who is a postgraduate at the University of the Gulf of Mexico, Shallow Waters (not her native habitat; she’s Australian, but emigrated to be closer to larger populations of her research subjects). Her focus of study is the reproductive biology of the invasive terrestrial species Homo sapiens – an animal which has of course been a source of tremendous concern amongst terrestrial biologists over the past thousand-ish lunar cycles, especially those whose research has a conservation focus.

Owing to a peculiar birth defect which gives her a faint but noticeable resemblance to the detested Homo sapiens (she has a serious malformation of the mantle and of two of her tentacles, which gives her a ‘face’ and ‘hands’), the Octoprof feels a strong and frankly embarrassing affinity for her research subjects. She has been criticized heavily for this unprofessional attitude by her fellow academics, most of whom would understandably prefer all research funds concerning homo sapiens to be focused on eradication measures.

It’s going to appear at the Minnesota Fringe Festival, 3-13 August, and is apparently trying to raise money to attend the event. I hope it can raise a surplus and use the excess to pay for cosmetic surgery.

How does it breathe? I don’t see a siphon, unless it’s those two tiny holes in the front of its cephalon — they’re so small it certainly can’t use them for propulsion. Poor thing.

Calling them transphobic is exactly like dropping a nuclear bomb on them!

I think I know what a metaphor is. It’s where you use a word or phrase that is symbolic of a situation, but isn’t literally a description. It is a comparison of one thing with another thing. You can use a metaphor to relate something abstract or unfamiliar to a concept a person is more comfortable with; hence the too-frequent comparison of the genome to a blueprint. From that example, you can see that a metaphor isn’t necessarily true, and can be misleading.

Another use of the metaphor is for exaggeration. For instance, if a student failed my genetics class, they could make the excuse “The prof was slaughtering students left and right! It was a Holocaust in there!” Perhaps it would be used for comic effect, but even at that, it’s dangerous: the student has both exaggerated the consequences of the course, and has seriously minimized the outcomes of the actual Holocaust. I trust most of you would be conscious of error in making that comparison. The result would not be to think the student is amusing, or to think that I was actually a brutal, unfeeling teacher, but to think that the student was a privileged young asshole. (None of my students have ever said such a thing — this is a purely hypothetical example.)

So what are we to think of the phrase “witch hunt”? There were real witch hunts, although there have never been any people with Satanic powers. As many as a hundred thousand innocent people in early modern Europe and America were falsely accused, tortured, and murdered in horrific ways. People still get accused of witchcraft, the Bible is still used to justify killing people for consorting with the Devil (who does not exist), and there are still benighted parts of the world where people are brutalized and killed for an imaginary crime. Every time you use the phrase “witch hunt” to describe an activity that has no chance of a victim ending up hanged or on fire, you’re diminishing the horror and desensitizing people to an openly evil history and an ongoing crime.

Yet for some reason it has become the first resort in any argument about merely academic dissent. Here’s a fantastic example: an academic wrote an article comparing “transracialism” to “transgenderism”. This is a bad, misleading metaphor, rather like comparing DNA to a blueprint, and people objected. I think it’s fair that sloppy scholarship ought to be vigorously criticized. So a letter was written.

While it is not the aim of this letter to provide an exhaustive list of problems that this article exhibits or to provide a critical response, we would like to note a few points that are indicative of the larger issues. We believe that this article falls short of scholarly standards in various areas:

1. It uses vocabulary and frameworks not recognized, accepted, or adopted by the conventions of the relevant subfields; for example, the author uses the language of “transgenderism” and engages in deadnaming a trans woman;

2. It mischaracterizes various theories and practices relating to religious identity and conversion; for example, the author gives an off-hand example about conversion to Judaism;

3. It misrepresents leading accounts of belonging to a racial group; for example, the author incorrectly cites Charles Mills as a defender of voluntary racial identification;

4. It fails to seek out and sufficiently engage with scholarly work by those who are most vulnerable to the intersection of racial and gender oppressions (women of color) in its discussion of “transracialism”. We endorse Hypatia’s stated commitment to “actively reflect and engage the diversity within feminism, the diverse experiences and situations of women, and the diverse forms that gender takes around the globe,” and we find that this submission was published without being held to that commitment.

Savage! Vicious! In an academic way, anyway. It never quite rises to the level of suggesting the rack, thumbscrews, or drawing and quartering, though. And yet, in an article titled This Is What a Modern-Day Witch Hunt Looks Like, it’s bluntly stated that…

This is a witch hunt.

Well.

Really?

It sort of takes one’s breath away. I guess you can call me Matthew Hopkins, the Witch-finder General, since I sometimes write strongly worded, angry criticisms of bad politics and stupid science, which is now apparently completely equivalent to the torture-murder of innocent women. We’re supposed to completely ignore the fact that poor scholarship of the sort being criticized actually does real harm to people, people who are often already marginalized and oppressed.

At least there’s one funny bit here. These same people who like to fling about the phrase “witch hunter” with indiscriminate abandon, and casually minimize the suffering of accused “witches”, are sensitive to another word: go ahead, call them “transphobic” and watch them squawk. How dare you insult them?

Our American madness

While our congress pats itself on its fanatical dedication to gutting health care, women are dying. This is a chart of maternal mortality in pregnancy per 100,000 live births.

Our health care system, among many other things, is broken. It is not the will of God or manifest destiny or any kind of positive American exceptionalism, because as the chart clearly shows, other countries do not have this problem to the same degree we have, and while they’re working to improve public health, we’re doing our damnedest to worsen it.

Thanks, regressive Republican vermin. You’re all traitors to humanity as well as to your country.

Perfectly innocuous, mundane video inspires hyperbole on the internet

I am mystified — the most trivial things get labeled with extravagant labels on the internet, and I’m experiencing hyperbole fatigue (actually, I wouldn’t be surprised if some of the annoying ads that are generated for this post are full of this crap). The latest example is this “viral video” that is being described as “bizarre“, “uncomfortable“, “revolting“, and “gross“. It’s none of those things. It’s routine and commonplace. It’s just a razor clam on an Oregon beach.

This copy has the most ordinary title: “clam digs into sand”.

My family used to dig for razor clams, and we knew how fast they could burrow. It wasn’t gross, it was wonderful: they dig by anchoring themselves with that muscular foot and expelling water to fluidize the sand around them, and then contracting muscles to pull themselves deeper into the muck, which then firms up around them. They were so fast at burrowing in that you needed special tools to keep up with them — a clam gun, which was a tube you’d push around the clam and then pull up to remove the clam and all the wet sand around it (that could be heavy work), or these narrow shovels that would let you dig fast. We’d walk along the beach or in the shallows, looking for spurts from their siphons or the little dimples they’d leave on the surface, and then you’d race to excavate them before they got away.

Here’s a video from the Washington state parks department on how to dig for razor clams.

They’re delicious, by the way. That clam is just one big hunk of almost pure muscle.

Also, that video shows what I’ve always thought of as a real beach: gray, cloudy, foggy, and wet, and going to the beach meant putting on denim and flannel and good solid boots, getting cold and damp, and coming home to a seafood feast. It was kind of the opposite of glamorous and weird, internet.

One class down

I tackled my big class, genetics, yesterday. Final exam graded, and final grades submitted to the registrar. Two smaller classes to wrap up, probably will get them done today, except that I’ve got another job to do: it’s time for the end-of-the-term lab audits by the discipline safety officer, who is…me. I get to spend my morning checking fire extinguishers and chemical waste containers and ticking check boxes.

Summer is almost here.

It is not pragmatic for a university to suck up to their enemies

I’ve been called tactless, among other things, and it’s a fair cop — I’m not very diplomatic. But I am definitely much more judicious than anyone in the Trump administration, I guess. Trump himself is a blundering nitwit, handling this whole Comey affair like a short-tempered, impulsive twit, and Sean Spicer, who is supposed to be good at public relations, was hiding from the press in the bushes.

And now, it’s Betsy DeVos. Poor Betsy. She gave the commencement address at a historically black college, Bethune-Cookman University. Not only is she the person in charge of dismantling the educational system in this country, but the Trump administration has consistently supported racist policies — Attorney General Jeff Sessions, have I said enough? She should have known what she’d get: students and parents booed her throughout the speech, turned their back on her, and some walked out. It was nuts that she was even there. It was amazingly clueless of her to agree to do it, and even more shocking is that she was invited to give that speech. What was going through the mind of Edison Jackson, president of the university? Not much, it seems. He has given three reasons.

But Jackson has staunchly defended his decision, telling reporters Wednesday, God is on our side, and when he’s for you, what does it matter who’s against you?

WTF? That’s a load of god-bothering fatalism right there. Why bother going to college? In’shallah, God will take care of his own.

He called DeVos’s visit an opportunity to engage and educate the secretary, and said she had met earlier with 12 Bethune-Cookman students who had offered her concrete policy suggestions.

That’s a slightly better reason, but it’s still somewhat delusional. DeVos has a long track record of desiring to happily gut schools, and I don’t think a meeting over lunch is going to change her.

Ah, but here comes the real reason.

But he also presented the decision as pragmatic. We are always about the business of making new friends, Jackson said. Her department controls 80% of the revenue that comes into our school. Why wouldn’t we want to do that?

You don’t want to do that, because her department controls 80% of your revenue. Fight back. Resist. It is inappropriate that these people should have so much power over public education, and it’s administrators who constantly concede greater and greater control who are part of the problem.

The students of Bethune-Cookman University who were vocal in their opposition to this anti-education Education Secretary have more integrity than the president of Bethune-Cookman University.

Look at these students!