I hear that women are made of exotic matter

The Nobel in Physics has been awarded for research on exotic matter, but I think you’d be better off looking for a physicist to explain it. I’m sure it’s good work and that the three scientists are deserving, but I just have to leave this fact on the table.

No Nobel Prize has come close to being equitably distributed by gender, but physics has the worst record of them all. Zero women have won it in the past 50 years. Exactly two women have won it ever.

Again, this does not detract from the accomplishments of Thouless, Haldane, and Kosterlitz, but it does make one wonder how much further physics would have progressed if it didn’t have a culture that discouraged half of humanity from participating.

Can I come in and tell you about the cult of Danio?

Now I know how a Mormon or Scientologist or Baptist feels when some heathen tries to earnestly explain their religion. This video is well done, but gives me a bit of the heebie-jeebies.

I started working on zebrafish in 1979 (I wasn’t the first, or even particularly close — that honor goes to the crew in George Streisinger’s lab), and all through the 80s our lab group had a reputation: at every meeting in every talk, we’d recite what was called the Zebrafish Litany, a listing of all the virtues of this quirky new model organism that nobody else knew much about. In fact, at the Friday Harbor lab meetings in developmental biology there was a kind of tradition where the students would linger in the auditorium late at night and mock the speakers and professors with imitations on the podium, and one year a group made fun of us by having a series of students march robotically to the lectern and recite the exact same series of words. And those words are in this video. How dare the unbelievers speak our catechism!

The video doesn’t quite capture the true nature of the Cult of Danio, though. Everything in it is about how zebrafish research contributes to the study of human diseases, which is a nice perk of the system, but we study the fish because the fish are fascinating, not because we are wannabe human disease researchers. Also, the part where he explains the flaws of the zebrafish, that they have many duplicated genes (so do we) and that they have unique genes not found in humans? Those aren’t flaws.

It is nice to see, though, that our orison is now part of the general public awareness of the zebrafish. That’s why we were saying it so often. Soon, you too shall be a believer. All praise George!

Autophagy wins a Nobel

Well, actually, Yoshinori Ohsumi has won the prize for his work on autophagy, a cellular process you may have never heard of before. The word means “self eating”, and it’s an important pathway that takes chunks of the internal content of the cell and throws them into the cell’s incinerator, the lysosome, where enzymes and reactive chemicals shred them down into their constituent amino acids and other organic compounds for reuse. What makes it interesting is that the cell doesn’t want to just indiscriminately trash internal components; there are proteins that recognize damaged organelles and malfunctioning bits and packages them up in a tidy little double membrane bound vesicle that fuses with the lysosome and destroys them.

At least, most of the time it’s selective. It was first characterized by Ohsumi in yeast, where, if you starve the cells, they start self-cannibalizing to survive. If you use mutant yeast that lack some of the degradative enzymes, they are unable to break down the materials being dumped into the lysosome, and the vacuoles just get larger and larger, making it relatively easy to screen for changes in the machinery for autophagy.

Autophagy in yeast. In starvation-induced (non-selective) autophagy, the isolation membrane mainly non-selectively engulfs cytosolic constituents and organelles to form the autophagosome. The inner membrane-bound structure of the autophagosome (the autophagic body) is released into the vacuolar lumen following fusion of the outer membrane with the vacuolar membrane, and is disintegrated to allow degradation of the contents by resident hydrolyases. In selective autophagy, specific cargoes (protein complexes or organelles) are enwrapped by membrane vesicles that are similar to autophagosomes, and are delivered to the vacuole for degradation. Although the Cvt (cytoplasm-to-vacuole targeting) pathway mediates the biosynthetic transport of vacuolar enzymes, its membrane dynamics and mechanism are almost the same as those of selective autophagy.

Autophagy in yeast. In starvation-induced (non-selective) autophagy, the isolation membrane mainly non-selectively engulfs cytosolic constituents and organelles to form the autophagosome. The inner membrane-bound structure of the autophagosome (the autophagic body) is released into the vacuolar lumen following fusion of the outer membrane with the vacuolar membrane, and is disintegrated to allow degradation of the contents by resident hydrolyases. In selective autophagy, specific cargoes (protein complexes or organelles) are enwrapped by membrane vesicles that are similar to autophagosomes, and are delivered to the vacuole for degradation. Although the Cvt (cytoplasm-to-vacuole targeting) pathway mediates the biosynthetic transport of vacuolar enzymes, its membrane dynamics and mechanism are almost the same as those of selective autophagy.

Taking out the trash is a vital procedure for cells, as well as for maintenance of your household, and there are cases where autophagy is implicated in human diseases. For instance, mitochondria are intensely active metabolically, and experience a lot of wear and tear. Your cells take old, busted mitochondria, tag them with proteins, and recycle them with a specific subset of autophagy called mitophagy, or mitochondria-eating. Some forms of Parkinson’s disease seem to be caused by defects in the mitophagy machinery, causing defective mitochondria to accumulate in the cell and impairing normal function.

Autophagy also seems to have some complex roles in cancer. It can be a good thing, in that early on if defective proteins and organelles accumulate, they can be sensed and destroyed, so autophagy in that case is a defense against cancer. However, cancer can also subvert that machinery and route the cell’s defenses right into the trash.

But also, autophagy seems to be involved in every step in cancer metastasis. This shouldn’t be a surprise, since autophagy is used to regulate the activity of the cell in all kinds of behaviors.

Schematic illustrating roles of autophagy in the metastatic cascade. Autophagy increases as tumor cells progress to invasiveness and this in turn is linked to increased cell motility, EMT, a stem cell phenotype, secretion of pro-migratory factors, release of MMPs, drug resistance and escape from immune surveillance at the primary site in some tumors. Many aspects of these autophagy-dependent changes during acquisition of invasiveness also likely contribute to the ability of disseminating tumor cells to intravasate, survive and migrate in the circulation before extravasating at secondary site. At the secondary site, autophagy is required to maintain tumor cells in a dormant state, possibly through its ability to promote quiescence and a stem cell phenotype, that in turn is linked to tumor cell survival and drug resistance. Emerging functions for autophagy in metastasis include a role in establishing the pre-metastatic niche as well as promoting tumor cell survival, escape from immune surveillance and other aspects required to ultimately grow out an overt metastasis.

Schematic illustrating roles of autophagy in the metastatic cascade. Autophagy increases as tumor cells progress to invasiveness and this in turn is linked to increased cell motility, EMT, a stem cell phenotype, secretion of pro-migratory factors, release of MMPs, drug resistance and escape from immune surveillance at the primary site in some tumors. Many aspects of these autophagy-dependent changes during acquisition of invasiveness also likely contribute to the ability of disseminating tumor cells to intravasate, survive and migrate in the circulation before extravasating at secondary site. At the secondary site, autophagy is required to maintain tumor cells in a dormant state, possibly through its ability to promote quiescence and a stem cell phenotype, that in turn is linked to tumor cell survival and drug resistance. Emerging functions for autophagy in metastasis include a role in establishing the pre-metastatic niche as well as promoting tumor cell survival, escape from immune surveillance and other aspects required to ultimately grow out an overt metastasis.

It may also affect Crohn’s disease and other inflammatory syndromes. There are mutated proteins associated with Crohn’s that are part of the autophagy pathway; macrophages carrying these mutations deliver bigger doses of inflammatory cytokines when stimulated. Selective autophagy plays a role in regulating the balance of exports from the cell.

Those are the mild diseases caused by defects in this pathway. Look up Vici syndrome, a heritable disorder that causes devastating problems for those afflicted. It’s caused by mutations in the EPG5 gene, which is an important regulator of autophagy.

It’s not just about human diseases, though. Autophagy is universal in eukaryotes: yeast have it, plants have it, animals have it. Genes in the pathway are studied in yeast and nematodes and flies and mice, so this is a common mechanism of regulating the internal traffic of the cell.

Jiang P, Mizushima N (2014) Autophagy and human diseases. Cell Res 24(1):69-79.

Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10(7):458-67.

Mowers EE, Sharifi MN, Macleod KF (2016) Autophagy in cancer metastasis. Oncogene doi: 10.1038/onc.2016.333.

Tom Wolfe’s great contribution to literature

Wolfe wrote this execrable book in which he denied evolution, among other very silly things. It was simply entirely wrong and built on a foundation of shoddy scholarship and vainglorious ignorance.

But I do have to credit him with one thing: he has inspired some of the most entertaining book reviews ever. I haven’t seen stuff like this since Twain’s review of Fenimore Cooper. Go enjoy EJ Spode’s review of The Kingdom of Speech.

Skepticism is so easily displaced by fantasy

We’ve seen it so many times before, you think we’d learn. The glib, charismatic con man, short on evidence but long on vision. The desirable dream: cure my fatal disease, show me proof of an afterlife, teach me how to unleash my psychic powers. We’re supposed to be good at recognizing those, and rejecting them. But it turns out that the con man just needs to tailor his fantasy to fit, and he can reach even the hard core skeptics. In this case, it’s the vision of shiny spaceship and a voyage to Mars.

mars

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We are not going to escape to other planets

earth

Why do people take Elon Musk seriously? I know he’s been successful with his car business, and SpaceX is making great progress, but every time he opens his mouth he sounds like a delusional maniac, or worse, he sounds like the Discovery “Five Year Goals” Institute. His latest extremely optimistic plans are rather unbelievable.

SpaceX founder Elon Musk has outlined his highly ambitious vision for manned missions to Mars, which he said could begin as soon as 2022 – three years sooner than his previous estimates.

He’s going to solve all the technical difficulties of that mission — and all of the expenses — in six years. I know the US made a commitment to land a man on the moon in a span of a decade (and succeeded!), but that involved a major effort by a nation, fueled by cold war competition. I don’t think Musk has that kind of clout.

Then, this is really unclear. I assume he’s only talking a small crewed mission in six years, not launching a rocket with 100 people aboard to Mars, but I don’t know — his optimism sounds like it’s going to explode out of the top of his head.

In order to achieve this goal, Musk outlined a multi-stage launch and transport system including a re-usable booster like the Falcon 9 which SpaceX has already successfully tested – only much larger. The booster, and “interplanetary module” on top of it, would be nearly as long as two Boeing 747 aircraft. It could initially carry up to 100 passengers, he said.

That can’t work as a Mars vehicle. A 747 holds 400-500 people in cramped quarters for short hops, but doesn’t need to carry elaborate life-support systems, food, water, and air, and all the fuel for a 260 day journey. But the highest capacity destination in Earth orbit, the ISS, has only 6 sleep stations and has held at most 10 people at once. So I’m not sure why he’s planning a large space bus right now. Especially when he freely states that the current cost of a seat on that bus would be about 10 billion dollars.

But at least he’s solved the really important issue of what to name his space ship already.

The first ship to go to Mars, Musk said, would be named Heart of Gold as a tribute to the ship powered by an “infinite improbability drive” from Douglas Adams’ science fiction novel The Hitchhiker’s Guide to the Galaxy.

And it wouldn’t be a Musk event without some mention of the locust mindset. We’re all gonna die if we have to stay on this huge planet we’re adapted to live on, so we’ve got to get a few people to the off-world colonies, which we know are all inhospitable hell-holes. But…but…EXTINCTION EVENT.

He said there were “two fundamental paths” facing humanity today. “One is that we stay on Earth forever and then there will be an inevitable extinction event,” he said. “The alternative is to become a spacefaring civilization, and a multiplanetary species.”

We know a few things about extinction events, having caused a few for other species. We know, for instance, that a major cause is habitat destruction, elimination of the environment to which the species is well-suited and capable of independent survival. If you want to foster the survival of a species, building a big steel-and-glass enclosure that holds a few representatives that you have to feed and care for artificially is only a stop-gap measure — you want them to thrive, you have to restore their environment fully.

Face reality. If planet Earth goes, so does humanity. It’s the end. Game over. Putting a few of our people in a self-imposed space zoo does not save the species, it only prolongs the agony briefly. If you really care about the problems facing humanity, and are thinking extremely long term, you have to appreciate that a species is part of a larger system that must be maintained.

So please do explore the universe and send rockets and people to other planets — I think that’s cool, and a part of what we overgrown monkeys do. But when you frame it as “saving the species”, I know you’re an ignorant fool and will stop trusting you to be competent at whatever other goals you have.