Get ready, world, scientists are going to use CRISPR/Cas9 on human patients for the first time, extracting a population of cells, modifying their genomes, amplifying them in tissue culture, and then injecting the modified cells back into the human host. It’s being done in China, where the ethical constraints are a bit more loose, which isn’t always good…but in this case, it sounds like a good, safe (as safe as experimental therapies can be) approach.

They intend to use CRISPR/Cas9 to knock out the PD-1 gene in immune system cells. PD-1 is a cell surface molecule on T-cells that inhibits the cells, and acts as a constraint on immune system activity. The “PD” is short for “Programmed Death”, and what it does is compel the cells to commit suicide when stimulated — so if immune system cells get a bit overzealous and go on a rampage attacking healthy cells, they can be switched off. The immune system has multiple checkpoints to prevent it from going rogue, and this procedure will remove one of them. By knocking out the PD-1 gene, the scientists are creating particularly unrestrained cells that they hope will do a more effective job killing cancer cells, because cancer cells are known to use the signaling mechanisms that tell the immune system to die.

Are there drawbacks and risks? There are always drawbacks and risks. This technique is a variation on an existing pharmaceutical approach, which uses drugs that inhibit PD-1 in cancer patients, so we know a bit about its effects — it’s just that taking out the whole gene with CRISPR/Cas9 is a dramatically thorough way of demolishing the molecule. But we do have some drugs, like Nivolumab and Pembrolizumab, that target PD-1 already and are in clinical trials. We’ve also experimentally knocked out the gene in mice.

So, we have an idea of what could go wrong, and in the immortal words of Dr House, it’s lupus. Or lupus-like effects. By jacking up the immune system and removing one restraint on its activity, you can get complex system-wide problems, which Dr House will tell you are pretty hard to treat, but at least they’re not as severe as terminal cancer. They are also editing a terminal cell type — it’s not going to proliferate — so eventually, we hope after they’ve killed cancer cells, the injected cells will die of natural causes and the effect will fade away.

This is not a treatment that affects the germ cell line, so these patients, if they survive, will not be passing on an edited gene to their offspring. It’s also got to be a rather expensive therapy that has to be customized for each new patient, so it’s not going to be routine. It is a first step into the exciting world of genetically modifying humans, though.

Who else remembers the days of the BBS? Back in the 1980s I used to hang out on various dial-up bulletin boards, before the internet. They weren’t truly interactive — some used only a single phone line, a few fancy ones could handle a couple of simultaneous connections, but generally you’d log in, browse a couple of messages other people had left, maybe leave one yourself, and log out again, all at 300 baud. When the fancy 1200 baud modems came out (I bought one that was military surplus), my old Apple II struggled to keep up with the furious data rate, and I actually wrote my very own telecommunications program — in 6502 Assembler, of course, using the wonderful ORCA macro assembler package — and took the daring step of cutting a lead on my mother board to enable interrupts, and building the program around a custom interrupt handler just so it would stop dropping characters. I was a true nerd.

It all came rushing back with this article in the Atlantic, The Lost Civilization of Dial-Up Bulletin Board Systems. I abandoned them in the 1990s when the Internet became ubiquitously available, although still often through dial-up lines from home. Apparently some tiny number of them still hang on. There are actually 20 dial-up BBSes still running, somewhere?

But every mass extinction has its holdouts. Even today, a small community of people still run and call BBSes. Many seek the digital intimacy they lost years ago; 373 BBSes still operate, according to the Telnet BBS Guide, mostly in the United States. Many are set up to be accessible via internet-connected tools like Telnet, a text-based remote-login protocol originally designed for mainframes.

Did any direct-access, telephone-dial-up BBSes survive the internet’s proverbial asteroid? Sure enough, there are about 20 known dial-up BBSes in North America. And of those, only a handful have been running non-stop since the mid-1990s. These are the true dinosaurs walking among us. Who dares to run such antique systems, and why? Have any of them been left running by accident like the BBS in my dream? I had to find out.

Yes, why? I want to know. It turns out that many of them are just kept up for nostalgia’s sake, but others are…are you surprised to learn that they’re maintained by delusional right-wing paranoids?

Ten years ago, when I dipped back into BBSes, I still got a sense that many sysops ran them to provide a libertarian alternative to the internet. Among them, the unoppressed who wanted religious freedom, the unsurveilled who wanted freedom from surveillance, and those prepping for the day when BBSes would provide shelter after the internet came crashing down.

It was never an alternative to the Internet. It couldn’t be. You’d have to argue that the Post Office was just a slow version of blogging if you go down that path.

Back in the 1990s, when Behe first came out with his idea of irreducible complexity, I recall that there was some consternation in our little community of anti-creationist activists. Behe had done something novel: instead of denying all of the accumulated evidence, he instead turned the focus on the gaps in our knowledge. It’s something of a cunning plan, if you think about it; the scientific literature is full of papers where scientists say that now we understand Step X, but we still need to figure out Steps Y and Z, so let’s work (and get funded) for Y. In a sense, it’s brilliant, because instead of relying on creationist ignorance to advance his argument, he would use honest scientific ignorance instead.

So, have we worked out every single step in the evolution of the blood clotting pathway? No? Then all the gaps are filled in with God Design. Flagellum? Nope. Must have been design then. Resistance to anti-malarials by plasmodium? Clearly, if you haven’t isolated every genotype in the progression of the resistance, there is room for an invisible magic man done did it.

His other clever shuffle was to admit that there are natural processes at work, so every evolutionary change is the consequence of both the understood mechanisms and what he claims are necessary miraculous events, but that you can’t always tell which steps are caused by mutation/selection, and which are Designed. Which means that the scientists have to do all the work of documenting every step, while Behe sits back, does nothing, and gives credit to his unnamed Designer for all the parts that aren’t done. As Matt Herron points out:

Dr. Behe admits (in The Edge of Evolution) that there is “…great evidence that random mutation paired with natural selection can modify life in important ways,” so his view is that life’s diversity and complexity are best explained by a combination of natural and supernatural processes. In fact, I think that’s a fair summary of intelligent design in general. So to falsify intelligent design for a particular example, it’s not enough to show that natural processes are mainly responsible for its origin. No, you’d have to show that supernatural causes played no role at all, no matter how minor.

That’s the funny business that has kept him going for a quarter century now. He doesn’t have to do the work of showing that any of his hypothetical supernatural mechanisms actually operate anywhere, he does not have to test for Design, and in fact he has zero positive evidence for any of the processes that he claims must have been ticking away for millions of years. Meanwhile, real scientists have been measuring and demonstrating the phenomena described by modern evolutionary theory — drift, selection, recombination, etc. — and identifying specific instances of these mechanisms in action. Behe shrugs them off. He’s built a rationalization that allows for the existence of natural processes while demanding that all of the gaps be filled in with his Designer…who seems to be a reflection of his Catholic faith.

It’s infuriatingly dishonest, but he’s found a thriving niche. All the scientists think he’s a kook, while all the creationists who are so gullible that they believe in a great flood and 6000 year old earth look upon him as some kind of super-scientific genius.

Just follow the simple steps in this video.

We haven’t raked the leaves that fall in our yard for years — it’s part laziness and partly because we have a corner lot in a windy part of the world, so they don’t hang around much. If we do anything, it’s to mulch them with our lawn mower and leave them in place.

And now I have vindication! we’re helping to protect the environment (warning: autoplay video at that link). I guess I’ll just keep on keeping on.

Now I just need a justification to stop mowing the lawn.