Monday, August 8, 2011

Wicked smart apes

I tried to hate it. I really did.

But despite all the Hollywood violence; despite its (inadvertent but dangerous) glorification of the life of a pet chimp and of having one; despite the digital movements that weren’t always quite right… I still enjoyed Rise of the Planet of the Apes.

[If you’re worried about spoilers, (A) Don’t read the title of the movie, and (B) Don’t read any further until you’ve seen it. But to be honest, I'm not sure I reveal anything that wasn't already revealed in the trailers.]

I can't control how apologetic I feel for liking this flick so much. As a human I care deeply what other humans think of me and my movie tastes. And in a weird way I care what chimps, bonobos, gorillas and orangutans would think of me liking it. I guess I shouldn't apologize for being human and I can't easily stop being such a dork.

Perhaps it was the near-future sci-fi possibility of it. Perhaps it was all the sneaky little throwbacks to the original flick. Perhaps it was the attempt to tackle issues of personal bias, emotions, and capitalistic greed in the world of science. Perhaps it was the way James Franco wore that little white lab coat. Perhaps it was my adoration of apes overpowering the fact that these were mere digitized computer actor-humans. Perhaps it was the triumph of the apes! Perhaps it was impossible to go anywhere but up from my subterranean expectations. Perhaps I’m just a human and we humans love our big loud, manipulative blockbuster movies, especially ones that ask, “What does it mean to be human?

The shows were all sold out on Sunday in West Warwick, so I’m betting most of my students will see this movie—if not this summer, then soon. And I’m sure to be fielding the questions they’re bound to have after watching it. You may have to field the same ones.

I may even use the movie as a teaching tool to help with topics like gene therapy, virus biology and therapeutic use, non-human disease models and test subjects, transgenic lab animals, and inheritance.

Although I’ve worked with custom-engineered virus vectors to modify and to shut down specified protein synthesis in epithelial cells, my experience stops there. And to help me try to make sense of this movie, I asked Ken and Anne to answer some questions that movie goers are bound to wonder.

Ken and Anne: Fire away.

Holly: In the movie Rise of the Planet of the Apes, a scientist invents a possible treatment for Alzheimer’s that regenerates neurons and they test it on chimpanzees in a fantastic lab (and the scientist also administers it to his father at home). The delivery system for the treatment is a virus vector injected into the bloodstream (for humans) or administered through a gas mask (for the lab chimps) that changes known genes associated with Alzheimer’s in humans (not chimps!). When a chimpanzee (who does not have Alzheimer's) is infected with the virus she becomes significantly more intelligent.

1. How does one test a cure for a human disease in non-affected non-humans?

Ken: We've not seen the movie but here are some guesses at your questions. In principle (far from practice at the moment), one could get such a vector into a person that could target the particular gene in cells, and replace it with a gene the vector carries. (If this were incorporated in the germ line of the mother or father, it would be passed on to their kids as part of their genome.) Testing simply would be taking a DNA sample (any cells--blood, cheek swab, etc) and looking for the sequence of the inserted gene. This is what is done to make transgenic mice (but the gene is inserted into an egg, not breathed in by an adult).

Anne: There are 2 things that normally would need to be tested in developing gene therapy; the system for delivering the genetic modification, and the efficacy of that modification. In principle they could/should be tested separately, so the delivery system would be tested on normal subjects before the efficacy of the cure is tested, so that, if it doesn't work, the researcher knows it's not because of the delivery system. Testing of many pharmaceutical products is done in similar stages -- first determine whether it's safe on normal people, then whether it actually cures. The first stage is often done on 'professional guinea pigs', people who make their living volunteering to test drug safety. But you're right, it's not the cure that's being tested on people without the disease, it's the efficacy or safety of the procedure.

2. The Alzheimer's (AD) cure not only heals neural degeneration (as evident in the human test case), but it improves cognition too and when both humans and normal chimps are infected their intelligence increases literally over night. Could that be possible? How?

Ken: It could (in principle) fix damaged neurons in the patient (this is at the moment largely fantasy but by now there may be some precedents--we're not up to date on what claims may be being made.) If the person's inherited genes that led to AD also led to poor cognition, and if changing the gene once their brain is developed could goose up the neurons' activities, then this, too, could occur in principle. Suppose for example that the problem were a neurotransmitter receptor that was somehow not very efficient, and this were replaced so that signals traveled between synapses more rapidly. Again this is all 'suppose' at present!

Anne: If intelligence is due to synapse speed, say, one could imagine that could be upgraded quickly. It's harder to imagine that the biochemistry underlying chimp intelligence is the same as that that causes dementia, and that therefore they'd have the same fix!

3. Also—and this is the real question I’m interested in discussing especially considering the recent Mendel-Wasn’t-Right theme here on the MT!—A female chimp who has been infected actually passes the positive genetic affects onto her offspring. They even remark how her son is intelligent because it's "in his genes." How could this be possible?

Ken & Anne: In the same way as related to #1 above, the offspring would inherit the faster-firing receptor gene and would be smarter.

All of this assumes that one gene change would work across genomic background variation, with no side effects, and all that. But the dream of real gene therapy has been to do what you're describing (again, we didn't see the movie). A good example would be replacing sickle cell hemoglobin (the beta globin gene) with a normal version, or replacing the mutant Tay Sachs or Cystic Fibrosis gene with normal sequences. But to be inherited it has to involve the germ line cells.

There are some known mechanisms that illustrate how such a dream scenario could be plausible. Cells have receptors that bring what binds to them into the cell (usually, this is for some normal cell response to the environment). A virus could be engineered to be taken into some specific cell, like a neuron, in this way. The virus could be designed so that genes it carries are made into RNA corresponding to the 'good' gene version, along with code for a protein like reverse transcriptase that turns RNA into DNA and inserts it into chromosomes could be used. The latter is how viruses currently incorporate into DNA and cause trouble; our genomes are littered with such inserted elements. The difference is that they insert only occasionally and even then into random places in the genome, or places of their choosing.

To get this into places of our choosing, we would have to engineer the system to recognize some sequence of the target gene area and insert the virus's passenger gene at that place, excising the current (bad) gene there.

In any cell in which this occurred, the transgene would have replaced the normal gene, and the job would be done for that cell. If in a sperm or egg precursor, then that would be transmitted to (half of) the person's offspring.

There are versions of each of these transgenic techniques already in practice, but in every case there are limits relative to the desired outcome, and they mainly work in mice that have already been prepared for the experiment by manipulating mouse egg cells. We use such transgenic mice in our own work here on craniofacially relevant genes.

There used to be a lot of hope for such gene therapy, but failures have led many if not most companies to give up the effort. Mostly what is still being tried (I think) is and has always been to administer something to a patient and change his or her genes, or insert a compensatory gene, in affected cells. Injections of such things into muscle to alleviate muscular dystrophy, or by inhaler to alleviate CF, or to fix immune system problems have been tried and probably some at least are still under test.

That still leaves movie goers wondering how someone, like Caesar-the-chimp’s mother in the movie, could contract a virus orally or through the bloodstream which somehow finds its way to the eggs or sperm and then inserts its DNA into those cells and modifies them. That’s the only way the modified DNA sequence could be inherited by future generations, like Caesar, but it's not outside the realm of plausibility. Just think of the evolutionary possibilities!


Luna G. said...

looking forward to seeing the simian flick. i'm curious about the light-speed social evolution. did they advance from small band level primates to a global conquering empire over night with this intelligence boost?

Holly Dunsworth said...

There has got to be at least one more movie in this series. That's all I'll say ;).

Holly Dunsworth said...

This discussion includes the writer/producer, an anthropologist (Paul Mullins), and Kanzi's pal Sue Savage-Rumbaugh who was "impressed" and "shocked" and has a lot of interesting comments!

Holly Dunsworth said...

Uh. Wait. You can pass along a virus to your babies. If the virus acts on the babies the same way it acts on the parents, which in this case makes them smart, then I guess that's how intelligence gets inherited by chimps without inheriting modified genes. (???)

Ken Weiss said...

A couple of things. First, if the virus incorporates into the genome, then it is a typical part of the genome thereafter. Even if the virus just inhabits cells, if it is continually transferred, it is part of the genome. It would be the genome definition that is wanting.

Other traits can be developed intra-uterinely and transmitted, like various physiological 'set points' related to blood pressure and so on.

This relates to our recent microbiome post (May 2012) on whose genome is it?

Holly Dunsworth said...

I think you should see the movie :)

Ken Weiss said...

We don't see many movies, but maybe we'll look at this one.....