Fact: Every cell in your body
contains exactly the same genes.
But not all of those genes
are equally important in each location
of your unique and exquisite corpus.
Which is to say: You don’t need
your eye-color genes, for example,
to be expressed in your left elbow,
nor to have any funny-bone antics
going on within your corneal amphitheatre.
Similarly, most all of the following interview
is different from its appearance in the print edition
of the Austin Chronicle.
And there is much more here – in this swath of
unexpurgated, pre-conflated, more deeply
science-oriented conversation – than in that brief,
SXSW Interactive-focused look at our talk
with UT geneticist Dr. Andrew Ellington:
Chronicle: Okay, so, theoretically – but using
technology currently or soon enough available –
take an average human being. What portions of them
would you engineer to allow them to survive better
in the Austin environment?
Ellington: First and foremost, especially in respect to SXSW,
I think you’re going to need some manner of hearing augmentation.
It’d be great if we weren’t all slowly going deaf from either noise pollution
or attending too many Sixth Street venues, and there are ways one can imagine doing that.
In particular, there’s a sort of revolution underway with a type of molecule called siRNA.
And, like its name implies, the RNA is the RNA that lives in us – and the si is just an engineered
variant that can help to change the expression of our genes. Now, the cool thing about this is
that people usually think of genetic engineering in terms of what’s called germ-line engineering,
where we’re gonna change your genome, it’s gonna be passed on to your kids, and
and generations of people will have the same properties.
But you can also do genetic engineering in much more transient form –
and that’s what siRNA allows. It’s the notion that you can transiently transform properties
such as the ability to hear better or to be better buffered against loud noises.
Chronicle: So when you say this siRNA is going to transform these properties,
do you mean they’d be transformed not just at the, what, the fetal or blastocyte stage,
but that you could make the genetic properties express themselves in full-grown human beings?
Ellington: Yes, full-grown human beings. But the siRNA wouldn’t cause a different expression,
it would change the expression that was already there. If you think of sound boards in a music studio,
all the tracks on different sliders, think of those as all the genes in your body. Your genes are all firing
at different rates and producing different amounts of stuff. What siRNA does is come in from the outside
to turn a knob down or push a lever up. It changes the overall ratios of expression of what’s
already present in you – to get better effects.
Chronicle: And depending on the siRNA they manipulate, would these changes
be of such a great magnitude that you might see physical manifestations?
Ellington: Absolutely.
Chronicle: Like, you turn up a muscle gene and the dude looks like he’s on steroids?
Ellington: That’s the perfect example – you’ve anticipated me way too well. Also, there are
natural variations of these things. Keep in mind that the thing we’re talking about is siRNA,
the thing that’s going to turn the knob, change the gene expression. And there are also
natural mutations that can occur from generation to generation that can also change
the gene expression. So there’s a particular gene called myo-D, and it’s more or less
the master regulator of all the muscles you have. And there was a kid in Germany
several years back, who was born with a mutation in his myo-D gene. And by age three,
this kid looked like he was about five or six years old. He had twice the muscle-mass of
a normal human of his age, and he was nicknamed Hercules. I mean, he was huge,
he looked like a body builder at age three, it was unbelievable … So there’s an example
of a single gene changing regulation – not induced by siRNA, but by simple mutation –
and it had a huge impact. Now there are, inside of us, natural counterparts to siRNA called miRNA –
these also have to do with turning up and down the switches. And in a particular type of,
I think it was a sheep, there was a mutation in one of the miRNAs that led to an incredibly muscled sheep.
So this is an example of both, one, how there are master regulators; and, two, how changing the way
those master regulators work – by mutations or, as I’m suggesting, by using siRNA –
can lead to large changes immediately. Not immediately like overnight,
but without mucking about a whole lot.
Chronicle: Okay, I don’t know where I picked this up, but years ago
somebody floated the idea that maybe things could occur in the adult life
of an organism, where a mutation would occur and that mutation would
affect the organism at the gene level, at the germ-line level.
Ellington: Sure, yeah.
Chronicle: So you’re talking about these siRNA that are transient.
But are there ways of, if you wanted to, using them that are not transient?
That would pass things on to the following generations?
Ellington: Yes, absolutely. You could introduce it into the gene line if you wanted to.
The problem is, most people are fundamentally, for whatever reason, fairly uncomfortable
with germ-line engineering. They get all squicky about it. I don’t, but a lot of people do –
and, honestly, that’s why we don’t see a lot more of it. So that’s why I like this notion of
transient engineering. At one level, it gets people used to genetic engineering in general,
and, at another level, if there really are firm, ethical, religious objections that has the populace
saying we can’t go there, this is another way to change the human condition and improve human health.
There’s no real difference between aspirin and siRNA except in its level of sophistication and how
it’s made and introduced. But it doesn’t change you any more than aspirin changes you.
Chronicle: How practically has this research been resolved so far?
Ellington: Well, that’s another interesting thing. There are companies, billion-dollar companies,
working on making this a reality, and they’ve made quite a bit of progress. They’re starting out
on chronic diseases or acute diseases that have no cures – just a way to get better entry
into the medical marketplace. So it’s coming along. But, as with many things, it’s coming along
through a regulatory system that’s very s-l-o-w and costs a huge amount of money.
Just like your average blockbuster drug from Merck or Pfizer or Glaxo or whatever
is something that initially costs an arm and a leg – so the companies can be obscenely profitable,
yes, but also so they can recoup their research costs. These things will come along slowly,
they’ll be very expensive, and they’ll have undergone every regulatory hurdle you can possibly imagine.
That said, they’re pretty much, I would argue that they’re pretty much ready today.
Except that we live in an environment where it would be frowned upon – extremely – to bring them into play.
I tease my lab – and I want to make very clear that this is just a joke – but I tease my lab sometimes
that, if we really run out of money, we’re gonna cook up a bunch of siRNA that can act on myo-D,
head down to the stadium, and make the football team twice as large.
Chronicle: When you say “transient” … is there a way that
you can just, like, click, it goes on, now it’s amplifying or
allowing expression of the gene. And then – can you turn it off just as easily?
Ellington: Right now the answer would be “sort of.” To the extent that we don’t have
practical working examples in humans, in something that we’re all taking or doing.
It’s a little difficult to say exactly how an antidote to it would work. But, in fact,
the simplistic answer is: Here’s a strand of siRNA, and we know how the nucleic acids match up,
so I’d just make another one that binds to the first one and turns it off.
Chronicle: Okay, here’s a question. Why would our RNA – or DNA –
any of our genetic materials … why wouldn’t they act like viruses
and sort of try to self-preserve, to maintain their status quo?
Like, “Get off my back, siRNA, I’m gonna keep doing what I’ve always done” …
Ellington: You’re absolutely correct to use viruses as an example. The way I characterize viruses,
they’re self-replicating nanomachines. That’s what they do. That’s their job. The pathogenesis
that viruses incur is secondary; they’re not out to kill our immune systems, they’re not out to
take down large swaths of the population by causing death – they’re just replicating and we happen to
get in the way at some level. And, in fact, many viruses are completely benign, we’re not always
talking about horrify things that kill the population. A machine is a machine, so when I say self-replicating
nanomachine … it’s like, if I’m trying to make a Lego robot and all I have is a gear, how big a robot can I make?
The siRNA is like a gear: On its own, not much there. But it’s not impossible to imagine that it could become part of
a larger system. And when you ask, “Where would that larger system come from?” Well, it could come from an
attempt to make a self-replicating nanomachine. People are working on making engineered viruses.
But the only thing I’d worry about as far as safety hazards and safeguards go,
is if we’re doing these transient modifications and
a virus comes roaming through the system –
a flu virus, HIV, what-have-you. And it might pick up the siRNA
and carry it to the next person.
But the siRNA on its own is not nearly enough of a machine.
This article appears in February 24 • 2012.