Speaker 1: Get in test with technology with tex Stuff from how
Speaker 1: stuff works dot com. Hey there, we one, and welcome
Speaker 1: to tech Stuff. I'm Jonathan Strickland and I'm luring voc
Speaker 1: Obama and today we've got our topic courtesy of a
Speaker 1: listener request. Yes, this is listener Mike via Twitter. I
Speaker 1: didn't write down his screen name, so one of the
Speaker 1: Mike's on Twitter, thank you sir yea and said, have
Speaker 1: you done a podcast on gene therapy? Is that something
Speaker 1: that at Blow the Mind would do instead? That's a
Speaker 1: stuff to blow your mind. That's the Julie Robert Julie
Speaker 1: doing their their science podcast, and we really we've talked
Speaker 1: about gene therapy a little bit on Tech Stuff in
Speaker 1: the past, we've never done a full episode on it.
Speaker 1: We've also talked about it on a sister podcast, the
Speaker 1: Forward Thinking Podcast all right, along with Joe McCormick. We
Speaker 1: we did a really great introduction of what jeans are
Speaker 1: and some of the really interesting cutting edge stuff going
Speaker 1: on in gene therapy. So if you would like to
Speaker 1: listen to that, we we highly recommend it. We think
Speaker 1: that we did a pretty excellent job. Yeah. Yeah, the
Speaker 1: fact we had Joe there too. You know, put facts
Speaker 1: in between the jokes that I made and the shaking
Speaker 1: of Lauren's head. It really was different from a tech
Speaker 1: stuff episode. No, of course, I'm proud of all the
Speaker 1: work we do, and then one was a great show.
Speaker 1: But we're going to give an overview of what genes
Speaker 1: are and some of the actual technical ways that scientists
Speaker 1: and doctors are working with gene therapy right now, because
Speaker 1: in the forward Thinking episode, it was more about the applications,
Speaker 1: right it was more about why you would use it
Speaker 1: and not how like how has it actually done? And
Speaker 1: it's kind of fascinating. Yeah. Absolutely, and and this is,
Speaker 1: by the way, one of those things that we kind
Speaker 1: of struggle with all the time of of you know,
Speaker 1: we'll we'll come up with a concept for a show
Speaker 1: and then go, how should we check with car stuff?
Speaker 1: Should we check with mind? Should we you know? Who
Speaker 1: should we ask? And make sure that we're not treading
Speaker 1: on their toes and re copying ourselves because we already
Speaker 1: did a forward thinking episode and really the answer is always, um,
Speaker 1: if it's interesting and there's more avenues within a topic
Speaker 1: to talk about, then then we'll go ahead and cover it.
Speaker 1: So let's start with the very basics. And but to
Speaker 1: start with the very basics, we've got to look at
Speaker 1: cellular biology. So anyone who was currently in middle school
Speaker 1: is going to be able to go on about this
Speaker 1: at length. I actually had to go back and look
Speaker 1: up all this information because middle school was a long
Speaker 1: time ago for me. And while I was originally interested
Speaker 1: in going into biology, yeah I was, Biology was number one,
Speaker 1: and then it's always terrible most mostly that was not
Speaker 1: my branch of science anyway, Biology and physics I love them.
Speaker 1: And then I got into college and I switched to
Speaker 1: English literature with a focus on Shakespeare, and now I
Speaker 1: talk about technology. So I mean it's a clear pathway. Yeah,
Speaker 1: logical progression so sells, you know, sells the basic little
Speaker 1: unit of life for for us, we human beings, and
Speaker 1: most of the stuff we tend to interact with that
Speaker 1: isn't super teeny tiny um cells have what is called
Speaker 1: a nucleus. It's kind of the brain center of a cell,
Speaker 1: the control center if you prefer, and they have a
Speaker 1: cell membrane, and both of these things are incredibly important
Speaker 1: with gene therapy. So within the nucleus you've got chromosomes,
Speaker 1: and chromosomes are made up of two things, DNA and protein.
Speaker 1: And the DNA is the that's sort of the very
Speaker 1: basics of what makes you you. And along those chromosomes
Speaker 1: are little sections of DNA that we call genes now.
Speaker 1: The genes their job is to code for the production
Speaker 1: of particular proteins, and that's what we call a gene
Speaker 1: expressing itself. When a gene is expressed, it's coding for
Speaker 1: a protein. And that's also important because with gene therapy,
Speaker 1: one of the goals is to introduce new genes into
Speaker 1: a cell so that a particular thing is express a
Speaker 1: particular protein is created, and it doesn't always work right.
Speaker 1: So and the reason for that is because gene therapy
Speaker 1: this is still a very young science and uh and
Speaker 1: sometimes the techniques we use have high success rates, sometimes
Speaker 1: they have low success rates, and so it may be
Speaker 1: that you're doing everything right but or as right as
Speaker 1: we know how to do right now, but it's still
Speaker 1: not you know, success rate right since it's so experimental.
Speaker 1: Right now, we're currently on using gene therapy to um
Speaker 1: to treat otherwise incurable diseases and particularly childhood diseases right
Speaker 1: and only in clinical trials for that matter, right. You
Speaker 1: you have to be part of a clinical trial, and
Speaker 1: the only gene therapy that is going on is being
Speaker 1: conducted on somatic cells. Those are those are body cells
Speaker 1: as opposed to reproductive cells, right, which means that any
Speaker 1: changes that are going on, and and the kinds of
Speaker 1: changes that we're making are either inserting normal genes for
Speaker 1: herring abnormal ones or altering the kind of on off
Speaker 1: switches of those genes. Um they're only going to affect
Speaker 1: the patient, and any hypothetical offspring of that patient would
Speaker 1: not would not would not inherit those those genetic changes,
Speaker 1: because again they're somatic, not the reproductive cells. So in
Speaker 1: another issue would gene therapy. Similar to that is that
Speaker 1: often the benefits that you experience with gene therapy are
Speaker 1: temporary in nature, and that you have to undergo multiple
Speaker 1: gene therapy sessions to have any lasting effect because they
Speaker 1: don't necessarily uh change the genome. It doesn't necessarily change
Speaker 1: everything like the actual uh way the cells are forming
Speaker 1: from that point forward in your body. Right, It might
Speaker 1: just affect the current expression of that current cell, that
Speaker 1: current gene within that current cell, and if that cell dies,
Speaker 1: then you know that's the the benefit you got from
Speaker 1: that one cell is over. Yeah. I'll also, genes are
Speaker 1: really complicated. They most of them make more than one protein.
Speaker 1: That average is three, which is something that we've learned
Speaker 1: from the Human Genome Project, which I'll be talking about
Speaker 1: a little bit later on. It just means that, you know,
Speaker 1: genes don't have they're not self contained bits of DNA,
Speaker 1: and they don't have strictly defined roles. Yeah, so you
Speaker 1: can't just say just get rid of that one, right, yeah,
Speaker 1: because it could be that a disease is actually the problem.
Speaker 1: You know, it might be the product of a few
Speaker 1: different genes, and then you have to figure out, well,
Speaker 1: which one of these genes is not behaving the right way,
Speaker 1: you know, which one is the mutated gene, which one
Speaker 1: do we need to replace? And then by replacing that
Speaker 1: gene are we causing any other issues? Is there some
Speaker 1: other problem that could happen as a result of going
Speaker 1: in and altering a person's genes. And this is, like
Speaker 1: I said, a very young science. So we're still learning,
Speaker 1: and that's one of the reasons why clinical trials are
Speaker 1: the only place, at least in the United States where
Speaker 1: you can get gene therapy and you know, because honestly
Speaker 1: it's not ready for a full rollout yet, certainly not now.
Speaker 1: So here we've got a cell, we've got that cell membrane.
Speaker 1: By the way, DNA does not pass through cell membranes.
Speaker 1: Cell membranes are semipermeable, right, which means that they allow
Speaker 1: some stuff through and they allow they keep other stuff
Speaker 1: either inside or outside. Now, DNA generally speaking, is something
Speaker 1: that cells want to keep inside. They don't like letting
Speaker 1: the DNA go flying out all over the place. It's
Speaker 1: a better idea, yes, So that means that if we
Speaker 1: want to introduce DNA into a cell, we have to
Speaker 1: kind of find a way of getting the DNA through
Speaker 1: the membrane without damaging the cell because clearly or the DNA,
Speaker 1: So if you kill the cell in the process, that
Speaker 1: that's not what we call youthful. We call that. We
Speaker 1: call that a fail that's that's generally speaking, that's a failure.
Speaker 1: You don't you don't want the cell to die. So
Speaker 1: finding a way to get DNA material into a cell,
Speaker 1: So getting a good gene through that cell wall without
Speaker 1: killing the cell has been really the main focus of
Speaker 1: genetic therapy over the last couple of decades. So there
Speaker 1: are a lot of different ways of doing it, and
Speaker 1: we could either go about this chronologically or we could
Speaker 1: try thematically or maybe alphabetically. But we kind of decided
Speaker 1: like the first one we wanted to look at is
Speaker 1: in a way, sort of the simplest, at least in concept,
Speaker 1: if not in practice. And I guess the we're we're
Speaker 1: going to cover two basic categories UM in this podcast
Speaker 1: today and a couple of sort of outliers and and right,
Speaker 1: there's a bunch more. We'll talk about that a little
Speaker 1: bit at the tail end of the episode, and I
Speaker 1: guess that we're sort of going chronologically a little bit. Yeah,
Speaker 1: it's a it's a little bit of a jump around.
Speaker 1: But but the first one we wanted to talk about
Speaker 1: is micro injection, which is more or less what it
Speaker 1: sounds like. Yeah, you're talking about a very very tiny
Speaker 1: needle going into a cell and injecting DNA material directly
Speaker 1: into either the cytoplasm, which is the the stuff inside
Speaker 1: a cell membrane just in general. That's that's the uh,
Speaker 1: both the fluid and all the little organelles and everything
Speaker 1: that are in a cell, or you're injecting it directly
Speaker 1: into the nucleus, which is where the d n A
Speaker 1: material is kept. So in other words, you are using
Speaker 1: a needle and you're just inserting the DNA directly there. Now,
Speaker 1: when you're talking about cell cells are I don't know
Speaker 1: if you know this, they're tiny. They're they're really little. Yeah,
Speaker 1: you might think that, uh, the needle that you're getting
Speaker 1: for techna shot is huge. Well it is pretty big,
Speaker 1: but to a cell, that's gargantuan and I'm nearly positive
Speaker 1: that many cells could fit inside. Yeah, so you need
Speaker 1: to find a very very fine needle and you have
Speaker 1: to be able to make. Really, you're not You're not
Speaker 1: gonna You're not gonna just stumble over one of those. Okay, well,
Speaker 1: I mean, you know, if you happen to stumble in
Speaker 1: a lab, you might, but I accept that you make
Speaker 1: an incredibly fine needle, and you actually you kind of
Speaker 1: need to. One of them is just less fine than
Speaker 1: the other one. The element is more of a pipette,
Speaker 1: and the reason for that is you have to immobilize
Speaker 1: the cell that you want to inject. You need to
Speaker 1: kind of hold it down because otherwise cells are sort
Speaker 1: of squid squiggly and yeah, they are. They do tend
Speaker 1: to squiggle. Okay, So so this this technique was really pioneered.
Speaker 1: The needle micro injection in general was pioneered by one
Speaker 1: doctor Marshall Barber in the early nineteen hundreds. UM. He
Speaker 1: was developing it to study bacteria and confirm the germ
Speaker 1: theory that was being developed around that time by a
Speaker 1: Cotchin pastor UM who would who would basically, um outline
Speaker 1: the entire germs make a sick kind of contract, which
Speaker 1: was revolutionary at the time. Right, it's still I'm still
Speaker 1: pretty glad that we have it, and I think I
Speaker 1: think it's great. So early on, like through the nineteen sixties,
Speaker 1: early on, I mean, this was a very slowly developing
Speaker 1: field of study. Uh. Microinjection was used to implant whole
Speaker 1: organisms and embryos into larger bodies. Then in the nineteen
Speaker 1: seventies we started implanting cellular organelles and molecules UM and
Speaker 1: other relatively large bits of stuff into cells. And then
Speaker 1: as we got into genetic study in the mid eighties,
Speaker 1: we began injecting stuff like proteins and DNA and RNA
Speaker 1: into cell nuclei. Right, So it obviously took quite a while.
Speaker 1: And the general process, again at least conceptually, is simple.
Speaker 1: You hold the cell still and then you inject the
Speaker 1: stuff into it. Yep um, it's it's all. It's all
Speaker 1: the same process, just just as a miniaturization of these
Speaker 1: technologies began to get gooder. Yeah, right, because because otherwise
Speaker 1: holding a cell still that's actually pretty tricky. They use
Speaker 1: these pipettes that use a little bit of suction that
Speaker 1: immobilize the cell, and then you have to have a
Speaker 1: micro manipulator that's something that allows you to make very
Speaker 1: very precise movements because you obviously you could not use
Speaker 1: a handheld hypodermic needle. You wouldn't have the precision to
Speaker 1: be able to to target specifically the nucleus with any
Speaker 1: level of confidence. I was, I was pretty good at
Speaker 1: duck Hunt, and I've got to say that I would
Speaker 1: not that I don't have that kind of precision. The
Speaker 1: hand eye coordination is pretty pretty uh remarkable. So yeah,
Speaker 1: they usually you have some sort of device that is
Speaker 1: designed to to study the needle and direct it properly.
Speaker 1: So has limitations. There are some big ones actually. Also
Speaker 1: in order to really use this technology, we we would
Speaker 1: have to start getting into them what we learned through
Speaker 1: the Human Genome Project, which um, which didn't really get
Speaker 1: started until the nineteen nineties. I mean, it came about
Speaker 1: after the Atomic Bomb Project in World War Two, actually
Speaker 1: because Congress charged the Department of Energies predecessor agencies with
Speaker 1: UM studying and analyzing genome structure, the replication, damage and repair,
Speaker 1: air and and consequences of genetic mutations. UM. So you know,
Speaker 1: especially those that were caused by radiation and the chemical
Speaker 1: byproducts of warfare energy production. Right. So, UM, the Genome
Speaker 1: Project completed its initial research a couple years ahead of
Speaker 1: schedule in two thousand three. And UM, that's basically where
Speaker 1: where we got most of our information. You know. That
Speaker 1: that that that is the spawn, that the dawn of
Speaker 1: gene knowledge, right, you know. Without that, obviously, we couldn't
Speaker 1: make any um, any knowledgeable decision about how to go
Speaker 1: about this at all. Right, we wouldn't know what was wrong,
Speaker 1: much less how to correct it, all right. And so
Speaker 1: that's that's why really everything that we're that we're talking
Speaker 1: about has happened in the past like two decades. Yeah,
Speaker 1: it's pretty exciting stuff. So this one does have micro injection,
Speaker 1: does have some drawbacks. A big one is that you
Speaker 1: can't really conduct this UH in vivo, meaning within the
Speaker 1: body of a patient, because you can't you can't immobilize
Speaker 1: the cells. You can't really use the micro manipulator to
Speaker 1: inject something directly. All this kind of stuff tends to
Speaker 1: be done in a laboratory, in a special lab dish
Speaker 1: in the glass, right, Yep. You usually have a solution
Speaker 1: and you end up using a little pipette to immobilize
Speaker 1: the particular cell you want to UH to to manipulate.
Speaker 1: And now a lot of times they would use bacteria
Speaker 1: for this sort of thing, the idea being that the
Speaker 1: bacteria would then transmit the DNA to other cells. But
Speaker 1: we'll talk more about that and probably a future podcast.
Speaker 1: It's it's really kind of immaterial to this UH. There
Speaker 1: was another downside. It's that you have to do it
Speaker 1: to one cell at a time, which is not terribly efficient. Nope.
Speaker 1: And another UH drawback to this approach is that you
Speaker 1: have to be really careful exactly where you inject that DNA.
Speaker 1: They found out that if they injected the DNA into
Speaker 1: the cytoplasm, it was far less effective than if they
Speaker 1: injected it directly into the nucleus are possibly because the
Speaker 1: electro light salute in the cytoplasm was degrading the DNA
Speaker 1: before it could do anything useful. Right, So, you know,
Speaker 1: just like we said earlier that just because you put
Speaker 1: a new gene into a cell doesn't necessarily mean you're
Speaker 1: going to see that gene express itself or be effective.
Speaker 1: But they found that there was much more effective if
Speaker 1: they did inject it directly into the nucleus. Uh So,
Speaker 1: I mean it's it's certainly useful within the lab, but
Speaker 1: within real world quote unquote settings where you're trying to
Speaker 1: work on a patient directly, it's not. Now, if you
Speaker 1: can develop an approach a cure like within the lab
Speaker 1: within there and then implant those cells into the patient,
Speaker 1: that might be a way to go. But in general,
Speaker 1: this tends to be something we think about in terms
Speaker 1: of learning more about what's working and what's not working,
Speaker 1: as opposed to an approach um actual therapeutic treatment exactly.
Speaker 1: So that kind of leads me to another one hydro
Speaker 1: dynamic pressure, which again sounds you know, it's pretty much
Speaker 1: what sounds like, I didn't read that much about this one.
Speaker 1: Tell me, tell me what it is, all right. So
Speaker 1: they found out that if you take a relatively large
Speaker 1: amount of DNA material, and so for a human we're
Speaker 1: talking about actually just a few millilets, but that's relatively
Speaker 1: huge amounts of DNA, and then you take a needle
Speaker 1: and you insert the needle into a blood vessel inside
Speaker 1: that person, and then you inject that relatively large amount
Speaker 1: of DNA very quickly into that blood vessel. Then this
Speaker 1: the hydrodynamic pressure will cause cells along the blood vessels walls,
Speaker 1: the indothelium, that's the layer that the lining. Uh, it'll
Speaker 1: cause them to become more permeable, as well as the
Speaker 1: perenchyma cells or paranchema cells. Now these are like tissue cells.
Speaker 1: So this is like the cells of stuff that actually
Speaker 1: does work depending upon whatever you know, Oregan, you are targeting.
Speaker 1: So let's say it's the liver, all right. Well, they
Speaker 1: found that also increases their permeability. So if you have
Speaker 1: that DNA material and you inject it very quickly into
Speaker 1: the blood vessel, then you can end up having a
Speaker 1: lot more of that. Yeah, it ends up a lot
Speaker 1: more cells are going to accept that DNA and potentially
Speaker 1: you will start getting that gene expression, you're looking for. UM.
Speaker 1: Couple of other downsides to this. Now they've they've been
Speaker 1: using this with lab animals, not with people. All right,
Speaker 1: so this is not something that's been tested on people,
Speaker 1: but they've tested on mice and rats and it never
Speaker 1: got to the human stage because well, because they found
Speaker 1: out that sometimes this causes some cardial problems in the
Speaker 1: car cardial and respiratory. Yeah. Yeah, So when they would
Speaker 1: inject the vein along the tail of these critters, the
Speaker 1: mice and the rats. They did it with a mouse,
Speaker 1: the mouse would start to seem to have trouble breathing
Speaker 1: for a couple of minutes and then recover and everything
Speaker 1: seems to be okay. Rats could sometimes stop breathe entirely.
Speaker 1: And they found that by massaging the abdomen's they could, uh,
Speaker 1: they could they could end up getting the rats to
Speaker 1: you know, kind of start breathing again. But they discovered
Speaker 1: that using this approach put a lot of pressure on
Speaker 1: the animals uh cardiovascular system, and that it would cause
Speaker 1: everything from labored breathing to uh, irregular heartbeat. Uh. They
Speaker 1: also discovered that the animals livers were expanding, sometimes up
Speaker 1: to two of their original size. I guess that weirdly
Speaker 1: makes sense. I mean, in terms of of liquid essentially,
Speaker 1: you're essentially overloading the system, right, you know. And uh,
Speaker 1: and so none of these um issues were permanent unless,
Speaker 1: of course, the animal did not survive that initial reaction.
Speaker 1: But the animals survived, then their various systems would return
Speaker 1: to normal, Like they're breathing and heartbeat would return to
Speaker 1: noble normal within a couple of minutes. Uh. Their liver
Speaker 1: would go back to being normal sized within about half
Speaker 1: an hour, and some of their other systems would take
Speaker 1: up to two days or a day and a half
Speaker 1: or so to get back to normal, but they started to.
Speaker 1: They also would very frequently start expressing whatever the gene was,
Speaker 1: so in front that side, it was a success. So
Speaker 1: all of these so far have been interesting, UM, but
Speaker 1: perhaps not the best way to actually treat human patients. UM.
Speaker 1: We've got a couple more to talk about. But first, Yeah,
Speaker 1: let's take a quick break to thank our sponsor. All right,
Speaker 1: we're back. So we've talked a little bit about a
Speaker 1: couple of different approaches that may we may never see
Speaker 1: used as far as human applications go. I mean, there
Speaker 1: are there's work in hydro dynamic to try and make
Speaker 1: it a something that we could use with human patients.
Speaker 1: But anything that would put that much stress on your
Speaker 1: cardiovascular system for someone who's already trying to undergo medical
Speaker 1: treatment is definitely not going to be the first choice,
Speaker 1: right right, No, So let's talk about um, well, let's
Speaker 1: talk about zapping cells. I was just thinking, you know,
Speaker 1: if we can't if we can't really stab a needle
Speaker 1: into a cell, if it's inside a person, and if
Speaker 1: we can't really expect to jab a bunch of liquid
Speaker 1: into a blood vessel and possibly cause a heart attack,
Speaker 1: maybe we could just shock the heck out of them. Yeah,
Speaker 1: that's clearly the next logical step. Um no, no, but
Speaker 1: actually it does make a lot of sense. Yeah, because
Speaker 1: I mean, we've got those membranes. They're not going to
Speaker 1: let that DNA just go right on in. So how
Speaker 1: do we convince it that we need to get this
Speaker 1: DNA from outside the membrane inside the membrane? Right? Okay?
Speaker 1: And one of one of the really cool and important
Speaker 1: facts about cells that that you that you need to
Speaker 1: realize here is it. Cell membranes are basically insulators that
Speaker 1: are separating two charged regions, the the electrolyte or ionized
Speaker 1: solution inside the cell and the electrolyte solution outside the cell.
Speaker 1: So so they can they can act as capacitors. They
Speaker 1: have they have capacitance. They do have capacitance, and if
Speaker 1: you overload that capacitance, things go wonky. Stuff happens, right, So,
Speaker 1: if you do it at the right amount of of charge,
Speaker 1: then it ends up creating these pores, these these temporary
Speaker 1: pores p o r e s. So you get these
Speaker 1: little holes that form in the membrane, and it's temporary.
Speaker 1: They will actually heal back up actually actually just a
Speaker 1: few minutes. Yeah, within a few minutes after zapping them,
Speaker 1: assuming that you're zapping them with the right amount of electricity,
Speaker 1: because that's really important. So if you if you do
Speaker 1: it at a low enough UH or well really it's
Speaker 1: short high voltage zapps um very low amperage, and so
Speaker 1: you're just doing these tiny little controlled zapps to the
Speaker 1: the cell membrane, these holes will open up and then
Speaker 1: within a few minutes after you've applied it, they'll close
Speaker 1: back up again. So while they're open, then you can
Speaker 1: coerce d NA to go in because DNA's are charged
Speaker 1: particle and right so so especially since you've just changed
Speaker 1: the capacitance of that membrane, it makes it easier for
Speaker 1: stuff to slip through when it's also charged. So you
Speaker 1: just you kind of you kind of corral it in
Speaker 1: so you're you're you're driving the DNA and it's not
Speaker 1: like it's just gonna you know, oh yeah, zip. You
Speaker 1: actually have to guide it yourself, yourself being if you're
Speaker 1: a scientist or doctor who's doing this sort of thing,
Speaker 1: obviously probably not like no, no, no, no, probably would
Speaker 1: not do this. I think Noel does want to stab
Speaker 1: me with stuff, but probably not in a medicinal way. Anyway.
Speaker 1: This is called electroporation. Obviously you're you've got the electro
Speaker 1: and the pooration. You've got the making the poor. So
Speaker 1: it all makes sense when you know what's going on.
Speaker 1: This was originally investigated in the nineteen sixties, so doctors
Speaker 1: began to experiment on cells within the lab that you know,
Speaker 1: they're not looking at in vivo yet working in the lab,
Speaker 1: and they were overloading the capacitance of the cellular membranes.
Speaker 1: They were just introducing small amounts of electricity. Actually, originally,
Speaker 1: what they were doing was They were using equipment called
Speaker 1: electrophoresis apparatus. An electrophoresis is the manipulation of charged particles
Speaker 1: through a solution. So if I have a solution that's
Speaker 1: neutrally charged, and I put some charged particles in it,
Speaker 1: like some negatively charged particles, let's say, and then I
Speaker 1: generate a negative charge and move it close to those particles,
Speaker 1: it's going to push them away, right, because like charges
Speaker 1: repel one another. So you can actually move stuff through
Speaker 1: a solution this way. And often in chemistry this is
Speaker 1: used to separate materials out from a solution. And in
Speaker 1: this case, it would be too convince d NA that
Speaker 1: needs to go through that gigantic gaping hole in the
Speaker 1: cell membrane right in front of it. And uh so
Speaker 1: what they did was they took this equipment that was
Speaker 1: meant to just guide charged particles, they short circuited it
Speaker 1: on purpose and tried to use it to zappa cell wall.
Speaker 1: So obviously, with this approach, it wasn't what you would
Speaker 1: call precise. So but they they saw what the effect was,
Speaker 1: but it wasn't fully controlled. Once once they got it
Speaker 1: more under control, though, oh yeah, yeah, because they did
Speaker 1: discover that it could affect the cell membrane. But they
Speaker 1: also discovered that you could fry a cell. But if
Speaker 1: you were able to get just the right amount of
Speaker 1: electricity at the right frequency of pulses, you could cause
Speaker 1: the cell membrane to create these pores and not harm
Speaker 1: anything inside the cell itself, which of course is obviously important.
Speaker 1: You don't want to kill the cell that you're trying
Speaker 1: to introduce the new gene into. Right Again, that is
Speaker 1: what we call a fail. Yeah, not not something you
Speaker 1: want to have happen. So uh for a long time
Speaker 1: they would work on this uh in vitro. So again
Speaker 1: in the glass, they would have a glass of cells.
Speaker 1: They would use a circuit that would encircle the solution
Speaker 1: that the cells were inside. And this solution in this
Speaker 1: case would be a conductive solution, meaning that it could
Speaker 1: also conduct electricity. You turn on the electricity for the
Speaker 1: right amount of time causes these pores to form, and
Speaker 1: then you would corral the DNA into the pores, and
Speaker 1: then you would check to see if the genes that
Speaker 1: you wanted to have expressed in those cells were in
Speaker 1: fact expressing themselves, either either making proteins or or etcetera.
Speaker 1: If they weren't, you made them listen to Madonna over
Speaker 1: and over until they got the message. I had to
Speaker 1: make that joke somewhere, Lauren, it might as well be here.
Speaker 1: You've got to make it fair enough, all right, So
Speaker 1: we allow you the Madonna pun. Thank you. So this
Speaker 1: was really promising, I mean, and in fact, it's promising
Speaker 1: beyond gene therapy. That's just one application of this particular technique. Right,
Speaker 1: These next couple of things that we're talking about UM
Speaker 1: are also really effective for UM for introducing drugs into Yeah,
Speaker 1: so let's say that you have a tumor and you
Speaker 1: need to have some sort of chemotherapy delivered to it. Now,
Speaker 1: tru sational chemotherapy is essentially affecting your entire body. You
Speaker 1: you are poisoning yourself. You're doing in a very controlled way.
Speaker 1: But yeah, and it's and and it and it can
Speaker 1: be absolutely debilitating. Yeah, I've got friends who have gone
Speaker 1: through it, and and it is it's hard to see.
Speaker 1: So if you're able to to introduce that medicine directly
Speaker 1: to the cells that you want to target, you can
Speaker 1: target a very localized area. UM. And and since the nineties,
Speaker 1: I think they have been researching how to do this
Speaker 1: in in the body and yes, yeah, in vivo and uh.
Speaker 1: And so that could mean that you have a very
Speaker 1: much more effective treatment that has fewer side effects. It
Speaker 1: doesn't eliminate the side effects, but it might make them
Speaker 1: less traumatic for the patient. So the en vivo approach
Speaker 1: is you might wonder, well, how could they use this
Speaker 1: electrical uh technique within the body. And it's not entirely pleasant, folks.
Speaker 1: They usually use either tiny electric plates or electrified hypodermic needles.
Speaker 1: Oh man, you're saying all the words that I want
Speaker 1: happening to my body better than cancer. Yes, So these
Speaker 1: they would they would go to the location of wherever
Speaker 1: it was they needed to introduce the genes. So let's
Speaker 1: say it's your liver again, because that's it's a large oregon.
Speaker 1: It's one that it's the one they think that they'll
Speaker 1: have the most success on early because it's a large
Speaker 1: oregon that's relatively easy to manipulate compared to some of
Speaker 1: the others. So yeah, they would. They they would have
Speaker 1: to either surgically insert these plates or they would have
Speaker 1: to use these needles to introduce the electric current. Yeah,
Speaker 1: and to to create the field exactly the way they
Speaker 1: want to to introduce the DNA material into your system. Um,
Speaker 1: it's pretty invasive, and that's one of the reasons why
Speaker 1: there are some researchers who are trying to find some
Speaker 1: other method to introduce gene therapy that's that wouldn't be
Speaker 1: as invasive as this approach. All right, I think I
Speaker 1: think didn't have a pretty bad reputation when it was
Speaker 1: when it was still in the in vitros. Yeah, you know,
Speaker 1: it wasn't. It wasn't great. Um, they were working with bacteria,
Speaker 1: and they were killing bacteria cells pretty frequently, and they
Speaker 1: really just needed one cell out of the batch to live.
Speaker 1: So right, if you're like, if you're like, there's a
Speaker 1: I gotta I got a couple of thousand cells in
Speaker 1: this in this dish and only one of them has
Speaker 1: to live, you don't necessarily go easy with the big
Speaker 1: old switch, that says fry Um. And so it did
Speaker 1: get a reputation for being a violent method of gene
Speaker 1: therapy delivery. But then that's because they were working with
Speaker 1: bacterial cells, not necessarily working with like and it wasn't
Speaker 1: it wasn't in a patient. Yeah, if they could had
Speaker 1: to be a little bit violent, right, but give it
Speaker 1: a bad reputation. Yeah. So then you've got patients who
Speaker 1: are like, I really don't want something where you're, you know,
Speaker 1: essentially putting a cell sized electric chair into my body.
Speaker 1: Please can we do something else? So yeah, there there's
Speaker 1: another approach that essentially creates the same effect, but it
Speaker 1: does it in a totally different mechanism. Right, sound operation, yes,
Speaker 1: son operation so saw No, you start to think that
Speaker 1: sounds like it might have something to do with sound,
Speaker 1: and it does. It actually uses ultrasound. So you use
Speaker 1: ultrasound at a particular frequency directed that the cells, and
Speaker 1: the cells will end up forming these pores just as
Speaker 1: they would with electroporation. Right, This was really pioneered in
Speaker 1: in this first decade of the century. And uh, basically,
Speaker 1: you put stuff that you want to get into a
Speaker 1: cell into what's called a microbubble or a bunch of
Speaker 1: microbubbles really, so exposing cell to to this ultrasound will
Speaker 1: create the pores, changing the membranes conductivity and making it
Speaker 1: easier for stuff to slip in. Right, and um, the
Speaker 1: same ultrasound will also burst the microbubbles, which will release
Speaker 1: the st up that you want to get into the
Speaker 1: cell in a place that makes it easy to kind
Speaker 1: of push in there. So interesting, So you have not
Speaker 1: only not only is it opening up the doors, but
Speaker 1: it unleashes the stuff that you want to deliver to
Speaker 1: the cell itself, and you don't have to worry about
Speaker 1: it being absorbed by the body some other way before
Speaker 1: it can get to where it needs to go, right right. Um.
Speaker 1: It can also burst the entire cell if you're not careful,
Speaker 1: so that's the thing that you have to watch out for. Bummer. Yeah,
Speaker 1: although from what I understand a lot of scientists refer
Speaker 1: to this as being much less invasive than the electroporation
Speaker 1: in vivo approach. Oh sure, sure, well, and any time
Speaker 1: that you're talking about ultrasound, it's something that can be
Speaker 1: applied um externally, Yeah, which is pretty cool. I mean
Speaker 1: I've actually seen ultrasound also being suggested as a means
Speaker 1: of directing nanoparticles to go straight to particular cells. So
Speaker 1: it's like having a nano sized r C car moving
Speaker 1: around the body. Doesn't work unless you're Martin Short and
Speaker 1: you've got uh Quaid inside of you. Dennis Quaid is
Speaker 1: inside of you, you know what I'm talking about. I
Speaker 1: I know, I know inner Space, Yes, I'm familiar with it.
Speaker 1: I'm I'm just thinking about the that that old Epcot
Speaker 1: Red Body Wars. Yeah, that was in the old Wonders
Speaker 1: of Life pavilion. That is sadly no more. I'm not sure.
Speaker 1: I'm not sure if I'm sad about that. That was
Speaker 1: not my favorite pavilion when I was a kids. Was great.
Speaker 1: Cranium Command even better. Guys, all right, Disney fans out
Speaker 1: there who know what I'm talking about with Cranium Command,
Speaker 1: right in and tell me whether or not you loved
Speaker 1: Cranium Command, because honestly, that is one of those attractions
Speaker 1: I wish Disney would bring back. Also, if anyone here
Speaker 1: happens to say work in the advertising department of Disney,
Speaker 1: um call us because we we will clearly do Disney
Speaker 1: as Yeah. So getting back into the actual gene therapy.
Speaker 1: So there are other methods we could discuss. There are
Speaker 1: a lot of things called viral vectors. And you might wonder,
Speaker 1: why why would you ever use anything that has the
Speaker 1: word viral in it. Well, well, there's there's a bunch
Speaker 1: of different of different vectors that you can use. Um
Speaker 1: and and and viruses are one of them. And this
Speaker 1: is so fascinating to me because you're using really virulent
Speaker 1: viruses and the kind of like like HIV or herpies
Speaker 1: from in order to you kind of scrape out all
Speaker 1: of the harmful DNA contained inside of a virus and
Speaker 1: put in whatever you want to get into a cell, right,
Speaker 1: and that sometimes can be RNA, can be DNA, or
Speaker 1: it can even be a chemotherapy drug like we said before.
Speaker 1: And the proteins on the outside of the virus, on
Speaker 1: on the virus shell itself act as kind of like
Speaker 1: a homing system, right. It will only end up interacting
Speaker 1: with particular types of cells, because that's what viruses are.
Speaker 1: They are they have this this uh, this the structure
Speaker 1: that has them interact with very specific types of cells.
Speaker 1: And they're very good at doing that. They're they're really
Speaker 1: good at at invading a system, finding the kind of
Speaker 1: cells that they that they want, and um and and
Speaker 1: and stuff in there replicating like crazy. Yeah, So in
Speaker 1: this case, instead of replicating, you would put in the
Speaker 1: material that a virus need to deliver, either genes or
Speaker 1: whatever you wanted. We'll talk more about that in the
Speaker 1: future episode, because that's an entirely huge topic that we
Speaker 1: could cover. Yeah. That and there's also um what's called
Speaker 1: these biodegradable nanoparticles, which is a similar a similar vector
Speaker 1: system in which you're directing um charged particles that are
Speaker 1: going to go to a specific place and do a
Speaker 1: specific thing. But um but instead of being kind of
Speaker 1: piggybacking on a virus, you're you're doing it with with
Speaker 1: nanoparticles that can be can be controlled through the properties
Speaker 1: of those particles gotch. So it's so it's a synthetic
Speaker 1: approach that kind of mimics what the virus does, but
Speaker 1: allows us to have an external control system where we
Speaker 1: say this particle we want to go here, and then
Speaker 1: it can do what it needs to do. There are
Speaker 1: other approaches that we could talk about and probably will
Speaker 1: talk about in future episodes. For example, impale affection. Uh
Speaker 1: does this have anything to do with staking vampires? It
Speaker 1: does not. Uh, Buffy had nothing to do with this, No,
Speaker 1: But it's pretty much what it sounds like. You know,
Speaker 1: you're impaling stuff, and you've got the right material on
Speaker 1: whatever it is you're impaling. So let's say that let's
Speaker 1: say that you're you've got to sell that's the size
Speaker 1: of I don't know, Spike and you've got you've got
Speaker 1: a delivery system that's the size of Buffy and the
Speaker 1: steak is covered in in uh in in strawberry jam,
Speaker 1: and she steaks Spike and now he's got strawberry jam
Speaker 1: in his system. That's essentially what this is. But we'll
Speaker 1: go into more detail in the future episode, I promise. Um.
Speaker 1: And there's also a laser beam gene transduction. We could
Speaker 1: go into that, but that's another one of those that's
Speaker 1: sort of on the developing side, and I thought that
Speaker 1: that would really lend itself well to a second episode
Speaker 1: if we decided to do that further down the line. Um,
Speaker 1: we really going to concentrate on the these are these
Speaker 1: physical exactly the ones where people are using technical tools
Speaker 1: right now to experiment and see which delivery systems are
Speaker 1: the most effective. Because again, just like just like I
Speaker 1: said with the very first one and every single one
Speaker 1: of these approaches, even being successful in introducing the DNA
Speaker 1: to the cell, does not guarantee that you're going to
Speaker 1: get the result you want. So it's one of those
Speaker 1: things that we're still learning those basics. Yeah, and you know,
Speaker 1: it's it's really it's really scary. Um, and a lot
Speaker 1: of the things that I've that we've talked about, I
Speaker 1: feel like we have ended on notes of of like
Speaker 1: and that's terrifying because, um, but it's also incredibly promising,
Speaker 1: you know, like I said at the beginning of the show,
Speaker 1: especially for children that have incurable, terrible genetic diseases that
Speaker 1: really have no other way of receiving therapy, this is this,
Speaker 1: This is their best shot, and it's wonderful, right, Yes,
Speaker 1: And while we're talking about just like you were saying,
Speaker 1: like these high risk approaches, the risk is going down
Speaker 1: over time because we learn more and we learn how
Speaker 1: to how to apply it more effectively. So I personally
Speaker 1: think this is a very promising area. And you know,
Speaker 1: we didn't even touch on gene therapy to do stuff
Speaker 1: like give you crazy awesome pecks or something, you know,
Speaker 1: like yeah, none of the sci fi. Yeah, there's there's plenty.
Speaker 1: We could do an entire episode about that too. About
Speaker 1: all right, well, let's assume that we have perfected gene
Speaker 1: therapy applications. Now we're able to go beyond just the
Speaker 1: medical approach and we all either um, look like ethan
Speaker 1: hawk or can shoot bees out of our hands. Yeah,
Speaker 1: dogs with bark and bees come out. Um, fantastic. Well,
Speaker 1: I look forward to our wicker Man future. Uh no,
Speaker 1: this this really is an interesting topic. It was certainly
Speaker 1: something that I I found fascinating as I researched more
Speaker 1: and more about it. Because I had heard the terms.
Speaker 1: I knew in general what was going on, but I
Speaker 1: didn't know from a technical goal level or even a
Speaker 1: cellular level, exactly what was happening. And it's pretty exciting stuff.
Speaker 1: So I'm very interested to see how this field develops
Speaker 1: over time. I'm hoping within our lifetime we start to
Speaker 1: see some of these diseases just get eradicated through gene therapy. Alright,
Speaker 1: so guys, if you have any suggestions for future episodes,
Speaker 1: you've got some sort of topic you think we should cover,
Speaker 1: and maybe your name is Mike and you know how
Speaker 1: to use Twitter, you can get in touch with us
Speaker 1: on Twitter, Facebook or even Tumbler. We are tech Stuff
Speaker 1: hs W at all three of those locations. Or you
Speaker 1: want to go old school and email us, Hey, you
Speaker 1: can do that too. Our email address is tech stuff
Speaker 1: at Discovery dot com and Lauren and I will talk
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