Gene Therapy with James Dahlman

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While it’s still in it’s formative stages, in the future, gene therapies might take the place of invasive surgeries or drugs. James Dahlman works at the intersection of nanotechnology and genetics, and discusses his work with experimentation, research design, and gene therapy applications.

Dahlman is an Assistant Professor in School of Biomedical Engineering at Georgia Tech and Emory University. Dahlman leads the The Dahlman Lab for Precision Therapies at Georgia Tech.


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Steve McLaughlin: You’re listening to “The Uncommon Engineer.” I’m your host, Steve McLaughlin, dean of the college.
Announcer: We’re just absolutely pleased as punch to have you with us. Please say a few words.

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Steve McLaughlin: Hi everyone, and welcome to “The Uncommon Engineer” podcast. I’m Steve McLaughlin, Dean of the Georgia Tech College of Engineering. Our podcast is all about how Georgia Tech Engineers make a difference in our world and in our daily lives. In this episode, we’ll be talking about gene therapy. It’s an experimental technique that uses a person’s genes to treat or prevent a disease. While it’s still in its formative stages, in the future gene therapies might take the place of invasive surgeries or drugs.

Our guest today is Dr. James Dahlman. He’s a professor in the School of Biomedical Engineering at Georgia Tech and Emory. James’ work is at the intersection of nanotechnology and genetics, specifically gene therapy. Welcome to the program, James.

James Dahlman: Thank you very much for having me. Pleasure to be here.

Steve McLaughlin: So, you know, we’re hearing lots in the news about so called immunotherapies where novel techniques of using your own immune system to attack disease, CAR-T, and maybe even CRISPR. Can you say a little bit about that and why this is such an exciting area?

James Dahlman: Yes. So I can say as somebody who works in gene therapies, it’s a very exciting time to be in this field right now. The potential for gene therapies is tremendous because they treat disease by going after the root source which is the genetics itself. I think that gene therapies can be sub-divided in to three buckets: In one bucket the goal is to produce a lot of the gene; in this case the disease would be caused by not making enough. The second bucket is designed to turn off genes; in this case the disease would be caused by producing too much. And then the third bucket, you’re actually going in and editing the genome itself; this is the newest form of genetic therapy but it still has some promise. 

There are many other examples. Some of the work that we perform in my laboratory is designed, again, to solve a very simple problem. If you want a genetic therapy to work, you need to get it to the right cell type. If you have cystic fibrosis and you want to change gene expression in the lung in order to treat the disease, you want that drug to go to the lung. You don’t want it to go everywhere else. Once again, the simple problem of getting the drug to the right place at its core is an engineering problem.

Steve McLaughlin: One of the things you talked about was turning off or silencing a gene. Before you talk about the specific therapies, can you give us a little bit of primer on what that really means?

James Dahlman: The easiest way to explain this is to go back to sort of biology 101, and that is DNA makes RNA which makes protein. So the DNA is like the blueprints—it’s what makes you, you. And the DNA’s job, or one of its jobs, is to produce protein which really does the work. So DNA will encode for a certain protein. If the DNA gets a mutation in it, it will encode for the wrong protein and that protein can cause disease. In the case of shutting off a gene, what we’re really doing is shutting off the protein production. And we can do this at two different levels: The first level is shutting off the RNA production, and the second level is by changing the DNA itself. The most advanced clinical trial so far work at the RNA level; they aren’t quite there yet with the DNA stuff.

Steve McLaughlin: Can you say a little bit about your own work and the kinds of things that are going on in your lab regarding silencing or turning off genes and what’s the application?

James Dahlman: It’s a really exciting time to be a scientist in gene therapy right now. My lab focuses on one simple problem: How do we get the drug to go to the right place? This problem lies at the interface of chemistry, of what we call nanotechnology, and biology because we are packaging drugs inside nanoparticles, which are just very small particles, in order to get them to go to the right tissue, and to protect them from being degraded and attacked by your body. So my lab focuses on developing nanoparticles that target genetic drugs to the right tissue. A nanoparticle is simply a small particle. I’m about 6 feet tall, and I am 1.8 billion nanometers tall. The systems that we create are about 50 nanometers in diameter. They’re little spheres. We package the genetic drugs, whether it’s DNA, or RNA, inside these little spheres, and the nanoparticles act as, almost, mail carriers that take them to the right cell type—the disease cell type—and help them avoid healthy tissues. This reduces side effects and it improves drug efficacy.

Steve McLaughlin: So I’m kind of imagining these nanoparticles, you know, with the therapies or drugs inside of them, and somehow they get in to your body, and they’re going throughout the body. How do they know where the right place to go is, and then once they find the right place to go, how do they then deliver the therapies to the tissue or the cells?

James Dahlman: It’s another great question and, again, it lies right at the interface of chemistry and biology and engineering. When you take an aspirin, the aspirin doesn’t have flippers or heat seeking technology that goes right to your headache; it kind of goes everywhere. When you take a genetic drug, if you didn’t target it in any way it would do the same thing. So the way I would think about this is you can divide the process in to two steps: The first step is getting to the right tissue. So just imagine that you’re a nanoparticle, you know, you’re minding your own business but suddenly you get injected into this blood stream. The blood stream is chock full of proteins and lipids and all sorts of stuff here. Your blood isn’t just water; it’s like a soup that’s full of all these biomolecules. So you may interact with some of the biomolecules, but you’re passing by the heart, you’re passing by the lung, you’re passing by the pancreas, the liver—all these organs. And every organ is going to look a little different to you. If we designed the nanoparticle the right way—let’s say for cystic fibrosis where you want to target the lung—we designed it in a way that the lung looks better to you than the liver, or the lung looks better to you than the kidney. And so you end up in the lung more so. That’s the first step: getting to the first place. 

Once you get there, there’s a second, very exciting and interesting step, which is getting into the cell itself. So although the biology and the biological processes that govern this are still somewhat unclear, we do know a few things which is that cells gobble things up actively. Just like us, cells need nutrients, and they get nutrients from their environment, from their neighborhood, if you will, and from the bloodstream. So cells gobble stuff up very actively. Ideally, your nanoparticle is designed in such a way with such a chemistry that makes it tasty to cells so they end up gobbling it up. This allows the drug to get into the cell where it can do its job. So again, I would sort of divide it in to two parts: First, getting to the right tissue and then, second, getting into the cell once it’s at the tissue.

Steve McLaughlin: So the delivery of the nanoparticles to the cells, that really sounds like an engineering problem. Can you say more about the drug delivery, because it’s so specifically targeted, what your students are doing with that?

James Dahlman: My students are developing what we call “DNA barcoding technologies.” And the easy way to think about this is we’ve developed technologies that allow us to perform a few thousand experiments all at once. The technology behind it is pretty fun. Think about it this way: We can make a giant library of nanoparticles. nanoparticle 1 might be small. nanoparticle 2 might be large. Nanoparticle 3 might have a positive charge on it. Nanoparticle 4 might have a negative charge on it. We can make thousands of different nanoparticles with different chemical structures. We don’t know which ones are going to work. So how can we test thousands? Well, the way we do it is we use DNA as a molecular tag. So nanoparticle 1 gets DNA barcode 1. All that means is nanoparticle 1 carries—instead of carrying a drug to turn off a gene, it just carries a little tag that’s a DNA sequence that we know. Nanoparticle 2 carries a different DNA tag: just a different sequence, again, that we know. And you can do this you know many times in a day. My students have made up to 250 Nanoparticles each with its own molecular tag within a day.

You can then mix all the particles together and administer them in a single experiment. You then isolate the DNA, and you can use deep sequencing—again, this technique that you spit in a tube and send it to or to 23andMe. We use that same machine that—the DNA sequencing machine—to analyze how all of those DNA sequences behaved at once. So if you do 250 different nanoparticles and 250 sequences, and you run your experiment and you take out the cells, and it turns out that barcode number 17 shows up in those cells more so than the other barcodes, that means that nanoparticle number 17 might do a good job. So this allows us to perform hundreds and thousands of experiments simultaneously. And actually using this process, we’ve been able to identify nanoparticles that do target new tissues and new cell types. So it’s pretty efficient. I think we can accelerate the development of drugs this way.

Steve McLaughlin: So let me get this right. This is incredible. So I think the way that people have done experiments for hundreds of years is they try one thing at a time; they try one therapy at a time and you then test that therapy. You’re saying, now you can do that same thing: Instead of testing one therapy at a time, you can test hundreds or thousands of therapies at a time. And I guess your goal is, in this case, it’s about the delivery of the nanoparticle into the cell, and all then you need to do, is read out and then examine the cell and see which of the nanoparticles got through. Do I have that right?

James Dahlman: Yes, that is exactly right. And I can tell you that it is a very exciting time to be in the lab right now because I thought up this technology a few years ago. It took a while to engineer it so that it was robust, but it is now working. And in a typical experiment now, one of my students will test about 250 nanoparticles, and we’ll analyze the delivery to, let’s say, 30 cell types. So 250 times 30 is what—whatever that is—7500 experiments performed at once.

The data sets that we’re generating now are so big and so much bigger than anything I’ve reported in my career, that we actually had to develop a bioinformatics pipeline to analyze the data sets because there was no pipeline to my field to analyze it. It’s pretty fun because what you can find is that let’s say nanoparticle 17 does well in lung cells, but really doesn’t do well in heart cells. Well, that’s great because you can have specific delivery to the lung, and so we can measure delivery to our target tissues as well as all of our, what we call “side effect tissues” or “off-target tissues,” in a single experiment. So we can do years of work basically in three days. And I think this is a real step-function change in the ability to do these experiments.

We are interested in commercializing this in order to get products to patients more quickly. The ultimate goal is to accelerate the development of genetic therapies, and I think this platform really does stand a chance to do that. We know that we’ve received a lot of interest from the field so far from companies that are already in the clinic, in fact, and they view this technology as very promising, and a way to accelerate how quickly genetic therapies actually make it into clinical trials and actually make it into patients. So we’re really excited about all of these opportunities.

Steve McLaughlin: So the idea of barcoding, you know, nanoparticles to get to tissues for addressing diseases is absolutely fascinating. How close is this to actually being used, say, in humans or how applicable is it to humans? And looking in your crystal ball, when do you see those kinds of things having an effect on patients?

James Dahlman: So I do think our work has implications for human disease. I’ll give you an example that’s pretty exciting right now: We have initiated a collaboration at the National Cancer Institute outside D.C., and this collaboration is with a surgeon. This surgeon does this very cool thing: He operates on patients that have liver cancer. He would do it anyway; it’s part of the normal procedure. And after he does the surgery to remove the tumor, he actually made a machine that keeps the tumors alive for about a week. And, as you can imagine, these things are very rare samples and they needed to be treated with respect. So one of the advantages of our system is we can essentially perform a few hundred experiments using one patient tumor instead of performing one experiment with a patient tumor. And although we haven’t started these experiments with him yet, I am hopeful that we’ll be able to start experiments like this where we’re screening directly in patient samples maybe within the next two years. That would be great. I think the key point here is that when you’re dealing with patient samples, and so I think it actually is an advantage of our system that we can test hundreds of things per sample instead of one thing per sample.

Steve McLaughlin: So you talked about the three different approaches to gene therapy, one of which was gene editing. I’ve heard about this technology called CRISPR—about what CRISPR is and the kind of work that’s going on in your lab?

James Dahlman: CRISPR is, arguably, the most exciting biotechnology discovery certainly of the 21st century, so far. Put succinctly, CRISPR allows us to edit the genome very easily. Even five years ago, if you wanted to take DNA and change the DNA sequence, you could do it using things called zinc fingers and talons, but it was going to take a lot of money, and it was going to take a lot of time. CRISPR does the same thing as zinc fingers and talons—it edits DNA, it changes DNA sequences, but it’s really, really easy to use. And so now, for the very first time, scientists can do something as simple as edit 10 different genes, 100 different genes, and see which gene causes a tumor to grow. You can accelerate these scientific studies. Therapeutically, CRISPR can be used to edit cells so that they target tumors more effectively. And in the future, CRISPR may be used to edit the genome inside human patients as well in order to turn off a gene that’s causing disease.

So from our lab’s perspective, we do a lot of work on CRISPR. CRISPR’s not going to work unless you get it into the right cell, and so from our perspective, we’re just trying to get it into that right cell. I will say, from a scientific perspective, CRISPR is one of the most, if not the most, exciting technological development I have ever been exposed to. It is changing how things are done.

Steve McLaughlin: I’d like to change directions just a little bit and hear you talk about your own path, maybe even from junior high or before, how you made your way to Georgia Tech and how you made your way to wanting to study this area and become a biomedical engineer.

James Dahlman: When I went to MIT and Harvard Medical School for my graduate work, I was in what’s called the HSC program. I started drifting more towards biology and medicine. So at MIT, I did my Ph.D. work in materials science, but you’re also forced to take two years of medical school at Harvard with the medical school students. And so I remember one very interesting day as a first-year graduate student walking out of a pathology exam at the medical school and then walking right in to a quantum mechanics exam after taking the bus—so it really does stretch your brain a little bit. As I got in to the medical school classes, it became clear that biology was just so elegant and it really is a beautiful science. It also became clear that engineering was going to play a huge role in the future of biology, and that’s definitely been the case. I came to this point by just following my natural love for science. I’ve never done science that’s boring to me, and I only do science I find interesting, and this has been a huge advantage.

Steve McLaughlin: Professor Dahlman, I have one last question for you: What makes you an Uncommon Engineer?

James Dahlman: I think the thing that is most uncommon about me as an engineer is the fact that I’m willing to, and excited by, the idea of merging completely different fields together. My lab right now is at the interface of genomics, chemical engineering, and nanotechnology. And as far as I know, we’re the only lab that’s sitting here. I think it’s a lot of fun to really be out there on the cutting edge trying to marry new fields together. I think that’s what really sets us apart.

Steve McLaughlin: Fantastic! Thanks very much, James. We really, really appreciate you being here.

James Dahlman: Thank you very much for having me. It was a real pleasure.

Steve McLaughlin: Be sure to tune in next month when we talk to Professor Brendan Saltaformaggio about cybersecurity.

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