Fixing our genes

Gene therapy holds big promises and big challenges
14 December 2017

Interview with 

Jakub Tolar, University of Minnesota


As you’ve probably guessed from the number of times we’ve covered it on previous podcasts, there’s a huge amount of excitement about the potential for CRISPR to treat human diseases. But what are the most promising applications? To find out, Ginny Smith caught up with Jakub Tolar, from the University of Minnesota...

Jakub - There are number of early adopters of this technology and one of the leading technologies is called gene editing. It basically means that you have a typo in the three billion letters of human genome and you just take that single letter that is incorrect and you exchange it for the right one.

Ginny - How do you go about doing that?

Jakub - It is absolutely fascinating because we have used what I would call “augmented reality” for this because we have generated molecules that don’t exist in nature and put together two functions that do exist in nature: One that binds DNA - that binds to a specific site in the DNA - and the other one that cuts DNA. So we put them together and these hybrid molecules, they don’t exist in nature, have been used in service of the gene editing, of the rewriting of the incorrect information that is in the blueprint of the genome.

Ginny - How do you get these brand new molecules into a living human?

Jakub - You are asking exactly the most important bottleneck of the whole technology, because the cell is very smart. It defends itself from any foreign DNA or any foreign particle such the ones that we would be using for gene editing. So to accomplish this, we are trying to be also smart and learn from nature. So we for example, modify the nucleic acids that we use for this or we encapsulate some of the proteins that we want to deliver so that it can cross the cellular membrane as well as the nuclear membrane, and gets to the heart of the nucleus where the DNA lives.

Ginny - You're effectively hiding it so that the cell can't tell that it’s something that it shouldn’t be letting in?

Jakub - Yeah, that’s a good term. We are effectively hiding it from the defence mechanisms that exists in each cell.

Ginny - This sounds really kind of sci-fi futuristic. Is this something that’s actually currently in use?

Jakub - Frist of all, there's nothing sci-fi about this. There are no miracles. I always cringe a little bit when I see “this is a medical miracle”. It almost never is. It’s a sequence. It’s a readout of a year or a decade long work of many, many people. So I think this is a predictable, incremental, very exciting pathway we are taking now.

Ginny - What kind of diseases is this currently being used for?

Jakub - The majority of the disorders that this would be helpful for are monogenic disorder. What that means is that a single gene is faulty in the whole genome of that individual that’s born with that disease. It would not be used at this time for what we call polygenic disorders which is many, many genes are affected by the disorder.

The examples of the diseases that this would be helpful for would be, for example, bone marrow failures. This is a state when kids are born with insufficient number of stem cells that are blood forming in the bone marrow and will eventually use them up and have no more to provide for healthy platelets and white cells and red blood cells. It can equally be used for liver disorders that are hampering the ability of the liver to detoxify or make new proteins that are necessary for healthy living. And as I showed in my comments, it can be used for skin disorders such as epidermolysis bullosa. It’s a very, very hard disorder even for some people to look at, but it’s a very equally important – at least for me – it’s a challenge for medicine and science and medicine to approach. And the hallmark of the disease is loss of skin. These are similar to a chemical or thermal burn and only this time, the burn is genetic.

Ginny - And this disease can be treated using these new molecules that you’ve created?

Jakub - That’s what we are working on. That is where we are headed.

Ginny - So how would the process actually work if you were to go in for gene editing treatment? What would it be like as a patient?

Jakub - So I think that the incremental safety levels needed that needs to be cleared I think are that these cells, skin cells, and perhaps other cells that make these all-important skin molecules (they don’t have to live in skin) called mesenchymal stromal cells will be corrected outside of the body of that individual and then her or his own cells will be given back to them.

Ginny - Okay, so the novel molecules wouldn’t actually be going into the body. That will be done outside.

Jakub - I would prefer that because I think it’s a whole new box of Pandora to go into the whole organism with a genetic medication.

Ginny - What could be the risks of this kind of gene editing technology? Is there a danger that it could edit in the wrong place for example and cause problems?

Jakub - You are very smart, yes! That is the major concern of ours and everybody else working in the field that inadvertently, the same mechanism that can lead to clean correction where we desire it can lead to undesired “correction mistakes” introduced somewhere else in the genome that would have clinical consequences.

Ginny - And what kind of effects could that have in theory?

Jakub - The most feared one is cancer. It has happened in the past with other forms of gene therapy. So people are especially sensitive to this and rightly so. Another one would be dysregulation of the human immune system. I can see that this can lead to autoimmunity problems as well.

Ginny - Do you think that this kind of technique will be developed and will be able to be used for more complex disorders that involve multiple genes or will they always too complicated?

Jakub - No. I am almost certain that this is headed to the direction that as we perfect it on the level of a single gene, this will advance to the polygenic disorders as well. One of the great advantages of this approach is that it’s modular. It can be like Lego. It can be put together from different pieces and you can combine different corrective molecules on the same molecule in the same cell.

Ginny - Now the million-dollar question: How long until these kind of technologies are going to be in widespread use?

Jakub - Million-dollar question but no answer because I think that there's a reason for why the future is unpredictable. We just don’t know. But if I take it from other parts of technology such as transistors - from a transistor in Bell’s labs to the transistor radio from Texas instruments, it’s about 10 years...


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