The novel process to treat immune disorders, demystified
Hint: It’s all about big DNA, baby
Jenaye Johnson, Kohava Mendelsohn, Nana Mohammed, Gayoung Lee • October 31, 2024
Nucleotides encode everything about us, from a speckle of freckles to how tall someone grows. But though that DNA is powerful in nature, one slight distortion in a gene could spell trouble for the body. [Credit: Gayoung Lee]
Developing gene therapy treatments requires innovative thinking and peering inside an individual cell’s genome to inquire what went wrong. Most methods involve editing genes within a single strand of DNA bit by bit to fix the harmful mutations that are linked to the patient’s disorder. It’s a tedious, costly, complex process that takes years to finesse — but if perfected, it could change the way we treat immune diseases forever.
The Truong Lab, a bioengineering group led by David Truong that investigates human immunology, has dedicated themselves to solving this exact problem. Their novel approach to gene-editing examines large stretches of DNA all at once instead of individual gene pairs. In Truong’s words, where someone might spell check a story word by word, their technique takes in an entire page and corrects every error at once.
How far has Truong’s group gotten in achieving feasible gene-editing? Are we close to treating patients’ unique health issues without charging an arm and a leg? And what on earth does it really mean to edit a gene? Step into the Truong Lab’s mind, where answers await.
(FADE IN whimsical music) Kohava Mendelsohn: This is DNA. It’s found in every cell. TRUONG: That DNA are these stretches of chemical molecules with what we call nucleotides A, C and G — different patterns. That DNA has the information for how that cell functions, what type of cell it is, who it likes to hang out with and how they coordinate to make tissues in your body. TRUONG: And between humans, DNA is also over 99.99% identical. So we’re all very, very similar to each other. We’re almost clones except in little bits of DNA here and there. Those little changes are what distinguish me from you. (FADE OUT whimsical music) Kohava Mendelsohn: But what happens if something goes wrong with a cell’s DNA? TRUONG: Mutations disrupt the function of that DNA. What happens is you have this string of codes. And let’s say you have a paragraph, like a word, and that’s a code. You literally get it like a misspelling in the word. The code is now read improperly. Kohava Mendelsohn: Some people with certain diseases or immune disorders are born with random mutations in their genes that keep their cells from behaving properly. So far, not much has been done to help these people. But now, David Truong’s lab at New York University is developing new gene therapy techniques to fix this problem at its root. TRUONG: Gene editing allows you to go straight to that exact spot on the DNA and then correct it … Spell check. Change it back to the right letter. TRUONG: The kind of technology we work on is what we call genome writing. So instead of looking at one word, we look at a whole page or even two pages, and then we basically change everything on the page to, say, a new story. (FADE IN curious music) Kohava Mendelsohn: Current gene therapies rely on patients waiting for donors that match both their age and immune system. It could take years. But the Truong lab’s methods — fixing really big sections all at once to create a universal cell — could be a game changer. If done right, their treatment could go straight from freezer to patient. LEVOVITZ: Right now we’re just looking to change this one segment that’s important for making sure that these cells can be used for cell therapy. Kohava Mendelsohn: That segment is HLA, found on chromosome 6. HLA regulates the immune system and is the make or break region that affects cell therapy success. (FADE OUT curious music) Kohava Mendelsohn: So what does large-scale gene editing entail? LEVOVITZ: We start on the computer. We have to basically design what we’re making. So we have a program that allows us to visualize the databases and the constructs that we’re making. LEVOVITZ: Then we’ll order whatever primers we need or DNA fragments. Measure the amount of each of our DNA fragments, then we can assemble that together using yeast assembly. We’ll have to check that the right assembly was made in the yeast. LEVOVITZ: Then we’ll grow the yeast, take the DNA out of the yeast and then put it into bacteria and then grow the bacteria. And that allows us to get a lot more of the DNA. Then we extract that, double check using sequencing if everything was assembled correctly. That sequencing is basically the final step. Kohava Mendelsohn: Afterwards, the lab inserts the newly assembled DNA into stem cells. Since they’ve targeted the HLA complex, the stem cells should replicate without triggering an immune system reaction that could reject the new DNA. Right now the Truong Lab has worked with cell cultures. They plan to expand to mice cells, and then to human trials. TRUONG: We fundamentally have gotten the genetic engineering part done pretty well. But now we’re very focused on how do we make lots of different cell types. TRUONG: So once we have our universal cells, our approach for manufacture in lots quantities of these cells that we’re interested in, and then new programming — now we can come up with new therapeutics. Kohava Mendelsohn: Therapeutics that, ideally, will be much cheaper than typical cell therapies, which can cost hundreds of thousands of dollars. TRUONG: Once we get that programming in, now we can address all kinds of diseases we couldn’t before, using cells themselves. This is very much a dream of the field of cell engineering. (FADE IN upbeat music) (FADE OUT upbeat music)
MUSIC:
“Lakeside Path” by Blue Dot Sessions | CC BY-NC 4.0
“Denzel Sprak” by Blue Dot Sessions | CC BY-NC 4.0
“Plate Glass” by Blue Dot Sessions | CC BY-NC 4.0
