Your genes: Off or on?

New MIT study brings researchers a step closer to effectively applying gene-controlling systems

Being able to manipulate genes could revolutionize countless fields, which is why researchers around the world have worked diligently to perfect gene-controlling systems.

Forget playing The Sims — this type of control has a greater effect than simply determining whether your character enjoys reading or working out. In fact, a system that controls genes has the potential to save millions of lives.

Fortunately, researchers at the Massachusetts Institute of Technology have brought the world much closer to this control.

In an MIT press release published on Sept. 3, researchers described their new approach — a system that allows scientists to control when certain genes are on or off at will. Their work was also published in the journal ACS Synthetic Biology.

The ability to turn genes on and off is fundamental to an understanding of biology, said Timothy Lu, professor of biological engineering and electrical engineering and the senior author of the paper.

With the new system, Lu and his colleagues Fahim Farzadfard and Samuel Perli, both MIT graduate students, are able to tune which genes they want to control selectively.

“If you actually look at the similarity between humans and related organisms, like, for example, monkeys, we share many of the similar genes,” Lu said. “But what really distinguishes us is when those genes are turned on and off, so that’s why it’s quite important to know and to be able to control when certain genes are on or off.”

How the system works
This new method of gene control arose from researchers’ desire to repurpose a former system, called the CRISPR system.

The CRISPR system consists of two primary parts. The first part involves a special DNA-binding protein called Cas9. The second part concerns RNA molecules. When viruses invade, bacteria defend themselves using the RNA.

The RNA produced from the CRISPR system binds to the Cas9 protein, and together, they target the virus and try to destroy it.

So, when viruses invade, the CRISPR system targets the DNA and slices it. By doing so, the CRISPR system was previously used to extract parts of a gene in an attempt to either disable them or replace them completely.

However, in repurposing the system, MIT researchers created a new method where they were able to control gene transcription. Instead of cutting a gene, this new system is able to target a specific gene and activate – or deactivate — transcription.

“We repurpose it to use it in yeast cells, like the cells people use to brew their beer, as well as human cells, and instead of having the CRISPR system cut DNA, it binds the DNA and can turn on and turn off when the DNA is copied to RNA,” Lu said. “So we’re no longer trying to cut it, but to use it to turn genes on or off.”

Lu said this new system is easy to use because others are much harder to engineer. If one wanted to use the older CRISPR method, one would have to do significant protein engineering, and protein is harder to engineer than DNA (which is so accessible that it can even be ordered online). This approach is faster, easier and cheaper — who wouldn’t want that?

Why do we need to turn genes on or off?
Lu said the turning on and off of genes actually allows the cells to function.

“In the case of cancer, there are certain genes that have the job to prevent cells from becoming cancerous,” Lu said. “If those genes are typically on, they contribute to maintain whether a cell is healthy or not. But if for some reason, you pick up a mutation and those things can shut off, then those cells develop cancer.”

So if a cell fails to do its job, Lu tries to figure out a way to prevent the cancerous or virus development from occurring.

“What we’re doing is really taking a page from how nature does things,” he said. “Nature uses gene expression – turning genes on and off — to basically control itself, too. So synthetic biologists come in and say, ‘Look, we can use the same mechanisms and use even newer functionalities of the cells we didn’t previously have by turning on or turning off specific genes at the right times.’”

Elise Reddington, a College of Health and Rehabilitation Sciences senior, thought of the benefits in terms of her major.

“With this, doctors could be able to treat certain diseases that before were considered untreatable,” she said. “With cancer, so many people suffer from it, so if they could turn the gene off, it would be a really big advancement.”

Lu explained that if a gene is turned on too high, it could actually cause bad reactions in the cells, causing them to become cancerous or mutated. If a virus infects a cell, those viruses also have genes, which get turned off because the virus needs them to replicate and spread disease.

This is why having the ability to turn genes on or off is crucial— researchers either want to determine the cancer causing genes or want to shut off the virus-promoting genes.

How the new approach functions
This new approach has allowed Lu and his research team to study biological systems more easily and to gain a deeper understanding of how they work. However, it has also given them a way to advance the synthetic biology field and to apply it to a variety of other fields.

One focus of the research involves cells that can sense and report on their environmental conditions. For example, a researcher may want to engineer a cell that can detect whether there are explosives in the vicinity of that cell’s living space, such as in water or dirt. To do this, one needs to modify that cell to accurately detect whatever the researcher is looking for and then to program it to properly process that information.

Gene expression is necessary to processing that information because it allows the researcher to take the information in. Lu said this could potentially be done using a sensor to detect something that can turn on or turn off a specific gene. Then, that gene can indicate whether the detection happened.

Another interesting application of this research could impact the medical field. If researchers are able to control cells, they will be able to detect if other cells have a certain diseases, such as cancers or viruses.

So, with this, it can trigger the production of an additional gene, which could potentially kill off the cancerous cells or viruses.

“I think it’s incredible and can be extremely beneficial,” said Nathalie Nader, a College of Arts and Sciences junior. “It can have so many amazing consequences such as disease prevention and cure cancer when they’re expressed.”

Producing a drug
While this system can detect diseases or viruses, it will also be valuable in creating more effective pharmaceuticals.

“Whatever drug you’re interested in making, you could essentially plug into that gene that is controlled by this,” Lu said. “There really is no upper bound to this in terms of what you want to do.”

Lu used the example of a protein called Erythropoietin (EPO), which is used to increase red blood cell counts in patients undergoing certain treatments. By turning on a gene that codes for EPO, researchers can get the protein produced. That protein will get drugged and have the direct effect it needs. With this system, EPO — as well as any other gene — can be turned on.

“Anything you can program in DNA, you can turn on with this system,” he said. “So it comes down to what you want the system to do. You have to identify the right proteins that do the right things for you.”

What’s next?
“The main thing now is to go toward application,” Lu said. “Because we’ve been able to show that these work in, for example, human cells, there’s a lot of diseases where we think that we can use this system to understand both the way the disease works but also to try to develop new ways of treating disease.”

Lu said he is also interested in curing neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease. Using this system, he said he and researchers hope to build circuits that can detect these diseases early on.

Thuy Tran, a CAS and SAR senior, said she understands that gene expression is not a new idea, but believes this new system could stretch across numerous scientific fields.

“I’ve read a lot about this — it’s been going on for quite some time and it’s not just going to help one field,” she said. “It’s not just biology. It’s also computer science and math. It’s a big work in progress for all fields.”