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Futuristic Fat-Fighting Fantasy: Using CRISPR To Tweak 'Bad' Fat Into Acting Like 'Good' Fat

Wikimedia Commons
Wikimedia Commons

Here's a sci-fi fantasy spurred by some very real — but early — new research published this week:

Imagine the pounds have been creeping up, so your doctor suggests a bit of CRISPR. Technicians extract some of your white fat cells — also known as "bad" fat cells because they store energy in places like bellies and bulges.

They use the gene-editing tool CRISPR to tweak the cells' genes. Now, those white cells function more like brown fat cells — the "good" kind that burn energy when you're cold or exercise.

Voila: your metabolism is adjusted so that you burn more calories and absorb glucose better. You're set up for weight-control success, instead of the common frustration of weight regain. Current-day liposuction is left in the dust. Your fat hasn't just been removed — it's been reengineered.

Back to current reality: Researchers at the Joslin Diabetes Center in Boston and elsewhere have just published "proof of concept" work that could eventually make that fantasy come true. They used CRISPR to make human white fat cells act more like brown fat.

"Then we transplanted the cells into mice," says Joslin senior investigator and Harvard Medical School professor Yu-Hua Tseng. "And we found the mice receiving the transplanted cells had a much-improved metabolism. Even when we gave them a high-calorie, high-fat diet, they gained less weight."

She says much more research is needed, but eventually, treatments for obesity could include CRISPR-ing fat cells. Here are some lightly edited excerpts from our conversation:

What did you do?

We used CRISPR technology to turn white fat into brown-like cells we named "human brown-like fat cells," or HUMBLE cells for short. (It's also a good reminder that as a scientist, I need to stay humble and continue to explore new ideas, new knowledge.)

Brown fat has a very unique feature, a unique protein expressed in it, called Uncoupling Protein 1, or UCP1. It’s a protein basically located in mitochondria, the power source of the cells, that can turn chemical energy into heat for dissipation. We know normal white fat doesn’t express the UCP1 protein. So we used CRISPR to turn on UCP1 expression in white fat, to wake up those genes so the white fat can start to express this important protein to dissipate energy.

We didn’t directly turn the white fat in mice into brown fat. We actually engineered human white fat cells into HUMBLE cells, brown-like cells, and then we transplanted the cells into mice, and we found the mice receiving the transplanted HUMBLE cells had a much-improved metabolism. Even when we gave them a high-calorie, high-fat diet, they gained less weight.

How big an effect is it?

The body weight changes are not a lot, but we see a pretty significant improvement in glucose metabolism — 5 to 10% --  which is very important, especially in diabetes. One of the problems with diabetes is that you have too much glucose in circulation and that causes many complications.

This was done in mice, but what are the prospects in humans? 

The exciting part of this study is that we engineered human cells. So one can picture that in humans, we could take a tiny bit of fat tissue from an obese individual, and then in the lab we could purify the precursor cells, we could engineer these cells with CRISPR gene-editing tools to make them become brown-like, become HUMBLE cells. Then the next step is to transplant these HUMBLE cells back into the individual.

This process of taking cells out and then transplanting them back into the same person is called autologous transplantation. Normally, you don’t need to worry about the cells being rejected by their immune system. It worked in mice, and I believe it would work in humans, but definitely we need to do a lot more research.

Is this a first? 

The idea of turning white fat into brown is not new. Even the idea of over-expressing this UCP1 protein has been done before: people created transgenic mice that over-express UCP1.

But what’s unique in our study is that we use human cells. This new CRISPR method allows us to directly target the UCP1 gene, which is dormant in white cells. And then we tested the effect of these engineered cells by transplanting them into mice.

There have also been efforts to develop pills to stimulate brown fat. Wouldn't a cell transplantation method like yours be very elaborate and expensive compared to a pill?

Some people may respond better to a certain pill but others may respond better to cell-based therapy. It might be expensive at the current time, but I believe with the advance of technologies in the future, CRISPR gene editing could become really routine in the hospital laboratory. So it wouldn't be very expensive, and it’s probably pretty safe. People could just go to the hospital and take out some cells and receive an injection.

These days, some people have liposuction procedures to vacuum out fat; with this method, they'd have their white fat sucked out, then engineered to function more like brown fat, and injected back in to help keep weight off?

That’s exactly what I’m picturing. I’m a big fan of science, and a lot of things that we see currently used in clinics were science fiction before, but nowadays they're just routine procedures. I believe if scientists from different fields work together, we can develop much, much better therapeutic methods to help patients.

How soon could you be testing this in humans? 

This is just a proof-of-concept study. I think if we are able to put together a team, we could test this in humans, but it’s hard for me to give you a defined timeline.

It sounds like years rather than months away.

Right, and we'd definitely want to do all kinds of trials and tests first to make sure it’s safe.

In this time of COVID, we're seeing that obesity and diabetes definitely increase the severity of patients infected with coronavirus. The most fundamental treatment for obesity, diabetes and metabolic disease is still lifestyle intervention — diet and exercise.

But at the Joslin Diabetes Center, we see patients who are genetically predisposed to obesity, diabetes and metabolic disease, or they've already developed certain complications, so medical treatment is definitely necessary. I hope our research can help these patients.

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Carey Goldberg Twitter Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth section.

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