Induced pluripotent stem cells. The name doesn't exactly roll off the tongue and it certainly doesn't conjure images of mice, fruit flies, monkeys, or any of the other classic model organisms used for basic biomedical research. These so called "model organisms" are just that; animals that help scientists model the way that the most promising human therapeutics in the collective pipeline will behave in humans. And now induced pluripotent stem cells, or iPSCs, are becoming an increasingly popular tool used for developing and testing novel drugs way before we expose any real human patients to them.
The upside to using model organisms is pretty obvious -- we minimize exposure of humans to potentially unsafe molecules. The downsides are many, but one big one is that sometimes potential new drug molecules look really promising when they are given to a mouse with a human-like disease, but then that same molecule does nothing (or worse, is toxic!) when it goes into human clinical trials.
Enter hiPSCs, or human induced pluripotent stem cells. Despite their uninspired name, hiPSCs always strike me as something straight out of science fiction. hiPSCs are cells that are harvested non-invasively from adult humans, from skin or blood for example, then grown in a petri dish with a special cocktail of molecules that seemingly turns back the hands of time. Indeed, after just a few weeks of exposure to the special sauce, some of the harvested cells revert back to the identity they had in the earliest days of the donor's existence in the womb. That is, the cells revert back to stem cells, and not just any stem cells, pluripotent stem cells - or those that are capable of generating ANY type of tissue in the human body!
It's almost as if all the personality that the blood or skin cells had, everything that made them different from other cell types, gets stripped away and what's left is a tabula rasa ready to have its sense of self re-written by an entirely new set of life experiences. A second cocktail of molecules can then be used to differentiate the hiPSCs into the type of tissue you want to study - muscle, neuron, lymphocyte, etc.
I think in a future post I might dive into how the special cocktails accomplish such a feat (if your curious, you should peruse the 2012 Nobel Prize in Physiology and Medicine page), but for now I wanted to highlight one example of how hiPSCs are transforming the way scientists discover, develop and test drug candidates.
In this article, scientists at the University of Texas collaborated with a company in Minnesota called Anatomic Inc. to generate spinal cord neurons from hiPSCs that started out as cord blood from an adult human female donor. The scientists wanted to generate spinal cord neurons so they could study chronic pain, which can be caused by out-of-control activity in the pain-sensing neurons in our spinal cords.
The entire article is devoted to convincing the reader that the hiPSC-derived neurons they made behave a whole lot like regular spinal cord neurons. Basically showing that the hiPSC neurons are a good 'model' for screening potential new pain drugs. The authors put the hiPSC-neurons through all kinds of tests, including showing that they respond to molecules like duloxetine (brand name Cymbalta), retigabine (brand name Trobalt), and the pufferfish neurotoxin tetrodotoxin (delicacy name fugu). Each of these molecules had the expected effect on the hiPSC-version of the spinal cord neurons grown in the lab, which supports the authors' claim that these cells are a reasonably good model of the real thing.
The scientists also exposed the hiPSC-spinal cord neurons to more than 700 new molecules and found that 39 of them inhibited the newly-minted neurons' activity. Any molecule that can inhibit the activity of these lab-grown pain-sensing neurons could be a potential candidate for a new drug that could alleviate real patients' chronic pain symptoms. I'm sure several scientists are following up on those findings because potential new pain therapeutics are few and far between and promise a high return on investment for whoever finds a silver bullet.
Just like the classical model organisms, hiPSCs are not a perfect model of what happens in the human body. The authors from UT recognize this and are up front about the limitations of the model neurons. They have an entire section of the paper devoted to sharing the ways the model neurons are different from real human spinal cord neurons. For example, they state that the hiPSC-spinal cord neurons didn't form synapses when grown in the lab. This means that any potential drugs that would normally work at synapses between neurons in human spinal cords wouldn't be worth testing on the hiPSC model neurons.
It's important to note that in no way will testing drugs on these hiPSC neurons totally replace human clinical trials. As long as the FDA continues to exist (and I sure hope it does), pharma companies will need to prove the safety and efficacy of any potential new drugs in real human clinical trials, even if they have lots of lab data to support their applications. But I could see testing on hiPSCs start to replace testing on the more common animal model organisms (mice, rats, monkeys, etc), especially considering the FDA's recent initiative to reduce animal testing in preclinical drug development. And this might be a step in the right direction.
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