What is the vision for regenerative medicine and the Wake Forest Institute for Regenerative Medicine?
Regenerative medicine is now several decades in the making, and a lot of technologies are now starting to be used in patients. Of course, the hope for the future, in terms of landscape, is to make sure that we can get more of these technologies into patients, and that we can benefit a larger number of patients over time.
The institute is working on more than 40 different tissues and organs. Our whole goal is to bring technologies to patients and to improve lives through regenerative medicine. A lot of the technologies that we have worked on are based on clinical translation. We currently have 15 applications of our technologies in patients. This includes flat structures, such as skin or tubular structures, as well as cell therapies, into various types of organs.
Part of your work is developing “organ on a chip” drug models. What is the accuracy and speed of those multi-organoid models compared to animal models or human trials?
One of the major advantages of the organoid model is that you’re testing the structures on human equivalence. One of the challenges with drug testing is that when it goes through the testing process before it gets to patients, cell lines are typically used. These cell lines are not necessarily normal human cells, they’re basically lines that have been created just for testing. Often they don’t represent the true human, normal cell.
And then you have the animal models. And unfortunately, animal models are not necessarily representative of human response. Because of that, the pharmaceutical industry spends tens of millions of dollars before they ever get a drug into a patient as a Phase I clinical trial. But the harsh reality is that 90% of the drugs enter phase one clinical trials never make it out. The organoid system is really a method by which we can design three- dimensional normal human cell tissue equivalence to use for drug testing, toxicity and safety.
You’ve also spoken about the implications for precision medicine. Can you expand on that?
There are many applications for personalized medicine. The one that I did mention was the one for cancer therapy. If a patient has a tumor, typically there is a choice of drugs that can be used against that tumor. But you do have to try those drugs in a patient to see if the patient responds.
Typically, it may take months before you know whether or not the patient is responding. By then, it may be too late. By then, the tumor may have advanced to the point that it may not be salvageable for the patient. Part of the strategy is to use these technologies to create tumors on a chip. We can test these chemotherapy agents on these personalized chips so that you can determine what the best treatment is for the patient before you actually start the first treatment.
What are the possibilities of regenerative medicine for COVID-19 research or future health crises?
One of the major things is to try to determine early signals of disease, and to understand what the biomarkers for that are. One of the challenges with COVID-19, and any future pandemics, is the fact that people don’t know where they’re infected or not.
There are many other ways to do that beyond antibodies. You can look at biomarkers such as how the tissues are responding to the infection. There is a whole range of opportunities in the area of biomarker development. Because by looking at current bacteria and viruses, as well as chemical and biological agents, you can start to define biomarkers. Those biomarkers really are when the injury first hits the cell.There are a lot of early signals that can lead you to a diagnosis.
These systems can be used extensively for biomarker development, not just for a pandemic like COVID-19, or a future pandemic, but even for disease states that people currently face, including early diagnosis of cancers, for example.
You’ve discussed replicating the blood-brain barrier as an application of your work. Can you describe that work, as well as what other opportunities that regenerative medicine opens up?
Believe it or not, the way an analog of the blood-brain barrier gets typically tested is to use a dog kidney disease cell line. That’s currently the standard to determine something like a blood-brain barrier. It’s been the standard for decades, and doesn’t accurately reflect what the brain does.
Part of the strength of the system is using normal human cells to create structures. You’re creating miniature organs. By doing that, you’re able to establish physiologically relevant systems that represent the human response much better. That way, when we create these miniature brain organoids, they have all the major six cell types that are present in the human brain in the same proportion. By doing so they’re able to recreate the miniature structure that has a lot of the properties that you would see in a brain, including a blood-brain barrier.
By creating these models, you can start to see how drugs can enter. You can start looking at systems that are more accurate, and you can create disease models. For example, we can create mini-strokes. It’s not just about establishing these systems for normal physiology. You can start looking at disease states. We’ve talked about creating a heart attack, or creating cystic fibrosis in the lung. We’ve done a lot of infection analysis for lungs with viruses and bacteria, including the COVID virus.
It is possible to create neurodegenerative diseases. Those models are more complex, because you’re looking at aging as part of the process. Obviously, you’re not going to keep these structures around for decades. These aging models are definitely more complex, but you can replicate the response better than you could in a cell line and better than you could in a two-dimensional model or in animal cells versus in a human analog.
What is the timeline for when an organ-on-a-chip can be widely used by pharma companies or when patients can have wider access to these precision medicine models?
These technologies are becoming more widely available. The future for these technologies is not just in establishing these models, but in looking at predictive modeling.
If we can catalog what the response to these organs are with existing, known compounds, then we can start to figure out what the structural relationships of these compounds that affect specific organs are, in terms of both toxicity and efficacy. Right now, as you are designing these drugs, you can look at the structure library and see if this molecule is more water-soluble, less water-soluble, etc, for example. You can know what the properties are of the molecule, but you have no idea what the molecule can really do in terms of being toxic to an organ.
And so by looking at known compounds, and then starting to look at new unknown compounds that are being developed, you can build this library. Then using AI, you can start looking at predictive algorithms. You can then look at the library and say, “I better not do XYZ with this model. I better not put this hydrogen group there, because I know if I do that, the liver will not like that.”
Is there anything else that you’re working on that you’re really excited about that you would love to be able to share or just something in the field that really excites you that you think you would love our audience to be aware of?
One thing I’m excited about is the establishment of this new consortium – the Humanoid Sensor Consortium – because it’s by bringing everyone’s know-how and resources together that we can jumpstart and advance the field further.
The goal of the consortium is really threefold. First is to help to develop current drugs for safety and efficacy. Second is predictive modeling. We can pool resources so that everyone can work separately with their compound, but really pool all this data together, and to work together to make sure that we can build a library to effectively do predictive modeling. That will benefit everyone long- term. The third element is personalized medicine, to help advance more personalized medicine applications.
What role do you think regenerative medicine can play in helping drug delivery technologists?
Some of the challenges present with drug delivery are making sure the medicine gets where it’s supposed to. An example of this is when we want to get medications into the brain, which is protected by the blood brain barrier. These technologies can help us to design drugs that can penetrate the blood brain barrier and we can show this through these miniature models to see which is the most effective at doing so.