Disease in a Dish: The Ultimate Personalized Medicine

John C. Reed, MD, PhD; Michael Jackson, PhD


December 04, 2012

Editorial Collaboration

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John C. Reed, MD, PhD: Hello and welcome to "Developments to Watch" from Medscape. I'm Dr. John Reed, CEO of Sanford-Burnham Medical Research Institute.

Recently the Nobel Prize was awarded in medicine and physiology for advances in genome programming. This has opened an exciting new area of stem cell technologies where we can now create models in the petri dish of patients' diseases. In just a few moments, we're going to chat with my colleague, Dr. Michael Jackson, our Vice President for Drug Discovery and Development, and share with you some of the exciting ways that this technology is creating new opportunities to tackle very challenging medical disorders.

Michael, you run the drug discovery and development operations here at Sanford-Burnham. Before that, you were running a large drug discovery operation for one of the major pharmaceutical companies. So you've spent many years in this game of hunting for new medicines, using things like advanced robotic screening.

Tell us about this new breakthrough in stem cell technology that allows you to create "disease in a dish" models using cells derived from stem cells. What is it all about?

Michael Jackson, PhD: It's a very exciting new advancement. It allows us to take patients' own cells and, if a patient has a disease that affects those cells, to measure that defect. This is done through advances in quantitative microscopy, mixed with or alongside of robotic drug screening; the 2 together are quite a spectacular shortcut to be able to see whether a medicine we already have today that is being prescribed for one disease might have utility in another.

Now, you say, how could that be? There are a number of very spectacular examples out there of drugs that have been used or developed for one indication and then later on have been found to have a different clinical utility. In the specific example we're talking about here with disease in a dish, we're initially focusing on rare diseases. With rare diseases, the children's cells all have a particular defect, and it's that defect that we can actually recapitulate and rebuild in a dish, the so-called disease in a dish. Then, using robotics and screening technology and using the kind of equipment you're seeing behind you here, to search in a systematic way and see whether any preexisting drugs that are already approved could move the needle and improve the defect in the child's cells.

Dr. Reed: Explain to us why you want to take the patient's cell and first turn it into a stem cell using this so-called induced pluripotent stem cell technology for which the Nobel Prize was just awarded.

Dr. Jackson: The stem cell technology aspect of it is really very exciting because it allows us to individualize this treatment. It allows us to take skin cells from a patient with a disease and deprogram them to an induced pluripotent stem cell. It's pluripotent, meaning that it can make different types of cell from the human body.

Let's take an example of a disease of the brain. Sadly, there are a lot of childhood diseases that result in abnormalities of brain development. We have not previously been able to generate neurons, astrocytes, or microglia -- the key brain cells -- from that patient. But by using stem cell technology, you can take their skin cells, deprogram them to a stem cell, and then reprogram them to make neurons, astrocytes, and microglia.

The key is that those neurons, microglia, and astrocytes carry the genetic deficiency of that individual, so they carry through the phenotype, or defect, which we can measure using sophisticated microscopy and other functional tools. We can then use that assay to search through drugs to try to find out what would reverse that defect.

Dr. Reed: That's a great example, because although the genetic defect is present in every cell in the body, the disease is often manifested in a specific cell type, like a neuron. So by being able to make that patient's neurons, their brain cells, now you've got their disease in the petri dish.

Dr. Jackson: Absolutely. Each of the cells of our body -- we're made up of several hundred, maybe 300 or 400 different cell types -- each of them has very specific functions that ultimately impact on the organism to operate normally. We are trying to bring that closer to normal by searching for and repurposing drugs that are already used for some other indication.

Dr. Reed: Can you share with us one example where you've done this type of work -- taking a patient's cells and screening a collection of US Food and Drug Administration (FDA)-approved medicines to see whether you can find any unanticipated benefits for medicines that we can pull off the shelf and maybe offer to a child with a life-threatening disease?

Dr. Jackson: Let's take an example, one that we have been working on here -- muscular dystrophy. Muscular dystrophy contains a number of different diseases, all of which ultimately result in a child not being able to walk or problems with the heart and even the brain. In this case, one particular set of genetic defects results in an inability of the muscle cells, and many other cell types in the body, to bind laminin. And it's that binding that allows the muscle cell to do its job and bind to the extracellular matrix. If you don't have that binding, the muscle cells are fragile, and the muscles don't work.

What we have done is gone to a family and taken cells from the mother, the father, and 2 brothers, one who was affected with muscular dystrophy and the other not. We've taken their cells and then, using a binding assay, were able to show that the affected child's cells do not bind laminin normally.

I can actually show you this on this screen here. Taking the cells and looking under the microscope, you're actually able to see that the parents' cells bind laminin normally, as shown in the red color staining. Of the 2 brothers, one of them is unaffected, as seen, and the affected brother really doesn't bind much laminin.

Now, I have an assay and can quantitatively measure the lack of binding, and I can search through the existing drug collection to see whether I can find a drug that will increase the laminin binding for that child's cell. It's very personalized medicine; it's for that child.

We've gotten examples from skin cells, cardiomyocytes, and myocytes, and now, because of the induced pluripotent stem cell technology, we have also made neurons from that child and can show that the precursors of neurons also don't bind laminin properly. So you can see how this works.

What was exciting was that when we first did the screen of our collection of FDA-approved drugs, we were able to find a compound that significantly reversed -- in a spectacular way -- the lack of laminin binding. You can see that on one of these slides here -- here's the unaffected brother, the affected brother, and then we give the drug and you significantly increase the laminin binding. That's exciting, because that's a direct possible repurposed drug for that child. So the clinician who is looking after that child sees this data and is excited by it.

This is a drug that has a cancer indication ordinarily, and now we're looking at doing a clinical trial -- not just with this one child, but with a number of children -- to see whether this drug could be a treatment for this disease.

It's not going to take 15 years to do that trial like it would if I were to find a brand-new chemical entity in a classic drug discovery paradigm where I have to do phase 1 testing, phase 2 testing, etc. In this case, because it's an approved drug, with an internal review board of a hospital and with the clinicians looking at the safety/benefit risk, these drugs can be evaluated in small cohorts of very highly characterized patients, in this case genetically characterized patients, to see whether these drugs would actually improve their disease.

Dr. Reed: Besides these rare diseases and the personalized medicine approach, what are the other benefits to the stem cell technologies, where you can produce these specialized types of human cells in large quantities, for a guy like you who's trying to discover medicines?

Dr. Jackson: The focus on rare diseases is the tip of the iceberg. What's exciting is the ability to generate large quantities of rare cell types -- until stem cell technology came along, we didn't have the ability to grow significant and almost unlimited quantities of highly characterized human brain cells. But it's not just brain cells; it's also cardiomyocytes and liver cells, or hepatocytes. Today's drug discovery process is still using cadaver-originating material to determine metabolism of the drugs that we try to take into the clinic. Clearly, if we can have an unlimited supply of true human hepatocytes that can direct us towards toxicity profiling, or cardiomyocytes that beat and function as a human cardiomyocyte does with the genetic diversity that represents the population, we really can get a new handle on de-risking our drug-discovery programs in terms of toxicity. That's one angle.

The second angle is that, for central nervous system diseases in particular, we really have not had much of an opportunity to look at the cell biology. Think of diseases of neurodegeneration, such as Alzheimer's or Parkinson's disease, for example -- these are diseases of cellular death and dysfunction. We can now model them, for the first time, in a dish with reproducibility. We're no longer relying on rat neurons. That's a big advance.

Dr. Reed: Michael, you've been involved in drug discovery most of your career, and here we're talking about how the stem cell technologies can be used in a personalized medicine context. What about its role in a broader sense, for drug discovery and for finding medicines that could benefit large populations of patients?

Dr. Jackson: What we've been talking about with disease in a dish is really part of a larger process that's likely to become mainstream in the next 2-5 years. Several challenges are coming forward at us. First, whole genome sequencing or increased sequencing of patients is starting to identify the genetics behind the disease. If you see a genetic variant in a person, how do you know it goes on to generate functional consequence? What I was just talking about, disease in a dish, is essentially one component of being able to determine that. You take their cells, you make stem cells, and you then make the cell that you believe that particular genetic variant might affect the function of. We would then be able to essentially monitor and measure that function, and, if it is penetrant enough to actually be altering that function, to give you something abnormal, that's information you can pass back to the clinician, and obviously back to the patient, about what they might want to do.

Of course, we then have a straightforward path to use that exact same assay based on that patient's cells to search through collections of compounds, one at a time or in combination, to identify something that would essentially reverse that defect to bring it back to more like normal.

How long would all of that take? Well, I think it really is in a relatively short period of time that we could imagine it. In the example I provided earlier, muscular dystrophy, we went from taking the children's and parents' cells to building an assay and doing a screening in a 6-month period.

The more we do the same disease time and time again, the faster that will be. You can imagine a whole business that is set up to monitor, at the cellular level, the function of an individual cell. Once that information is determined, if it's abnormal, we can search for drugs that would reverse that defect. The time taken to actually then have an impact on the patient could, of course, be very rapid, as we were discussing earlier. The hurdles to take repurposed or approved drugs and test them in a new indication is relatively low because they're already considered safe.

Dr. Reed: Michael, when you talk about taking a patient's cell, establishing one of these diseases in a petri dish model of their disorder, and then screening collections of existing medicines to try to correct that problem, you're not actually talking about correcting the genetic mutation in their DNA, right?

Dr. Jackson: That's correct. This is no gene therapy. We do not think of this as directly correcting a defect in the same way as gene therapy corrects something. The repositioning or repurposing of drugs is seen more as a holistic resetting and a bringing of the cells back to the homeostatic point they need to be at to function normally.

You can think of this a little bit like a lemon car. Early on, a child is born with a bit of a defect in one function, one particular component -- that's the only component that's really wrong. You need to try to find a way to not exactly replace that component, but to allow other compensatory mechanisms to kick in. It's not so important that the tire pressure's a bit low because you can find other ways to compensate for it. Not a very good example, maybe, but you can see how compensatory mechanisms kick in. In fact, we know they exist because 2 individuals with the same genetic mutation in the same critical gene go on to develop a disease with different levels of severity. This indicates what we already know from biology: that there are other compensatory pathways that we are looking -- with drugs -- to switch on or upregulate to minimize the defect.

Dr. Reed: Michael, this is very exciting. It reminds me of my pharmacology professor in medical school who taught us that no drug has a single mechanism. All medicines, even though they're specifically designed to bind to certain cellular target and modulate it, also interact with many other cellular proteins. And if we can use this technology to unmask those interactions, sometimes we can find unanticipated benefits.

Dr. Jackson: Absolutely. Obviously, one of the key attributes of most of the medicines that we have on the shelf is that they're relatively safe. So that's the first thing when you're thinking about reusing them for something else -- that you can tick that box. You still have to get a lot of people agreeing that it's safe enough, but your point about multiple activities for a drug is now well understood and well recognized. In fact, many of the drugs on the market today were initially developed for one indication, and later, having been experimented in animals or more likely in humans, go on to show an activity, something unexpected, which is where they ultimately find their big utility to mankind.

Dr. Reed: I hope you enjoyed our chat today with Dr. Michael Jackson. Please join us for other editions of "Developments to Watch" on Medscape.