Jan Nolta

Show Notes:

[0:00:02] Dr. Jan Nolta's Background and Journey to Davis

[0:01:50] Return to UC Davis as Director of the Stem Cell Program

[0:04:51] Practical Applications of Pluripotent Stem Cells

[0:08:01] Introduction to Regenerative Medicine

[0:09:52] Different Approaches for Liver and Heart Procedures

[0:14:27] FDA Regulated Clinical Trials and Cell Manufacturing

[0:16:34] Growth Period and Delivery of Stem Cells

[0:22:45] Stem Cell Therapy Success for Blood Disorders

[0:25:13] Direct Injection vs Intravenous Injection: Understanding the Difference [0:25:19] Intravenous Delivery for Overall Body Treatment

[0:25:56] Tissue Engineering vs. Cell Engineering in Regenerative Medicine

[0:28:39] Amplified Signals in the Blood System for CAR T Therapies

[0:30:13] MSCs and Turmeric: Alternative to Cell Therapy

[0:32:30] Graft Rejection and Potential of AI in Stem Cell Matching

[0:35:02] Funding Challenges in Clinical Trials and Access to Therapies

[0:36:13] Stem Cells in Cancer Treatment

[0:39:40] Memory T-Cells and the Future of Regenerative Medicine

[0:44:50] The potential of transformative medical technologies

[0:47:11] Overcoming pushback on novel and advanced technologies

[0:48:56] Revolutionizing Treatment for Non-Healing Ulcers

[0:51:19] Stay Curious and Enthusiastic: Advice for Students

Unedited AI Generated Transcript

Dr. Jan Nolta's Background and Journey to Davis

Brent:
[0:03] Welcome, Dr. Jan Nolta. Thank you for coming on today.

Jan:
[0:06] Yeah, thank you for having this. Really excited to do it.

Keller:
[0:10] We'd love to start off by hearing a little bit more about your story.
How did you get to Davis? What got you into stem cells and also regenerative medicine?

Jan:
[0:18] Great question. So I started out as a girl in a small town in Northern California, Willows.
It's like a truck stop between Sacramento and Redding, and I grew up with a single mom, definitely first-gen professor.

[0:35] I went to Sac State on scholarships, and then I was taking, I graduated from Sac State. I was working in the blood gas lab here at UC Davis.
It was very different back then. I'm not even going to say what year that was.
And then I signed out in a paper to go work on the blood-forming stem cells, hematopoietic themselves with Dr. Don Cohn in Los Angeles.
So, I got an interview, drove there, really old, broken down truck, lost the clutch on the grapevine, still made the interview the next morning, they fixed it up at a gas station, made the interview the next morning, got the job, worked with Don for 15 years, and that is where I got my passion for translational medicine, working with MDs, and working to try to take exciting discoveries at the bench into clinical trials to help the patients.
And then worked with him 15 years, went to the Midwest for five years, Washington University, and then came back to UC Davis. I got recruited as the director of the Stem Cell Program in 2006, started in 2007. Really glad to be here.

Return to UC Davis as Director of the Stem Cell Program

[1:50] It's been a fast ride since I got back.

Brent:
[1:52] We've done a lot. That's amazing.
So, could you talk to us about what are stem cells and where do they come from?

Jan:
[1:59] Yeah. So, basically two types of stem cells. There's the adult stem cells.
So, we all have those in our body.

[2:06] Hematopoietic or blood-forming stem cells. They work to self-renew themselves in the bone marrow and make your blood cells every day. A lot of different types of blood cells.
You have some skin stem cells, some intestinal stem cells. They're constantly working to regenerate.
If your liver gets damaged, say a night of partying or something, those liver stem cells will work to regenerate the liver to exactly the same mass as the cells that you killed off.

[2:33] So those are the adult stem cells. All over our bodies, different types, stem and progenitor cells. And when people think about stem cells, what they really think about is the other type, which are the embryonic or pluripotent stem cells.
So we used to use embryonic stem cells, those come from embryos left over in in vitro fertilization clinics.
And very talented people can take that inner, they can grow them up for a couple days, take the inner cell mass and make a cell line out of it.
We don't really use those here anymore. What we use is the induced pluripotent stem cells.
Those we take from a little sample of the patient's skin, we make a nice lawn of skin cells in the lab and then we turn those back in time by opening all the chromatin so that they resemble the embryonic stem cells and they are pluripotent.
They can be differentiated into any tissue of the body and those cells are really exciting. So two main types, the adult stem cells, they're already focused, they know what they're going to make, and then the pluripotent stem cells that will make any tissue in the body.

Brent:
[3:36] And then you said you took it from the patient's skin. So will you individualize the stem cells per patient?

Jan:
[3:45] That was initially the thought. It turns out to be very cumbersome, lengthy, and expensive.
That was the original goal when this was discovered. Dr. Shinya Yamanaka discovered this technique over a decade ago and got a Nobel Prize for it since then.
Just taking a little, it's like a little skin biopsy, kind of like piercing your ear, little plug of skin, and we could grow a lot of cells out of that, add compounds that turn them back into these embryonic-like stem cells.
We initially thought that we would make everybody their own cell line and we can make organs for them and everything, but it takes like two months to make this cell line, to grow it up in enough.
Enough quantity. So now what we really do with those that's most useful is disease in a dish.
So we can take a skin sample from a patient with a rare genetic disease, grow them up in a dish, differentiate them into neurons, and then see what's wrong with their signaling pathway, where can we intervene with a drug, where can we intervene with gene therapy to return them to normal.

Practical Applications of Pluripotent Stem Cells

[4:51] And so that's the most common use for those cells right now.
And it's really cool because it has all of the patient's genetics.
We can't go in and sample the neurons in their brain, but we can make the neurons basically from that patient. That's fascinating.

[5:05] For the clinical trials, people are working on different cell banks that would match a large range of people that have that type of protein on their cell surface.
They're called human leukocyte antigens, and that's what needs to be matched.
You've heard of Be The Match for for bone marrow transplantation.

[5:23] If you make a pluripotent stem cell line that has the HLA types or human leukocyte antigen types that match a lot of people, then that could be used for those people theoretically.

Brent:
[5:34] Okay, yeah, that's awesome.

Keller:
[5:35] Is the move away from embryonic stem cells, is that an ethical move or is that more because the other kind is more personalized?

Jan:
[5:44] It's because the other type is just easier. I mean, there are ethical considerations, but there are a few approved embryonic stem cell lines that have been out there for a long time and those are being used in some clinical trials.
For us, the iPSCs, the induced pluripotent stem cells are just more interesting because we can look at the different genetics.
The embryonic stem cells that come from the IVF clinics, that would match theoretically one person.
Whereas we can find somebody that has this great diversity of HLA types and make a line from them and that might match thousands and thousands of other people, so it's more broad with the IPSCs.

Keller:
[6:23] Could you define HLA types briefly? Hmm.

Jan:
[6:28] Yeah, very important. It's human leukocyte antigens. So, you have those, the main types, three from your mom, three from your dad, and those will be on all your cells, basically.
So, when they go for, I mean, there are others that are minor types, but those are the main types they look to match if you would need a bone marrow transplant from somebody else's bone marrow, for instance, or a kidney transplant or something like that.
That's what they screen for. Okay. And so, we can find patients that have those that are very broad, like HLA-2A is on a lot of people. And so, we can just get a skin sample from them and make a line. Yeah.

Brent:
[7:04] And if those match, they're more likely to have a successful outcome?

Jan:
[7:07] Yeah, they won't reject the cells if we transplant them, right?
So, that's your immune system looks for cells that aren't your own and would just eradicate them. And so, they have to match. That's right.

Keller:
[7:19] And could you give us also a brief breakdown of blood?

Jan:
[7:22] Yeah. So, blood comes from the bone marrow stem cells and they hang out in your bone marrow for your whole life.
You know, if you get to be 120, they will be in there just pumping out the blood cells and that's the white blood cells, red blood cells, megakaryocytes that make the platelets for clotting if you get cut or injured, just all the different types of cells.
You have monocytes and and granulocytes that take care of your, part of your immune function in the tissues, and then the T cells and B cells that are your immune cells.
And those all come from the bone marrow or hematopoietic stem cells.

Introduction to Regenerative Medicine

Brent:
[8:01] So now that we have a bit of a background on some of the biology, could you talk to us about what is regenerative medicine?

Jan:
[8:10] Yeah, regenerative medicine is basically using, what we think of it is using your own body to heal itself.
So we would take the stem cells out of the person, some type of stem cells, take them to our clean room facility.
It's called a good manufacturing practice facility. We're very lucky to have a very large one here at UC Davis.
We would take those cells in there and grow them out, maybe differentiate them a little bit into what we want, maybe genetically engineer them, and then transfer them back to the patient.
And where we would put them back in the patient depends on what the issue was, If it was a non-healing ulcer, they might go onto the skin.
If it's some problem with the blood formation, they would go back to the bone marrow.
We just put them into the bloodstream, and they find their way back to the bone marrow.
There are clinical trials to restore neurons in patients, which is really interesting.
Those have to be obviously put into the brain.
They can't cross in from the blood, so that's a brain surgery.
But regenerative medicine can also be...
Using different molecules or matrices to kind of help the body heal itself from injury.
And so, matrices are what the cells would lay down as kind of like a carpet that they attach on to.
And we have some colleagues here in the bioengineering department that are working on some really cool different proteins to do that.

Brent:
[9:39] That's awesome.

Keller:
[9:40] Are there any locations when you put back in the cells that are like non-intuitive I guess? neurons, like obviously you'd have to go to the brain.
Are there any that you found to be random?

Different Approaches for Liver and Heart Procedures

Jan:
[9:53] Well, I guess for the liver, we would go in through the portal vein and that's the circulation into the liver.
For the heart, just into the arteries and they seed out into the heart.
You don't always want to go just like poking into the heart to put things back in.
We have I have a brilliant researcher here, Dr. Deb Liu, that's working on bioengineered pacemaking cells, bioengineered pacemakers, because kids that get an electronic pacemaker would have to have like eight surgeries during their life as they grow.
It wouldn't be strong enough as they grow up, and so she wants to make one.
She can make little ones in a dish, which is really amazing, and they beat, you know, it's very cool.
Wow. From those induced pluripotent stem cells.

Brent:
[10:39] That's amazing. And then you mentioned the Good Manufacturing Facility.
Could you briefly describe what that is?

Jan:
[10:44] Yeah, GMP facility, a good manufacturing practice as opposed to bad manufacturing practice.
It's heavily controlled by the Food and Drug Administration.
We have standard operating procedures, which is a recipe for everything.
We follow it to the letter.
The cells come from the patient, are taken into that facility.
We have six individual suites here. So we could be manufacturing cells, manufacturing, expanding, or growing up, or differentiating or engineering the cells from six patients at the same time each day.
You put on like a space suit to go in there so you don't infect the cells with anything. You don't want any of your skin cells falling into the dish or anything.
And we grow the cells basically in a culture of media that's sugars and proteins and we use that to mimic the human body.
We keep them at body temperature and infuse oxygen and carbon dioxide into the incubator for them. and just we have bioreactors in there and we can grow them up into very large numbers and return them to the patient.

Brent:
[11:52] And then since it's FDA regulated, does that make the process post-discovery a lot easier to get approved by the FDA?

Jan:
[12:02] Yeah, so we start out, we apply for a pre-IND meeting with the FDA that's investigational new drug and they think of the cells as a drug once they're manufactured and grown up in the facility.
And then they'll tell us what we need to do to get to the clinical trial.
And when we've done all of that, we submit a big package electronically.
We used to have to fax it in the olden days, crazy.
We submit a big package of paperwork with all the certificates of analysis and everything the FDA wants to see, all the trial runs, the engineering runs, everything that we've done. And that's an investigational new drug application.
And only once they have reviewed that can a clinical trial start.

Brent:
[12:45] It. And then.
Could you briefly like describe the FDA approval of stem cells in America right now versus some other countries and why people have to travel sometimes to get the medicine?

Jan:
[12:59] Well, it's, FDA approves, you know, as I just discussed, FDA approves only the cell type for that indication.
And so, you can't just say, I'm going to make some cells and I'm just going to give it to people.
But there are these non-approved clinics that will pop up like next to 7-Eleven and they'll say, hey, I'm going to give everybody stem cells.
And FDA has had no oversight over them. You don't know what they're doing.
They could be using dirty saline. You have no idea what they're doing.
And they're just basically taking a, what they usually do is to take an injection of fat from a patient, go into the back room, spin it down so that some of the cells fall out of it, and then they'll re-inject it somewhere into your body.
And so, they are supposed to have a big sign that says, not FDA regulated, but they don't because they're under no guidance.
Pete Yeah. KS And so, people unfortunately do believe that those places are legitimate and they will go to them, and if they can't find one and in the United States, they'll go to another country to get them.
Now, there are some places that are legitimately using stem cells, but when you get an aspiration of fat like that, stem cells are about one in a million, and even in the bone marrow, the stem cells are one in a million.
So that's not really a stem cell infusion. It's a cell infusion.
It might do something. it might be anti-inflammatory.

FDA Regulated Clinical Trials and Cell Manufacturing

[14:27] But it's just not regulated. So for the FDA regulated clinical trials, it's one type of cell manufactured in one way with the certificates of analysis for everything that's going to touch it, making sure it's clean, sterile, just what you think, no toxins, no heavy metals, no arsenic, you know, nothing in it before it goes back into your body.

Brent:
[14:51] Yeah. So when do you think these therapies will be commercially available?

Jan:
[14:57] A lot of them are commercially available. So one of the areas we work in is CAR-T, that's chimeric antigen receptor T-cells.
And that is for relapsed cancer patients with leukemia or lymphoma.
And what we do is to take some cells from their immune system bring it into that clean room, GMP facility, add a gene that will make a receptor protein on the surface of all of the T-cells and that protein recognizes the cancer cells.
Sorry. And when the T cell attaches to the cancer cell, it blows it up.
So there are several of those that are commercially available and approved by the FDA and they're products.
So they can be prescribed and insurance will reimburse them.
And we're working on clinical trials to develop more of those.
We have our own homegrown CAR T's here for our patients in clinical trial.

Keller:
[15:53] Is that part of the California CAR T program? Yeah, yeah.

Jan:
[15:56] Always trying to improve, trying to get them to more patients.
So those, the commercial products are, you know, about half a million dollars and you need private insurance to cover those and we can make it for a lot less, but we're constantly trying to improve on the different genes, what the receptor would see, the efficacy.
And to make those useful also for solid tumors as well as the leukemia and lymphoma, which are the cancers of the blood system.

Growth Period and Delivery of Stem Cells

Keller:
[16:34] And a quick question on like the growth period for the manufacturing on site, how long does it generally take to grow up the stem cells to where they're ready to get reintroduced?

Jan:
[16:43] It's been 12 days. We recently got FDA approval to trim that down to eight days.
You have to do all the testing and everything and make sure they're sterile and everything. And they get you get grown up in a bioreactor, and then you do all the testing, and then the next day you would take them to the patient.
And interestingly, we're now allowed to take them to the patient fresh, which is really good, because like sushi, fresh is best.
And often for these products, like if you're using the commercial product, it would arrive frozen in liquid nitrogen.
We have a team, the Alpha Clinic, they're amazing. They handle all the logistics of the products.
They would take those frozen bags under liquid nitrogen over to the patient, take a water bath, take sterile water and thaw it next to the patient and then hang it on the IV pole so it could go back into the bloodstream.
And that's part of the formulation and delivery.
But fresh, it can come directly from our GMP facility over to the hospital, over to the cancer center for infusion.
And cells don't really like to be frozen. They tolerate it, but they don't love it. So we lose some of them and some of the function.
So it's really great to be able to do the fresh ones.

Keller:
[17:50] So there's a noticeable change in yield and function?

Jan:
[17:54] Yeah, yeah, depending on the type of stem cell. So CAR T's are pretty resilient.
The bone marrow and cord blood stem cells, you know, the hematopoietic stem cells are also found in cord blood, as well as the bone marrow, the blood-forming stem cells. Those are pretty resilient. They don't mind being frozen so much, but we have other types of stem cells that just really don't do so well.

Brent:
[18:14] And then you said cord blood, is that about the umbilical cord?

Jan:
[18:18] Yeah, yeah, umbilical cord. So we run the California Umbilical Cord Blood Collection Program.
Where we are, we get a, there's a $2 fee on every birth certificate in California that goes into a pool of money, and we administer that, and we use that money to hire umbilical cord blood collectors at the hospitals that have the most diverse birth rates throughout the state.
And this is to try to, I was talking about those HLA antigens and Be The Match.
Is to try to get more diverse cord blood units into the national inventory so that people have a better chance of matching, especially if they're mixed race.
It's very hard if you're mixed race to find a bone marrow match.

Keller:
[19:05] Is that a recent initiative or has that been going on for a while?

Jan:
[19:09] It's been going on for at least eight years we've been running that.
Yeah, it was really exciting. Yeah.

Brent:
[19:15] Do you need patient approval to take the blood cord, like the umbilical cord?

Jan:
[19:20] Yeah, so it's after the healthy baby is born, and then the placenta gets delivered, and they collect the...
The baby's already taken, and it's fine.
People are afraid it somehow hurts the baby to take this, but it's really after the birth, the baby has been clamped and doing fine.
So the blood is collected. There are a lot of stem cells left in that cord blood, because it was really going around and nurturing the baby. And they're very young, very potent stem cells, and they make a lot of blood.
They can self-renew for a long time, many years.
And the mom does consent to that.
And we also get a sample of her blood to make sure there are no viruses present or anything in that unit before it goes to one of the public cord blood banks.
And they do further testing on it.

Brent:
[20:12] And then isn't there also a commercial side of that where you could save your baby's stems, like stem cells?

Jan:
[20:19] There is, yeah. That's the, so we're collecting for the public banks and that means anybody could, any bone marrow transplant center could search that national inventory.
But there's also private banking and you could save your baby's own cord blood and pay those banks to keep it for if that child needed it later on.
How long does that last? At least 20 years. It's been tested at least 20 years. Probably longer.

Keller:
[20:47] Yeah. And what are some of the major stem cell therapies right now?

Jan:
[20:52] The major stem cell therapies, I mean, bone marrow transplantation was the original one. That's been going on for years and years.
Taking, you know, for a patient, usually with cancer, they have to have all of their cells ablated and that means they get a radiation and chemotherapy so that they can't make any blood anymore.
And then they would get a blood forming system from another person.
That's bone marrow transplant. Also cord blood is used for that.
Now, we're able to...

[21:21] For patients that have a genetic disease, we're able to do that by taking their own bone marrow stem cells, inserting a copy of the gene that's broken in them, a normal functional copy, using viral vectors, gene therapy, and then give them just light conditioning and return those cells to them.
And so I started my career working on bubble baby disease, ADA deficiency, adenosine deaminase deficiency.
It's a failure of the immune system just due to one enzyme in kids and they really can't go out of their house. They have to be sheltered.
It's called bubble baby because they kind of live in a bubble.
So I worked for the first 15 years of my career with Dr. Don Cohn in Los Angeles, developing therapies for that.
Took the cord blood when the baby was born, add the normal copy of the functional gene, and then return those cells to the child.
And now, I went off to have my career and to grow the team here, and Don's team has continued to work and has functionally cured 50 kids of that disease, and hopefully more.
That was an interesting story because a company licensed it and then decided it wasn't going to be profitable.
And then Don's group got it back with help from the California Institute for for regenerative medicine and UCLA. And so they have it back now and they're poised to treat more kids. There was a pause.

Stem Cell Therapy Success for Blood Disorders

[22:45] But that's the clearest success from stem cell therapy, aside from just the routine bone marrow transplantation, is the blood-forming hematopoietic stem cell gene therapy.
And it's being used for a lot of different diseases now. We're working toward a clinical trial for sickle cell disease to cause the red blood cells to be normal and not to sickle, basically.
Other things, other gene therapies, instead of stem cell therapies, just gene therapies that are getting very popular are from adeno-associated vector.
That's a tiny little virus. We completely gut it. We put the gene of interest into the middle of it and return that into the bloodstream of the patients.
And it can go kind of throughout the body and add a good gene, if the patient's missing, like if they're missing one enzyme.
And so, those two are the most common success stories that we see right now.

Keller:
[23:41] And for these gene therapies, are there multiple sessions, or how does the treatment itself work?

Jan:
[23:46] Is it one go? You get it once, you get it once, yeah.

Brent:
[23:49] And then, could you maybe highlight a bit more at a broader level what the major differences are between the cell therapies and the gene therapies?

Jan:
[23:58] Yeah, so cell therapies.
It either just uses the cells that we make from the induced pluripotent stem cells or take out of one patient's body and return them to another or take out of the patient's body and return it in some altered form. Those are cell therapies.
There's a gene therapy that uses cells, so that's cell and gene therapy.
So we would take the cells out like I had just been talking about, use a viral vector to transfer a good gene in, or maybe to transfer in machinery such as CRISPR to edit the gene, and then return those cells back.
And then just gene therapy, people usually think of the AAV, it's adeno-associated vector, and that's that little tiny vector I was just talking about that can carry like one gene, and it can carry it throughout the body.

Brent:
[24:45] Can you control where it carries?

Jan:
[24:48] People are trying. There are different capsid proteins, it's a great question, different capsid proteins that have a better targeting for different tissues, such as is AAV capsid nine will go across into the brain after intravenous infusion.
So the cells can't do that, but that little vector can. If it has that coat on it, the capsid is the coat that the genetic material has carried in.

Direct Injection vs Intravenous Injection: Understanding the Difference

Keller:
[25:13] And could you talk about the difference between direct injection and intravenous injection?

Intravenous Delivery for Overall Body Treatment

Jan:
[25:20] Yeah, intravenous goes into the bloodstream and the bloodstream carries it pretty much throughout the body.
But for things we're working on, Clinical trials for critical limb ischemia, for instance, that's where patients with diabetes, mostly with diabetes, don't have sufficient blood flow down into their feet, into the extremities, and we would locally inject those cells into the muscle to try to grow the blood vessels down farther into the ischemic hypoxic tissue. That's amazing.

Brent:
[25:49] Yeah.

Tissue Engineering vs. Cell Engineering in Regenerative Medicine

Keller:
[25:56] Is there a difference between tissue engineering and gene, like cell engineering and tissue engineering? Is there like a distinction between those two or are they a similar process?

Jan:
[26:05] Sometimes, yeah, because there's a big tissue engineering meeting and they're actually making like chunks of tissue, which is great, you know, using those engineered extracellular matrix proteins for the cells to hang on to, maybe layering the cells.
The terms can be used interchangeably, but there really is a bioengineering aspect to tissue engineering. And like I mentioned, Dr.
Deb Liu's work making the bio pacemaker, she's actually using a bio printer to lay down ink that's proteins that have cells attached in different layers.
So, fibroblasts and pacemaking cells in different layers, which is really cool.

Keller:
[26:44] Yeah, that's amazing. You can almost like build it out to like different working systems in the tissue engineering.

Jan:
[26:50] Yeah, yeah, and you have to understand what proteins should be in there, what's most like the native tissue.
Also people are doing that a lot for skin, for non-healing ulcers or burns or things like that.

Brent:
[27:02] Oh wow. And then kind of jumping back to what we started to talk about with the CAR T therapies.
Could you talk about cytokines and how they play a role in that?

Jan:
[27:17] Cytokines are the growth factors for the cells. And so when we take the cells out of the body, we have to add, you know, GMP approved, certified cytokines or growth factors that have been made by a company in a pure system.
We have to add those to get the cells to grow.
When we return the CAR T's to the patients, they are going throughout the body and blowing up the cancer cells And they send out signals to the body that says, we have a major infection here.
It's like when you get the flu, we have a major infection or something's going on. The whole immune system needs to come in. You guys need to come help us.
And those signals are cytokines that they cause the body to make.
And it's called a cytokine storm for CAR T's. And sometimes it can be really a lot and dangerous if there's a high leukemia burden going around in the patient, for instance.
The T-cells will be super activated and blowing up a lot of cells and sending out the signals for the other cells.
But by now, the field knows how to give the patients different drugs to temper that a little bit so that it still works really effectively, but so that it's not causing damage to the patient.

Keller:
[28:33] So that tends to be more effective and more, I guess, local leukemia, like less spread out.

Amplified Signals in the Blood System for CAR T Therapies

Jan:
[28:39] The T-cells will go throughout the body and find the leukemic cells wherever they're hiding in the lymph nodes, in the spleen, wherever they are, but it's really in the blood system that the signals get amplified the quickest, I think.
So, because that's just going all through, all through the body.

Brent:
[28:58] And then I know a large part of regenerative medicine is supposed to be like anti-inflammatory.
Could you speak on the role inflammation plays in a lot of these different diseases?

Jan:
[29:09] Yeah, that is a great question. So we work with a type of stem cell from the bone marrow, the mesenchymal stem cell, also called mesenchymal stromal cells.
And they're in the bone marrow, they nurture and support the hematopoietic or blood-forming stem cells. They're also throughout your different tissues.
Those cells, we grow them out in the GMP facility or in the lab, in a bioreactor, and they are remarkably anti-inflammatory.
And so they would be the first cells on the scene.
If you get a cut or injury or damage, it would be the first ones on the scene to kind of modulate and to start the cascade of the tissue repair and send those signals out to the other cells saying, nothing's wrong here, don't get really excited, T-cells don't come blow up this tissue even though it's damaged, we're gonna get it all fixed.
And so they send out those cascades and the first signals are the anti-inflammatory signals.
So we can grow those cells out and return them to the patients to really modulate inflammation.

MSCs and Turmeric: Alternative to Cell Therapy

[30:13] For instance, after a bone marrow transplant, there might be graft versus host disease where the new cells coming in say, this is not quite, you know, I talked about those HLA types.
The new cells coming in and say, this is not quite ourself and we're just gonna start killing all the tissue.
But the MSCs are approved to, in several countries, routinely be infused into the patients to stop that type of inflammation.
And interestingly, you asked earlier, you were interested in food and stem cells relation, but the pathways that the MSCs use are exactly the same pathways that are incited when patients eat turmeric.
So I would say just eat turmeric.
Don't go through the cell therapy if you don't have to.

Brent:
[31:03] And then the MSC is the mesenchymal stem cell.

Jan:
[31:05] Mesenchymal stem or stem cell, yeah.

Brent:
[31:07] And then...
Could you also describe that the mechanism maybe a little bit more of what causes inflammation than what causes the resolving of the inflammation?

Jan:
[31:19] Yeah, inflammation is just when something's wrong in the tissue or wrong in the gut.
Maybe you don't have the right probiotics there and they're just these, you know, I mentioned that the cytokines are the good growth factors and they help the cells grow.
There are other things like TNF, tumor necrosis factor, and things like that, that get secreted into the blood and they cause a lot of inflammation.
And it's a signal that things just are not right.
And there are some diseases that just have a lot of inflammation.
If you get a cut and it's infected, there'll be a lot of inflammation around there. And it's a signal to try to call the immune system in to say, do something about this.
You know, clean this up or do something. but it can get really out of hand.
And so that's where the mesenchymal stem cells come in and say, okay, we can quench this down, don't get too excited, but we need granulocytes to come in and eat up all these bacteria and monocytes to come and start calling the immune system in so it's really, it's like a whole little world when you look at a cut in the tissues.

Graft Rejection and Potential of AI in Stem Cell Matching

Keller:
[32:30] And you briefly talked about the stem cells rejecting when they're in the host in some cases. Is there ever the case that the host will reject the stem cells?

Jan:
[32:39] Yes, yes. Unfortunately, that's why we really have to have all these diverse cord blood with the different HLA types. The patient can just flat out kill off all the cells and reject them.
That's called a graft rejection. And then….

Brent:
[32:57] With like the increase in AI technology, are you able to start looking at the genomes of the stem cells that you would potentially input and then the genome of the patient to then have a way higher likelihood of it like matching?

Jan:
[33:11] Yeah, that will be a great application for AI in the future.
It's definitely the future of all medicine and probably stem cells too.
The question is, you know, who's going to pay for that? So right now, Yeah, it always comes down to the price tag.
So right now we have kids come in with neurological disorders, they might have autism, they might be having seizures, and it's expensive to get the whole genome sequence.
It's like, who pays for that? Insurance doesn't want to pay for that.
They just want the patient to get some drug and be treated. And so fortunately we have a clinic here and we have ways to get that covered, but it needs to be more routine.
I think we can cure anything if we understand exactly what's going on.

Brent:
[33:53] Do you think insurance will be accepting of regenerative medicine more? Yeah. Yeah.

Jan:
[33:56] No.

Brent:
[33:57] Is that because they want the best for their patients or they're kind of forced to?

Jan:
[34:01] Yes. I mean, it would be best for the patients and overall it would be a lot cheaper to cure the patient rather than to keep treating them for the chronic disease and many hospitalizations.
I mean, it depends on what the disease is, but for a lot of things like sickle cell, the patients go into crisis all the time. They come into the ER, they need to be treated, they need medications.
This would be a one-time hematopoietic stem cell gene therapy.
It doesn't actually cost us that much in the GMP facility to do it.
And getting insurance to cover the costs of that would be much, much cheaper for them than just treating that patient for the lifetime of their suffering.

Keller:
[34:49] And do the, like, the costs tend to be lower if it's going, if the treatment's going through a school like Davis has, like, the Comprehensive Care Center, does that tend to have more mechanisms to assist the funding or not really?

Funding Challenges in Clinical Trials and Access to Therapies

Jan:
[35:02] Well, it's an interesting thing because for, Or I mentioned that there are several of the CAR-T therapies, for instance, that can be prescribed.
So to get to the point where a drug, a cellular therapy drug, can be prescribed, they have to go through phase one, phase two, and phase three clinical trials. The phase three clinical trials are hundreds of patients, and they're remarkably expensive.
And that's where the companies need to recoup their costs. So as an academic center, we can treat patients on clinical trial.
And then when we learn from that clinical trial, we can improve it and go to the next clinical trial and keep doing that. But there is a rule where insurance companies cannot pay for the products administered in the clinical trial.
So somebody has to pay for it. So that's where we get grants or our university pays for it.
We're very lucky for the California CAR-T that you mentioned Our CEO, Dr. Lubarsky, has been funding that program.
And that's just to help our patients, to help everybody get access to these therapies, because he's a good guy.

Brent:
[36:09] That's amazing, we need him.

Jan:
[36:10] Yeah, we need him, yeah.

Stem Cells in Cancer Treatment

Brent:
[36:13] Is there an application for stem cells in cancer? Because one thought I had was, if you inject stem cells into a cancer site, say, would it take on the form of the cancerous cells?

Jan:
[36:26] It's a good question. There could be some fusion, but the...
The treatment for cancer right now is just to completely ablate the whole patient and then to put new good stem cells from somebody else in.
The MSCs, the bone marrow stem or stromal cells have been used to try to act like a Trojan horse to get a killing molecule into that cancer.
But unfortunately, they'll do that but they don't really know what to do and they see the cancer as is kind of like a non-healing wound and they try to vascularize it and help it.
So it's kind of a battle to see, can they deliver the ricin antibody or whatever it is to the cancer before they can help it grow?
So that's really an evolving field.
But the CAR T cells, the immune cells, definitely for solid tumors, that's a hugely active area that we and many others are working in to try to use the CAR T's for breast cancer, prostate cancer, brain cancer.

Brent:
[37:34] Okay, so the CAR T therapy will translate to many different forms.

Jan:
[37:38] Many cancers, yeah.

Brent:
[37:39] Okay, that's amazing.

Keller:
[37:40] Which ones is it currently most applied for?

Jan:
[37:43] Well, we use it right now for leukemia and lymphoma. Those are the cancers of the blood forming system and that's where the approvals are.
But there are clinical trials going for basically any type of solid cancer you can think of. Yeah. Melanoma is a huge one.

Brent:
[37:57] Okay. So, with the CAR T therapy, would the part that you edit and then re-implement into the cell just be changed depending on what type of cancer it is? Okay.

Jan:
[38:06] Yes, it's that the T cell receptor, naturally, you would have some T cells in your body, just not enough of those.
They would have a receptor that sees the antigen that's on the cancer cell, and people have worked long and hard to identify these kind of silver bullets, that one protein that's on the cancer cell that we could really attack, use to attack.

Brent:
[38:27] And then how similar is that to, I think, the treatment that everyone is more familiar with now after the pandemic of antibodies and matching the proteins on the antibodies of coronavirus?

Jan:
[38:41] Yeah, it's very similar. It's just that we engineer the T-cells to always have that receptor to find that antigen.

Brent:
[38:49] I don't know, yeah.

Keller:
[38:51] And in what stage of the growth process does the engineering come into play?

Jan:
[38:57] Well, we take the T-cells from the patient's blood, they come in for apheresis, they sit in the apheresis chair and we collect some of it and, you know, return the plasma and just get the white blood cells from them.
And those come over to the GMP facility and really that evening we add the vector into it to engineer them and then we grow them up for eight days.

Brent:
[39:19] Okay.

Jan:
[39:20] So, and then they hopefully go back to the patient if we got enough cells and everything's good and clean.
So if the patient accepts those cells, when it remakes them, it will continue on remaking the- Yeah, yeah, the T-cells will go, they become memory cells and they stay in the bone marrow. So if you relapse later, they should theoretically come back up.

Memory T-Cells and the Future of Regenerative Medicine

Brent:
[39:40] Yeah, and that's because the immune system almost has a memory, correct?

Jan:
[39:43] It does, it does, yeah.

Brent:
[39:44] Could you expand on that a little bit?

Jan:
[39:45] Yeah, they're called memory T-cells and they just, they hang out in the bone marrow weight until, you know, they make enough of themselves to constantly go through the bloodstream and the body and the lymph nodes and take surveillance of what proteins are around.
And if they see that cancer antigen again, they will start expanding.
So, hopefully, the CAR T's will do the same.

Brent:
[40:08] That's amazing.

Keller:
[40:09] You know, the mechanisms behind the memory cells, like well understood, because their memory like broadly, on more like psychological levels, not super well understood, are those mechanisms clearly stated?

Jan:
[40:20] It's just, for the T-cells, it's just if their receptor gets engaged, they get a signal to make more of themselves to start really proliferating.
So, if they find their target and then that, you know, other cells are being called in. It's all orchestrated by monocytes and the antigen-presenting cells.
There are cells that will, they'll take the proteins from the a cancer cell, kind of chew them up and put little antigens out on the surface, like T-cells, hey, check this out, there's something new here.
And then the T-cell comes and sees it and goes, whoa, let's start dividing.

Brent:
[40:57] And then you said monocytes, that's a white blood cell, correct?

Jan:
[40:59] Yes, it is, yeah.

Brent:
[41:00] Okay.

Jan:
[41:01] Yeah, monocyte macrophage, it's a type of differentiated white blood cell from the bone marrow.

Brent:
[41:06] Yeah, so people should just think about it like the white blood cell is the immune system, it goes, it recognizes the bad parts of the cells or with bad cells, and then it adds the receptor onto it to then bind to the T cells, which will then go and like.

Jan:
[41:21] Yeah, the T cells would already have the receptor. It's just once they lock in, they'll be stimulated to proliferate.
So it's like a lock and key mechanism. It just blows them up.

Brent:
[41:31] Yeah.

Keller:
[41:32] Where do you see the future of regenerative medicine going?

Jan:
[41:36] I think, so after the experience with the bubble babies and, you know, the company licensing it, and then deciding that that's not enough patients that they can make a profit, I think academic healthcare centers need to do this as part of patient care.
And I hope that it becomes more broadly accepted, at least the, you know, the, stem cell gene therapies, things can become more mainstream and that academic health centers and GMPs will play an even bigger role.
Nothing against companies, but this is so specialized and it's really so cumbersome.
And for rare diseases, there are so few patients, it's just not profitable for the companies and we should be doing it as hospitals and academic centers.

Keller:
[42:36] And do you think the application will just come with time or are there certain roadblocks?

Jan:
[42:40] It's starting, yeah. A lot of us are talking about it. I have leadership roles in a few committees, and this is the wave that's coming, so it's really exciting.

Brent:
[42:49] So, if you're looking at a hockey stick growth pattern, it's kind of like just starting to build up before it really takes off.

Jan:
[42:55] Yeah, it's a new paradigm. But, you know, the insurance companies are listening.
And the big one is, you know, the CMS, the Medicare, Medicaid, they provide so much insurance to so many people. And once they come on board, there'll be a sea change.
Right now, it's some private companies that are listening, some private insurance companies and players. Yeah. Yeah.

Brent:
[43:19] Do you think there'll be a way to get the private businesses behind any of the therapies?
Because if we were able to solve like heart issues and- Yeah, yeah, yeah.

Jan:
[43:29] Things for the, I was talking about for rare diseases, because that's kind of where my heart is and where my training's been, and I think that's where the academic centers play a role.
But yeah, if there's a cure for diabetes, if there's a cure for heart issues, you know, skin problems, non-healing ulcers, then yeah, the companies will absolutely be behind that.
And especially if it's a universal product, if it can be made to match or to work for a lot of people, not just specialized for one person.
When we use the hematopoietic stem cell gene therapies, that's for one patient. And it's cumbersome.
It's not the model for big pharma.

Brent:
[44:06] Yeah.

Keller:
[44:07] Yeah.

Jan:
[44:08] Yeah. But something like a biological bandage, absolutely, they'll take it on. Yeah.

Brent:
[44:13] How does a biological bandage work?

Jan:
[44:15] That's it. We're actually working on one with Dr. Rivka Isarov.
It's a material that would go onto a non-healing ulcer, a burn, or a pressure sore, and it's embedded with those mesenchymal stem cells that help heal the tissue and some other magical things that help heal the tissue.
And it can be stored for a couple of weeks on a gel in the fridge and the cells remain potent. So, There's no reason that big pharma shouldn't be.
Really after this type of thing.

Keller:
[44:46] Yeah.

Brent:
[44:46] That's awesome.

Keller:
[44:47] And you called it magical and it really does seem that way.

The potential of transformative medical technologies

Jan:
[44:50] Yeah. We've affectionately called that the magic patch in the lab, but you know, we don't want to act like, oh, it's just so secret, you know? I mean, it's just some proprietary stuff. Yeah.

Brent:
[45:01] Oh, yeah, yeah.

Keller:
[45:02] Do you think these technologies could really shift the relationship we have with disease long-term? It could potentially allow us to be the generation to end cancer?

Jan:
[45:12] Absolutely, absolutely. And I think, you know, a lot of the surgeries right now, like amputation of a limb because there's a non-healing ulcer, I think those are going to be seen as really barbaric in the future.
Like, why did we ever have to do that? Because we could just heal it.

Keller:
[45:25] Wow.

Brent:
[45:26] What do you think the general timeline on that would be if you- Things are going so fast now.

Jan:
[45:32] It's taken, you know, the 30 years of my career. I hate to say I'm that old, but the 30 years of my career to get all of these tools in place to really understand the biology of the cells. Now we need to really respect the biology of the cells and use it to our advantage.
And you can't really change what the cells do that much. You have to respect the immune system, work with them.
And now that we get all that and we can sequence everything and we can use AI, I think it's gonna be really logarithmic, the increase in the field.

Brent:
[46:03] That's amazing. And then could you describe some of your current roles at UC Davis?

Jan:
[46:10] I write grants.
None of this gets done without grant funding. So I, yeah, I work with different teams, I help them put together their grant package. We have an amazing group.
I just meet back to back every day with different teams that are searching for funding to do these things. So that's the academic healthcare system.

Keller:
[46:33] What makes a good grant? Because I know that's a big part, even in like, as for some undergraduates, they have to work on writing grants to do.
There's small research, like what should students take away as some skills?

Jan:
[46:43] Well, for us, we have to have some efficacy and sadly, the reviewers will look more, I mean, it's the TikTok and, you know, Instagram generation.
The reviewers will look more at a good picture or a good figure and the legend of that than anything you want to write in the text. So, you have to have the data. You have to show, okay, here are the cells not working, here are the cells working.
Wow, this really has potential. Please fund me to do more of this and and to get it to patients, and that's really what we do.

Overcoming pushback on novel and advanced technologies

[47:11] So fortunately, we have foundations for all the different rare diseases, all the different therapies, and the foundations raise money for those first pieces of data to go into the grant.
It's the seed funding. And then we use that, once it's really feasible and we're really excited about it, then we can write a great, exciting grant and say, this has the potential to help this many people Um, over their lifetime, the cost of their treatment would be this many millions of dollars. We can do this for 47,000.
Give us money to test it, please.
But for a student, remember that a lot of the reviewers are older and exhausted at the end of the day and you don't get time during your day to review anything.
So, just make it really clear and really straightforward and good graphics really help.

Brent:
[48:04] Okay and then have you ever had pushback with some of these technologies being so novel and advanced that the reviewers or the people peer reviewing maybe don't fully understand it and then therefore will reject it?

Jan:
[48:19] Yeah engineering the mesenchymal stem cells has been something I wrote a edited a book on it over a decade ago and it's been before its time until now We just finally licensed our patent to have these cells making vascular endothelial growth factor to stimulate the blood forming system for critical limb ischemia.
Finally got the patent licensed and we're moving toward the clinical trial.
So we've been working on that about a decade and everybody was just like, oh, you don't want to engineer these cells for whatever reason.
It was just so far before its time and so outside the box.

Revolutionizing Treatment for Non-Healing Ulcers

[48:56] It was really hard to get there, but now we're there, and we're moving toward the trial. And my stepdad died from non-healing ulcers and had to have an amputation, so I really lived through that.
And for that particular disease, you know, a home healthcare nurse will come every two days and debride their wound, and it's painful, and it's costly.
And this therapy that we're developing, it's like tens of thousands, not millions.
Why not just heal the ulcers and get the blood flow back down into the foot instead of doing these things?
Unfortunately, right now, the reason that that was so hard to fund, the insurance companies, most of them, look at amputating the foot as a cure for non-healing ulcers in diabetics.
That's a cure. away the problem. But unfortunately, the life expectancy is about six months after an amputation. CB Oh, wow.
DRH So, yeah. So, you know, it's just slowly chipping away at these paradigm changes and showing that there's a better way to do this stuff.
That's mostly what I do.

Brent:
[50:06] No, we need that, yeah.

Keller:
[50:08] What can students get, what can students do to get involved with regenerative medicine?

Jan:
[50:13] Yeah, we have five or six different training programs here.
You can apply to one. I'm PI of the EDUC4, it's from California Institute of Regenerative Medicine, which is awesome. That's our state STEM cell funding agency.
And they fund, they fund a undergrad training program. Dr. Alice Tarental is head of that one. That's called the COMPASS.
And then for grad students, postdocs, and MD fellows, we have the EDUC4, it's not very catchy, but that was the term.
And you get a stipend, and you get money for research.
So apply to those, volunteer for the labs. We have, let's see, 29 labs here that love to have interns.
And it's a really robust ecosystem here.
We also have training programs for Sac State and Humboldt State students, and we have a high school training program.
We're just getting ready to welcome our high school interns, 10 of them, for the summer to work in our lab. Yeah. So the whole spectrum.
And we also train the MDs that want to be in this field, the young MD fellows.

Keller:
[51:18] So yeah.

Brent:
[51:18] That's amazing.

Stay Curious and Enthusiastic: Advice for Students

Jan:
[51:19] The whole spectrum.

Brent:
[51:21] Is there any advice you want to give students or anyone listening?

Jan:
[51:25] Stay curious, stay enthusiastic. I love the questions you guys are asking. That's awesome.
But just, you know, I take people into the lab if they just seem really curious, scientifically curious and just enthusiastic.
It doesn't really matter what you've done in the past. If you've had some biology, it can apply. So, just- That's amazing. Yeah.

Keller:
[51:47] Sweet. Well, it's been very inspirational. Thank you.

Jan:
[51:50] Thank you. It's been my pleasure.

Brent:
[51:52] Thank you.