Stem Cells and the Bigger Picture Ophir Klein, MD, PhD

Science benefits from stability in terms of being able to take the risks that are important. You can't have people on such a short leash that they're wondering what's going to happen in the next few weeks.

AI in the clinical setting is driving major transformations all the way from data analysis (thinking about new medicines) through the translational part of the spectrum, and then into the clinic and how we're taking care of patients.

If you were going to share one thing, many adult diseases actually have their origins in childhood. And so, how can we think about leveraging our pediatric healthcare for adulthood and vice versa?

Ophir Klene: Dr. Klein, so great to have you in. It's great to see you by the way.

Dr. Klein: Likewise. Yeah. And there's so much to cover. The show, as you know, is the pathway to peak performance and we talk about all the things that you've done, and you have done quite a bit.

Ophir Klene: So, number one, what's your charity that you're choosing?

Dr. Klein: I chose the National Foundation for Ecodermal Dysplas, which is a charity that helps people with this rare disease called ectodermal dysplasia. And one of their main issues is that they're missing teeth, but they also have other parts of their body that don't work properly. So, I've been involved with them for a long time and it's a great organization.

Ophir Klene: Yeah, that's a crazy situation, right? Where you don't develop adult teeth.

Dr. Klein: Or actually, or any teeth sometimes. And so the remedy to that is going to be like a dental implant at some point in time once you reach maturity of the jaws. And actually, the biggest issue that they have is that they don't develop any of what are called ectodermal appendages, of which teeth are one, but also sweat glands, sebaceous glands, and hair. And so their biggest medical issue is actually hyperthermia because they don't sweat. So, that can lead to severe illness or sometimes even death.

Ophir Klene: Hyperthermia meaning that they get too hot.

Dr. Klein: Exactly. Yeah. That's wild. Well, that's a fantastic charity. Well, thank you guys for supporting them.

Ophir Klene: Well, thank you for bringing it. We really appreciate that. Well, you are an MD/PhD. Which is, you know, I don't know what else is next. You're going to be a rocket scientist or something. I'm sure.

Dr. Klein: I wish I had an MBA actually. I feel like that would have been useful.

Ophir Klene: Okay. Well, you know, I think you know where to go to get one, right? So the reality is that you have done so much.

The Klein lab in San Francisco at UCSF—we have to dive into the study of what you're doing there and how that evolved—and we talk about Cedars-Sinai and all of the things. But let's go all the way back to where it starts for you. Tell us about the beginning. How do we get to this pathway of peak performance? Because you are truly a peak performer.

Dr. Klein: Oh, that's very nice of you. I grew up in the Bay Area. My parents are from Israel and they were initially here for a short period of time and then I ended up staying for almost 40 years. I would say both of them were, in different ways, kind of inspired me to do the kinds of things that I do. My dad was originally a scientist and then got into business. He came around during the early days of the high-tech era and worked at places like Intel when they were small companies. Ever since I was a little kid, I just saw his amazing work ethic and drive and the joy that he got out of accomplishment. The main takeaway was that he worked really, really hard, but he never wasn't just that he didn't complain about it; he seemed to actually get energy from it. And my mom is an artist and has a very different take on life, but I think also I learned a lot from her, particularly the way she interacts with people. She has a very wide circle of friends and from all walks of life and really kind of connects with and engages with people. I would say both of my parents actually, when I look at my brothers and myself, we have elements of that, but they really have that—they're both very, in their own spheres, kind of, very high performers, very magnanimous and sort of outgoing.

Ophir Klene: So you start off in school. At what point in time do you sort of get the inkling that, "Hey, I want to be a doctor?"

Dr. Klein: You know, for me it was pretty late actually. I was initially more drawn to the humanities and social sciences, and even when I got to college, I ended up being a Spanish literature major. I liked science when I was growing up, but I was never sure that that was the path for me. And then when I got to college, actually, a lot of it was my dad kind of really encouraging me, "Just take some science classes, see if you like it. Don't close yourself off too early."

It turned out I signed up for this chemistry class my first semester in college, and I had this really terrific TA... She encouraged me to go work in a lab, and I really just fell in love with being in the lab. The courses were interesting, but working in the lab, even at that very early stage where you're not doing very much as a freshman, but still just observing the process of discovery, was like a light went off. I felt like this would be a great way to spend a life. Ever since then, I've really liked it. It took me a while to decide that I wanted to have my own lab and be a faculty member, but I always knew that just being in that lab environment was very gratifying. A year or two after that, I started to think about what I was going to do next, and I considered a wide range of options, including things like still looking at getting a PhD in Spanish.

One thing that I would say carries through everything is I've been really lucky with the mentors that I've had. If I had to identify one theme that I'm grateful for, it's that. The first lab that I worked in was Paul Alvisadus's lab... And then I decided I was going to switch into biology, so I went to this guy Dan Koshlin's lab... And I heard at that time about these MD/PhD programs, which actually Dan discouraged me from pursuing because he says you've got to either be a scientist or a doctor. But for some reason, the idea of trying to combine those two things really resonated. I had started volunteering in a hospital to kind of see what it was like to work with patients. I applied for these programs and then I went to Yale for medical school and did a PhD in this guy called Dan Deo's lab, and that was another really fortunate mentorship situation because Dan was a great teacher...

From there, I decided to go into pediatrics. I can tell you more about why I decided to do that, but that was a great decision for me. And then pursue clinical genetics as a subspecialty. And then I came to UCSF where I had another outstanding mentor, who was Gail Martin, and she really, I would say, if there's one person that kind of got me convinced about a life in science, her vision and commitment and passion was just really an inspiration. I still interact with her even though she's retired now.

Ophir Klene: Wow. So, mentorship was really a big piece of the...

Dr. Klein: Yeah, for me that was the key thing, and that's the thing that I try to think about in my own group and with other folks that I interact with because I know just how transformational those experiences were. I feel really lucky.

Ophir Klene: What do you think it was about you that made them want to do that?

Dr. Klein: That's a good question. I think people respond to, first of all, that you appreciate the mentorship. And I think it's very much a two-way street. It's a mutual relationship that both people have to feel like they're getting something out of it. And I didn't understand this when I was younger, but now I really get the idea that actually a lot of times as a mentor, the relationship is as beneficial for you. Not just in terms of feeling like you're helping somebody, but also because you can develop new ways of thinking. Young people, they may not be that experienced, but they're often very smart and they can bring a lot of new perspectives to the table. I think also for me, I like to help people who have drive and a desire to succeed. That's more fun than feeling like you're kind of pulling somebody up and trying to convince them that they should want to do something.

Ophir Klene: You know, you don't just sort of all of a sudden arrive there. It's a ton of work that you've put into it. So, along the way, do you ever have any questions about whether or not you were...

Dr. Klein: Definitely. Yeah. I was not one of those. I always admired those people who were like a laser and just, you know, "I know exactly where I'm going and what I'm doing." It wasn't that I was constantly struggling... I remember probably the biggest questioning moment that I had was a couple years into medical school. This is getting back to what I was saying before about what one of my mentors, Dan Koshlin, had said about you really can't do, if you think about medicine and science, they're both full-time jobs. I think that that first kind of dawned on me when I was partway through medical school, and I liked a lot of aspects of clinical medicine, but I also wanted to do science, and I was kind of thinking about how can I do this.

I just sort of thought, "Well, should I just choose one or the other?" And I remember this classmate of mine who... we talked her through and she was like, "Look, you know, you're kind of partway into this thing. You don't dislike any part of it. You're just worried about what's going to happen next. So why don't you look at it as just part of your life's journey completed and then nobody's going to force you to do anything afterwards? You can still do what you want, but you'll be much happier." She said this as somebody who had tried and started and stopped various things. She's like, "You know, you'll be much happier if you just finish this and then decide what you want to do." And that was a helpful conversation for me.

Ophir Klene: So we get to UCSF. There's a lot to unpack there. Where do we start?

Dr. Klein: UCSF was a really important part of my life and I think one of the hardest decisions I ever had to make was whether I should leave or not. I was there for a total of about 20 years. I came as a clinical genetics resident. Although we call clinical genetics a subspecialty of pediatrics, it actually became its own field of medicine.

Ophir Klene: So I think it warrants actual explanation.

Dr. Klein: So in medicine, we have what are called primary fields of medicine: Internal Medicine, Pediatrics, Surgery. And they all have various subspecialties... And my field of clinical genetics used to be a fellowship that you did after a residency. And then around when I started training about 20 years ago, they converted it to become a residency. So now, clinical genetics is a primary field of medicine alongside pediatrics or OB or Internal Medicine.

I did a pediatric residency at Yale, and then I came to UCSF to do a clinical genetics residency and also did a postdoctoral fellowship in Gail Martin's lab, the woman that I was talking about. She made a number of very important discoveries. I would say her biggest thing that she's most known for is she coined the term embryonic stem cell and was the first person along with people in her former lab to isolate them.

That was the first few years at UCSF. And then I was really fortunate to get a faculty position at UCSF. It was a little bit of an unusual move because when I was doing my clinical genetics training, seeing patients, and my work in the lab, there was a kind of serendipitous confluence of those two areas. In the lab, I started working on mouse mutants, and we found some that had tooth abnormalities... And then in the clinic, I had this continuous realization of how important the craniofacial complex—the mouth and the skull—were in terms of genetic syndromes. Something like two-thirds or three-quarters of syndromes have some effect... on the face.

This was an opportunity to sort of answer this question that I'd had for so long about how do you integrate being a scientist and a physician. And one way to do that is if your clinical work and your scientific work are related in some way. That resulted in the Craniofacial Center at UCSF looking for a clinical geneticist. And I was able to get a joint appointment between Craniofacial, which was in the school of dentistry, and Pediatrics and Genetics, which were in the school of medicine. They put together this package that enabled me to stay, and I was very appreciative of that.

Ophir Klene: That's a really interesting piece of the story, a joint appointment and teamwork around that. Was that difficult to put together or did it naturally flow together?

Dr. Klein: I think it was not trivial for them, but it was a combination, I think, of them wanting to grow these kinds of interactions, and they felt that there probably weren't a lot of people who would be in a position to do that. That's something that I, when I do recruiting now, also think a lot about is sort of how you capitalize on opportunities if you have somebody who has a specific skill set or combination of interests... Timing is really important.

Ophir Klene: I mean, that was my experience at UCSF with what we worked on building there, and has even more so been my experience now since moving almost four years ago to LA and launching a new children's health effort which is definitely a marathon and not a sprint. The overall effort is a very long-term one and hopefully in the long run is going to produce a real impact on the community and on the region and even beyond that.

Ophir Klene: For sure. I mean that is a ginormous job, an incredible organization. Cedars-Sinai is just, I mean that's cream of the crop.

Ophir Klene: Going back, I wanted to ask you about the day that you got your own lab. What did that feel like?

Dr. Klein: Now it's sort of half a lifetime ago, but at the time it was a really... In a lab, you write your name on everything because that way when you take it to the get dishwashed or to another room, you know, you make sure it doesn't get mixed up with other people's stuff. And so, writing your name on all the beakers and ice buckets and everything is a super exciting feeling. You feel very proud and also a little bit anxiety-provoking because all of a sudden you realize, you know, like with any effort... you're in charge and it's really up to you to make sure things work and try to uphold standards. Everything from budgeting to recruitment to the direction, all those things are on your plate. There are people who naturally want to be in a leadership role and feel like it's an honor and a privilege and they kind of are excited about taking that opportunity and making something out of it.

Ophir Klene: And you did a lot of great work there. You want to talk a little bit about that?

Dr. Klein: Yeah. Well, I feel like we're still very much as a lab on this scientific journey and have figured some things out, a lot more to come. One piece of advice that I got from my postdoctoral adviser, which I still think about a lot, is you can be very targeted when you are in science or you can be open to new discoveries, new findings. And I think both of those have pluses and minuses. If you're overly targeted, obviously you can miss some great thing that happens... but if you're kind of all over the place and always chasing this new shiny object, you're not going to get things done.

She said, "You know, I always followed what was interesting to me, but then I made sure to get it done." So that's kind of how I have always thought about it: if there are new directions we should definitely consider them, but we should consider them in the context of are we going to be able to actually get things done and make an impact.

I was really very focused on the craniofacial complex and the oral cavity. Initially, we came up with a basic science problem that has important clinical correlates, which is around tooth renewal and regeneration. This is a problem that affects a lot of people. In terms of morbidity, it's actually a huge area in human health. So we started off by saying, what are examples of what can we learn from nature? And I learned about something which still fascinates me to this day, which is that there are many mammalian species that are able to continually grow their teeth throughout life. We use the mouse as a model, but you can see this in many other species like elephants or walruses or rabbits.

We set out to understand the mechanisms that underly this ability to grow teeth continuously in other animals with the idea that nature has figured this out... and then perhaps bring things back to patients at some point. As a community, there's been a fair amount of progress in understanding the genes and cellular processes that are involved in enabling this continuous growth.

Ophir Klene: I mean the work that you're doing is such a long haul. Along the way there have to be moments of 'aha,' like great satisfaction, right? But there also probably is that moment where you're like, "I'm wandering."

Dr. Klein: That is the absolutely hardest part of science is that in some cases, you know, 90% of what you're doing is troubleshooting... I've had that not infrequently in my lab. Somebody told me once, it's actually the only thing you have control over in science is when you're going to stop a project, because you can't really make something work if it's not going to work. But that's a hard thing to do because there's the sunk cost. And so you're kind of always wondering, "Well, if I just do a little bit more, will I redeem all the effort that went into it?" I think it's one of the skills that you learn as you get older. It's not as fraught of a thought process as it used to be to look at a project and just say, "You know, in order for us to make this what we would like it to be, it's just not really worth the additional investment." But yeah, I think that that question is probably the single hardest thing in science.

Dr. Klein: I think that that's an important point that I always try to convey to people who are outside of science, especially with everything that's going on right now, is that science benefits from stability in terms of being able to take the risks that are important for the significant advances, the blue-sky kinds of approaches. You can't have people on such a short leash that they're wondering what's going to happen in the next few weeks. The way to encourage high-risk, high-reward science is to have a stable base.

What we do, and what I think academic science is best at, is the fundamental discovery science that to really lay the foundation. The reason for that is because... that's just not what industry is interested in; it doesn't have the time scale to work at the most basic discovery level.

Ophir Klene: I would imagine... that stability and knowing that your attention has to stay on the endgame and trying to discover and work through that when funding is in question, that's anxiety-provoking.

Dr. Klein: Yeah. And I think like in many spheres of life, one of the big questions is when you're looking at the scientific enterprise as a whole, what's the best way to allocate resources? I think in the US historically, we've done a pretty good job of that, and that's my concern about what's happening right now is we're taking a system which is not perfect... but has performed well relative to most other systems, and we're jeopardizing it.

Dr. Klein: I think it's at the simplest level, it's hard for everybody. For people who are more novelty seeking or open to change, it's still hard for them to change, but they can deal with it. But then you have a lot of people who any change is just really hard for them. And so that means that when you're in an administrative or leadership role, not only you have to figure out what changes are you going to make, but then you're thinking about how are you going to get people who are constitutionally inclined for stasis to be... and it just seems like everything is accelerating now, and things are... I look in healthcare, it's a very dynamic situation.

Ophir Klene: You made a major move. I mean, you had a very comfortable situation.

Dr. Klein: Yeah, I agree. I feel like it was a hard decision in the sense that... if you have a situation that you're really happy in, and I always felt like this at UCSF, not just that I enjoyed the work, but I really enjoyed my colleagues and I felt really well supported... I had nothing that really made me want to leave.

But then I was presented with this what I felt was a unique opportunity. I had looked at some things over the years that were really interesting, but the one that came along in Cedars was unique, and that was to... I think we're the only place in the country right now that's making this big of an investment in growing a child health enterprise including clinically and academically and research at this level. The number of recruitments that we've made and investments that we made are really just very remarkable.

I was thinking about that recently. This was a big change for me also in terms of the role and the types of interactions that I have. And I definitely feel like I've made some mistakes, and hopefully learn from them. I look at that as a growth opportunity. When I was looking at this, I had this conversation with one of my brothers who said, "You know, if you try to weigh all the pros and cons, you're going to have a really hard time. You just have to decide, you know, you have one life... and you have to decide if a change is what you're feeling is good right now." And at the end of the day, that sort of was what the deciding factor for me was. I'd been at UCSF at that point... about 20 years. And I liked all of it, and I could also imagine what the next 20 years would look like. Whereas with moving to Cedars, I didn't really know, and that in of itself was kind of what enabled me to make the decision.

Ophir Klene: So it was sort of like maybe a seesaw, right? You have this super excitement about this new opportunity... but also the fear and trepidation probably around, okay, these are uncertain outcomes. And it's a big move. I mean, your entire life is here.

Dr. Klein: Yeah. I mean, personally, professionally, I lived except for medical school in the Bay Area my entire life. And that has been hard. It's a lot better now. When I first got to LA, I expected because it was in California that it would be more similar to the Bay Area, but it's actually very different in a lot of ways. I think one of the biggest ones is in San Francisco, I used to walk everywhere... whereas in LA, it's very car dependent. That's actually one of the reasons we decided to get a place that's closer into the hospital was to be able to walk a little bit more.

Ophir Klene: I think now that you're there and you've settled in... you feel like the work that you're doing is very gratifying and you're really heading in a really exciting direction.

Dr. Klein: Yeah. Yeah, I would say that. I've definitely been a learning curve... But overall, I'm really gratified and grateful for the experience and I feel very proud of what we're accomplishing there as a team. That's another thing that's interesting about this job is actually most of what's going on is not me doing it. It's the folks that I'm lucky to work with who are doing it. And it's watching these really terrific people doing what they do and working on how to integrate that. I feel like it's the idea of kind of being the conductor of an orchestra. Part of what your job is is to make sure that the sum is more than the individual parts.

Ophir Klene: You're creating something... maybe you could describe what you're really trying to do there? What's happening?

Dr. Klein: The vision is to build a premier tertiary and quaternary pediatric health enterprise, both in terms of providing outstanding clinical care and doing cutting-edge research. We're not a freestanding children's hospital... We're part of a health system which takes care mostly of adults and more and more now of children. The commitment that was made to us at the beginning was, "If you do a good job and you perform, then we'll continue to invest." And that's been the case.

We feel like that's one of our big advantages compared to traditional children's hospitals is that we have a huge obstetric program. We have the largest number of births in LA. That then feeds into child health, which then feeds into that continuum of care into adulthood. And one of the ideas that our new head of research is pushing is that many adult diseases actually have their origins in childhood. And so how can we think about leveraging our pediatric healthcare for adulthood and vice versa?

Ophir Klene: I'm curious what you think is the most exciting part of the work that you do at this point in time.

Dr. Klein: I think that's a really good question about contributors to disease. Clearly nature and genetics have a part of it, and everything that happens outside of you, whether it's the psychosocial environment you're in or the physical environment you're in, the microbial environment you're in, all of those contribute. To me, the most exciting part... is the ability to integrate all these various pieces of data. Not saying your DNA is more important than your microbiome or than your home environment, but how do we look at all of these inputs together and try to help people be as healthy and happy and productive as they can be.

Ophir Klene: I'm curious what your thoughts are on AI in the clinical setting.

Dr. Klein: I see that there are major transformations going on all the way from the most basic parts of the biomedical enterprise in terms of data analysis, like you said, thinking about new medicines, through the translational part of the spectrum, and then into the clinic and how we're taking care of patients. There are huge opportunities... There's also a lot of challenges, whether you're talking about mistakes that the AI can make and built-in biases and inequities... So it's important for us to not just use AI but also study how we're using AI. These technologies are very powerful and also have some kind of built-in limitations that we have to keep in mind. I'm not so much worried that it's going to eliminate doctors or eliminate nurses... but I do think that it's going to have major impacts that we have to be aware of and invest in studying so that we use them as well as we can and try to prevent harms.

Ophir Klene: What do you think the most exciting stuff is happening in stem cell science right now?

Dr. Klein: What I think is really amazing is how the tools that just a few years ago seemed so far away from implementation into patients are every month or every week or sometimes every day you're reading about new approaches. Most recently, the steps forward with the xenotransplantation—organs grown in animals—moving more and more towards being clinically used, but you could say that about so many different things: immunotherapy and CAR T cells and, more controversially now, people are talking about work that's being done with human embryos.

There are so many different domains in which the promise that we had talked about for so long in the lab is moving into the realm of the clinic. I don't want to suggest that any of this is easy or doesn't have important ethical considerations... But there are so many opportunities right now that we just couldn't dream of five, let alone 10 years ago. To me, actually, the biggest challenges right now are on the economic front. Not that the science isn't hard, but it seems like we really have an engine right now scientifically that you can see how this is going to unfold over the next decade. How we're going to pay for it is not obvious.

Dr. Klein: I've been lucky that actually since I moved to LA, I've been learning from this guy about kind of functional movements. And I realized as getting older that sort of joint mobility and flexibility is really important. It makes me feel like I can move a lot better.

Ophir Klene: It's crazy too, you if you start training that way, you realize how much... we push, we pull, we right? But when you start moving, rotating, how difficult some of those exercises actually are, how far away we've gotten from our ability to be flexible and mobile.

Dr. Klein: And how much you can actually recover that you feel you've lost.

Ophir Klene: So true. Right. It doesn't take that much. The standing desk has been great because during the day, I'll just start doing stretches, and it's amazing to see how quickly you can tighten up in the legs, the back, and all that stuff.

Ophir Klene: What would you say to anyone that's really pursuing it (a career in medicine)?

Dr. Klein: First, I would say that I feel so lucky that I ended up in medicine as a field, both in terms of the feeling of helping people and also how interesting it is. For me, it's been incredibly fulfilling and gratifying. I highly recommend it as an area to go into. It's not for everybody. I do think that, like all aspects of life, medicine is going to be changing a lot in the coming years. And so, I would encourage people, I think it's great to have a goal and to say, "This is a specific field that I want to go into," but you know, keep your eyes open and be flexible.

In my case, I actually initially thought I was going to go into one field and I for various reasons decided to change it, and I'm glad I did that, because you don't know as a college student what it's actually going to be like. And you might have a feeling that a field, when you see it either as a patient or an outsider, is one way, and then when you actually figure out each of these fields is very different in terms of how you spend your day-to-day life. So, just be open to seeing what they're like. And that's actually a built-in part of the medical education system, which is good that you get exposure and you don't have to decide at the beginning exactly what you want to do.

Ophir Klene: Well, phenomenal to have you here. It's been really fun for me. So good to see you and I always enjoy spending time with you.

Dr. Klein: Thank you. No, this has been super interesting. I've enjoyed the conversation.

Ophir Klene: Hey, thanks everyone for watching the show. Please remember to like, comment, and subscribe. It really helps us out here at the channel. And share the video with someone who might be interested in supporting the charity that our guest mentioned in the episode. Thanks again. We'll see you soon.