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The Future of Vaccines: An Interview with the Doctor Who Created the First Fully Humanized Immune Systems in Mice · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

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  I'm Holly Wayment, and this is Pediatrics Now, cases, updates,
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  and discussions for the busy pediatric practitioner.
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  Click on the link in this podcast for a free credit that may include CME,
• 0:13
  MOC, or ethics credit depending on our topic or podcast.
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  I am so honored today because here in the podcast studio with me is Dr.
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  Paolo Casali. He's the University of Texas Ashwell Smith Professor and Distinguished
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  Research Professor, Microbiology, Immunology, Molecular Genetics.
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  He's Professor of Medicine at the University of Texas Long School of Medicine.
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  Dr. Casale, first, thank you so much for being here in the podcast studio today.
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  My pleasure. So you and your team have accomplished something that is so amazing
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  and so interesting and will affect medicine for countless years to come.
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  So you all have created the first humanized immune system in mice.
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  Well, thank you for your kind words. Actually, this is not the first humanized
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  mouse. humanized mice have been.
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  Had been attempted to be constructed since the 80s, the late 80s,
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  when there was an urgent need to model in vivo the human immune response to HIV.
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  And so those were the first, so to say, humanized mice.
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  In fact, those precursors of humanized mice were very rudimental.
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  Very primitive, and they really didn't quite, those mice never quite mounted a good immune response,
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  to antigens or viruses, whatever,
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  immunogen.
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  And this has been really the shortcoming of the different varieties of humanized
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  mice throughout the last many years.
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  And I think it's proper to say that our mice are the first fully humanized mice,
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  the first mice with essentially a 100% human immune system.
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  So you and your team are the first to create mice with a fully humanized immune
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  system. And fully functional.
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  And fully functional. It's incredible. So, what does this mean for medicine?
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  Well, I think it's a simple and complex answer.
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  But first one, we have to define what humanized mice mean.
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  And what it means is these are mice with a fully, virtually,
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  or fully, as one could argue here, human immune system.
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  So the mice are mice, but they are immunodeficient mice, virtually without immune system, so to say.
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  And this mice accept a graft consisting of human hematopoietic stem cells and
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  these are the cells that will give rise,
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  will proliferate and differentiate and give rise to a whole human immune system.
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  And these stem cells are hematopoietic,
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  meaning they are stem cells that will give rise to cells of the immune systems.
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  But of the lymphoid lineage, such as BAD lymphocytes, myeloid systems,
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  such as granulocytes, neutrophils, and macrophages.
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  And then once grafted in immunodeficient mice,
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  again, then within a number of weeks, you will have those mice fully constituted
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  in the immune system, functional immune system.
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  Now, how that is done, it's important to understand what the potential of these humanized mice is.
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  So it is done by crafting hematopoietic, human hematopoietic stem cells from
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  core blood, from neonatal core blood.
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  And so we take cold blood with the help of the OBGYN department.
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  Fresh cold blood, we purify the hematopoietic stem cells from that cold blood,
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  and then graft within 24 or 48 hours of birth this sort of special immunodeficient mice.
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  Those are pups, they're neonates, and we graft those mice intracardically with a small insulin needle.
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  And the grafting is
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  done in the left ventricle to maximize the dissemination of stem cells throughout
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  all districts of the bodies so that those stem cells will become resident of
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  wherever bone marrow will develop.
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  Now, these are special immunodeficient mice in that they carry a mutation on
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  the CKIT receptor, and they are referred to as W41.
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  We did not generate these immunoleficient mice.
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  These mice have been available for about four years.
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  The interesting thing is that nobody really took advantage of them to...
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  To create immunized mice with a fully functional immune system.
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  More precisely, I should say that the two different groups,
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  one in Minnesota, the other one in Germany, who created these immune-efficient
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  mice with the same mutation, W44 mutation,
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  actually did craft them with human hematopoietic stem cells and they did quite
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  full characterization of the developing immune cell elements.
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  But they didn't really do much of functional studies on the immune response
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  potential of these mice.
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  And this is what we have done. What we have done, which has been different from
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  any other humanized mouse,
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  has been the crafting in intracardiac grafting and,
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  importantly,
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  the hormonal conditioning with estradiol, with estrogen, of male or female pups.
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  And this is what really has made a big difference in terms of the development of the immune system.
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  And the functioning, and the differentiation, further differentiating, I should say,
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  further differentiation of immune cell elements once these mice were challenged,
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  were immunized with different conjugated optins, and those are main-made molecules.
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  But how many years in the making has this been? It has been five years.
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  Is this a dream that you've had for a long time to accomplish this?
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  Or how, Paolo, can you tell us about how this came about, how you got into this? How I got into it?
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  I think my age has played a major role in it.
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  In that experience, I should say.
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  My many years of research in immunology have always been, has certainly always
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  been with the human immune system and immune response in mind.
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  But my research has always been very basic, very molecular,
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  very much into the cell, namely B cells, B lymphocytes, which are the cells
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  that make antibodies, and very much with a molecular genetic flavor,
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  very much about regulation of genes that encode antibodies.
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  Cross-reaching somatic permutation of those genes.
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  And with my aging, I became, I have become.
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  Much more determined and, I should say,
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  much more motivated to do something that will have an immediate relevance to vaccine development,
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  to the human antibody response, but particularly antibody response,
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  because I always worked on B lymphocytes, and as I say, antibody genes.
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  And I should say that my persuasion is not only mine, has become stronger and
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  stronger than if you want a good vaccine.
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  You need to be able to generate a good antibody response, one that is very specific
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  and neutralizing a virus or a bacterium or whatever else or a toxin.
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  And so once we have become more and more familiar with the intimate molecular
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  mechanism that underpins the generation of a mature antibody response,
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  again, one that matures, one that that is highly specific and can neutralize microbial agents.
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  And one has certain features, regular features in the antibodies.
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  And that is, again, those antibodies are generally IgG or IgA,
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  and they're invariably actually somatically mutated.
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  In the variable region of the antibody molecule.
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  And this is what provides a substrate for the selection of high-affinity mutants,
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  submutants, I should say,
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  in those B-cell codes that are selected by the antigen driving the response, such as the HA,
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  the glycoprotein spike of influenza virus, virus or the surface antigen on bacteria,
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  Fragilin in Salmonella, for instance.
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  And so the idea was, at this point, we need to be able to do.
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  Experiment in vitro in a 100% immune system.
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  Because if we can do that, then we are in the position of, finally,
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  of being able to do vaccine development.
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  Vaccine testing of drug, if not development, but certainly testing,
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  particularly, well, in any case, of drugs.
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  Immune modulators such as checkpoint inhibitors in the case of the antibody
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  immune response to tumors, solid tumors, and many other things that one cannot do.
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  To this day, if you develop a vaccine, the last step the FDA wants you to efficacy,
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  before going even to phase one in non-human primates.
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  Non-human primates are not exactly human. They're very similar,
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  very close to us, incredibly close to us, but in many ways are not exactly human.
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  This is perhaps not even the major obstacle in the use of human primates.
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  One problem with human primates is that they are so close to us that you don't want,
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  I certainly don't want to do what has been done with human primates, with those primates,
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  non-human primates, for many years in the whole story of HIV, for instance.
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  Certainly, many things have been done with those non-human primates that shouldn't
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  have been done, and which today are not accepted and not done.
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  Because of cruelty? Yes.
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  And unnecessary experiments. experiments. So this will reduce,
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  the amount of testing that needs to be done on non-human primates.
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  Hopefully, if these mice turned out to be really what they are,
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  I'm being very cautious here, but they turned out to be really what they seem
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  to be, and I think they are,
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  then you could do,
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  a lot of vaccine development because you're dealing with an in vivo human immune system.
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  And you cannot do that in humans for ethical reasons. Yes.
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  It will help dramatically pave the way for even better vaccines,
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  more targeted vaccines.
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  Yes. And then when it comes to tumors.
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  It's already been with a few THX mice. Targeted therapies? These are our mice.
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  Here, actually, we are collaborating with giving our mice to a couple of groups
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  working with different tumors, solid tumors.
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  So this investigator grafts tumor tissue from humans into the mice and then
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  studies the overall reaction to that tumor. more.
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  And that reaction is human, be it inflammatory or immune, explicitly immune response.
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  Wow. So I started some investigatory, I started doing that.
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  You worked, Paolo, for many years as an immunologist.
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  And so instead of retiring, like a lot of people do, you really revved up your
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  research and the urgency to make a difference and get this done. Yes.
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  And the NIH offers experience and knowledge, but it also offers security.
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  I was always well-funded with the NIH.
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  But at this point, I could afford to do something that I was not funded for.
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  Really? That's amazing.
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  We're going to do it. I'm going to make this happen, right? That's right.
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  Can you tell for us a practical example in, say, for pediatrics?
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  Well, one thing that we already did with these mice, again, we refer to them
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  as THX mice, three true human X mice.
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  This was not me. This was our development office.
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  So one thing that we already did, and it's published in this paper that you
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  mentioned, is we vaccinated these mice with a messenger RNA Pfizer COVID vaccine.
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  Using the schedule, an immunization schedule, which is the same as for humans.
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  And the mice made a neutralizing, strong antibody response neutralizing to SARS-CoV-2.
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  Those are human antibodies, obviously, and we analyze in details the molecular
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  genetic makeup and molecular composition of that response.
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  So again, that's good.
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  We did the same, and that's published as well, with purified Fragilin from Salmonella.
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  We immunized those mice with Fragilin and showed that they mounted a neutralizing
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  antibody response to salmonella,
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  neutralizing, as assessed by in vitro, the classic colony neutralization in petri dishes.
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  But then we also show that the THX mice vaccinated with flagellin survived,
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  fought and survived infectionally like flagellin.
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  The non-vaccinated ones died. So the neutralizing response mounted by the vaccinated device.
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  It was a protective response, protective from infection. Wow. Those mice survived.
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  I lost a little weight. Wow. They made it. Wow. The other ones died, all of them died.
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  And Paolo, I'm imagining it when all the scientists at NASA and the landing
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  is happening in space and there's lots of excitement.
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  When you all realized you had done this, can you describe for me what it was
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  like or what the feeling was like?
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  Or is it dramatic like that? Or it's more you're in the lab, you knew it was coming?
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  I just, I'm trying to imagine the moment when you realize this is,
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  you did it. That's a good question.
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  The climax or the outcome of the death was tempered by the fact that this is so labor intensive.
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  They went front and get there. It's okay.
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  It's so tedious, so labor-intensive. Labor-intensive, yeah. Can you tell me
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  what you were feeling when you realized?
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  That's, in many ways, what was expected. And so, you know, science these days,
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  particularly biomedical science, it's very incremental in province.
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  So it's very different from 50 or 80 years ago. You knew the rocket was going to get there. Right.
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  So do you, what's the next step? What's the plan from here now that? That's a good question.
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  We are trying to do different things using DHX-Vis.
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  Certainly the decision has been made on my part to do any experiment from now
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  on in THX mice so there are different things we are doing we are uh.
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  I've identified actually a transcription factor that is critical for the maturation
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  of the antibody response.
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  It's critical for the expression of AID, activation-induced cytodiaminase,
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  which acts on DNA and diverts the DNA repair machinery of B lymphocytes to act
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  to effect class-rich DNA recombination.
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  And somatic hypermutation. I say divert.
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  I say it diverts, but in fact it's a physiological process.
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  It diverts the physiological process of DNA repair,
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  which comes into place,
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  comes into being in a major way when you go to the beach and you're in the sun
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  and all the DNA repair over you.
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  So that process is physiological, but a process in bilinphocytes that enables
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  the maturation or the affinity maturation of those antibodies,
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  meaning enables the generation of submutants with a much higher specificity for the antigen.
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  Again, be it viral glycoprotein or bacterial components.
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  Toxin, bacteria toxin. That process is physiological as well,
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  but it's really a diversity, diverting of the more general process ongoing in your body all the time.
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  And whenever there is a mutation, it needs to be corrected in the DNA.
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  So we have been working on that, and we have been working on that in vitro, as well as in mice.
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  And now, for the last little stages of that overall investigation.
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  We are using THX mice.
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  So whatever we will find, or actually whatever we are proving,
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  attempting to prove, will be even more relevant because it will be in a human
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  system in vivo. That's for instance one thing.
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  There are other things who have identified a transcription factor that seems
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  to be critical for the maturation, the generation, I should say,
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  of mammary B lymphocytes.
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  Mammary B cells or B lymphocytes, we refer to them as immunologists as B cells.
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  Those B cells, the generation of those B cells is critical for the effectiveness of a vaccine.
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  If a vaccine cannot induce degeneration on memory B cells, then it's not a good vaccine.
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  It's not a vaccine. Because those are the cells.
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  After the vaccination, it will persist in your body for months and years,
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  and they will be recalled, reactivated, when the same antigen comes in again.
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  For instance, if those B cells are generating response to influenza vaccine,
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  influenza virus vaccine, and then in a couple of years, you will come across that virus.
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  That virus will reactivate those cells. Those cells will proliferate and further
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  differentiate and make tons of antibodies to the plaques.
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  Wow. So understanding, getting
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  to know what are the critical transcription factors and what are the other factors
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  that are critical for the generation of memory B cells is critical for vaccine development.
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  In the future, do you see other humanized organs in mice?
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  I mean, are we going to have a fully humanized mouse?
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  Or what is the future? It sounds like science fiction, but it's medical science now.
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  Well, it's interesting. That's a very interesting question.
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  In fact, prior to the development of our mice, which because of hormonal conditioning,
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  And I think actually that deserves a few words.
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  Because of malconditioning, they develop a fully human immune system.
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  Prior to that, different attempts were made to graft,
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  again, earlier humanized mice with human fragments of human thymus for instance
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  to promote the T-cell differentiation of those mice or craft other.
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  Are fragments of other organs in the attempt
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  of, again, promoting a better differentiation of the immune system.
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  So one could speculate, or it's not a big speculation, that you could graft actually,
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  organs or pieces of organs, fragments of organs, such as liver or something else, human.
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  So that in this case, you would study as targets of the immune immune system
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  or the human immune system,
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  targets of autoantibody response, SIS.
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  We show that our mice can mount an autoimmune response, which is really,
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  to all effects, similar as the autoimmune response in human lupus.
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  So one can certainly foresee that. But I want to go back to the hormonal conditioning.
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  The hormonal conditioning that is critical for the full development of the human
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  immune system in THX mice is in fact estrogen condition.
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  So these mice, once they're grafted, they even rise to a certain extent to all immune element,
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  which happens at the age of 20 weeks, 18, 20 weeks, then the mice are put on
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  estradiol E2, estradiol E2,
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  and that's the most potent and the most abundant estrogen.
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  Particularly in females, and we put E2 in water, so the mice,
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  the little mice drink water and they get E2.
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  Now interesting, the blood concentration of E2 that derive, that are generated
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  by the drinking E2 in water at a very small concentration,
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  they are actually very physiological for humans.
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  In female or male THX mice, adult THX mice, the blood concentration we do is
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  around 60-70 picolams per ml.
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  In women, depending on the different stages of the cycle,
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  the blood concentration is from from 30 to 500 picoderms per hour,
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  or even 1,500 picoderms or more in pregnancy.
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  So both female and male THX mice have the same relative ego by human physiological levels.
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  That makes a huge difference.
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  But in the overall differentiation of the immune system, as well as in the immune
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  response once the whole immune system is differentiated.
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  I mean, a lot of people think of mice as pests, but really they could be helping
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  to save humanity. Oh, they always did.
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  Hundred years. And we need to think about that. But even more so now with,
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  with this, it's just, it sounds incredible, but,
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  Mice won't ever become like people mice, right?
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  But the fact is that those mice have a full immune system, but a human cell
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  did not mate to the young mice.
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  So they can reproduce, but they reproduce as mice.
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  It's the same immune deficient mice.
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  So they have to be constructed.
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  Humanized mice have to be constructed. And this is why we have several triangles,
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  goals, meaning one male and two females, and 10, 12 cages all the time,
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  breeding those immune-deficient mice.
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  And then we keep crafting new pups.
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  And so we have quite a few at any time, quite a few THX mice.
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  Do they look different than other mice? Not really, actually.
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  And actually interesting, they are very healthy and they live a normal mouse life.
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  We have constructed already 500 THX mice and we never seen any pathological reaction or anything,
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  any short life.
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  So that's good. are, I think, a question that one wants to ask, why estrogen?
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  Well, and that came from two things.
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  One, there is a lot of anecdotal literature going back quite a long time,
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  and no systematic study was ever made.
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  But it's well accepted that women mount a much better antibody response to viral
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  and bacterial vaccines than men.
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  And there are many papers, mostly anecdotal again.
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  Not great journals, but it is accepted. I certainly embraced it.
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  And the second point is that we have published three or four or five very basic
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  papers in the last many years.
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  Particularly two or three in journal biochemistry, one in natural immunology in 2010 or 97.
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  And those were very basic papers in which we show that a transcription factor,
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  which is L3-4, which is very important in the differentiation,
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  development of drosophila, But it's also very important in the differentiation
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  of B cells, of mammalian B cells,
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  and the regulation of the expression of AID,
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  which at the moment, as I say, is critical for the generation of mature antibodies to die of AID.
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  And we saw that, we showed that clearly in those couple of papers,
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  that Oxy-4 is actually under regulation by E2, by estrogen,
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  by estradiol E2.
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  In that E2 actually after it binds ER estrogen receptor alpha binds to the promoter
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  of that gene of oxy-4 gene and promotes the expression of oxy-4 and then oxy-4
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  promotes the expression of AID.
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  So that was the molecular underpinning for really going ahead with estradiol
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  conditioning. Additionally, the fact that we could put E2 in water of COVID made it very easy.
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  A lot of our listeners have to deal with patients who are vaccine hesitant.
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  Is that particularly frustrating for you as well?
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  How there's this, as we all know, people who may not understand and there's
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  so much misinformation out there.
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  It's something our listeners have to deal with. Is it worth spending the time
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  with this patient who thinks that the vaccine is going to hurt them?
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  It's, I have no words. I mean, that's no words. What can you say? Yeah, it's just...
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  I mean, to me, the most troubling thing is that.
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  Those beliefs are germane to all sorts of different people,
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  well-educated people, wealthy people
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  who have access to all sorts of information as much as other people.
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  So that's the troubling, that's very troubling.
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  Very troubling. And for the practitioners, though, who day in and day out are
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  trying to promote the vaccines, I think it's pretty, it's so impressive that
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  they're doing that on the front lines.
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  Yeah, it's a struggle. I can't imagine how frustrating it is having to deal with that every day.
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  And it's so inspiring, though, to see what you're doing.
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  You worked for many years at the University of California.
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  Yes. And before that you lived in Italy, that's where you're from. Yes.
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  I went to medical school in Milano, University of Milano. And you still go back
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  there, you have a house there?
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  Yes, I go back. Not very often, but I'm lucky because this is a house in the
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  mountains, north of Milano. And I share it with my sister.
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  What do you love about Italy? Not sure what I love.
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  I know you said you don't miss it. You love living in Texas and in the United States.
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  What I love about Italy are Ferraris, Maseratis, and not so much Lamborghinis.
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  But there is a whole history about all that. When I went to the,
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  probably a lot of us have been watching the Olympics, and I went to the 2002
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  Olympics and went to a lot of the events and the award ceremonies and the houses of the athletes.
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  And I got to go to the the Italian house
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  oh yeah and then I I had dinner
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  with the some of the athletes and and it was
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  my first time I was a lot younger then but first
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  time saying where I was so surprised when I said so do you want to move to America
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  and they were just like like why would we want to do that we love our country
• 36:15
  and I'm like I thought a lot of most people wanted to move to America and I
• 36:20
  was I felt so embarrassed that they're like no we're having a fun time but We
• 36:24
  love our country. All the people did move to America.
• 36:28
  At the end of the 19th century, beginning of the 20th century,
• 36:33
  they went to Ellis Island.
• 36:35
  Yes. But the many Italians in Hong Kong, I heard that. Yes.
• 36:41
  Everywhere, actually, in Chicago, in California. Bank of America was founded
• 36:46
  by two brothers, Italian brothers. Oh, really?
• 36:50
  And here on Pediatrics Now, we love quotes. I love quotes.
• 36:54
  You have a favorite quote that pertains to what we're talking about.
• 36:58
  If you think that research is expensive, try disease.
• 37:03
  Yes. That's a great one. And that was by? By Mary Lasker. And that's from the?
• 37:10
  The same as the Lasker Award. Who is that person? Can you tell us about the person?
• 37:14
  Well, actually, it's a very wealthy family.
• 37:19
  And the Lasker Award has always been considered the American Nobel Award.
• 37:26
  Many Laskar awardees went on to receive the Nobel Prize, and many didn't.
• 37:37
  Or several men did not.
• 37:41
  Paolo, anything else you want to say about this that we didn't cover?
• 37:46
  This has been such an honor, and it's so fascinating.
• 37:49
  Thank you for your kind words.
• 37:53
  I think that what you want to say is, well, women are better than men.
• 38:00
  That's the best demonstration.
• 38:02
  It has been in the making.
• 38:05
  A lot of our pediatricians are women, more women, much more women,
• 38:09
  many more women than men. That's great. That's wonderful. Because when I was in medical school.
• 38:15
  Most of everything were men pediatrician and it's changed now it's changed when
• 38:22
  I was at Cornell I was teaching actually I was teaching the host immune defense course.
• 38:30
  And this is in New York in Manhattan the upper east side so I did that for many
• 38:37
  years and it was it was very nice it was very different,
• 38:43
  compared to my to my middle school years, because Sandy, while all is very small,
• 38:52
  and every class, a culinary is 101, 101 students.
• 38:57
  And so, 100 students, 101 students are many, few enough for me.
• 39:05
  The course was seven weeks, six, seven weeks, depending.
• 39:10
  I was almost got to know Not all of them, but many of them.
• 39:14
  And when I was reading them, half of them were women, half of them were girls.
• 39:19
  Just feeling as unusual, very unusual sight.
• 39:23
  Because when I was in medical school, well, there were really quite a few women, but how many?
• 39:30
  I don't know, perhaps 20% maybe already, which was really quite a change.
• 39:38
  And thank goodness it kept changing. It kept changing.
• 39:41
  And I so admire our listeners helping children on a daily basis.
• 39:47
  Is there anything you want to say for the hope of the future to the doctors who are listening?
• 39:55
  Well, I think that a lot of things can be finally done in vivo in humans.
• 40:02
  In mice, not in humans, but it's a human immune system.
• 40:06
  Now, this is not the answer to everything. But certainly, you know,
• 40:11
  vaccine development, again, checkpoint inhibitors, it's also important.
• 40:18
  Many other monoclonal therapeutics. It's quite incredible to me that my lab
• 40:27
  in New York was at a cutting edge in the 80s,
• 40:33
  early 90s, in making human monoclonal antibodies.
• 40:36
  Today, 80% of the drugs under consideration by the FDA are human monoclonal antibodies.
• 40:45
  Right. It's incredible. Yes. And, you know. That must feel good.
• 40:52
  Yes and no, because back then I should have continued making human monoclonal antibodies.
• 41:00
  But it's interesting. thing, that was also the time when computing power increased
• 41:07
  exponentially at the beginning.
• 41:12
  Believe that, well, you can model anything three-dimensionally.
• 41:17
  Why do we need to go to the trouble of making human aminoclonal antibodies?
• 41:24
  Once you know what the antigen is, you can design a molecule that can lock in,
• 41:31
  need not be a monoclonal antibody.
• 41:39
  And and the structural crystallography and resolution you do.
• 41:45
  At the end, almost 40 years later, 35 years later, the truth is that nature does it right and easy.
• 41:55
  We are back, we have been back making monoclonality about this.
• 42:00
  The modeling didn't get us anywhere.
• 42:04
  With respect, I should say, we qualify my statement.
• 42:07
  Didn't get us anywhere in terms of coming up with molecules that have the precision,
• 42:15
  the specificity and affinity of an antibody in neutralizing something,
• 42:23
  in locking onto something, the antigen, again, B, D, whatever phylogenetic structure of the digester.
• 42:30
  We went back to antibodies.
• 42:33
  That's full circle. from, I'm talking about the late 80s, early 90s, so 35 years ago.
• 42:42
  We thought that, well, we had an incredible progress back then of structural
• 42:48
  studies and modeling, and now we are again.
• 42:53
  Again, that's incredible.
• 42:55
  Monogonal antibodies are useful.
• 42:58
  In my generation, we would think, you know, we would think making good vaccine,
• 43:05
  good antivirus, or good neutralized antibody therapeutic.
• 43:09
  But in fact-
• 43:12
  Antibodies are used to over your cholesterol. The most incredible application
• 43:20
  that one would never have thought of. It's incredible.
• 43:25
  Anything else, Paolo, you want to mention about your next step or anything we didn't cover?
• 43:31
  Yeah, my next step, I should be retiring at this point. So you are really going to retire? I'm not.
• 43:38
  You're not going to? Everybody tells me.
• 43:44
  Dr. Paolo Casale with the University of Texas Health Science Center at San Antonio.
• 43:49
  Thank you so much for being on Pediatrics Now. Thank you.
• 43:52
  Music.
• 43:54
  My pleasure. But you're going to keep working. You're not retiring.
• 43:57
  I keep working. I'm not retiring.
• 43:58
  Don't forget to click on the link in this podcast for free credit that may include
• 44:06
  CME, MOC, or ethics credit, depending on our topic or podcast.
• 44:13
  I'm Holly Wayment. Our website is pediatricsnowpodcast.com.
• 44:18
  My email address is on there. Please send me a question or episode ideas.
• 44:25
  Thank you for listening. I'll see you next time.
• 44:30
  Our sister podcast is Pediatrics Now for Parents.
• 44:34
  It's meant to be one less thing you have to say in the exam room.