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[Narrator] Looking for fascinating conversations with industry thought leaders.
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for the best our university has to offer.
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Welcome to We Are IU.
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Welcome to We Are IU.
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[JD Denny] I'm your host, JD Denny.
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Today I'm talking with IU's doctor, Richard DiMarchi.
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Doctor DiMarchi has been a key player in the development of Ozempic
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and similar GLP-1 drugs, which have provided
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patients outstanding health and weight loss effects.
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We're here in his lab at the Chemistry Building on the IU Bloomington campus.
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Richard, good to see you.
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Welcome to We Are IU.
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Why has Ozempic and the drugs that have followed made such a big impact?
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[Richard DiMarchi] The reason
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why it's made such a difference is because it's transforming people's lives.
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I mean, we're now at a point where we are managing excess body weight
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in a way that we traditionally would
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manage excess glucose, excess cholesterol,
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excess, blood pressure.
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And so it is changing, people's lives.
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And, I must say, I'm just,
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overjoyed with what we have witnessed to this point in time.
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[JD Denny] Can you talk about, like, the the maybe on the individual level,
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the kind of results people are seeing
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and maybe starting with where we were with Ozempic.
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And I know that these drugs have just really made advances and gotten better.
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[Richard DiMarchi] There is a spectrum of responses.
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But but for those who have have done, I'm done.
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Well.
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The the outcomes have been truly spectacular.
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The median response
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to these registered drugs in, obese subjects
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that don't have Ko diseases such as diabetes,
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can be anywhere from 15 to 20
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and even beyond, percent reduction in body weight for.
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So for someone who has a body weight
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starting at 100kg, roughly 220 pounds,
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that can represent as much as a decrease of a pound per week over the course
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of a full week, as much as a 50 pound reduction in their body weight.
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There are individuals that are part of what has been termed
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the 100 club that have lost over 100 pounds.
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And, you know, they share with me how, dramatic and transformative
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that has been to lose the quality of their life.
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And obviously,
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that is a compliment that I receive on
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behalf of the so many individuals that were a part of allowing this
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to get to this point of being the medicines that they represent.
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[JD Denny] Amazing.
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And I'd like to get back into some of that science,
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but maybe you could take us back first
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five decades, perhaps
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as you started your, your career in, in in this field.
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[Richard DiMarchi] I arrived at Indiana University as a graduate student in the summer of 74.
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So I think that's, about 50, 51 years.
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Right.
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And my interest was in the chemistry of these large molecules,
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so-called macromolecules, peptides and proteins,
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because we were unable at that point in time
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to make molecules of this complexity
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in a laboratory setting that looks similar to the one we have here.
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And I always believed that if we could make these molecules
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that we would find, miraculous uses,
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for them, insulin was precedent setting.
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But remember, at that point in time, it was being extracted
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from the pancreas of pigs and cows.
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Growth hormone was being extracted from the brains
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of cadavers to be given to children.
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And even follicle stimulating hormone, a hormone used to
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promote fertility, was being extracted from the urine of nuns.
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And so this, this this was not pharmaceutical
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industry, basic business
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and but but if we could get control of the chemistry
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I always believed that we would find,
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as I said, miraculous uses for these substances.
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And nothing speaks louder than, these, anti-obesity peptides.
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But there were steps leading up to this that were showing us the way.
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[JD Denny] So if we go back there, I love that phrase.
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Getting control of the chemistry, making the molecule.
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So what does that mean? Take us.
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So we're in the mid 70s, and that's not really possible.
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You're you're pulling these from from natural places.
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And where does the lab enter.
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[Richard DiMarchi] Yeah.
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So as I finished my graduate work here on protein chemistry
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and in a state of the art laboratory, led by, a principal investigator named,
5:18
professor Frank Gerd, I, I,
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went to finish, my,
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my formal education with a postdoctoral fellowship
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at the Rockefeller University, with with a fellow named, Robert Bruce Merrifield.
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That, had developed
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chemical procedures for making these peptides,
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you know, around bottom flasks and fume hoods of the type that you see in this,
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this laboratory.
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And so as I left the Rockefeller, I joined Lily, who was a first mover
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in working with the California biotech company named Genentech in producing
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human insulin in those, those those, those microorganisms in bacteria.
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So at that point, we had the emergence of chemical procedures
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and biochemical procedures for making these molecules,
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and it was left for us to determine what can we do with them.
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You know, additional sense, what what therapeutic outcomes
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might we achieve with this new founded chemistry?
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[JD Denny] So help me with the timeline now we're into the 80s.
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I would suppose, and further advances now that you've got
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some of the the biotech available to you, where does it work?
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[Richard DiMarchi] So I arrived in, in Indianapolis, the first days of 1980,
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81, 19, 82 was when there was the first registration,
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the end of 1982 of, of human insulin.
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That just got better and better as the decade proceeded.
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And in 1983,
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the gene allowed for this hormone
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that we know as GLP-1 glucagon like peptide one
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was reported in in nature by an investigator who had been at Kaiser
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biotechnology and had just moved to the University of Chicago
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and, Svetlana moy Chev yens Holtz, who were instrumental in characterizing
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that substance, showing its biology in cells and and animals.
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But the big question was would this translate to humans?
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And and the bigger observation was would it translate beyond diabetes?
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[JD Denny] And if I have it right, what what you developed here at IU
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and kind of had conceptualized before, that was the technology
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that kind of leads to the GLP one drugs that we see today.
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So what does that look like between 2000 and 3 and let's say
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2015 or 16, where it starts to get to market.
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[Richard DiMarchi] Right.
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So at the time that I arrived that I, you you it was it was established the,
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the GLP-1 itself had these, these, these special properties,
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the ability to control hypoglycemia, the ability to control body weight.
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And it was a matter of seeing what
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degree of efficacy that you could get in, in patients.
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I chose not to replicate that work.
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We had begun work on other related hormones, and along the way
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we began to see similar properties in their ability to decrease body weight.
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And so what we began to ask was, could you chemically integrate
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these different hormonal activities into a single molecule?
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There was no precedent for doing that at this, this point in time.
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And what we did in collaboration, with with with with my my, my partner,
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Matthias Chubb, who was a professor of psychology at the University
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of Cincinnati and did all of the animal experimentation is demonstrate that,
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yes, when we put two of these hormones, GLP-1, together with glucagon
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or GLP-1, together with GIP,
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or eventually all three into one.
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We we we significantly
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increase the, the performance of these, these peptides and that,
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that, that peptide, the integration of two hormones
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was showing a bump in, in efficacy from a mean weight
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lowering of about 15% to 2021, 22%, which is
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a 50% increase.
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[JD Denny] So let me take it back a second, because that breakthrough would require
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kind of getting outside of conventional thinking.
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And you've talked about that.
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Can you talk about that a little bit more, how the university setting
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allowed you to kind of, get to this type of breakthrough?
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[Richard DiMarchi] Yeah.
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Universities are unique and they really foster and promote
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inventive research, creating knowledge that just didn't exist
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or flies in the face of conventional, conventional knowledge.
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You know, we know what we know.
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We know what we don't know.
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But there's this bigger space of we don't even know what we don't know.
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And as you do your experiments, you learn things that you just didn't know before.
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And so if you look at the performance of these triple agonists, right,
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as spectacular as they are, I've been been asked,
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so what's, what's so great about one plus one plus one equals three.
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But but if you understand the story, it was one plus zero.
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Minus one equals three.
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And that is this, this this this component of glucagon had been
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thought to be necessary to antagonize because it raises blood glucose.
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It it it it it increases metabolic rate.
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And as a result you are less fuel efficient.
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You lose weight when you integrated in with GLP.
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You get the best of both worlds, right?
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The GLP is buffering the undesired consequences of glucagon and glucagon.
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Is turbocharging the ability to lower body?
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When you bring in GIP, you get an additional element
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of of of efficacy improving metabolic sensitization.
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But it was only when you combine them together that you begin to see this, this,
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this additivity really synergy to achieve superior patient patient outcomes.
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And, and a university again has provided the ability to do that.
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You do this basic inventive research in an unencumbered environment.
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The venture community provides funds to translate it,
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to show that it's more than just cells and animals.
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And it is the pharmaceutical companies that largely have the muscle,
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the capabilities to register these drugs,
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doing them in large number of patients across the globe.
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And all three are necessary,
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but each tend to be more deeply capable in different domains of the value chain.
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[JD Denny] Right.
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And within that university setting, IU has been extremely supportive
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along the way. Is that.
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[Richard DiMarchi] Yeah.
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So it's I, I u part of it IU has been spectacular in providing me
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the space quality students I chose to locate in Bloomington
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because of the history and the excellence, in chemistry.
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Right.
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Remember, fluoride was developed here, you know, and placed into toothpaste.
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Think of how many patients have benefited from from that.
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A phenomenal.
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So there's just such a tremendous rich history on this,
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on this, this, this campus that is more than chemistry.
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It's biology and and just the the environment
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is so conducive to creative thought.
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Just walk this campus. See the liberal arts.
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It's it's just it just promotes,
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you know, orthogonal thinking.
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[JD Denny] You know,
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I want to get into the science, but I want to take you back, though,
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for a second to those early years
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and why you decided on IU in the first place.
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And I think it has a lot to do with that history.
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And that reputation at the time in biology and chemistry.
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Can you speak to that?
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[Richard DiMarchi] Well, there's, there's there's a spectacular history.
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But but for me, the reason why I came to Indiana
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is because the textbooks that we had use for educating
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undergraduates in biochemistry had been written by two professors.
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One of them, then chairman of chemistry, Jean Cortez and Henry Malone.
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And, I just happened to, to meet with, with with Jean Cortez,
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in a lecture he was giving while I was an undergraduate in Florida.
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And he convinced me of the excellence that the the department had
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in protein chemistry, which is what I wanted to study.
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And it turned out
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to, to be a lifelong, association,
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you know, as John Denver said, going home to a place you'd never been before.
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And, I didn't think that I would be here for the,
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the 50 years that I'd been associated with with Indiana.
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But it is it's just a manifestation that that university
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such as Indiana University, certainly Purdue is as well.
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Notre Dame are magnets for foreign talent that we need.
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So badly in the state of Indiana to diversify
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how we view the world, how we view, technical problems,
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because diversity, should be should be celebrated in my mind
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because it helps us see things differently.
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[JD Denny] That's great.
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And and maybe we could move into that science a little bit.
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I mean, seriously, how do these things work?
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But how does it how is it that these diabetes drugs
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and the, the chemistry and the thought and the and the path
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that you took leads to appetite suppression and this dual efficacy?
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How in the world.
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[Richard DiMarchi] Yeah.
15:12
Right.
15:12
So, so so GLP-1 as a hormone has has several notable activities.
15:18
And I mentioned it it stimulates insulin synthesis.
15:22
It stimulates insulin release when you're hypoglycemic
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which makes it ideal for the treatment of,
15:28
maturity onset diabetes.
15:31
But it also has a profound ability in the gut
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to stimulate a to, to suppress appetite.
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And that is the so-called gut
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to brain communication that is telling you that
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you have received nourishment and you've received enough nourishment.
15:49
Stop eating right. You're now satiated.
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And so that property is
15:55
a fundamental importance to decreasing body weight.
15:58
But improving insulin sensitivity lowers insulin levels.
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And insulin is is anti-slip lytic.
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It's stabilizing your fat deposits.
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That works against losing losing weight.
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You then complement that with glucagon,
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which is a catabolic hormone working in the opposite direction.
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And what you create is, is a fuel cycle, meaning you are synthesizing
16:23
and degrading, macromolecules, glycogen, protein.
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And and in doing that you're consuming energy.
16:31
You consume energy, you lower your body weight.
16:34
And GLP-1 is the last component further decreases the,
16:40
your,
16:40
your appetite and improves metabolic sensitivity.
16:44
It's not just insulin, it's leptin.
16:46
It's all these endogenous hormones that are involved
16:50
in your physiological control of body weight.
16:53
And so you get this spectacular outcome.
16:56
It's that concert integration of these,
16:59
these hormones that achieve this spectacular result.
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[JD Denny] Let me take a swing at a I'm a lay person.
17:06
Let me take a swing that it's suppressing the appetite, which I get.
17:09
But also what you're saying is that it
17:11
makes the body more efficient at the molecular level.
17:15
And it allows even.
17:16
It's almost like turbochargers, the kind of weight loss that you're
17:20
talking about.
17:21
You're taking in less, but you're using less, more efficiently.
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[Richard DiMarchi] That's that's correct.
17:25
But but we have had appetite, suppression.
17:29
You know, fed amines have been used.
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And what over time you lose efficacy.
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Tacky for lax right.
17:35
They no longer longer respond.
17:38
And so it's more than just appetite suppression.
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As I said in glucagon,
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what you're purposefully doing is adding a catabolic substance.
17:47
You are making yourself fuel inefficient.
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This is like taking a high energy, high
17:54
efficiency automobile and making it a gas guzzling.
17:58
And in so doing right, you are losing weight.
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But you have to do that in a way that is safe in a chronic mode.
18:06
And that's why the integration with GLP-1,
18:10
that's why the integration with with with chip.
18:13
And it's tough to do chemically.
18:15
This is the equivalent of of a Rubik's Cube.
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If you've ever tried to get three faces just right.
18:21
And when you go for that third phase after getting two, correct, you end up,
18:27
disorganized in those those first two phases.
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I am as, as as proud of the work that my students
18:34
and my associates have done in bringing us the chemistry,
18:38
because that's where the miraculous biology derives.
18:44
Right?
18:44
The pharmaceutical industry, at the end of the day,
18:46
is a precious chemical school of business.
18:48
We sell chemicals, and in this instance they're macromolecules.
18:52
[JD Denny] And now major breakthrough.
18:54
We we have the weight loss.
18:55
We have all of the benefits.
18:59
But it becomes wildly popular.
19:00
And with that it gets into kind of a mainstream.
19:04
Could you talk to any kind of myths or misconceptions or or problem?
19:09
I know shortages became an issue.
19:11
Like maybe speak to some of those
19:14
types of issues.
19:15
[Richard DiMarchi] And here there were some,
19:18
pragmatic issues to be dealt with.
19:20
Can you make enough of this peptide to supply the demand
19:24
because the demand, exceeded,
19:27
the, the capacity.
19:29
And so that that was one the second was the fact
19:31
that these are parenteral products, they have to be injected.
19:34
And that is not the preferred or conventional way of administering drugs.
19:39
We we tend to lean towards, taking an oral tablet.
19:45
Each day.
19:47
But, but I think when you talk about myths,
19:50
the one that resonates with with me are, are these vanity drugs?
19:55
Are these being used for cosmetic purposes?
19:57
Are these being used for medicinal purposes?
20:01
And that is one where I've often found we are attacking
20:07
the obese as opposed to attacking obesity.
20:11
You know, we don't chastise, hypertensive
20:14
subjects or diabetics for taking their insulin
20:18
or taking their Ace inhibitor or their calcium channel blocker.
20:21
Right.
20:22
But in this instance, because there is this, this,
20:25
this cosmetic appeal of lowering body weight,
20:30
we're
20:31
leaning heavily on people who choose to decrease their body weight.
20:35
Now, using pharmacology is a supplement for a proper lifestyle.
20:41
I'm not arguing that these drugs,
20:45
should be used where you can control your appetite,
20:48
where you control your energy expenditure with, with, with, with exercise.
20:53
In fact, that should be the foundation.
20:56
But but decades of history, human
20:59
history has shown us that is insufficient,
21:02
because if it were not, we wouldn't have this epidemic of obesity.
21:07
And obesity is clearly correlated with hypertension,
21:11
with rheumatoid arthritis, with type two diabetes,
21:15
with osteoarthritis and endocrine dependent carcinomas.
21:20
So this is being used for good medicinal purposes.
21:24
And if that doesn't satisfy the people who find need to criticize
21:30
those who are using these drugs, I would lean to the wisdom of Billy Joel.
21:34
No. Okay.
21:36
This is my life.
21:38
Okay?
21:39
Go ahead with your own life.
21:41
Leave me alone. Right.
21:43
If I want to use these drugs and they've been registered
21:45
and shown to be safe, and I can access them,
21:48
and I can afford them by God, let people do it.
21:51
We color our here, we cut our hair, we color our fingernails.
21:55
Right?
21:56
People do surgery on their eyelids, on their eyes, often for cosmetic purposes.
22:01
God bless them. Right.
22:03
It's not for me to judge.
22:04
[JD Denny] That's right.
22:05
And just to put a point on what you said, that obesity,
22:09
it can lead to these other issues either right away or over time.
22:16
And and it's almost as a public health measure.
22:19
It is reducing the obesity, but also everything that comes with that
22:23
or could come with it.
22:24
[Richard DiMarchi] It's not a small public health dilemma.
22:28
I mean, we're talking about a third, roughly a third of the adult population
22:33
that is, of excess body weight
22:36
or overtly obese or extremely obese.
22:39
And it has these huge consequences.
22:43
And so what I see with the success of these drugs
22:47
is a transition, occurring
22:51
where instead of being exclusively focused on treating health
22:57
right, treating disease, we're now looking to strengthen health.
23:00
Well, that's what vaccination was was
23:03
doing in a, in a, prospective way is diminishing
23:07
the risk that you would have an undesirable, outcome.
23:12
And so can we use now this as a foundation
23:16
to strengthen muscle, to strengthen bone,
23:20
not to increase, cognition,
23:23
to extend health span, maybe even lifespan.
23:27
But but that last decade of life is is where we see these catabolic consequences
23:33
of obesity and just aging in general.
23:37
And so can we make that a healthy a period,
23:40
which diminishes the cost for society financially,
23:44
but certainly for the patient in terms of, quality of life.
23:49
[JD Denny] That's where we are now.
23:50
Maybe we could take it a little bit forward looking.
23:53
And I I've heard you speak of, of just kind of biotechnology generally.
23:58
I mean, where do breakthroughs
24:00
like this in the endocrine system and with these hormones,
24:04
what does that lead you to think about with other functions of the body?
24:09
[Richard DiMarchi] Yeah.
24:09
You know, when, when when you're driving your car, you look in the side view mirror
24:13
and it says objects that are in your rearview mirror are closer than you.
24:17
You appreciate.
24:18
And so when I think about the 50 year journey, 51
24:22
to be the exact, it all seems,
24:26
as if it occurred yesterday, when in fact it has been been a half century.
24:31
But what we were doing then, as I indicated,
24:34
was rudimentary relative to what we have today.
24:37
And it's not just these macromolecules for treating obesity.
24:41
It's a host of other diseases where antibodies and proteins,
24:47
antisense RNA based,
24:50
drugs have had a profound effect on, on on diseases.
24:55
We couldn't even begin to, to, to, to manage.
24:59
And so now jump ahead, take us 51 years forward.
25:02
We're in the year 2076.
25:05
That's the tricentennial year.
25:07
And and think about what is going to happen in that period
25:11
relative to what has happened in this first 40
25:14
to 50 years of of biotechnology.
25:17
You know, it's akin to Lindbergh crossing the Atlantic in the late 20s.
25:21
And then we're on the moon in the late 60s, 40 years.
25:25
What does that mean in a biological sense?
25:28
You know, back in the days of the 70s, we didn't understand the the science,
25:33
the molecular basis of vision, the molecular basis of immune recognition.
25:37
It's all known to us now, right?
25:39
We can manage obesity.
25:41
What about memory?
25:42
What is the mom like?
25:43
You're the basis of a memory.
25:45
Will we be able to intervene
25:49
in maintaining memory, in restoring memory and growing memory?
25:54
If you think there's jealousy right now of vanity about somebody,
25:59
decreasing their body weight by 20%, imagine if your neighbors
26:03
is able to increase their cognition by their IQ by 20%.
26:07
Is that going to make the rest of us feel a little dumb?
26:10
Are we going to be compelled to want to be that smart?
26:13
You know what is the limits of human intelligence?
26:17
How empowered can a single brain and a community of brains be?
26:22
And can they solve the societal problems that that that plague us?
26:27
Can we increase empathy?
26:28
Can we make oxytocin people
26:32
more, interpersonal, no less of the
26:36
the societal challenges that come from overt,
26:41
aggressive behaviors?
26:42
You has been of seminal importance, you know, my time on on this
26:47
this this campus has driven my creativity,
26:52
beyond that which I,
26:54
have experienced, in other, other locations.
26:57
I don't know what what it is,
26:59
but there's a certain magic for me in being here, and I.
27:03
And I'm so enormously grateful to the administrators,
27:08
that have supported the work and made me welcome here.
27:12
And doubly so to the scientists who have done the work.
27:16
I'm just I'm just, pleased to have had a career in being part of it.
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[JD Denny] That's wonderful.
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Thank you so much for your time, Richard. Appreciate it. Pleasure.
27:24
[Narrator] Thanks for joining us for another episode of We Are IU
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Your Home for fascinating conversations with thought leaders,
27:33
legends, and visionaries from the university we know and love.
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New episodes available monthly at myiu.org.
Richard DiMarchi is a Distinguished Professor of Chemistry and the founding Chair in the Gill Institute for Neuroscience at IUB. DiMarchi is a member of the National Academy of Medicine and the National Inventors Hall of Fame. His research was key to the discovery and development of the GLP-1 drugs that have transformed the treatment of obesity and diabetes.
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