Robert Langer is a professor at MIT and one of the most cited researchers in history, specializing in biotechnology fields of drug delivery systems and tissue engineering. He has bridged theory and practice by being a key member and driving force in launching many successful biotech companies out of MIT.

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EPISODE LINKS:
Bob's Lab Website: https://langerlab.mit.edu/
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Bob's Wiki: https://en.wikipedia.org/wiki/Robert_S._Langer

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OUTLINE:
0:00 - Introduction
3:07 - Magic and science
5:34 - Memorable rejection
8:35 - How to come up with big ideas in science
13:27 - How to make a new drug
22:38 - Drug delivery
28:22 - Tissue engineering
35:22 - Beautiful idea in bioengineering
38:16 - Patenting process
42:21 - What does it take to build a successful startup?
46:18 - Mentoring students
50:54 - Funding
58:08 - Cookies
59:41 - What are you most proud of?

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a conversation with Bob Langer, professor at MIT and 1 of the most cited researchers in history, specializing in biotechnology fields of drug delivery systems and tissue engineering.

He has bridged theory and practice by being a key member and driving force in launching many successful biotech companies out of MIT.

This conversation was recorded before the outbreak of the coronavirus pandemic.

His research and companies are at the forefront of developing treatment for COVID-19, including a promising vaccine candidate.

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And now, here's my conversation with Bob Langer.

Do you see a connection between magic and science?

I think magic can surprise you, and I think science can surprise you and there's something magical about science, I mean making discoveries and things like that, yeah.

So and then on the magic side, is there some kind of engineering scientific process to the tricks themselves?

Do you see, because there's a duality to it.

1 is you're the, you're sort of the person inside that knows how the whole thing works, how the universe of the magic trick works.

And then from the outside observer, which is kind of the role of the scientist.

You, the people that observe the magic trick don't know, at least initially, anything that's going on.

Well, I think the duality that I see is fascination.

You know, I think of it, you know, when I watch magic myself, I'm always fascinated by it.

Sometimes it's a puzzle to think how it's done, but just the sheer fact that something that you never thought could happen does happen.

You know, sometimes It's something that you might dream about and hoping to discover, maybe you do in some way or form.

What is the most amazing magic trick you've ever seen?

Well, there's 1 I like, which is called the invisible pack.

And the way it works is you have this pack and you hold it up.

Well, first you say to somebody, this is invisible, and this deck, and you say, well, shuffle it.

They shuffle it, but they're sort of make-believe.

And then you say, okay, I'd like you to pick a card, any card, and show it to me.

I said, well, put it back in the deck, but what I'd like you to do is turn it upside down from every other card in the deck.

And I said, do you wanna shuffle it again?

And I said, well, so there's still 1 card

upside down from every other card in the deck.

1 card upside down from every other card in the deck.

So I said, well, it just so happens in my back pocket, I have this deck, it's a real deck, and I show it to you, and I just open it up and there's just 1 card upside down and it's the 3 of hearts.

I can, if I don't I would have probably brought it.

As of today you have over 295,000 citations and H index of 269.

You're 1 of the most cited people in history and the most cited engineer in history.

And yet nothing great, I think, is ever achieved without failure.

So the interesting part, what rejected papers, ideas, efforts in your life were most painful or had the biggest impact on your life?

I mean, I've had plenty of rejection too, you know, but I suppose 1 way I think about this is that when I first started, and this certainly had an impact both ways, You know, I first started, we made 2 big discoveries and they were kind of interrelated.

I mean, 1 was I was trying to isolate with my postdoctoral advisor, Judah Folkman, substances that could stop blood vessels from growing and nobody had done that before.

Part B is we had to develop a way to study that, and what was critical to study that was to have a way to slowly release those substances for more than a day, maybe months.

And that had never been done before either.

So we published the first 1, we sent to Nature, the journal, and they rejected it.

And then We revised it, we sent it to science and they accepted it.

We sent it to science and they rejected it and then we sent it to nature and they accepted it.

But I have to tell you, when we got the rejections, it was really upsetting.

I thought I'd done some really good work and Dr.

Folkman thought we'd done some really good work and, but it was very depressing to, you know, get rejected like that.

If you can linger on just the feeling or the thought process when you get the rejection, especially early on in your career, what, I mean, you don't know, now people know you as a brilliant scientist, but at the time, I'm sure you're full of self-doubt.

And did you believe that maybe this idea is actually quite terrible, that it could have been done much better, or is there underlying confidence?

Well, you feel depressed, and I felt the same way when I got grants rejected, which I did a lot in the beginning.

I guess part of me, you have multiple emotions.

1 is being sad and being upset and also being maybe a little bit angry because you feel the reviewers didn't get it.

But then as I thought about it more, I thought, well, maybe I just didn't explain it well enough.

So you say, well, okay, I'll explain it better next time.

And certainly you get reviews, and when you get the reviews, you see what they either didn't like or didn't understand, and then you try to incorporate that into your next versions.

You've given advice to students to do something big, do something that really can change the world rather than something incremental.

How did you yourself seek out such ideas?

Is there sort of a rigorous process or is it more spontaneous?

It's more spontaneous, I mean part of it's exposure to things, part of it's seeing other people, like I mentioned Dr.

Folkman, he was my post-doctoral advisor, he was very good at that.

You could sort of see that he had big ideas and I certainly met a lot of people who didn't.

And I think you could spot an idea that might have potential when you see it, because it could have very broad implications.

Whereas a lot of people might just keep doing derivative stuff.

But it's not something that I've ever done systematically, I don't think.

So in the space of ideas, how many are just when you see them, it's just magic?

It's something that you see that could be impactful

Yeah, it's sort of hard to say because there's multiple levels of ideas.

1 type of thing is like a new creation, like that you could engineer tissues for the first time or make tissues from scratch from the first time.

But another thing is really just deeply understanding something and that's important too.

So sometimes you could think of a new technology or I thought of a new technology, but other times things came from just the process of trying to discover things.

So it's never, And you don't necessarily know, like people talk about aha moments, but I don't know if I've, I mean, I certainly feel like I've had some ideas that I really like, but it's taken me a long time to go from the thought process of starting it to all of a

So if you take drug delivery for example, is the notion, is the initial notion kind of a very general 1?

That we should be able to do something like this?

And then you start to ask the questions of well, how would you do it, and then digging and digging and digging?

I mean, there are many different examples.

The example I gave about delivering large molecules, which we used to study these blood vessel inhibitors, I mean, there we had to invent something that would do that.

Sometimes it's really understanding what goes on in terms of understanding the mechanisms.

And there are many different parts to it.

Over the years we've invented different, or discovered different principles for aerosols, for delivering genetic therapy agents, all kinds of things.

So let's explore some of the key ideas you've touched on in your life.

So first let me ask, how complicated is the biology and chemistry of the human body from the perspective of trying to affect some parts of it in a positive way.

So that you know, for me especially coming from the field of computer science and computer engineering and robotics, it seems that the human body is exceptionally complicated and how the heck you can figure out anything is amazing.

I mean, we're still just scratching the surface in many ways.

But I feel like we have made progress in different ways.

And some of it's by really understanding things like we were just talking about.

Other times, you know, you might, or somebody might, we or others might invent technologies that might be helpful on exploring that.

And I think over many years, we've understood things better and better, but we still have such a long ways to go.

Are there, I mean, if you just look, are there things that, are there knobs that are reliably controllable about the human body?

If you consider, is there, is there, so if you start to think about controlling various aspects of, when we talk about drug delivery a little bit, but controlling various aspects chemically of the human body, is there a solid understanding across the populations of humans that are solid, reliable knobs that can be controlled?

I think that's hard to do, but on the other hand, whenever we make a new drug or medical device, to a certain extent we're doing that, you know, in a small way, what you just said.

But I don't know that they're great knobs.

I mean, and we're learning about those knobs all the time.

But if there's a biological pathway or something that you can affect or understand, I mean, then that might be such a knob.

Yeah, well, I'll give an example which goes back to what I said before.

So when I was doing my postdoctoral work with Judah Folkman, we wanted to come up with drugs that would stop blood vessels from growing or alternatively make them grow.

And actually people didn't even believe that those things could happen.

What does it mean for a blood vessel to grow and shrink and why is that important?

Sure, so a blood vessel is, could be an artery or a vein or a capillary and it provides oxygen, it provides nutrients, gets rid of waste.

So the blood vessels end up being very, very important.

And if you have cancer, blood vessels grow into the tumor and that's part of what enables the tumor to get bigger and that's also part of what enables the tumor to metastasize, which means spread throughout the body and ultimately kill somebody.

So that was part of what we were trying to do.

We wanted to see if we could find substances that could stop that from happening.

First, we had to develop a bioassay to study blood vessel growth.

That's where we needed the polymer systems because the blood vessels grew slowly, took months.

So after we had the polymer system and we had the bioassay, then I isolated many different molecules, initially from cartilage, and almost all of them didn't work.

But we were fortunate, we found 1, it wasn't purified, but we found 1 that did work.

And that paper, that was this paper I mentioned in Science in 1976, those were really the isolation of some of the very first angiogenesis and blood vessel inhibitors.

So let's, first of all, polymer molecules, big, big molecules.

What is the process of trying to isolate this whole thing simplified to where you can control and experiment with it.

is some plastics and rubber, and that means something that has structure and that could be useful for what?

Well, in this case, it would be something that could be useful for delivering a molecule for a long time, so it could slowly diffuse out of that at a controlled rate to where you wanted it to go.

So then you would find the idea is that there would be a particular blood vessels that you can target, say they're connected somehow to a tumor, that you could target and over a long period of time to be able to place the polymer there and it be delivering a certain kind of chemical.

So that it would deliver the molecule or the chemical that would stop the blood vessels from growing over a long enough time so that it really could happen.

So that was sort of what we call the bioassay is the way that we would study that.

All of it, in other words, the bioassay is the way you study blood vessel growth.

The blood vessel growth, and you can control that somehow with, is there an understanding of what kind of chemicals can control the growth of a blood vessel?

Sure, well now there is, but then when I started, there wasn't.

And that gets to your original question, so you go through various steps.

We showed that A, such molecules existed and then we developed techniques for studying them.

And we even isolated fractions, groups of substances that would do it.

But what would happen over the next, we did that in 1976, we published that.

What would happen over the next 28 years is other people would follow in our footsteps.

I mean, we tried to do some stuff too, but ultimately to make a new drug takes billions of dollars.

So what happened was there were different growth factors that people would isolate, sometimes using the techniques that we developed.

And then they would figure out, using some of those techniques, ways to stop those growth factors and ways to stop the blood vessels from growing.

At that, like I say, it took 28 years, it took billions of dollars, and worked by many companies like Genentech.

But in 2004, 28 years after we started, the first 1 of those, Avastin, got approved by the FDA.

And that's become 1 of the top biotech selling drugs in history.

And it's been approved for all kinds of cancers and actually for many eye diseases too, where you have abnormal blood vessel growth.

So in general, 1 of the key ways you can alleviate, so what's the hope in terms of tumors associated with cancerous tumors?

What can you help by being able to control the growth of vessels.

So if you cut off the blood supply, you cut off the, it's kind of like a war almost, right?

If you have, if the nutrition is going to the tumor, and you can cut it off, I mean, you starve the tumor and it becomes very small.

It may disappear or it's gonna be much more amenable to other therapies because it is tiny.

You know, like chemotherapy or immunotherapy is gonna have a much easier time against a small tumor than a big 1.

I mean, it seems like a very clever strategy in this war against cancer.

Well, you know, in retrospect, it's an obvious idea, but when Dr.

Folkman, my boss, first proposed it, it wasn't, a lot of people thought he was pretty crazy.

And so, in what sense, if you could sort of linger on it, when you're thinking about these ideas at the time, were you feeling around in the dark?

So How much mystery is there about the whole thing?

How much just blind experimentation, if you can put yourself in that mindset from years ago?

Yeah, well, there was, I mean, for me, actually it wasn't just the idea, it was that I didn't know a lot of biology or biochemistry, so I certainly felt I was in the dark.

But I kept trying and I kept trying to learn and I kept plugging, but a lot of it was being in the dark.

Quantum mechanics and physics is a theory that works incredibly well, but we don't really necessarily understand the underlying nature of it.

So are drugs the same in that you can, you're ultimately trying to show that the thing works to do something that you're trying to do, but you don't necessarily understand the fundamental mechanisms by which it's doing it?

I think sometimes people do know them because they've figured out pathways and ways to interfere with them.

And sometimes people make serendipitous discoveries and they don't even realize what they did.

So what is the discovery process for a drug?

You said a bunch of people have tried to work with this.

Is it a kind of a mix of serendipitous discovery and art Or is there a systematic science to trying different chemical reactions and how they affect whatever you're trying to do, like shrink blood vessels?

Yeah, I don't think there's a single way, you know, a single way to go about something in terms of characterizing the entire drug discovery process.

If I look at the blood vessel 1, yeah, there, the first step was to have the kinds of theories that Dr.

The second step was to have the techniques where you could study blood vessel growth for the first time and at least quantitate or semi-quantitate it.

Third step was to find substances that would stop blood vessels from growing.

Fourth step was to maybe purify those substances.

I mean, before you have an effective drug, you have to show that it's safe, you have to show that it's effective, and you start with animals, you ultimately go to patients, and there are multiple kinds of clinical trials you have to do.

If you step back, is it amazing to you that we descendants of great apes are able to create things that are, you know, create drugs, chemicals that are able to improve some aspects of our bodies?

Or is it quite natural that we're able to discover these kinds of things?

You know, The way I look at your question, the fact that we have evolved the way we've done, I mean, it's pretty remarkable.

What are the difficult problems in drug delivery?

What is drug delivery, from starting from your early seminal work in the field to today?

Well, drug delivery is getting a drug to go where you want it, at the level you want it, in a safe way.

Some of The big challenges, I mean, there are a lot.

I mean, I'd say 1 is, could you target the right cell, like we talked about cancers, or some way to deliver a drug just to a cancer cell and no other cell?

Another challenge is to get drugs across different barriers, like could you ever give insulin orally, could you, or give it passively transdermally, can you get drugs across the blood-brain barrier?

I mean, there are lots of big challenges.

Can you make smart drug delivery systems that might respond to physiologic signals in the body?

Oh, interesting, So SMART, they have some kind of sense, a chemical sensor, or is there something more than a chemical sensor that's able to respond to something in the body?

I mean, you know, 1 example might be if you were diabetic, if

you had more, got more glucose, could you get more insulin?

Is there some way to control the actual mechanism of delivery in response to what the body's doing?

I mean, 1 of the things that we've done is encapsulate what are called beta cells, those are insulin producing cells, in a way that they're safe and protected.

And then what'll happen is glucose will go in and cells will make insulin.

So from an AI robotics perspective, how close are these drug delivery systems to something like a robot?

Or is it totally wrong to think about them as intelligent agents?

And how much room is there to add that kind of intelligence into these delivery systems perhaps in the future?

Yeah, I think it depends on the particular delivery system.

of course, 1 of the things people are concerned about is cost, and if you add a lot of bells and whistles to something, it'll cost more.

But, I mean, we, for example, have made what I'll call intelligent microchips that can, you know, where you can send a signal and release drug in response to that signal.

And I think systems like that microchip someday have the potential to do what you and I were just talking about, that there could be a signal like glucose and it could have some instruction to say when there's more glucose, deliver more insulin.

So do you think it's possible that there could be robotic type systems roaming our bodies sort of long term and be able to deliver certain kinds of drugs in the future?

Some day, I don't think we're very close to it yet, but some day, you know that that's nanotechnology and that would mean even miniaturizing some of the things that I just discussed and we're certainly not at that point yet, but someday I expect we will be.

So some of it is just the shrinking of the technology.

That's a part of it, That's 1 of the things.

In general, what role do you see AI sort of, there's a lot of work now with using data to make intelligent, create systems that make intelligent decisions.

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Robert Langer: Edison of Medicine | Lex Fridman Podcast #105