STH - E29 Dr. Derek Lowe - Blogging & Drug Discovery

[00:00:00] Welcome to this episode of Sciences The Human Podcast. I'm your host, Simranjit Singh, and

[00:00:21] I'm here with none other than Derek Lo, who is a medicinal chemist, a blogger and author.

[00:00:28] He is currently a director in chemical biology and therapeutics at Novartis Institutes of

[00:00:35] Biomedical Research. And Derek is also the author of a popular blog called In The Pipeline.

[00:00:42] Derek, welcome to the show.

[00:00:44] Oh yeah, thanks for having me.

[00:00:47] Yeah, I'm really excited that we could chat. You know, when I first started this podcast,

[00:00:55] I was actually going around to different professors' offices and meeting them in person.

[00:00:59] But then when I wanted to kind of connect with people further away, I ended up being more virtual.

[00:01:04] And now by virtue of the pandemic, all of my podcasts have been virtual.

[00:01:09] So it has been kind of a change. But I'm really happy that we could connect virtually and have a chat.

[00:01:19] Yeah, for sure. Yeah, I enjoy doing this sort of thing.

[00:01:23] There's always a lot to talk about, which is actually kind of why I started the blog because

[00:01:29] it turns out that you can write about drug discovery and Maitkham and keep it going for years.

[00:01:35] Yeah, and you definitely have a pension for that.

[00:01:40] And I mean, I've covered so many different topics on your blog.

[00:01:44] And why don't we start there?

[00:01:48] So yeah, so your blog In The Pipeline, great reading, great writing.

[00:01:55] And so you mentioned that as part of the reason that you started it was to just kind of,

[00:02:01] you have the opportunity to discuss so many different things going on.

[00:02:05] So are there any, so I know you kind of talk about drug discovery as a whole different drugs

[00:02:14] and kind of dive into different technologies.

[00:02:18] Is there any particular topic that kind of jumps out at you as something that you're most excited to discuss on the blog?

[00:02:28] Yeah, that's a good point. I think that some of the breaking news stuff falls into that category

[00:02:36] and that may just have more of an urgency to it.

[00:02:39] But overall, as you notice, I do kind of wander from topic to topic and that's deliberate

[00:02:46] because I try to do some, you know, if I do a hardcore chemistry type post,

[00:02:52] then I'm not going to do another one the next day.

[00:02:55] Or if I do one that's all like about patents and IP, I'm not going to do that again.

[00:03:00] So I kind of want people to feel that if they didn't find, you know, the latest post to be anything particularly interesting,

[00:03:08] they can be pretty sure that it's not going to be like that tomorrow.

[00:03:11] Now, maybe it'll be something else uninteresting, but it will be something else.

[00:03:15] But for the most part, I just keep a folder in my literature manager.

[00:03:22] I use a freeware program called Sotero.

[00:03:24] I just keep a folder marked blog fodder and as I find interesting looking papers and news items,

[00:03:32] I drop them in there and when it's sometimes I have an idea,

[00:03:36] okay tomorrow I have to write about X, but other times I just sit down and open up the blog fodder

[00:03:41] and take a look at it and see, all right, what's something that I haven't written about much recently that's interesting.

[00:03:48] Yeah, so it sounds like your, what you're most interested in the moment is something that you haven't visited in a while.

[00:03:57] Yeah, yeah, exactly, exactly.

[00:04:00] And I don't mind, for example, writing the posts about patent issues,

[00:04:05] but I can tell that that's not everyone's favorite topic in the world.

[00:04:12] I think you either find that stuff really dry or it's like, you know, that's more interesting than I thought.

[00:04:18] And I'm kind of in that latter camp, although I would not like to be a lawyer,

[00:04:23] but so I definitely, you know, keep the, keep the pedal back on that one.

[00:04:30] And I know that not everyone is a synthetic organic chemist who reads the blog.

[00:04:35] So if I do a big post on some new reaction, I'm not going to hit him over the head with more of that.

[00:04:40] But yeah, there's a lot of interesting stuff out there.

[00:04:43] I mean, when I started the blog, to be honest, I've told people there's a lot.

[00:04:47] I thought I would run out of material in about a year.

[00:04:51] So I'm obviously wrong about that.

[00:04:53] Yeah, especially since you kind of have a self renewing well of things to draw from

[00:05:02] because, you know, academic literature is always growing.

[00:05:04] There's new news items all the time, right?

[00:05:08] Right.

[00:05:09] Yeah.

[00:05:10] So it's a great place to kind of draw from.

[00:05:14] I feel a little bit like an old New Yorker cartoon.

[00:05:20] George Booth, who passed on recently, he's a 90-something years old,

[00:05:24] but he had one where a guy was looking at his TV and the newscaster saying,

[00:05:27] you know, this is John Thompson saying that's all there is.

[00:05:31] There is no more until tomorrow when there will be more.

[00:05:35] Exactly.

[00:05:37] Yeah.

[00:05:38] And so you've had the blog going since 2002, right?

[00:05:42] Oh God, yes.

[00:05:43] I would not have believed that if you told me that in 2002.

[00:05:47] Not for a minute.

[00:05:48] Well, your 20th anniversary.

[00:05:50] I mean congratulations on that.

[00:05:52] That is quite an accomplishment.

[00:05:55] I can't believe it.

[00:05:56] 20 years of Blather, it's amazing.

[00:05:59] It's a good thing I typed quickly.

[00:06:01] Yeah.

[00:06:02] But I mean it's a well-constructed Blather that people seem to enjoy.

[00:06:07] I think how to use that as a tagline.

[00:06:10] Very well constructed Blather.

[00:06:12] Yeah, but feel free.

[00:06:14] But yeah, so over 20 years I mean since 2002,

[00:06:18] how would you say your blogging has changed or has it changed?

[00:06:23] Have you kind of changed your approach or the topics you write about?

[00:06:29] Yeah, I wonder that too.

[00:06:32] It's funny because when I go back and read earlier stuff,

[00:06:36] I would think, man, that's pretty good.

[00:06:39] I don't know if I'm writing stuff that is this interesting now.

[00:06:43] The good thing is though, I first started feeling this just a few years into the blog.

[00:06:50] And then I realized that all of the old stuff seems kind of interesting to me, almost all of it.

[00:06:56] And it's because I don't immediately remember writing every word of it.

[00:07:02] So I'm approaching it a little bit more cold.

[00:07:05] Now in the case of something that was 16, 17 years ago,

[00:07:09] I may be approaching it pretty cold, but I think that's where that effect comes from.

[00:07:14] So when I try to factor that out, the blog seems to sound a lot like it has for a long time.

[00:07:25] So either I'm in a rut or I have a very consistent authorial voice.

[00:07:31] Yeah, I probably go with the latter on that one.

[00:07:36] Yeah, I write a lot like I speak.

[00:07:40] People have told me that when I get interviewed,

[00:07:43] I remember doing some interview hit a few years ago,

[00:07:47] and when we finished up the people recording said,

[00:07:50] okay, that makes it easy.

[00:07:52] We're not going to have to edit anything out of that.

[00:07:55] So I write like I speak.

[00:07:58] So reading the blog is kind of like being stuck in the elevator with me.

[00:08:03] Yeah, that's not such a bad thing.

[00:08:06] Yeah, that's great.

[00:08:10] And I mean, yeah, over time, you know, of course,

[00:08:15] maybe there could be some changes or in your case,

[00:08:18] maybe there is a profound consistency.

[00:08:21] And that is part of the charm of your blog,

[00:08:26] part of the voice that people enjoy.

[00:08:29] And like you said, you speak the way you write

[00:08:32] or you write the way you speak.

[00:08:34] And so it kind of, you know, it makes sense

[00:08:37] why your blog is so incredible.

[00:08:40] I think that's one of the things that you need

[00:08:42] if you're writing in this format is a distinctive voice

[00:08:48] and probably a consistent one too

[00:08:51] because that will keep people coming back if they like it

[00:08:54] and it will keep people away permanently

[00:08:57] if they don't like it, of course.

[00:08:59] You know, that's the other thing,

[00:09:00] but you would probably keep them away too

[00:09:02] if every time they took a look at your stuff

[00:09:04] it was something totally different.

[00:09:07] It was something, you know, long and convoluted and dour

[00:09:12] or something really quick and light and breezy

[00:09:14] or something that sounded great or senseless

[00:09:17] or stupid, you know, different every time.

[00:09:19] People aren't going to come back for that.

[00:09:21] So that's my niche.

[00:09:24] And I'm never going to have, you know,

[00:09:27] 30 million followers reading this.

[00:09:31] There aren't 30 million people who are interested in this stuff

[00:09:34] as far as I can tell.

[00:09:36] But there still are a lot of people who are interested in it

[00:09:39] and probably quite a few who are interested

[00:09:41] and haven't come across the blog yet.

[00:09:43] So hey, come on down.

[00:09:45] Yeah, yeah, absolutely.

[00:09:47] And yeah, so your blog has,

[00:09:50] you know, the first started it, was it kind of

[00:09:53] completely independent online

[00:09:56] and then eventually made its way to the science website

[00:10:00] or how did that come about?

[00:10:02] Yeah, I started out on Blogspot back in 2002

[00:10:07] because it had such a miniscule barrier to entry.

[00:10:10] That's what got me started doing it.

[00:10:13] I was starting to read some of the early blogs

[00:10:15] and enjoying that and I thought, I could do this.

[00:10:18] In fact, I would like to do this.

[00:10:20] I've always enjoyed writing and speaking

[00:10:23] about these sorts of topics and venting my opinion.

[00:10:26] So there it was an opportunity to be right in front of me.

[00:10:29] That went on for a bit.

[00:10:31] And then a fellow who was running another domain

[00:10:34] called Quaranti.com.

[00:10:36] And you have to be a pretty long time reader

[00:10:38] to go back to the Quaranti days.

[00:10:40] But Quaranti.com was attempting to turn into

[00:10:45] sort of a portal site with a lot of biomed and tech stuff.

[00:10:51] That didn't quite materialize.

[00:10:54] There used to be several blogs on it,

[00:10:56] of which I was one.

[00:10:57] Then those gradually disappeared.

[00:10:59] Then the portal stuff kind of decayed.

[00:11:01] And after a while, I looked around

[00:11:03] and realized that I was pretty much

[00:11:05] the only thing left on the domain.

[00:11:07] And I never really found out what happened there.

[00:11:10] But it was obvious that I was going to have

[00:11:13] to find another home because there really were not

[00:11:16] the resources to keep it running,

[00:11:18] much less to improve anything.

[00:11:20] But just keeping it running was not so easy.

[00:11:23] I'd had several offers over the years

[00:11:26] to move the blog and its content over,

[00:11:28] but none of them seemed quite right

[00:11:30] until the folks at AAAS and Science contacted me.

[00:11:34] I thought, yeah, that could work.

[00:11:37] Yeah, seems like it's a good home

[00:11:42] for the blog.

[00:11:44] It has been.

[00:11:45] They have very good technical support on the back end

[00:11:49] and they made it clear upfront

[00:11:52] that this would be complete editorial independence

[00:11:55] and it has been.

[00:11:56] No one has ever batted an eye about anything I've written

[00:12:00] no matter how bizarre.

[00:12:02] Well, that's great.

[00:12:04] You always hear stories of smaller independent projects

[00:12:09] being acquired by larger corporations

[00:12:13] and suddenly the corporation has an opinion.

[00:12:17] Right?

[00:12:18] So that's pretty amazing that you've kind of been able

[00:12:21] to maintain editorial freedom, yeah?

[00:12:23] Yeah, they told me, they said,

[00:12:25] we think that your freedom to express yourself like this

[00:12:29] is actually one of the key features of the blog

[00:12:32] and I agreed with that

[00:12:33] and I was happy to hear it from them.

[00:12:36] Yeah, well that's great.

[00:12:38] Another thing I was really curious about

[00:12:40] is the name of your blog in the pipeline.

[00:12:45] Of course, being in science and now in drug discovery

[00:12:49] it kind of, I put my own preconceived notions

[00:12:53] on what that means

[00:12:55] but where did you come up with that title in the pipeline

[00:12:59] and how, what was your goal

[00:13:03] in terms of reaching the public with that title?

[00:13:06] Oh yeah, well I wish I could take credit for it

[00:13:09] but it was something that someone else came up with

[00:13:13] and I thought, yeah, that's pretty good

[00:13:15] because it's a general phrase

[00:13:16] but also has the specific connection with the drug pipeline

[00:13:20] and it's vague in general enough

[00:13:22] where just about anything could march under that banner

[00:13:25] so I thought let's do it.

[00:13:27] So I can't take credit for that

[00:13:29] but it's been a perfectly good title that served me well.

[00:13:34] Yeah, yeah, it is a good title

[00:13:38] and in terms of the different aspects

[00:13:44] of drug discovery that you end up talking about

[00:13:48] different phases of the pipeline

[00:13:51] I guess you can call it

[00:13:52] different parts of the drug discovery pipeline

[00:13:56] So in your day job, let's call it

[00:14:00] where are you in that pipeline?

[00:14:04] Oh yeah, well I tell people

[00:14:06] that if you're going to stick with the pipeline metaphor

[00:14:09] I'm back where the water is starting to seep out of the bare rock

[00:14:13] way back there

[00:14:15] and I've always been back in like very early stage research

[00:14:21] trying to come up with new targets

[00:14:24] or being there when the assay is being put together

[00:14:29] for some new project

[00:14:30] or right when screening hits start to emerge

[00:14:32] and we start to see if there's any sense in them

[00:14:35] that's as far as I've been

[00:14:37] I have in my career been on projects

[00:14:40] that we handed off to clinical development

[00:14:44] but I don't think I've ever had anything go past phase two

[00:14:49] Maybe not even phase one now that I think about it

[00:14:52] and in recent years I haven't really been on projects

[00:14:56] that are headed toward the clinic

[00:14:58] I've been on really weird, difficult ones

[00:15:02] that are a lot of fun to work on

[00:15:04] but no one expects them to generate a clinical candidate

[00:15:07] by the end of the third quarter if you know what I mean

[00:15:10] But I've worked in a lot of different therapeutic areas

[00:15:13] over the years

[00:15:15] Yeah, so early discovery and so you're saying that not

[00:15:20] not too much of what you worked on

[00:15:22] has successfully made it past clinical trials

[00:15:24] which really kind of

[00:15:26] it speaks to the difficulty of drug discovery

[00:15:29] It does

[00:15:30] and it speaks to just in general what the success rate is

[00:15:34] and it's quite low

[00:15:36] Yeah, and that to me is the central fact of the drug industry

[00:15:42] Everything that seems weird or hard to explain

[00:15:47] about the way the drug industry works

[00:15:50] I think almost all of those things

[00:15:53] tie back to that very high failure rate

[00:15:56] probably around 85% of everything that goes into the clinic

[00:16:00] and of course that number doesn't take into account

[00:16:02] the number of things that never even make it into the clinic

[00:16:05] and I've certainly worked on a lot of those

[00:16:08] There's no other industry like it

[00:16:10] There's really not

[00:16:12] I mean what I tell people is you know

[00:16:14] 85% of Boeing's airplanes

[00:16:18] I suspect can leave the ground

[00:16:20] 85% of Toyota's cars can roll down a road

[00:16:24] 85% of Pizza Hut's pizzas are as good as they're ever going to be

[00:16:28] 85% of our stuff crashes and burns

[00:16:31] Yeah

[00:16:34] Yeah, and I think

[00:16:37] that's usually one of the justifications

[00:16:42] given for how expensive drugs end up being

[00:16:47] Oh yeah, oh yeah

[00:16:49] It's not a bad one

[00:16:51] It's not a perfect rationale but it's not a bad one

[00:16:53] you could definitely start there

[00:16:55] I would tell people look if you want to know why your drugs are so expensive

[00:16:58] it's me

[00:17:00] I've been working in the business now

[00:17:02] well maybe a few other people like me

[00:17:04] I've been working in the business now since fall of 1989

[00:17:08] and I have never put anything on a pharmacy shelf

[00:17:12] Yeah, and that's not a slight on you personally

[00:17:19] That's just the nature of research

[00:17:23] the nature of drug discovery

[00:17:25] Yeah, that's what I tell people

[00:17:27] is that it's not necessarily because I'm a bozo

[00:17:30] It's just really very hard to discover drugs

[00:17:34] Yeah, and

[00:17:36] People don't like hearing that over and over

[00:17:38] but it's true

[00:17:40] Yeah, that's definitely something that I've gotten more exposure to

[00:17:45] in the last half year or so

[00:17:48] So coming out of my PhD and working in drug discovery at our business

[00:17:53] has been pretty eye-opening

[00:17:55] learning quite a lot about how targets are selected

[00:18:00] just how things move through the pipeline

[00:18:03] through onward to clinical trials

[00:18:06] and the success rate as we discussed is pretty low

[00:18:11] but those few percentage that are hits

[00:18:16] and make it through end up helping potentially a lot of patients

[00:18:20] Absolutely, that's what keeps you going

[00:18:22] and if you define yourself

[00:18:24] this is a good thing you bring this up

[00:18:27] because I noticed this in my first few years in the industry

[00:18:30] if you define yourself, your self-worth

[00:18:35] as am I putting drugs on the pharmacy shelves

[00:18:40] you're going to have a bad time in this business

[00:18:43] because that's such a rare event

[00:18:45] and frankly a good amount of that is out of your control

[00:18:50] It really is

[00:18:52] Time and chance happeneth to them all

[00:18:55] and I'm not saying that I'm not suggesting the Old Testament

[00:18:58] a lot of these failures are due to things that we did not

[00:19:02] and frankly could not anticipate

[00:19:04] Son of a gun, it turns out this kinase is not as important

[00:19:08] in that disease as everyone thought

[00:19:10] The only way to find out was to make an inhibitor for it

[00:19:13] or oh boy look at that

[00:19:15] it turns out this enzyme actually does two other things

[00:19:18] in the body that we didn't know about

[00:19:20] now we're hitting them all

[00:19:22] some weird tucks when you do this and this compound

[00:19:25] and we don't even know what the mechanism is

[00:19:27] so this stuff will drive you crazy

[00:19:30] if you take it all on your shoulders

[00:19:32] and decide it's your fault

[00:19:34] and I saw people kind of washing out of drug discovery

[00:19:39] because they couldn't stop doing that

[00:19:43] they couldn't stop taking it personally

[00:19:45] when their great ideas didn't work

[00:19:48] most great ideas don't work

[00:19:50] the success rate is something that you have to come to terms with

[00:19:54] Yeah, that's a great point

[00:19:56] and I think some of that might be a carryover from academia

[00:20:03] you know because in academia the pursuit is always okay

[00:20:08] at least in biology right it's always okay

[00:20:11] deeper biology, deeper understanding

[00:20:13] let's make this discovery, publish a paper

[00:20:17] and then if you are unable to do that

[00:20:20] or unable to do that to the level that you are expecting

[00:20:23] you feel like a failure

[00:20:25] Right

[00:20:27] Now it really is a carryover from academia

[00:20:30] and there's for organic chemists coming into drug research

[00:20:34] there's another carryover that can really earth them too

[00:20:37] Traditionally the industry has liked to hire people who've done

[00:20:41] very difficult synthetic organic chemistry

[00:20:44] like total synthesis of natural products and things like that

[00:20:48] and the reason for that is of course

[00:20:50] if you can put up with that work

[00:20:52] you can put up with anything

[00:20:54] I mean that's one reason

[00:20:56] and by that I mean that you really have to deal with an awful lot of problems

[00:21:01] that just come at you from out of the blue

[00:21:04] Holy crap, you know my protecting group fell off

[00:21:07] oh god this was racemized

[00:21:09] why doesn't this react

[00:21:11] one carbon homolog different compound reacts great

[00:21:14] why doesn't this and on and on and on

[00:21:16] so you have to solve a lot of widely varied problems

[00:21:21] that are coming at you all the time without warning

[00:21:24] that really is good preparation for doing drug discovery

[00:21:28] so that's why the companies have wanted that

[00:21:31] but the problem is that in academia that kind of work

[00:21:35] really

[00:21:38] needs a certain kind of chemistry

[00:21:40] you end up doing very rarefied cutting edge

[00:21:46] sorts of chemistry to try to get these reaction schemes

[00:21:50] to work and not have 110 steps in them

[00:21:54] but a natural product is never going to have just a few steps

[00:21:57] well not many of them

[00:21:59] you're not going to do that in industry

[00:22:01] you're not going to start off on an 18 step preparation

[00:22:04] of some compound

[00:22:06] you're fired

[00:22:08] most compounds don't work

[00:22:10] you're not going to spend 18 steps making something

[00:22:12] that has a very good chance of not working

[00:22:14] what you're going to do instead is a whole bunch of reactions

[00:22:17] some people end up thinking are beneath them

[00:22:20] because they have been doing

[00:22:23] extremely tricky variations

[00:22:26] of the retro Zambizi rearrangement

[00:22:29] at step 33

[00:22:31] and then they find themselves doing a whole bunch of

[00:22:34] transformations and metal catalyzed couplings over and over

[00:22:38] I wish I was able to

[00:22:44] picture the reactions that you just described

[00:22:47] but it's been a while since I did organic chemistry

[00:22:52] well let's put it this way

[00:22:54] those reactions I just described are things that my grandmother

[00:22:57] where she's still with us would be able to do with no problem

[00:23:01] they're not the sort of thing that you picture yourself doing

[00:23:05] as a highly trained organic synthetic

[00:23:09] jock working at the cutting edge of human knowledge

[00:23:12] and that's the realization that people have to come to

[00:23:15] in academia chemistry is

[00:23:19] it's kind of like the motto under the Metro-Goldwyn-Mayer line

[00:23:23] in the movies where it says

[00:23:25] ours, grantee, artists

[00:23:27] art for art's sake

[00:23:29] chemistry for chemistry's sake

[00:23:31] why do we do it? because it's hard

[00:23:33] because it's elegant because it's tricky

[00:23:35] because no one's done it before

[00:23:37] that's not why we do drug discovery

[00:23:39] we do it to make a drug

[00:23:41] and if the fastest, most straightforward

[00:23:45] cheapest, easiest way to make a drug

[00:23:49] is by doing a bunch of reactions that you learned about

[00:23:51] in your first semester of sophomore undergraduate organic

[00:23:54] great, perfect

[00:23:56] those reactions are fast and cheap and easy

[00:23:58] and they tend to work

[00:23:59] that's the best

[00:24:01] so chemistry is a means to an end

[00:24:04] it's not an end in itself

[00:24:07] right and I think

[00:24:09] so that is maybe

[00:24:12] an introduction to a description of medicinal chemistry

[00:24:16] would you say?

[00:24:18] it is

[00:24:19] chemistry in the service of making medicines

[00:24:23] and of course you can do some really elegant synthetic chemistry

[00:24:27] you can do some elegant medicinal chemistry

[00:24:29] when you have an insight about the SAR

[00:24:32] or about why your compounds

[00:24:34] half life or absorption has a problem

[00:24:37] and you manage to fix it which is not all that common

[00:24:40] but you manage to fix it

[00:24:42] you can do some really satisfying elegant work there

[00:24:45] you have to take pride in those things

[00:24:47] because whether or not this compound makes a drug

[00:24:50] or whether or not this project turns into something great

[00:24:54] that's largely out of your control as I said

[00:24:58] yeah, that makes sense

[00:25:01] being comfortable with

[00:25:05] doing your best at whatever that contribution

[00:25:09] whatever that project at the moment is

[00:25:11] definitely is a way to kind of

[00:25:15] have

[00:25:17] let's say emotional longevity in the drug discovery game

[00:25:20] that's a good phrase

[00:25:22] it's a good phrase for it

[00:25:24] now at the same time

[00:25:26] advice that I also give people when they're starting out in this business

[00:25:29] is walk around and talk to folks

[00:25:32] especially people outside your area

[00:25:35] for the chemists, they should go down and talk to the people

[00:25:38] running the primary assay

[00:25:40] or the secondary selectivity screens

[00:25:43] find out how they do that

[00:25:46] I think a good way to give people talking is just to say

[00:25:49] you know

[00:25:51] how do you guys

[00:25:54] do this in such a reproducible manner

[00:25:57] or what's the thing about this that you really wish were different

[00:26:00] you know, what really gets on your nerves about doing these assays

[00:26:04] that would be great if you could do but we don't know how to do

[00:26:07] people will start talking about that

[00:26:10] and you will learn a lot if you're listening

[00:26:13] talk to the people who do the animal assays

[00:26:16] to the formulations folks, the toxicologists

[00:26:19] all of the talk to the patent attorneys

[00:26:21] you will learn an awful lot

[00:26:23] and you will find yourself becoming more than just a synthetic organic chemist

[00:26:27] which is essential

[00:26:29] because as you go on in your career

[00:26:32] you need to be able to show

[00:26:35] a larger number of abilities

[00:26:38] and more understanding about what's going on

[00:26:40] otherwise you will cripple yourself professionally

[00:26:43] and scientifically

[00:26:45] yeah that's a great point

[00:26:48] being able to

[00:26:50] talk to people outside your own field of expertise

[00:26:53] and absorb their

[00:26:55] either concerns, questions

[00:26:57] and their knowledge is definitely

[00:27:00] a great way to

[00:27:02] increase your own understanding of the

[00:27:04] oh yeah, oh yeah

[00:27:06] the peripheries surrounding your field

[00:27:08] it helps a lot

[00:27:10] to be able to

[00:27:12] understand a bit about what these other folks are talking about

[00:27:15] so when someone is saying

[00:27:17] okay, we got a problem

[00:27:20] there's more than one

[00:27:23] start codon in this protein

[00:27:25] and we're getting all sorts of different

[00:27:28] it really messes up

[00:27:30] when you start dealing with

[00:27:32] introns and exons

[00:27:34] you need to know what they're talking about

[00:27:36] more if they say okay we need to express this

[00:27:39] in some other system

[00:27:41] other than Baculose SF9

[00:27:43] because the glycosylation patterns all messed up

[00:27:46] that would be a good thing to know about

[00:27:48] so all these things, if formulations tell you

[00:27:51] okay we have really tight tolerances on the

[00:27:53] micronization for this

[00:27:55] it's a good thing to know what they mean

[00:27:57] yeah absolutely

[00:27:59] so I mean yeah

[00:28:01] my background is more on the biology side

[00:28:04] so for me I definitely

[00:28:06] want to take opportunities to talk to

[00:28:08] chemists for example

[00:28:10] and learn more about

[00:28:12] what the medicinal chemists are doing

[00:28:14] we're loads of fun

[00:28:17] yeah I can see that

[00:28:20] that's for sure

[00:28:22] so Derek you got your

[00:28:25] PhD in organic chemistry

[00:28:28] at Duke University

[00:28:30] it's true

[00:28:31] so I just wanted to

[00:28:33] kind of ask a question from our mutual friend

[00:28:36] our mutual friend is Ian Taylor

[00:28:38] who is the chief scientific officer at Arvinus

[00:28:41] so Ian was saying that I should ask you

[00:28:44] what makes Duke so great?

[00:28:47] yeah I may be the wrong person to ask that

[00:28:50] because

[00:28:52] yeah it's

[00:28:54] I don't know without going into all the details

[00:28:57] I was kind of glad to finish up my PhD

[00:29:00] and spray gravel in the parking lot

[00:29:02] on my way out

[00:29:04] so it's

[00:29:06] a lot of people

[00:29:08] find that their PhD years

[00:29:10] they can look back on many parts of it

[00:29:12] with nostalgia or those were the days

[00:29:14] but there are a lot of parts of it where those were not

[00:29:16] the days and I had quite a few of those days

[00:29:18] I was glad to

[00:29:20] I was glad to finish it up

[00:29:22] and get moving on to something else

[00:29:24] yeah I'm

[00:29:26] I'm right there with you

[00:29:28] I finished just earlier this year

[00:29:30] but yeah I was definitely

[00:29:32] you know learned a lot during the experience

[00:29:34] but I was definitely happy

[00:29:36] to move on from there

[00:29:38] yes in fact it's to the point

[00:29:40] where if I run into someone

[00:29:42] and it doesn't happen often but it has

[00:29:44] if I run into someone who just had such a great time

[00:29:47] while they were in grad school

[00:29:49] I just look at them like there's some kind of

[00:29:51] alien being that's just

[00:29:53] beamed down in front of me

[00:29:55] yeah I

[00:29:57] I mirror that sentiment

[00:30:01] but so your graduate work was in

[00:30:03] organic chemistry so

[00:30:05] something I was wondering is

[00:30:07] why organic why not inorganic

[00:30:11] yeah I just found

[00:30:13] organic to be the kind of chemistry

[00:30:15] I was interested in

[00:30:17] I mean I grew up as a kid being interested

[00:30:19] in all kinds of science and stuff

[00:30:21] of course I read huge amounts

[00:30:23] of things I was really into

[00:30:25] I don't know world

[00:30:27] history and things like that too

[00:30:29] but I always liked

[00:30:31] the sciences and as a kid

[00:30:33] circulated around between chemistry

[00:30:35] and biology

[00:30:37] and astronomy and whatever

[00:30:39] else I could get my hands on

[00:30:41] and I'm still interested in all those things

[00:30:43] but when I got to college

[00:30:45] I didn't even know what I was going to major in

[00:30:47] and chemistry seemed

[00:30:49] like as good a thing as any I mean it was one of those

[00:30:51] sciences I liked so let's go for it

[00:30:53] and

[00:30:55] you take your first year chemistry course

[00:30:57] and say yeah okay this is chemistry

[00:30:59] you know there's pretty dry

[00:31:01] chemistry can't be anything but dry honestly

[00:31:03] but when I got to second year

[00:31:05] organic I thought huh

[00:31:07] this is really pretty

[00:31:09] interesting putting these things

[00:31:11] together like this all these crazy reactions

[00:31:13] like a really big complicated

[00:31:15] board game

[00:31:17] almost but we don't even know all the

[00:31:19] rules and people keep inventing new

[00:31:21] pieces and I think

[00:31:23] when I heard about

[00:31:25] its application to

[00:31:27] drug discovery

[00:31:29] and the idea of

[00:31:31] structure activity

[00:31:33] relationships and making things that

[00:31:35] fit into

[00:31:37] proteins and stuff in the body to affect

[00:31:39] disease I thought oh wow

[00:31:41] that's just great and I never really look back

[00:31:45] yeah and was there

[00:31:47] kind of

[00:31:51] particular moment or a particular

[00:31:53] class or professor that

[00:31:55] helped you

[00:31:57] make that connection

[00:31:59] from organic chemistry as an academic

[00:32:01] pursuit to how it could be

[00:32:03] utilized for drug discovery

[00:32:05] yeah I mean

[00:32:07] the organic professor

[00:32:09] at Hendrix college where I did my

[00:32:11] undergraduate work in Arkansas was

[00:32:13] a fellow named Tom Goodwin who just recently retired

[00:32:15] he was an excellent teacher

[00:32:17] of organic chemistry

[00:32:19] and also a man

[00:32:21] with a pretty warp sense of humor which I

[00:32:23] appreciated greatly in fact it was

[00:32:25] good to see that you could actually be

[00:32:29] an efficient

[00:32:31] very effective chemistry professor

[00:32:33] and still be that bizarre

[00:32:35] good home was great

[00:32:37] and I worked for him

[00:32:39] the summer after

[00:32:41] that sophomore year

[00:32:43] I worked for him as a summer intern

[00:32:45] on a project

[00:32:47] trying to do some total synthesis of

[00:32:49] natural products and the natural product

[00:32:51] was a chemotherapy

[00:32:53] agent called metanzine pretty difficult

[00:32:55] structure but

[00:32:57] I realized that the reason that we

[00:32:59] were making this was it had this

[00:33:01] medicinal activity

[00:33:03] it did things

[00:33:05] to people and for people

[00:33:07] you weren't just making this bizarre structure

[00:33:09] because someone you know

[00:33:11] just went up and drew something bizarre

[00:33:13] on the whiteboard you were

[00:33:15] making it because this was something that was found

[00:33:17] in nature and it really had

[00:33:19] activity and I think that's probably the first

[00:33:21] thing that got me thinking on this

[00:33:23] yeah

[00:33:25] that is a

[00:33:27] that's a great way to kind of

[00:33:29] get your interest peaked and

[00:33:31] be able to because you're learning all these things

[00:33:33] and then suddenly you discover oh there's

[00:33:35] this new way that I can

[00:33:37] apply what I've learned

[00:33:39] it's always exciting

[00:33:41] and of course this was a fairly

[00:33:43] complex structure as was

[00:33:45] the one I worked on later in grad school

[00:33:47] but you would look at it even

[00:33:49] before I had done any real

[00:33:51] medicinal chemistry you'd look at the thing and think

[00:33:53] I wonder what would happen

[00:33:55] if this methyl group were gone

[00:33:57] I wonder what would happen if it were

[00:33:59] a trifluoro methyl instead

[00:34:01] what if this oxygen

[00:34:03] in this ring over here were a nitrogen

[00:34:05] or an in-methyl what would happen then

[00:34:07] those are all legitimate questions

[00:34:09] but of course on these complicated structures

[00:34:11] they're very very hard

[00:34:13] questions to answer

[00:34:15] so you would get this

[00:34:17] curiosity about you know here I am

[00:34:19] spending all this time trying to make this exact

[00:34:21] structure this exact structure and that's

[00:34:23] what you get tired of after a while

[00:34:25] but I thought you know it would be really

[00:34:27] need to be able to make a bunch of other things

[00:34:29] that look like this and see what they do

[00:34:31] are they still chemotherapy agents

[00:34:33] are they still antibiotics what happens

[00:34:35] that's mid-chem right there

[00:34:37] yeah that's that's a great summary

[00:34:39] of med-chem yeah

[00:34:41] and

[00:34:43] could you you kind of touched on this

[00:34:45] a little bit earlier where you suggested

[00:34:47] that it's always

[00:34:49] a great idea to talk to people that are

[00:34:51] outside your immediate area

[00:34:53] of expertise but could you

[00:34:55] offer some additional pieces

[00:34:57] of advice for up and coming

[00:34:59] chemists or up and coming

[00:35:01] biologists people that are looking to

[00:35:03] to get into

[00:35:05] drug discovery and kind of see what it's

[00:35:07] about sure

[00:35:09] yeah I've touched on a couple of the ones

[00:35:11] that I make sure to tell people about

[00:35:13] one of them is that

[00:35:15] you are

[00:35:17] doing applied science now

[00:35:19] not

[00:35:21] science for science is sake

[00:35:23] as a lot of academic research is

[00:35:25] so you have to get used to the idea

[00:35:27] that

[00:35:29] well for chemistry for example

[00:35:31] the reason drug companies hire

[00:35:33] chemists is that is the only way

[00:35:35] that they have yet found

[00:35:37] to produce a whole bunch of drug-sized

[00:35:39] interesting molecules

[00:35:41] to order if they could find

[00:35:43] some other way to do it other than that

[00:35:45] they would fire everyone immediately

[00:35:47] because we're very

[00:35:49] expensive we create

[00:35:51] horrible waste streams

[00:35:53] I mean everyone would like to be

[00:35:55] rid of us we tell terrible jokes

[00:35:57] so

[00:35:59] but there's no way around that

[00:36:01] and various attempts have been made

[00:36:03] over the years to do that to ditch all of us

[00:36:05] in favor of something else but it's never worked out

[00:36:07] but that's the thing

[00:36:09] you're there

[00:36:11] as part of a larger goal

[00:36:13] making a new medicine

[00:36:15] and everyone in the other departments

[00:36:17] is there for that too they're not there

[00:36:19] just because doing this activity

[00:36:21] is a noble thing

[00:36:23] all by itself even though it may be

[00:36:25] that's not why they're paying you so that's

[00:36:27] the first thing is to figure out your

[00:36:29] place in the world

[00:36:31] and that you're not

[00:36:33] as a synthetic organic chemist even though

[00:36:35] you may be really really good at it

[00:36:37] and these other pieces can let you down

[00:36:39] you know

[00:36:41] unexpected talks

[00:36:43] weird picking the wrong targets

[00:36:45] so be ready for that

[00:36:47] so I got to that one the other one was to walk around

[00:36:49] and broaden your knowledge that's key

[00:36:51] beyond that

[00:36:53] I guess some of the other things I would say is

[00:36:55] never talk yourself

[00:36:57] out of an easy experiment

[00:36:59] and I've

[00:37:01] come across other people saying that Francis Crick

[00:37:03] and his memoir

[00:37:05] what mad pursuit

[00:37:07] he talks about that too

[00:37:09] he says basically

[00:37:11] if you can get

[00:37:13] something to work without too much trouble

[00:37:15] just go ahead and try it

[00:37:17] see what happens

[00:37:19] and he says don't listen especially to

[00:37:21] negative predictions

[00:37:23] that you might have about why

[00:37:25] this probably won't work because of X

[00:37:27] and Y and Z

[00:37:29] you can talk yourself out of everything that way

[00:37:31] people have talked themselves out of

[00:37:33] Nobel prizes that way

[00:37:35] just try it

[00:37:37] abandon your pride

[00:37:39] some people have this idea

[00:37:41] that if they're really

[00:37:43] a top class scientist

[00:37:45] they should be able to walk up to that white board

[00:37:47] put their hands on their

[00:37:49] temples and think real hard

[00:37:51] till steam starts to come up out of their collar

[00:37:53] and reach up

[00:37:55] and write down an amazing idea

[00:37:57] there it is inspiration

[00:37:59] that's bull

[00:38:01] a lot of great discoveries come

[00:38:03] from people who are like

[00:38:05] well I don't know if this is going to work or not

[00:38:07] but let's try it

[00:38:09] or you know this has a pretty low chance of working

[00:38:11] but let's try it

[00:38:13] Isaac Asimov once said that the

[00:38:15] sound of a real scientific breakthrough

[00:38:17] is not someone running down the hall yelling

[00:38:19] Eureka

[00:38:21] it's somebody looking at a flask

[00:38:23] or a piece of paper and going

[00:38:25] huh that's funny

[00:38:27] exactly

[00:38:29] that's what it is

[00:38:31] so you have to

[00:38:33] as I say abandon your pride be willing

[00:38:35] to try some crazy flaky stuff

[00:38:37] every so often

[00:38:39] just I would say

[00:38:41] budget a little fraction of your time

[00:38:43] to trying

[00:38:45] ideas that

[00:38:47] are not necessarily on the main

[00:38:49] path of what you're doing or you don't

[00:38:51] necessarily think have a tremendous chance of working

[00:38:53] one of the best compounds ever

[00:38:55] made in my career was about one step from

[00:38:57] being a practical joke

[00:38:59] really

[00:39:01] yeah I sent this thing in

[00:39:03] and it had a functional group in it

[00:39:05] that I admit is a little bit outside

[00:39:07] the usual run of mid-chem

[00:39:09] but I'd seen something like it in

[00:39:11] the Journal of Medicinal Chemistry so I thought

[00:39:13] hey this looks like it would fit

[00:39:15] right into these compounds we're making

[00:39:17] I'm going to make me some of those so I did

[00:39:19] and I got a personal letter

[00:39:21] personal note back in the old days

[00:39:23] of you know physical notes being delivered

[00:39:25] in those interoffice

[00:39:27] envelopes personal note

[00:39:29] from our head of chemistry saying I don't want to see

[00:39:31] anything else like this from you

[00:39:33] so

[00:39:35] I waited until he went on vacation the next

[00:39:37] week to send in the other ones I've made

[00:39:39] and one of them turned out to be the best

[00:39:41] compound we had made on the project up till then

[00:39:43] beats the potency

[00:39:45] and selectivity record sent us off down a whole new

[00:39:47] avenue of exploration they gave me stock options for it

[00:39:51] turned into the down payment on my house

[00:39:53] in Connecticut and all because I ignored

[00:39:55] my director of chemistry and made this

[00:39:57] weird compound I'd never forgotten it

[00:39:59] Wow so you

[00:40:01] you've heard of your first Derek Lozazz to ignore

[00:40:03] your director

[00:40:05] Yeah he did say that

[00:40:07] and I do say that but

[00:40:09] deliberately trying to make yourself

[00:40:11] come up with great results by doing that all the

[00:40:13] time is kind of like washing

[00:40:15] your car to make it rain

[00:40:17] it doesn't quite work

[00:40:19] in that direction remember Murphy's law

[00:40:21] yeah anything that can go wrong will go wrong

[00:40:23] applies to itself

[00:40:25] if you depend on Murphy's law

[00:40:27] or Murphy's law will go wrong

[00:40:29] Yeah that's an interesting way of looking at it as well

[00:40:31] A profound thought

[00:40:33] Yeah I think

[00:40:35] I think we'll leave it there

[00:40:37] I mean great conversation

[00:40:39] Derek thank you so much

[00:40:41] I appreciate your time

[00:40:43] Yeah

[00:40:45] I'll definitely

[00:40:47] link to the blog when this is up

[00:40:49] and you know

[00:40:51] thanks so much for

[00:40:53] your conversation

[00:40:55] words of wisdom

[00:40:57] and for being on the show

[00:40:59] Yeah well I was glad to do it as you can see

[00:41:01] I enjoy talking about this stuff I can go on for an extended period

[00:41:03] Well we might have to

[00:41:05] have you on the show again

[00:41:07] Yeah sure

[00:41:09] There's more topics to be covered

[00:41:11] That's for sure

[00:41:13] Alright thanks Derek

[00:41:15] Yeah thanks a lot

[00:41:25] Termination of Current Scientist of Human Episode

[00:41:29] Stay Breathy