The Power of Plants to Pulverize Coronavirus

Jolie Hales:
I swear the loudest lawnmower of my life is just outside my house. Oh, the joys of working from your closet. Hello everyone, I’m Jolie Hales.

Ernest de Leon:
And I’m Ernest de Leon.

Jolie Hales:
Welcome to the Big Compute Podcast. Here, we celebrate innovation in a world of virtually unlimited compute, and we do it one important story at a time. We’re talking about the stories behind scientists and engineers who are embracing the power of high-performance computing to better the lives of all of us.

Ernest de Leon:
From the products we use every day, to the technology of tomorrow, high performance computing plays a direct role in making it all happen, whether people know it or not.

Jolie Hales:
Okay, Ernest. To kick this off, I have a question for you. What is your favorite national park?

Ernest de Leon:
This may surprise many people, but it’s Joshua Tree.

Jolie Hales:
Oh, really? That’s not too far away from me.

Ernest de Leon:
No, it’s not. I happened upon it on accident driving between California and Texas one year.

Jolie Hales:
Oh, really? Did you just get lost and ended up in a national park?

Ernest de Leon:
No. What ended up happening was I was driving back home and I hadn’t decided where I was going to stop the first day. I happened upon Joshua Tree, and I liked the area. I said, well, I’ll just stay here the night. I stayed at some random like holiday Inn or something. I don’t even remember what the hotel was, but so I went in and kind of drove around in there and was amazed by it. This is the first time I went there. Then obviously I went back to it later and stayed for a few days in the area and walked around the entire area several times after that, and to this day, it’s my favorite national park.

Jolie Hales:
Yeah. I haven’t been to Joshua. For me, it’s tough to pick. I grew up in Utah, so I was totally spoiled by being surrounded by all these beautiful national parks. But I guess if I had to pick a favorite national park, it would probably be Glen Canyon. That’s only because it includes Lake Powell.

Speaker 3:
[inaudible 00:02:09].

Jolie Hales:
And Lake Powell is where I spent a lot of my childhood, and I have a lot of crazy memories there, both the awesome memories, but also completely terrifying, am I going to survive this sort of memories in a lightening storm? My boat sank when I was on it in the middle of the Lake and I was marooned on an island, but all of those memories just … I don’t know, I’ve got this kind of special place in my heart for Lake Powell.

Ernest de Leon:
Yeah. Lakes in general are great.

Jolie Hales:
I don’t know. There’s something about just being out in the water, in nature, but have you ever heard of, and this has to do with our episode, transition into our actual subject. Have you ever heard of Gifford Pinchot National Forest?

Ernest de Leon:
No, I haven’t.

Jolie Hales:
Okay. I hadn’t heard of it either. Apparently, it’s in Washington state, and it’s near Mount St. Helens, which you’ve probably heard of.

Ernest de Leon:
Yes.

Jolie Hales:
As you might imagine, it’s filled with lush, green trees that are stretching up to the sky. You’ve got your flowing streams, your cute little squirrels and your animal life, mountain views, pretty much everything that you might expect from a national park in a state that gets a lot of rain, so everything’s pretty green. Back in August of 1962, something happened there that later resulted in saving and extending the lives of millions of people.

Jolie Hales:
I want to take you back to that day in August in 1962, and I want you to imagine that it’s this nice, cool summer day. It’s at this Washington National Park. The temperature was in the low 60s with clouds overhead, and then there was this guy. Imagine this man in his 30s, standing and looking at a group of trees with his hands on his hips. This man’s name is Arthur Barclay, and he’s a Harvard trained botanist who works for the US Department of Agriculture. He’s basically nearing the end of his four month trip across the Western United States where he’s been collecting samples of trees and weeds and shrubs and seeds, anything plant related that he can find. The hope was that something he collected would contain natural chemicals that could potentially be used in medicines down the line.

Jolie Hales:
Here he was, he’s standing in Gifford Pinchot National Forest, and he’s looking at this 25 foot tall evergreen tree. It’s not like an evergreen tree that looks like a Christmas tree like we might think of as an evergreen tree. Instead, it has these thin kind of crooked branches that spread out in every which way and it’s covered in flat wide needle-like leaves and little red berry looking things. Arthur Barclay casually just basically pointed to the tree, and then his team of botanists got to work collecting samples like they had been doing for weeks. No one really knew anything about this tree. They just knew that they were supposed to collect samples of plants at random, and this is the next one in sight.

Ernest de Leon:
Interesting. I wonder what kind of tree that is.

Jolie Hales:
The tree was called a Pacific yew. Have you ever heard of that? It’s Y-E-U?

Ernest de Leon:
I’ve heard the term yew before, not Pacific yew is a type of wood that has been used to make natural fishing poles, if you want to call it that.

Jolie Hales:
That’s so funny that you know that, because that’s totally true. There’s a few different kinds of yew trees and shrubs and whatnot, and they’re used to make like fishing rods and bow and arrows and all that kind of stuff. This lawnmower is literally right outside my house.

Ernest de Leon:
I heard it that time. I haven’t heard it up until right now.

Jolie Hales:
This guy, I swear, he’s like, ooh, I bet there was a podcast being recorded in that house. I better take my leaf blower and hang out for 20 minutes. He’s never going to leave. This particular tree is a type of yew. There’s a few different types, and it’s called a Pacific yew. Basically, as Arthur Barclay’s team clipped samples of it, and then after a while he moved onto the next plant.

Ernest de Leon:
It must be so interesting to be a botanist.

Jolie Hales:
I know. I would love to just spend time out in nature and look at plants. I don’t think that’s all they do. I guess that’s what I think of when I think of a botanist, just going out and hanging out with plants. This is in 1962, where Arthur Barclay and his team are collecting these samples of the Pacific yew. Now, fast forward through 31 years of research, testing, politics, which we know something about these days, and controversy, and the Pacific yew was saving lives. Now, specifically, what I mean by that is molecules from the Pacific yew tree bark led to the creation of Taxol or paclitaxel, which is actually a chemotherapy drug that has now been used to treat millions of patients with ovarian cancer, breast cancer, lung cancer, cervical cancer, pancreatic cancer, and others. But it all started with that simple plant sample collected in the middle of Washington in August of 1962.

Ernest de Leon:
That’s amazing. I often run across various people in general who always make the comment that there are so many yet undiscovered chemicals or molecules like this, especially in places like the Brazilian rainforest. This is super interesting, but imagine those places where human beings have not gone or cannot easily get to because of logistics and terrain.

Jolie Hales:
Right, it makes you wonder what’s out there that we could be using. That’s basically what this episode is about. I really had no idea how many of our modern day pharmaceuticals actually originated from plants, but there have been quite a few. Everything from Metformin, which is used to treat type two diabetes to morphine, that basically helped me get some sleep during a painful 52 frigging hour labor when my son was born. Those two types of drugs and others have originated from chemicals pulled directly from plants.

Ernest de Leon:
A lot of times, it’s just a matter of having access and getting a large enough population sample to determine what these substances can actually do for people.

Jolie Hales:
Since plants have often kicked off the drug discovery process for medicines, today, the question is being asked on whether or not there’s a natural substance out there that could help us with, I mean, do you care to guess?

Ernest de Leon:
Ebola, or would it be COVID?

Jolie Hales:
It would be COVID. It would be COVID. I know, it’s that one virus you haven’t heard of.

Ernest de Leon:
At all. Yeah, I have no idea what it is.

Jolie Hales:
Like never. I figure since COVID doesn’t seem to want to leave us alone, we might as well use another episode of this podcast to try to figure it out. Today we’re going to talk to an undercover superhero, as we say, who’s had this question, can plants help us treat symptoms of coronavirus? Asking that question was this man.

Jerome Baudry:
My name is Jerome Baudry. I am a professor at the University of Alabama in Huntsville.

Jolie Hales:
Jerome specializes in…

Jerome Baudry:
Computational biology with a particular focus on drug discovery.

Jolie Hales:
Which he’s been doing for 20 years, both in Europe and the United States. When he isn’t pushing the boundaries of scientific research, Jerome prefers …

Jerome Baudry:
To do nothing at all.

Jolie Hales:
What you like sit on a bench and just sit?

Jerome Baudry:
Pretty much, pretty much. I must say I greatly enjoy that.

Ernest de Leon:
I can’t disagree with him at all. I often find great joy in doing absolutely nothing given the pace of our actual careers.

Jolie Hales:
I’m jealous of you being able to do nothing. I can’t just sit there and do nothing very well. I mean, my brain goes crazy, and then I think of all the things I could be getting done that I’m not doing.

Ernest de Leon:
Yeah. I’m not saying I do it often. It’s very rare. But the times when I get the opportunity to just relax and do nothing, they’re treasured, because nowadays, I think everybody is just so busy. I think humans have generally lost the art of doing nothing.

Jolie Hales:
He says he does like to meditate, which is technically doing something, though he says traditional meditation with yoga or controlled breathing with his eyes closed, that all drives him nuts. Instead, he likes to lose himself in contemporary repetitive music. I don’t know if you’re familiar with Philip Glass.

Ernest de Leon:
No.

Jolie Hales:
I actually didn’t know Philip Glass super well, but I went to go listen to him. Since we don’t have the rights to play actual Philip Glass music, I scoured the online royalty free music world to find an imitation. Jerome is a Philip Glass fan, and he’s also a fan of Stanley Kubrick movies and Russian literature.

Jerome Baudry:
Sometimes it feels like you’re reading a telephone directory. It’s full of names and very little action, but I kind of like it because it has this kind of slow pace, slow rhythm, which I find very meditative.

Jolie Hales:
You’re saying that you’re a pretty uptight, high-strung kind of personality is what I’m gathering.

Jerome Baudry:
No, I’m a very metal guy. I like to, at least I think I am, I like to just contemplate. I think contemplation of nature, of arts of appreciation is what really fulfills me with joy, just being around my family, my spouse and children. That’s what I like, even if it’s to do nothing at all actually.

Ernest de Leon:
That’s pretty amazing. I actually have to give Jerome props for that. Having the ability to kind of slow down and just enjoy things, I think is great. I think many of us lack that.

Jolie Hales:
He thinks, interestingly enough, that his personality is a countermeasure to the fast paced supercomputing world he lives in.

Jerome Baudry:
I’m been working a lot lately on trying to use old kind of supercomputers to accelerate the discovery of new drugs and new pharmaceuticals against quite a lot of different diseases. In my level, I’m particularly interested in mental health and in the inflammation diseases. But as you can imagine, something happened in a few last months, and that is COVID 19 crisis, and we have been part, we have been playing a big role, I think, the national, international, actually efforts to try to accelerate greatly the discovery of a potential pharmaceutical against this disease.

Ernest de Leon:
Yeah. This is just part of a larger trend we’ve seen even through our own podcast series of, scientists having to pivot away from things that they traditionally worked on and start looking at COVID through the lens of the type of work that they did before.

Jolie Hales:
Yeah. So, no one was planning to study COVID-19, because it basically came out of nowhere, which means that every working scientist who is now in the fight against COVID had to stop what they were working on, no matter what it was, and switched directions. Jerome actually found out that the coronavirus existed pretty early when a colleague by the name of Roy Magnuson started to suspect that the virus that had sprung up in China probably wasn’t going to go away.

Jerome Baudry:
And kind of said, “Well, this one has all the fingerprints of the big one kind of, the one that you would see in the horror movies or disaster movies.” So, it kind of freezed the attention of everyone.

Jolie Hales:
So, Jerome got to work, suddenly focused on this new virus.

Jerome Baudry:
Everything went extremely quickly from there.

Jolie Hales:
Not only did the virus take over his work, but it affected his family. In fact, Ernest, I know that someone in your own family was hit by the virus, if I remember right. what was that like?

Ernest de Leon:
That’s right. It was actually my sister who is an RN and works in a hospital. She got it from an asymptomatic person who entered her ward during the initial surge of the pandemic. She had fairly significant symptoms, nothing that put her in the bed or in a hospital. She actually recovered at home, but it was still pretty scary because we were early on in this pandemic and we really didn’t understand everything we understand now in terms of treatment and therapy and what’s causing people to get infected or anything like that. For us, it was very concerning.

Jolie Hales:
That’s some scary stuff, especially so early in this entire situation. Talk about hitting close to home when your own sister gets it. As I was talking to Jerome, actually, you and he have that in common.

Jerome Baudry:
My sister in France got the disease quite early on actually, but she …

Jolie Hales:
Your sister had COVID?

Jerome Baudry:
Yes, yes she did, and she did well. It was uncomfortable for her, but fortunately, she was part of this fraction of the population for which turns out to not be that big a deal.

Jolie Hales:
I think it’s interesting that both you and Jerome has had a sister who has caught COVID, and as of my interview with Jerome, my family had somehow managed to avoid it. But I actually just found out a couple of days ago that my own brother and his wife both have COVID right now. So, they’re at home, and I shouldn’t laugh, but it’s kind of funny because for them, they are lucky to be asymptomatic. My brother completely asymptomatic, and then my sister-in-law just has a prolonged headache. They’re both in their twenties and don’t have any high-risk kind of conditions for it. Then they have a little baby that, thank goodness COVID, doesn’t affect children too badly, for the most part. So, lucky them. But it’s interesting, they live 350 miles away, and we were actually in that town and I wanted to see him, but I was worried about COVID.

Jolie Hales:
So, we ended up just seeing them for five minutes, but we were outside with masks on 15 feet apart. Then it was the next day that we found out that they were positive, and so I’m so glad that we were following these measures that we’ve been encouraged to take, because the last thing I want to do is catch COVID and then spread it to a higher risk family member. So, all three of us, you, me, Jerome, we all have a sibling who has had COVID, and that just goes to show how personal this pandemic is.

Ernest de Leon:
Absolutely. Now that we’re in the, I guess this will be the third surge, because there was a spring surge, a summer surge, and now we’re kind of in this hockey stick of the third surge. I’m a student of history in many different aspects, and I immediately look to the 1918 pandemic and started reading articles about it as soon as this one hit, just to kind of understand what happened last time.

Jolie Hales:
Yeah, and the bigger wave was in the fall, was exactly where we are right now.

Ernest de Leon:
Exactly.

Jolie Hales:
The first wave in the spring was actually really small, barely did anything. It was this time of year that most people died in 1918. I can just express that I’m so grateful that we have the scientific knowledge that we do and the technology that we do, and the speed of the technology that we do, so that we can try to accelerate drug discoveries and whatnot, to be able to fight this virus. For Jerome, that’s why when the opportunity came up to join this fight against COVID, he was totally onboard.

Jerome Baudry:
I’ve been working on this kind of research for a long time. Before being in Alabama, in Huntsville, I spent about 10 years at Oak Ridge National Lab at the University of Tennessee, Knoxville.

Jolie Hales:
To those of you who follow high-performance computing, you know that it’s not just Oak Ridge National Lab, it’s The Oak Ridge National Lab, which is home to some of the top supercomputers in the world, including a two and a half million core machine called Summit, which was the number one top supercomputer in the world before it was just dethroned a few months ago by the Fugaku supercomputer in Japan.

Jerome Baudry:
I was quite comfortable with using supercomputing for medical and pharmaceutical research.

Jolie Hales:
Jerome wasn’t just familiar with doing this kind of research, his group at the Oak Ridge Center for Molecular Biophysics actually developed a lot of the super-computing technology that would be necessary for this kind of COVID-19 study. When HPE Cray offered drum direct access to one of their supercomputers to do some COVID research together, Jerome wasn’t about to say no.

Jerome Baudry:
My history of developing supercomputing technology for drug discovery was kind of the catalyst that met me join this research.

Ernest de Leon:
If you listened to our previous episodes, we talked about several different studies that went around COVID. One of them had to do with fluid dynamics and how particulate flows around different types of rooms and elevator or a grocery store, a classroom, musical instruments we talked about. We also talked about what the molecules or the coding of the COVID virus look like. I’m curious to see what the outcome of this particular study is going to be.

Jolie Hales:
Jerome said he’s from a completely different angle than the past studies that we’ve talked about.

Jerome Baudry:
What we’re trying to do is to find a drug, all drugs that will be active against the virus.

Jolie Hales:
When he says drug, it’s good to note here that, that drugs work differently than vaccines. With a vaccine, you purposefully expose your body to the virus in a sort of controlled way so that your immune system can recognize it and destroy it, and then create antibodies that will hopefully protect you from that same virus in the future. Well, hopefully.

Ernest de Leon:
Right. As we discussed in the last interview with Rommie Amaro in her research, the coronavirus is quite adept at camouflaging itself once inside the human body. So, it is necessary to have multiple different ways to attack this thing other than just vaccines.

Jolie Hales:
Long live marshmallow peeps in space spiders. If you don’t know what I’m talking about, the last episode help you, or hurt you.

Ernest de Leon:
If you’re diabetic, it’ll kill you.

Jolie Hales:
Yeah, for real. But okay, to back up just a bit, when a virus invades the body, it attaches itself to a living human cell in order to survive like a little parasite. Then it forces that human cell to create everything that the virus needs to survive and multiply.

Jerome Baudry:
They have not been invited and they’ve not been properly introduced to us, but yet they do.

Jolie Hales:
What a rude thing to do.

Jerome Baudry:
Oh mean.

Jolie Hales:
The virus uses the hijacked cell to multiply and expand throughout the body, wreaking havoc on the person infected. But if we could somehow figure out a pharmaceutical treatment, a pill or some kind of drug that could prevent the virus from functioning, we might be able to prevent it from making an already infected person extremely sick.

Jerome Baudry:
We’re trying to teach them a lesson by preventing them from doing that.

Jolie Hales:
Jerome says that the way a drug like this could work is by having a drug send the sort of warrior molecules through the body of a person already infected with COVID-19, and then having those molecules basically track down the virus and either prevent it from entering a human cell, or if it’s already entered one, trap it inside that cell and prevent it from being able to hijack the controls and multiply itself and spread.

Jerome Baudry:
It’s kind of the grain of salt or the grain of sand that you would put in a clock and stop the clock from functioning.

Jolie Hales:
If the virus is trapped within a cell with no way to multiply, then the infected person is probably going to feel a lot better than they would have otherwise.

Ernest de Leon:
What would it actually take to figure out that kind of pharmaceutical treatment?

Jolie Hales:
Well, that’s just it. Through all of human history up until recently, medicine has pretty much been just trial and error. There’s in fact, this really interesting article by Evan Andrews of the History Channel that I found online, and we’ll link to it in the episode notes, and it talks about some of the medical techniques that have been practiced since ancient times. For instance, I’m sure you’ve heard of bloodletting.

Ernest de Leon:
I sure have.

Jolie Hales:
Yeah. Every time I see it in like a historical movie or read about it being practiced in a biography, I just want to reach through time and shake the so-called doctor by the shoulders and say, “You’re making things worse. What are you doing?” But bloodletting was practiced for thousands of years. Back then, I wouldn’t have known any different. For those who aren’t familiar, it’s basically when a doctor would cut a sick person’s vein and drain their blood, thinking that it would help them get better.

Ernest de Leon:
This reminds me of one of the Star Trek Next Generation episodes, where data is supposed to go looking for some radioactive material on this planet that has a very non advanced civilization. Something happens to him and he loses his memory. So, he has the container with the radioactive material with him and wanders into this town of people who, again, are not modern, and doesn’t know who he is, what his name is or what this container is. Well, this, I think, it’s a jeweler opens up the case and sees the radioactive metal and thinks that it would make good jewelry. So, he starts making jewelry out of this, and the entire town, not everyone, but the people started getting very sick.

Ernest de Leon:
The funny part is there’s a character, a woman who is supposed to be a doctor/scientist, and she does exactly this, she’s making up all of this science as she goes that has nothing to do with the truth. It takes a while for them to actually figure out what happened. This is exactly what happened back then. People just made things up based on what they thought was happening. In most cases, it probably made it worse.

Jolie Hales:
The thing that I love about that example is that it illustrates perfectly exactly historical medicinal practices just like bloodletting. But then number two, of course you would mentioned a Star Trek reference.

Ernest de Leon:
Of course.

Jolie Hales:
I think every time we record a podcast, you got to slide some Star track, some Lord of the Rings in there. It’s amazing.

Ernest de Leon:
I think our audience appreciates it.

Jolie Hales:
Oh, absolutely. Are you kidding me? We’re all a bunch of nerds. Then there are other ineffective medical practices that existed as well, like drilling a hole in a person’s skull to help treat an illness, or this one’s kind of like your Star Trek example, rubbing mercury on your skin, or even digesting it, which was actually thought to have killed Chinese Emperor Qin Shi Huan in 210 BC, which is kind of interesting because it appears he survived multiple assassination attempts over the course of his life, only to die from ingesting mercury pills thinking that they would grant him eternal life.

Ernest de Leon:
Yes. I remember when I was younger, my dad commented how, when he was in high school, the teachers would give them mercury to …

Jolie Hales:
Oh my gosh.

Ernest de Leon:
… not ingest, but as part of a science class, and they would let them like roll it around in their hand, rub it in their fingers, all these kinds of things that now you would never allow a sane person to do, but they just didn’t know back then.

Jolie Hales:
Yeah, and it wasn’t that long ago. I mean, we’re talking your parents.

Ernest de Leon:
Right. One generation back. Who knows how many of those people died from mercury poisoning without even knowing? Because it wasn’t until later that it was discovered that this was incredibly toxic to human beings.

Jolie Hales:
Even though we don’t have all the answers, I’m grateful that medicine has become more scientifically advanced. As it has, drug discovery started to take place more in the laboratory instead of just these trial and error sessions on random people. Thank goodness. That’s when medical treatment really started to advance and save lives in great numbers. I mean, if you look at life expectancy charts, they changed completely in the 1950s, because that’s when medical technology and research really started to take off in a scientific way.

Jerome Baudry:
Normally, if you work in the pharmaceutical industry, you chop the virus into little pieces, into proteins, and you try to put all the proteins in test tubes, and you screen tens of thousands drug candidates. You put them in the test tube and you just see whether or not that rare candidates will stick to the proteins that are coming from the virus.

Ernest de Leon:
It’s essentially still trial and error, but taking place in test tubes rather than on human subjects.

Jolie Hales:
Right. This can take a lot of time and a lot of test tubes.

Jerome Baudry:
They would pipette tens of thousand rare candidates in tens of thousand test use, in tens of thousand little tiny fractions of protein and see what sticks.

Ernest de Leon:
That sounds like an excrutiatingly long process.

Jolie Hales:
And it is apparently. Going back to the Pacific yew tree found in that Washington National Park, in that case, it took more than, get this, 30 years of test tubing and whatnot before that cancer treatment was actually available to the public. It’s a totally amazing breakthrough, but can you imagine if it took 30 years for us to find and develop therapeutics for COVID-19? Today, thankfully, we can look into this stuff a lot more and a lot quicker with, drum roll, please, supercomputers. Yay.

Ernest de Leon:
That’s right. Supercomputers allow us to do all kinds of things that were not possible 50 years ago, a hundred years ago. It is amazing what scientists like Jerome and many others are doing with these.

Jerome Baudry:
Instead of using test tube, which takes a long time, it costs a fortune, we’re doing it with computers because we know how to calculate, how to predict if a drug candidate will stick to this part of the virus or that part of the virus.

Jolie Hales:
They do this by computationally simulating how hundreds of thousands of chemicals collected from natural substances would interact with the coronavirus.

Jerome Baudry:
Our simulations are based on models to calculate how much a given pharmaceutical will be happy or not to stick to a given protein from the virus. So, we reproduce the test tube screening that would take a long time and a lot of money. Calculate interaction between the atoms that are coming from the protein of the virus and the atoms that are making the substances we’re interested in. So, it’s very much based on physics and physical chemistry.

Ernest de Leon:
Instead of putting the chemicals in a traditional test tube, they put them in a digital test tube and basically run the experiment digitally.

Jolie Hales:
That’s exactly what they do.

Ernest de Leon:
Where do they get the chemical profiles to run through the supercomputer?

Jolie Hales:
These chemical profiles are from substances that have pretty much been collected by scientists for years. Just like how Arthur Barclay harvested the Pacific yew.

Ernest de Leon:
Or Laura Croft.

Jolie Hales:
Or Laura Croft, or Indiana Jones.

Jerome Baudry:
They are found in plants. They are found in algae. A lot of them come from tropical regions, actually. It’s just because of biodiversity of the tropical regions is known to be usually larger than the biodiversity at more temperate or colder regions, so we have a lot of sea organisms that give interesting compounds as well. At the same time, they need to be close to the coast, otherwise, no Indiana Jones will be diving at 10,000 feet to harvest, although some do. It’s a combination of opportunities to harvest them and chemical diversity. So, we have a lot of compounds that come from these regions, but also, some compounds that are not far from more traditional plants that we see at … or latitudes. The sources are diverse and include everything, from plants to animals or animal like, and fungi.

Jolie Hales:
Basically, chemicals have been extracted from plants that are found wherever scientists can put boots on the ground, or even get a diver to reach in the water. If there’s a plant out there, scientists are interested in learning more about its chemical composition and have already been collecting as many samples as possible for decades. One reason scientists do this is because it’s actually a lot easier and faster to find chemicals that can be used in therapeutics than trying to create a therapeutic completely from scratch.

Jerome Baudry:
Evolution has already spent the last few million years fine-tuning very special chemicals [inaudible 00:31:23] from some very special functions. Instead of manufacturing synthesizing molecules totally out of the blue, let’s take advantage of this millions of years of evolution that has done a great deal of chemical work for us, and try to see if nature has already provided us a key for the door we are trying to open. Now, we still have to try all those keys, but we may not have to invent it from scratch basically.

Jolie Hales:
Once a plant sample has been collected, scientists have to extract the chemicals from that plant, which is no small effort. I actually watched a few videos on how to do this, and it’s basically a lot of test tubes and lab coats mixing together and separating things very precisely over a few hours or a few days, and then evaluating them on a computer.

Ernest de Leon:
Until they can take a look at the chemical profiles.

Jolie Hales:
Yes. Thanks to advances in technology, scientists like Jerome can take those chemical profiles and then run them through a supercomputer to simulate how each chemical would interact specifically with the coronavirus.

Jerome Baudry:
We must have screened 200,000 compounds.

Ernest de Leon:
200,000 is a large number. In what timeframe are we talking here?

Jolie Hales:
They can screen all 200,000 compounds in a single day through a supercomputer.

Ernest de Leon:
I think my iPhone can do the same thing.

Jolie Hales:
Oh yeah, your iPhone might be cool, but it ain’t that cool. Care to guess how long it would probably have taken to do this number of simulations 25 years ago?

Ernest de Leon:
750 years.

Jolie Hales:
That’s actually a pretty good guess. Jerome says that if we would have even had the capability to run these exact simulations this way back then, it would have taken us 500 years to do what we can do in a day 25 years later. You said 750, that’s actually not too far off.

Ernest de Leon:
Not when you’re talking about the age of the earth in billions of years.

Jerome Baudry:
And that’s why computational approaches are so important, because you can screen much faster and much cheaper than you would otherwise if you were just pipetting things in test tubes, and we do it very, very quickly.

Jolie Hales:
Not just quickly, but cost-effectively as well.

Jerome Baudry:
It costs about, say $20 to screen one chemical in one test tube. Say if you have 200,000 chemicals …

Ernest de Leon:
200,000 times 20 bucks equals …

Jolie Hales:
$4 million, and that’s not including the work hours, which would have taken weeks to months to even years to go through that many chemical compounds manually. I suspect years.

Ernest de Leon:
Yeah, absolutely. It’s clear that supercomputers are rapidly accelerating the process here. So, have they found any results?

Jolie Hales:
Well, see, that’s where it gets really interesting to me. Out of the 200,000 chemicals, I would have guessed with no scientific background, of course, that maybe 10% or so of those chemicals would be somewhat effective against COVID, but I would have been quite wrong.

Jerome Baudry:
We found that a few of them, not that very many, about 125 of them were predicted to be particularly interesting, potentially blocking some of the proteins of the virus to function. We found 100 needles in very large tray stacks of chemicals from nature.

Ernest de Leon:
Did he 125?

Jolie Hales:
Yep.

Ernest de Leon:
Out of 200,000?

Jolie Hales:
Yep. That’s less than 1%.

Jerome Baudry:
I would say that’s quite typical actually.

Jolie Hales:
Really?

Jerome Baudry:
Yeah. Very few needles in this haystack.

Ernest de Leon:
What kind of chemical compounds are we talking about here?

Jolie Hales:
All different kinds, apparently.

Jerome Baudry:
A lot of them have been used, sometimes for forever almost, to treat some elements.

Jolie Hales:
When I asked for names of them, Jerome didn’t even know where to begin.

Jerome Baudry:
There’s nothing like acetaminophen that everybody has been using forever, and suddenly you find out, oh, it could work. No, this also seems a bit more obscure, but a lot of those compounds have been already described to be used traditional medicines in the regions they are coming from for things that sometimes I have to do is infectious diseases and sometimes have nothing to do with it.

Ernest de Leon:
Just about anything goes.

Jolie Hales:
I guess, if they have access to a chemical profile from a natural substance, my guess is they ran it through the machine, and it is worth noting here that from the harvesting to the chemical extraction, to the analysis, and pretty much everything in between, everything is very precise and scientific. You can’t just go eat the exotic weeds that you have in your backyard and then be cured of all ailments.

Jerome Baudry:
The compounds themselves are dangerous. If you touch the plant, you’re not going to die.

Jolie Hales:
That’s good.

Jerome Baudry:
However, it doesn’t mean that you can just go and choose a plant and be COVID-19 free. As a matter of fact, if you put something in your mouth and eat it, if it’s a plant, it can be very toxic. Even the molecule itself is potent. Potency means that it does something to ourselves, and there is a reason why we drink coffee or smoke cigarettes, which I would not advocate for, although coffee, yes I would, or eat chocolate because it does something to ourselves.

Jolie Hales:
Oh, I’ll advocate for the chocolate, for sure.

Jerome Baudry:
Yeah. The chocolate is a must absolutely. But those things do go into our brains, into our livers, and they do their job, chemically speaking, and so be careful about what you get into your system. The same molecules that can save you at a given dose, can kill you at another dose. Something being called a natural product, doesn’t mean it’s benevolent. There’s a lot of work that needs to be done to make sure that you take it the right way. It can kill you, which is a way to solve your problems, I would say, but probably not the one you want to use.

Ernest de Leon:
All I could think about throughout this statement is the people who are trying to push essential oils claiming they cure cancer. Normally, that would be a joke, but not today. We have people trying to ingest bleach.

Speaker 5:
Austin emergency room doctors are urging people not to drink bleach. Coronavirus is a virus that is hard to treat and is causing people to resort to desperate measures.

Jolie Hales:
They call it high performance computing, but is it really living up to its name? I mean, how much has really changed in the last 15 years? Since the revolutionary jump to cluster computing, there have been new core types, new ways to queue jobs, but no real seismic shift, until now. Introducing Rescale, the intelligent control plane that allows you to run any app on any infrastructure totally optimized. Innovators are moving away from the traditional data center-only model and stepping into the future where computing truly is high-performance. Visit rescale.com/bcpodcast to learn what a modern approach to HPC can do for you. Rescale, tomorrow’s HPC, today.

Jolie Hales:
Now that these potentially effective chemicals have been identified, they can move into the test tube phase.

Ernest de Leon:
But now they’re working with 125 chemicals and test tubes rather than 200,000.

Jolie Hales:
Yeah, just from a supplies cost perspective, that’s about $2,500 instead of 4 million.

Jerome Baudry:
So, those molecules, those 125 needles are very, very, very interesting, either because they will be working by themselves. We can take them and maybe they would work in blocking the virus entirely, preventing it from infecting cells, or, and it is more likely, we will still need to modify them a little bit, but the modifications will be small and affordable and fast to perform, because nature will have provided us the right mold, so we just have to fine-tune, so to speak, the chemicals.

Ernest de Leon:
It sounds like often, the chemical found in a plant turns out to be a starting point.

Jolie Hales:
That’s exactly right. In fact, going back to Arthur Barclay, from the beginning, discovering that Pacific yew tree in Washington, once they discovered and developed the drug Taxol, originally, the thought was to keep creating the drug using those natural chemicals that were directly extracted from the plant. In fact, in the early 1980s during Taxol’s phase two human trials, which is 10 years before the drug actually hit the market Taxol was shown to shrink 30 to 60% of ovarian cancers, which had never been seen before from a drug at the time. That was like a huge deal. But then after doing the math, The National Cancer Institute realized that in order to provide Taxol to every ovarian cancer patient, they would need to create 240 pounds of the drug, which meant chopping down 360,000 Pacific yew trees.

Jolie Hales:
That’s just to treat ovarian cancer patients. Taxol could also benefit many patients with other cancer types, which would mean chopping even more trees down.

Ernest de Leon:
I think I see where this story is going, but my guess is there weren’t enough of those trees to spare.

Jolie Hales:
Exactly. Since Pacific yew trees are really only found on the Northern West Coast of the United States and a little bit on the same coast in Canada, and they only grow an average of eight inches per year, it means that they’re likely a few hundred years old. So, you couldn’t just plant and grow new Pacific yews for medicinal use, and harvesting them in great numbers could lead to frankly, their extinction. So, they have this dilemma, do we keep chopping down trees to save cancer patients until there are no more trees to chop or only develop a small amount of the drug and somehow pick and choose who received the treatment.

Ernest de Leon:
My guess is that those weren’t the only two options, but neither one of those is good.

Jolie Hales:
Yeah. Earnest, I know you’re like way too smart to be like the respondee, I swear, because you’re like, I wonder where this is going.

Ernest de Leon:
Well, when you tell an engineer, there are only two options, they’re going to come back and say, no, there are many more than that.

Jolie Hales:
And there was. Thankfully, there was this third option, and that was to study the original molecules, and then try to create the same drug through a process called semi-synthesis.

Ernest de Leon:
Interesting. I guess they’re trying to bridge that gap and move from pulling these as natural substances to generating a synthetic equivalent.

Jolie Hales:
That’s exactly what my understanding is, is that semi-synthesis, like you’re explaining, is that process where chemists use chemical compounds from the natural source, like the Pacific yew tree, and they use it as a starting point to create a drug. The result is a drug that can be created synthetically patterned after the one that is already naturally made.

Ernest de Leon:
That makes a lot of sense. They literally find something that works in nature and figure out how to create it without nature, and that’s mainly because, once they understand the chemical composition, then it’s just a matter of recreating that synthetically.

Jolie Hales:
When it came to Taxol, back in the ’80s, that actually turned out to be an incredibly complicated process for this particular chemical compound, and it took 10 years to get from human trials of the Taxol created from the natural tree to being able, to market semi-synthetic versions of the drug in the early 1990s.

Ernest de Leon:
By finding a way to create Taxol semi-synthetically, they may have not only saved the lives of cancer patients, but also the Pacific yew trees from extinction.

Jolie Hales:
Yep. In the case of Jerome and the 125 substances with potential, some of those could eventually end up as a semi-synthetic drug or as a natural drug. The key is that the discovery for both of these drug types originally came from a natural substance, like a tree or an animal.

Ernest de Leon:
Right. Actually, some of the things he mentioned, in addition to trees and animals like fungi or algae are things that can be grown quickly and harvested quickly as opposed to a tree or an animal where you start getting into ethical concerns.

Jolie Hales:
Yeah. Then of course there’s the synthetic drug discovery process, which basically means that the lead is discovered in a lab instead of in a natural substance. So, pretty much from beginning and end, those kinds of drugs are created in a lab. But that can be really hard to do, right? So, it’s not what Jerome’s team is aiming for with this particular research. They have these 125 needles out a 200,000 chemical compound haystack, and Jerome is now sending those to a lab in Memphis to do some testing and validation.

Jerome Baudry:
We haven’t been doing the discovery. We think we found the needles, and now this lab is going to test those needles to verify which ones are real needles and which ones are not. We do not expect all of them to be true positives, to rework, but we would hope that we are going to find maybe 10% or 20% of them. That will be fantastic. Even the one, as a matter of fact, even two, but if we are statistically very right, maybe 5% to 10% of this 100, so maybe five to 10 molecules will actually turn out to be at some level of potency against the virus.

Ernest de Leon:
He’s hoping that five or 10 of these chemicals will work out.

Jolie Hales:
Yeah, and it narrows down even more from there.

Jerome Baudry:
There is a big difference between a substance doing its job in a test tube and the same substance being efficient and potent in the human body. As a matter of fact, this is one of the reasons why drugs are so complicated and so expensive. It’s because most of the things that work really well in the lab, and that’s still where we are right now, in the lab, most of a pharmaceuticals that are doing really well in the lab will fail. They will be found to, not only torpedo the virus proteins, but torpedo pretty much every things they can put their hands on, including our own cells, which is not a good either. As a matter of fact, 95% of the molecules that do really well in the lab fail in clinical trials. Most of what you are very excited about in the lab will fail for this very reason, because they are promiscuous protein, that’s our name, because it will not be specific enough against the virus, and it will happily to go and bind to a lot of things that you don’t want them to touch in your body.

Ernest de Leon:
I just want to follow, Jerome started out with 200,000 chemicals, which through supercomputing, were narrowed down to 125. Out of that, 125, only five or 10 are expected to show real promise, but if 95% and 98% of drugs that succeed in the lab fail in the human body, then we’re talking about maybe one of these chemicals realistically helping to fight COVID.

Jolie Hales:
Yeah, isn’t that insane? From 200,000 to one.

Ernest de Leon:
That’s insane, but that’s what needs to happen here. Right? We have to narrow these down as best as we can before we ever get to the human trials, because that’s where the real risk happens.

Jolie Hales:
Right. And it really does feel like finding this needle in a haystack, especially when you look at it with these kinds of numbers. Apparently, it’s totally normal. Going back to the story of discovering the drug in the Pacific yew tree. It’s interesting to note that from 1960 to 1981, the NCI-USDA program that the Taxol came from, had screened more than 14,000 plant extracts and more than 16,000 extracts from animals. Then, in the more than 20 years that they were working on this, out of these 30,000 natural extractions, only Taxol was on the path to actually becoming a drug. Now, a few other natural substance candidates eventually followed, but the process was clearly very slow going, but only in recent years, advances in technology have accelerated the drug discovery process in a major way.

Ernest de Leon:
Well, they just hadn’t discovered essential oils yet.

Jerome Baudry:
This approach has been around for a couple of decades, even more of the pharmaceutical industry. What is happening now is that, because of the power of supercomputing, we can use it to screen very large databases of chemicals, the kind of scale I was mentioning here very, very fast times.

Ernest de Leon:
So, what supercomputer did they use?

Jolie Hales:
HPE Cray gave Jerome access to the supercomputer called Sentinel, which has about 4,000 cores and computational power of 200 trillion calculations per second, or 200 teraflops.

Jerome Baudry:
It’s about if the entire population [inaudible 00:48:37] was performing 20,000 calculations at the same time.

Ernest de Leon:
That’s pretty amazing to think that this machine can do that many copulations per second.

Jolie Hales:
Jerome says that this kind of compute power is necessary.

Jerome Baudry:
It takes a lot of computational power to describe all the atoms that would essentially be meeting each other in the actual test tube, in the wet lab. How they mean interact with each other, the geometries, how the torpedo is going on the boat, so to speak, and all the forces that act between all this atoms, it’s based on a lot of things. You do have a lot of atoms in a test tube. So, we do need this computational power to perform at this scale.

Jolie Hales:
Jerome says he started out screening about 10,000 compounds per day, but eventually got to the point where he can run a million compounds in a single day by using Sentinel as a delocalized machine by way of Microsoft Azure’s Cloud. Just to give you an idea beyond that, the Oak Ridge Summit computer that we mentioned earlier, that is number two on the top 500 list, that computer would have the power to run a billion compounds per day. So, compute speed is really not an obstacle these days for research like Jerome’s.

Jerome Baudry:
Now, part of the reason is that everyone is putting resources into it, obviously. When half of the resources of the planet are put on the project, it’s like a moonshot. I mean, we are going fast basically, but it was a potential to accelerate by an order of magnitude the drug discovery process.

Jolie Hales:
And accelerate, it has. Jerome said that not only does supercomputing make science go faster, but it changes the traditional approach to research

Jerome Baudry:
Instead of analyzing and explaining what happens in the laboratory, which is already quite difficult and valuable, we are able to predict what will happen in the laboratory, and that has totally changed the way we do research.

Ernest de Leon:
Yeah, it’s been interesting to see how, even in the development of technology, what used to be more of a trial and error process is being driven more by predictive analysis models, where we know much more about where to start.

Jerome Baudry:
The way that it changes the psyche of the young scientist, I belong to a generation when, where we had a problem, we had to derive an analytical solution to it, and then we would run the numerical [inaudible 00:50:59] to solve this well-defined analytical solution.

Jolie Hales:
But now instead …

Jerome Baudry:
Run 100 tests and find the 10 that works basically, and stop wondering about why it works, but just make it work.

Jolie Hales:
That mindset is one thing that those in high-performance computing and those in the pharmaceutical industry have in common.

Jerome Baudry:
Fail early, fail cheap, and that’s what HPE allows us to do, to fail early and to fail cheap, and to fail massively, which doesn’t sound great, but it actually is extremely valuable.

Jolie Hales:
But Jerome didn’t always think that way.

Jerome Baudry:
The pharmaceutical industry has taught me to accept failure as a PhD and postdoc from quite prestigious places, if I may say so myself. Failure was a personal, a horrible thing. It’s my mentor in the pharmaceutical industry, I will remember that forever, Dr. [inaudible 00:51:51] who told me, “Just give it a try,” and the liberating aspect of this notion was totally new to me, and has indeed has allowed me to succeed. On the other hand, I understand, I mean, Huntsville, that’s where US Space Exploration program started. NASA started here, von Braun came here from Germany after World War II. We cannot just send one android Saturn V on the moon and see which one succeeds and which ones fail. The nature of the problem has also lent itself to this trial and error acceptance, and it’s because we are virtualizing reality. We can, in virtual worlds, afford to fail.

Ernest de Leon:
That’s absolutely right. There definitely has been a paradigm shift. When I was coming up in college, in undergrad and graduate in the computer science program, you were obviously failing repeatedly as you were learning all this stuff, but once you got into the, let’s call it the real world, you often were taking your designs to extreme lengths, trying to deal with corner cases. That probably wasn’t the most efficient way to attack the problem. Now, the tech sector has kind of shifted to this fail fast mentality, which is much better, lean operation. This fail fast mentality is now enabling both science and tech to very quickly and de-risk what would have been incredibly risky having to do this in labs, on humans, etc.

Jolie Hales:
That’s interesting that you say that, because I come from the entertainment industry, and I’ve been in the tech industry for about a year now. When I first entered the tech industry, the executive who brought me on board looked me in the eye and said, “I need people who can fail fast.” That always stuck out in my mind because I had never been in a role where that was the mindset.

Ernest de Leon:
Yeah, absolutely.

Jolie Hales:
It’s so interesting that the way computing has had this ripple effect, I mean, not only changing the speed and the power behind research, or even changing the outcome, which obviously it has, but the very way we approach research in general, and Jerome sees more changes for good on the horizon.

Jerome Baudry:
What we can do now is look at gazillions of different test tubes in a day, what we will be able to do in five to 10 years, I think, instead of looking at test tubes, we’ll be looking at organisms, we’ll be able to simulate the answer of you or the answer of me if we are given a drug.

Jolie Hales:
Oh man.

Jerome Baudry:
As a matter of fact, we treat every cell as the same right now. We know that’s not exactly what happens in reality. You may be reacting very well to a pharmaceutical while that very same pharmaceutical may make me sick, or allergic and whatnot. The second reason why pharmaceuticals fail in clinical trials is because some of us will live, will benefit, but 5%or 10% of us may have some heart conditions that will prevent us from benefiting from it. Usually, so much liability involved that usually the program is canned entirely.

Jerome Baudry:
When we can address that, we will be able to, not only discover molecules that could do well, but also red flag the ones that will very likely totally fail, and then we will solve the 15 years and $2 billion problem of the cost and time it takes to discover a drug, but we are not there yet. Right now, we are very happy at the teraflop and petaflop. We’re going to go exascale and zettascale, I would say, and then we can stop. But what we can addressing every individual, instead of just addressing every test tube.

Ernest de Leon:
Right. Jerome brings up a good point that predictive analysis, AI, a lot of these things are going to be brought to bear in addition to supercomputing, not just the raw computing power and number crunching, but things like predictive analysis. It’s important to keep funding research like this, because it’s not just one area that this works on. The more money that’s put into just supercomputing in general and AI and predictive analysis, deep neural nets, these impact so many areas of human life, and not only that, it creates a feedback loop, where the more money you put into supercomputing, the faster you’re able to advance material science, which generates the materials that go into building the next generation of supercomputers.

Jolie Hales:
I couldn’t agree more.

Jerome Baudry:
If you needed even an egoistic reason to found this kind of research is because by doing so, you found yourself. You are investing in your own future. You are investing, as a matter of fact, in building your own reality, and that we all exist together. If this terrible crisis of COVID-19 has taught something is that we are all in the same boat.

Jolie Hales:
That seems to be an ongoing theme with all of these interviews that we’ve been doing about COVID-19. This thing affects all of us. So, we have to work together to fight back and win. Yeah, I’d say we’ve come a long way since bloodletting.

Ernest de Leon:
We sure have, and Jerome is absolutely right. Specifically with a pandemic, we have to work together, because if we don’t ensure that a vaccine gets to every human on the planet, this pandemic, or this virus will still reside in hotspots and will just re-trigger another pandemic over and over when people travel through these areas. We kind of don’t have a choice.

Jolie Hales:
I don’t even know what to say to that.

Ernest de Leon:
Yeah. It’s pretty bad.

Jolie Hales:
But hopefully, everything will be okay.

Ernest de Leon:
Yeah. It’s like the musicians on the deck of the Titanic.

Jolie Hales:
That’s so sad.

Ernest de Leon:
Playing, what was it? A closer walk? Well, I don’t know what they were playing when the thing went down.

Jolie Hales:
No, near my God to thee.

Ernest de Leon:
There you go, as it went down.

Jolie Hales:
I like to think there’s enough lifeboats for everybody.

Ernest de Leon:
Yeah. Unfortunately, with 7 billion people, there’s not.

Jolie Hales:
There are. We’re building the lifeboats. Ernest, we’re building them with supercomputers.

Ernest de Leon:
Well, let’s hope so.

Jerome Baudry:
We are all in the same boat. We’re all in this together. We find solutions together or we don’t find solutions at all.

Jolie Hales:
So, if you’re wondering what will happen with the 125 compounds from Jerome’s study, they’re still being studied in the lab as we speak, but you can keep tabs on their progress by going to the episode notes page on bigcompute.org, and there we’ll be sure to provide you with all kinds of links and information so that you can keep track of what’s going on.

Ernest de Leon:
If you want to help us get the word out about the Big Compute podcast, please leave us a five-star review and follow us on any of our social media channels.

Jolie Hales:
Yes, tell a friend. Oh, we found out that we, tan tararan, are in the top 10% of podcasts globally, which was a nice surprise. But as a type A personality, now I want to get in the top 5%.

Ernest de Leon:
Or the top 1%.

Jolie Hales:
Yeah, Why limit ourselves, right? This is the era of high performance podcasting. So dumb.

Ernest de Leon:
Of course, special to undercover superhero, Jerome.

Jolie Hales:
How can you just transition like …

Ernest de Leon:
Yeah, we’re leaving that one to lie on the dirt. Of course, special thanks to our undercover superhero, Jerome Baudry, not just for speaking with us, but for the amazing work he’s doing in the fight against COVID-19.

Jolie Hales:
Yes. Who knows? I mean, maybe someday someone we love will be treated with a therapeutic discovered through Jerome’s research.

Ernest de Leon:
It’s possible. See you next time.

Jolie Hales:
Bye.