Phase Space Invaders (ψ)

Episode 14 - Syma Khalid: New ways to fight bacteria, the bacterial envelope, and kindness & openness in academia

• Miłosz Wieczór • Season 2 • Episode 14

Share episode

Send us a text

In the fourteenth episode, Syma Khalid and I talk about the challenges we're faced with when trying to understand the environment of the bacterial cell envelope, and the outer membrane in particular. We discuss how the lessons taken from the computational study of these structures can inform the design of future antibacterial agents. Then, we move on to consider strategies for making the scientific environment of one's research group a place to thrive, develop, and live a happy and fulfilling life.

Welcome to the phase space invaders podcast, where we explore the future of computational biology and biophysics by interviewing researchers working exciting transformative ideas. Today. I am talking to Syma Khalid a group leader and the professor of computational microbiology at the university of Oxford. Saima is well known for her pioneering contributions to our understanding of the bacterial cell envelope. Through the lens of computational methods. The cell envelope involves all the structures and layers. That's contributed to the selective uptake of compounds in the trends in bacteria. So just as you can imagine, Syma's research bleeds into fundamental questions about bacterial drug resistance. And the design of anti-microbial agents of the future. So we start the conversation exactly by discussing our understanding of the bacterial outer membrane and all the factors that contribute to its role as a formidable selectivity filter. Revise the lessons learned from computational biophysics research on bacteria, specific proteins and lipids. And whether how this can inform medicinal chemists or biotechnologists of the future. Then we move on to talk about philosophy for running a lab and choosing one's values as a group leader. And how following kindness openness to diversity and understanding for different life paths. Can contribute to human flourishing resilience and the overall happiness we're left with even if we still have to get a project proposal funded at the end of the day. Hope you're ready to go.

milosz-host950_2_06-14-2024_172240:

Okay. Syma Khalid, welcome to the podcast Oh,

squadcaster-b62b_2_06-14-2024_162240:

thank

milosz-host950_2_06-14-2024_172240:

you

squadcaster-b62b_2_06-14-2024_162240:

for

milosz-host950_2_06-14-2024_172240:

having me

squadcaster-b62b_2_06-14-2024_162240:

So Syma,

milosz-host950_2_06-14-2024_172240:

you're very well known in the community for your commitment to one particular, but also fascinating compartment of the biological space, which is the bacterial outer membrane. And on the podcast, we've so far had some conversations before that, that hinted on the usefulness of microbiology in general, to, you know, our general understanding of biology and disease, but also for technology in particular nanotechnology. What are the lessons we can take from those bacterial systems in terms of for once, but also perhaps computation.

squadcaster-b62b_2_06-14-2024_162240:

Um, I think, first and foremost, I mean, I think the lessons we can learn are that the biology is, I mean, it's just exquisitely designed to achieve its functions. So, bacteria, As I'm sure many listeners are aware they have to survive oftentimes in conditions of very scarce nutrient availability. They have to survive in conditions where they are in dense populations. And there are many types of bacteria coexisting in these environments where they are very scarce nutrients. And so they have to be adapted very, very well. And when you think about it, what, you know, at the ultimate level, what is adaptation? It really comes down to molecules and the way they're arranged. Because that's kind of in a way, I suppose, if we think about a biological unit, the smallest unit we have is molecules. And so I guess for me, it's just trying to understand how at the molecular level it all works It all fits together and there's a kind of choreography. that has to happen that then achieves these phenotypes that we see. But then there is no single experimental technique that will allow you to see, say, for example, as high a resolution as you can achieve with x ray crystallography, but at the same time, see the movement that you might get to see in sort of using fret or something like that. Computation sort of bridges that. It allows us to see the high resolution of the structural techniques, but it also gives us the movement, you know, with the caveats, of course, that they're models and we have short timescales.

milosz-host950_2_06-14-2024_172240:

Right. so what is really special about the bacterial outer membrane, right? I understand it's a kind of very porous, loose filter. Right.

squadcaster-b62b_2_06-14-2024_162240:

Well, I'm going to disagree with you and say that I think it's, it's not porous at all, and I think that's the issue, right? So the outer membrane is the very first barrier that anything that is attacking the bacteria, whether that's another bacteria, whether it's attack from an antibiotic, whether it's a attack by a bacteriophage. But the first barrier it encounters before it gains entry into the cell is the outer membrane. So the outer membrane is like a coat of armor which is surrounding this bacteria. And so it has to be, it has to be very clever. It has to be impermeable to harmful substances, but at the same time it has to let in essential nutrients. So it's selective, but it's rigid, and it's it is generally highly impermeable. And it turns out now that we're also beginning to see that there's a higher order, right? That the proteins and lipids are not just randomly positioned across this surface, but there may be, or they certainly in E. coli, there is a higher order to that. And those are the details which are only just emerging now.

milosz-host950_2_06-14-2024_172240:

right by higher order, you mean spatial organization that things cluster together.

squadcaster-b62b_2_06-14-2024_162240:

Yeah. Yeah. So we're learning now largely from, initially anyway, from, um, some beautiful work that was done at some university college London using atomic force microscopy, in Bart Hugenmund's group by Georgina Benn, where they showed that actually The proteins tend to be clustered in highly densed, we call them islands, but then there are other regions which tend to be lipid rich. And so there's this sort of phase separation, if you like, which had previously not really, um, it's just not even been considered, I guess.

milosz-host950_2_06-14-2024_172240:

That sounds beautiful yeah and well, I guess it's also the capsule, right? So there are proteins that are secreted and kind of stay on top of the outer membrane. how does this affect the whole thing

squadcaster-b62b_2_06-14-2024_162240:

Yeah, I mean, yes, some bacteria have this capsule layer. So as though things were not complicated enough. On top of all of these horrible sugary lipids, which are really sticky because of all the hydrogen bonds they can form. Then on top of that, you have this capsule layer, you know, again, also you see these beautiful patterns emerging in these layers. And they further rigidify the whole thing, which makes it very, very impenetrable. And then you start thinking, well, if we are going to design antibiotics, where do we even start? Is it going to be polar? Is it going to be hydrophobic? What kind of characteristic will this antibiotic have to have? Because in a way it will encounter all of chemistry as it tries just to get through the outer membrane, right?

milosz-host950_2_06-14-2024_172240:

Right. I was just thinking about that because there's this whole narrative that we're kind of running out of purpose antibiotics, right? And that that's a, dire situation to be in From the modeling, do we start to understand what kind of features we can engineer into new antibiotics that will make them, you know, more generalizable, more universal?

squadcaster-b62b_2_06-14-2024_162240:

I think it's a really good question and a really good point. And obviously, this has been a goal of many, many years. simulation studies over many years, and I think bizarrely, in some ways, but in other ways, maybe it's, uh, it is easy to understand, is that only recently, people have started realizing that when we do these computational studies, we have to include realistic models of the membranes. It's not okay just to say, well, these are the lipids, let's see if the antibiotic gets through. Because in real life, Those membranes are jam packed full of different types of proteins, each with their own surfaces and different characteristics. But, you know, some, some details are beginning to emerge now. So we're beginning to find, for example, mechanically, where is the weakest region of that membrane? What would you target? But I think other approaches which are, which are very elegant are ones that say, for example, how do bacteria kill each other? Let's look at how they do it, and we get inspired by them, because they're the best at doing it, and they tend to be very specific. How do viruses that target bacteria, so bacteriophages, how do they do it? Can we look to them for inspiration, rather than this, I guess, traditional medicinal chemist approach, which has been, this small molecule works, To a point, let's tweak it, make it work in a different way, right? So it's a completely different philosophy to that.

milosz-host950_2_06-14-2024_172240:

Right. From my virology class, I remember that even bacteriophages are not immune to resistance, right? There's this beautiful arms race going on for millions of years where they keep inventing new ideas to kill each other. What are your favorite techniques or ideas that we can take from, those wars, biological wars that are going on and kind of repurpose to

squadcaster-b62b_2_06-14-2024_162240:

Well, I think,

milosz-host950_2_06-14-2024_172240:

purposes.

squadcaster-b62b_2_06-14-2024_162240:

I mean, I guess I'm quite biased because I work very closely, with Colin Clantas, who's a world expert on bactericins and colicins in particular. So how, you know, bacteria use these bactericins to penetrate into their enemies and kill them. And so that seems to be, I like it because it seems to be a tangible and very selective way for them to kill each other rather than, you know, Something like type six secretion where they just randomly are firing out weapons at each other. So that, that seems to be nice, but there was a, another approach which I've read about a bit and I talked to someone who was working on, it's called the Trojan horse approach, where, for example, we know these tombi, so called tombi dependent transporters. They have these molecules called siderophores, and they are the natural substrate for these proteins. And so, what we can do is we can take the natural substrate and attach to it, The bactericidal elements, right? And so it recognizes its substrate and lets that come in, but attached to it is the harmful element. So that seems like a nice way to, if you like, fool nature. I'm not sure we can ever ultimately fool it too well, but it seems like a kind of sneaky and nice way to do it. Yes.

milosz-host950_2_06-14-2024_172240:

I think if we, eventually develop a kind of arsenal of blocks, right, this might be the way to go. Like if you have 500 combinations and each of these combinations can develop resistance, but then if you can just conjugation and make, fragment based design, maybe it's a way to go. Also using the fact that if I remember correctly, the peripterism has a different oxidative. State so you can also have things that are reactive under reducing conditions,

squadcaster-b62b_2_06-14-2024_162240:

Yeah. Yeah, absolutely, and I guess anything that we can do that does not involve modifying a protein, because bacteria can easily combat that by modifying proteins, right. At the genetic level.

milosz-host950_2_06-14-2024_172240:

right?

squadcaster-b62b_2_06-14-2024_162240:

we can take things like modifying lipids, so LPS, for example is now being, targeted or things like that, which are a bit harder to do, I think maybe, maybe a more elegant approach, but it, I guess I'm a bit worried that part of me always thinks that the bacteria will eventually outwit us

milosz-host950_2_06-14-2024_172240:

alright, what is the role of the LPS from a computational biophysicist's perspective? Does it rigidify? Does it just make a crowd on top of the membrane? Does it somehow filter things as well? That's an interesting thing that doesn't get discussed much, right?

squadcaster-b62b_2_06-14-2024_162240:

I think we're just scratching the foot surface of what LPS does. for sure it's very, very sticky. It moves very slowly. And so some years ago in my group we calculated the free energy barriers for small molecules to penetrate through LPS compared to phospholipids and you see big energetic differences. and so we know that it creates, an energetic barrier. It creates a kinetic barrier, but now we are also beginning to find that actually it acts as a glue to hold proteins close to each other. And so, you know, it's it likely has many roles, right? I think it's unlikely that. Nature will have gone to the trouble of evolving and developing this lipid, which has four to six hydrocarbon tails, lots of chirality in its sugars, different patterns of phosphorylation, all of this complexity for one function. It's likely to have many functions, I think.

milosz-host950_2_06-14-2024_172240:

Right. I can see. So it's a whole, interesting world of optimizations evolution. But then we have to reverse engineer.

squadcaster-b62b_2_06-14-2024_162240:

Yes,

milosz-host950_2_06-14-2024_172240:

Okay, but you are at Oxford and you have a sizeable group, right? I think. How many people do you have in your group?

squadcaster-b62b_2_06-14-2024_162240:

uh, maybe 15 or 16, I guess. So and there are still a few in Southampton at the moment.

milosz-host950_2_06-14-2024_172240:

All right. So, so there are

squadcaster-b62b_2_06-14-2024_162240:

So we're sort of spread over two sites.

milosz-host950_2_06-14-2024_172240:

in parallel. So what's your philosophy for, keeping the group happy, let's say, and productive?

squadcaster-b62b_2_06-14-2024_162240:

Um, I think they have a fair bit of, you know, sort of freedom in terms of scientific freedom, but also working patterns freedom. I usually like my group members to be in by 10 a. m. start, which doesn't seem particularly early to me. And if anyone ever wants to work from home or work from the library, I don't think I've ever said no to anyone in 20 years of having my own group. I've never said no to someone asking for a holiday. So I think those kind of things are important. You know, important to me that people feel comfortable where they work, in terms of keeping my group happy. We also have quite a lot of group social activities and typically I ask them what do they want to do?, And so we're pretty relaxed. I mean, oftentimes if I've had a particularly bad day, sometimes I just walk out of my office, go into the lab and say, all right, guys, I've had a terrible day. Does anyone want to come to the pub and we might just get up and go, um, or, you know, so I think we're quite. Or if it's a nice day outside, I'll just walk outside and say, Shall we, shall we just go for an ice cream and everyone gets up and we will go. So I think it's quite relaxed in that way.

milosz-host950_2_06-14-2024_172240:

that's great. Yeah. Alluding to what you mentioned before. I mean, we're discussing the question of people going to industry versus academia. And I think this is one thing that people might in the industry, the relaxed aspect. Right. But you wanted to point out that, you know, of course, there's nothing wrong with going into the industry. Of course, it's a different world. So the time people take to their PhD might be, uh, you know, time to get new skills and grow us a scientist, but eventually grow up. And you have to choose. So what's your, take on that?

squadcaster-b62b_2_06-14-2024_162240:

I think the bottom line is to be happy, I would say. For me, that would be, if you're going to set a goal, I mean I would say that a good goal to have would be to be happy and content in life. That doesn't have to be, I have to be a professor by this age, or I have to be a CEO by this age. Because I guess when you get to be as old as I am, you sort of do realize that life throws many things along the way. Right? And I always say to my, My PhD students and my postdocs that in this period of time, many things will happen to you, you will grow, you will change, your politics may change, your friends may change, your relationships will make up and break up, health may change, all these things that you don't expect and you cannot write an equation for, right? These unexpected things happen and so if you set very definite goals, You may find that that doesn't work out that way. And so there are many, many routes and many pathways, I think, to be happy and content. And so that can seem a sensible one. The other thing that's really important for me is that as long as you're, is you're happy and content, there is no hierarchy, I think. Academia is not better than industry. Industry is not better than academia. The only thing that's better is what's better for you, as an individual. And so, yeah, I'd like to, I'd like to support them in, in that in anything they want to do, really,

milosz-host950_2_06-14-2024_172240:

Right. I think still great things come out of the industry. Right. Yes.

squadcaster-b62b_2_06-14-2024_162240:

I mean, take a look at AlphaFold,

milosz-host950_2_06-14-2024_172240:

Oh,

squadcaster-b62b_2_06-14-2024_162240:

right?

milosz-host950_2_06-14-2024_172240:

Yeah, they don't get us much good rep in the narratives, but in the outcomes,

squadcaster-b62b_2_06-14-2024_162240:

Everyone's using it, right?

milosz-host950_2_06-14-2024_172240:

a good variety.

squadcaster-b62b_2_06-14-2024_162240:

Yeah.

milosz-host950_2_06-14-2024_172240:

Yes. Yes. And also, as you say, I think living a bit of wiggle space for things that are not just purely science people more. down the line, right? Whether it's social connections or, you know, hobbies or all those things, to stick to in terms of in times of hardship.

squadcaster-b62b_2_06-14-2024_162240:

Yeah, absolutely. It's not going to be your papers that are going to comfort you when you're feeling down. It's going to be your friends and family, right? And so these, these, these relationships, to keep them Maintain them, I think is very important.

milosz-host950_2_06-14-2024_172240:

Yeah, and that brings us also this question of, inclusivity, right? That

squadcaster-b62b_2_06-14-2024_162240:

Sure.

milosz-host950_2_06-14-2024_172240:

mentioned So if you make an environment that's welcoming.

squadcaster-b62b_2_06-14-2024_162240:

Yeah, absolutely. I mean, I would say in my group, we cover a range of ethnicities, social groups, nationalities, genders, sexualities. I think, you know, we're really pretty diverse. and to be honest, Oxford is in general. But within my groups, I can sort of, sort of certainly say we, we tick many, many boxes in terms of diversity. And it's not, it's not even an issue, you know, it's something where I feel we, everyone can feel comfortable and that, I think that for me has been a strength throughout, it's been the same throughout my career. My group has always been pretty diverse.

milosz-host950_2_06-14-2024_172240:

I can see how this, helps individuals, even the ones who are locals. Right. Because that gives you such a, a feeling of being in the world in a, in a sense, right? Uh,

squadcaster-b62b_2_06-14-2024_162240:

people who come in, it helps to, as you said, it develops a kind of empathy for people around you because there are challenges that come from being in different societies and coming from different backgrounds that I think we don't consider unless someone tells us or talks to us or we encounter people from those environments

milosz-host950_2_06-14-2024_172240:

right. I myself hang out with different geopolitically stressed, nationalities and I can definitely See how, you know, how that develops a sort of feeling for, I don't know if you call it emotional or social intelligence, but yeah,

squadcaster-b62b_2_06-14-2024_162240:

Yeah, I agree. I think it is.

milosz-host950_2_06-14-2024_172240:

to work on so yeah, would that, would you make it a recommendation for all groups to work on the emotional intelligence and wellbeing?

squadcaster-b62b_2_06-14-2024_162240:

I think so. I mean, I don't know how, how one ensures that. Think if you have an environment where people feel comfortable to talk about pretty much anything then the rest follows. Yeah. If that environment exists, then the emotional intelligence and all those things will come because at some point someone will say something you disagree with, or someone will say something which is outside of your comfort zone. And then as a human intelligent adult, you have to find a way of dealing with that. That is still constructive

milosz-host950_2_06-14-2024_172240:

right,

squadcaster-b62b_2_06-14-2024_162240:

So I think you wouldn't match.

milosz-host950_2_06-14-2024_172240:

have,

squadcaster-b62b_2_06-14-2024_162240:

Sorry.

milosz-host950_2_06-14-2024_172240:

no, I'm just thinking like, there are, you know, there are countries that have naturally a lot of diversity through immigration. There are countries that don't have this way of building, diversity, right? So you have to find other ways. I'm thinking, you know, for example, my country of Poland, we back in the day didn't have that many non Polish students or professors, thinking how to generalize this to a more robust recipe. But of course, if you have this opportunity, it's a good thing use,

squadcaster-b62b_2_06-14-2024_162240:

Yeah, I mean, I think I guess these days one can always do things also online, right? Setups, discussion groups. So for example, if, if one doesn't have it in a particular research group, you could have say a friendly or sister research group in a different country that does have it, and then have these sort of discussion forums or I think the world has become smaller now with the advent of online and remote working so that that sort of thing is possible.

milosz-host950_2_06-14-2024_172240:

Totally. You can see the patterns of connectivity. We've got now movements to also integrate more countries into this broad network of, of collaborators. That's always laudable

squadcaster-b62b_2_06-14-2024_162240:

Yeah, absolutely, and I guess about diversity and all the sort of social things, which I think, you know, I think are equally important to the science. I think maybe I haven't always thought that, you know, like sort of when you're younger and you're very, very career focused, maybe you think those other things are just sort of fluffy hand waving things that you have to do to keep the funders happy or,

milosz-host950_2_06-14-2024_172240:

Hmm.

squadcaster-b62b_2_06-14-2024_162240:

you know, but I think as time has gone on and realized that actually they, they are equally as important as the science,

milosz-host950_2_06-14-2024_172240:

And

squadcaster-b62b_2_06-14-2024_162240:

terms of creating a happy environment.

milosz-host950_2_06-14-2024_172240:

right, right, this hyper focus and productivity, I mean, some people say, we're all smart here. So let's distinguish ourselves by being nice and caring for the broader well being, right?

squadcaster-b62b_2_06-14-2024_162240:

Yeah, I think one of my mentors here in Oxford, Carol Robinson, said that, you know, she, she was saying that when she set up her Kavli Institute here, um, in, in the building that I'm in right now, one of her fundamentals that she wanted to base it on was kindness. And, you know, it was not. for sure, just a box ticking thing. It was, she was doing it from the start and her ethos was before anything else, kindness. And it really stayed with me that actually, this is incredibly important.

milosz-host950_2_06-14-2024_172240:

Right. Because we already got plenty of people who are intrinsically driven.

squadcaster-b62b_2_06-14-2024_162240:

Yeah. Yeah.

milosz-host950_2_06-14-2024_172240:

push them with a stick or even the carrots. They can invent themselves.

squadcaster-b62b_2_06-14-2024_162240:

Yeah.

milosz-host950_2_06-14-2024_172240:

So that's, yeah, that's a great opportunity to focus on the on the well being. Exactly.

squadcaster-b62b_2_06-14-2024_162240:

Yeah. I think so.

milosz-host950_2_06-14-2024_172240:

Okay. for the conversation and sharing the great points. The experiences. I appreciate your time.

squadcaster-b62b_2_06-14-2024_162240:

All right. Well, thank you very much for having me. It's been fun.

milosz-host950_2_06-14-2024_172240:

Yeah, thanks a lot and have a great day.

squadcaster-b62b_2_06-14-2024_162240:

Thank you.

Thank you for listening. See you in the next episode of Face Space Invaders.