It's all about light. It's all about controlling materials. It's all about nanomaterials, molecular materials and hopefully it's going to have a little

bit of everything for everybody who's got interests in light, photochemistry, molecular nanomaterials, chemistry, biochemistry. And that's a take home message, take home message in the group, take home message I want to leave you with. We all embrace this concept, we hope we all embrace this concept of structure and function

and the relationships they have in chemistry and biochemistry and this of course means if you can control that you can eventually control technology developed from those types of materials. And whether you like it or not we do believe and agree with Madonna that it's a materials world and everything should be treated as a material whether it's a new material, an

old material, existing materials going to new applications or new applications being developed by benefiting on existing materials. Our research group and research center is based on material science, understanding them better, using them better and whether they're biomaterials, what you're looking at here are actually different structures of kidney stones, these are calcium oxalate

kidney stones. If you would have asked me three, four years ago that we'd have manuscripts in kidney stones as an organic chemist I would think you were crazy. It must be me being crazy because we've published several things on how kidney stones grow in the body, understanding their structure, they're just a material. They're a nasty material, a material we don't want to have but you have to treat

them as a material or a material scientist. Or nanostructure materials, many of the things that we do with our collaborators are based on nanostructure materials, nanoparticles, I'll give you some examples of those. But the core of my research group is based on what we would call dynamic materials. Materials that respond to stimuli and do something.

And so today what I'll talk about is mainly these dynamic materials and specifically photochromic materials, materials that respond to light and I should really just use the term photochromic and I'm trying to convince myself and rehearse myself to say photo responsive because photochromic means as you'll see they change color, photo responsive means they

react to light because we're much more interested in other applications than color and I'll show you many examples of that. And then eventually we'll talk about photo responsive nanostructures and how those can be potentially used in potential applications. In fact this entire talk is going to be full of nothing but potentials because although

we're trying to drive these materials towards applications, it's still a long way to go before we can do that. So I'm going to start with photo responsive materials. I wish I could take any credit for the development of this wonderful class of compound, these dithymal ethines, two thiophene rings linked together by that central alkene, in

this case a perfluorinated cyclopentene. Masahiro Irie pioneered these in the late 80s, early 90s, huge amount of research has come out of that group and others worldwide since. Very appealing type of compound, very appealing chemistry, relatively easy to decorate, synthesize and what it is, it's a hexatriene that I've drawn here in orange and many people

in this audience work with them or understand them or have read papers about them but to remind you, hexatrienes undergo photo cyclic reactions to make this new carbon-carbon single bond and a conjugated backbone. These compounds overall tend to start in a colorless state as shown in the vial here

because you have cross-conjugation between the two aromatic rings, cyclize, make that new bond, make this linearly conjugated pathway and you get color. And the color depends on what you decorate on the outside of this conjugated pathway.

Of course, the longer the pathway, the more red-shifted that is. So you can have seven different compounds as you see here, seven different colors when you radiate those with ultraviolet light. Irradiate the colored forms where they absorb, that same bond that was formed will break, revert them back to the ring-open form and drive the compounds back to a colorless state.

And of course, you can mix colors. You don't need to use seven compounds to make seven different colors. You can just have the three primary colors and here's what Tony's done ages ago where he took some of the compounds, three of the compounds, mixed them in different ratios, polymerized them and you can see whether you have the three colors, two colors or one color

in solution or the solid state, you get color mixing. And this is the very appealing fact about color is you don't need to have individual colors. You can mix and blend colors as long as you have the reds and the yellows and the blues. And I can't resist, I can never resist telling a story at this stage about my younger son

when he was about four. We had one of those disinfecting pucks that you put in your toilet tank and it keeps the tank from getting moldy and it's that blue color in the water. And I still remember the squeals of delight when he figured out that he could turn the water in the bowl green. But the idea of being able to convert one color to another by mixing is core to our chemistry.

Because these molecules absorb light differently, it means that you can also convert them from one color to another in a selective way. And what we have here are the polymers and the solid state and we've just masked them off and we use different types of light to trigger the different reactions. And whether you use two different wavelengths of UV light to trigger in this case the red

or the red and the yellow, you get selectivity or if you then use visible light to drive one of them selectively back, you can see depending on the type of light we use, we can switch one, two, three, revert back and with an algorithm of light create

different colors from now one set of polymeric compounds. Not so happy with the green in the case of the polymer with all three colors in it. We're close to it but here you can see one of the polymers where all we've done is mask them off, different wavelengths of light. You can see you have different types of UV light. Sometimes you have to use more than one wavelength.

You have to de-colorize one after coloring them but eventually you can drive a system to where you get all of the colors by one type of polymer. But that's color. That's not what I want to talk about today. As I've already mentioned, color is very appealing but color is really only appealing because you can tell which isomeric state you're in, whether you have the ring open

or the ring closed state. It's also appealing for the grad students because they always know which of the spots on their TLC or on their column is their photochromic one, go after the one that's colored. But you have a lot of other different compounds, a lot of different functionality, decorating the outside of that structure and the decoration, those functional groups,

are what dictate the properties and that's what allows you to use the molecules in different potential applications. So here are a select few molecules that my group has made over the past several years and you can see that they all have this central hexatriene. And we put different groups on the outside and those groups drive these properties.

So you have two isomers. The two isomers can be inter-converted with light. UV light in one direction, visible light in the reverse. The light modulates the function because the function is dictated by those structures. And if we had several more lectures, I'd be able to go in length over many more examples of what we do.

We can show you how we can modulate the fluorescence and phosphorescence from metallic coordinated structures, single porphyrin molecules, simple ligands, more coordination, even conjugated polymers. In all these cases, you can turn bright states to dark states

by converting the molecule from a ring-open form to ring-closed form where your emission properties are very different, solution, solid state. You could even do it from nanoparticle surfaces. I'll show you more examples of this later in the talk, how you can control properties of emission based on what state that molecule is in.

If I also had more time, I could talk about how we can modulate chirality and we can turn off and on chirality. Many of these molecules we've made are based on this this helicine backbone where you have in the ring-open place flexibility of those arms, so it's achiral.

And then when you ring-close it, because of the steric bulk of these two arms, they overlap each other and you get what's, in English, what's called a washer where the two arms pass each other and are forced to be either this hand in this or this hand in this. And then you can break that chirality, destroy that chirality again.

I could also show you examples of how with our collaborator at UBC, Michael Wolff, we do a lot of work in modulating metals, metals coordinated to these ligands, and how we can turn off and on different properties of metals and in some cases use the metal to create new properties in the photochromic compound. You can change the way the molecules inject charge,

the way that the molecules accept electrons, accept holes, where their redox potentials are. Big application in this area, at least in my mind, is in electrochromism. We had several years ago discovered some compounds where UV light undergoes or drives this ring-closing reaction, takes light-colored to dark-colored solutions.

These are the ones that you can irradiate with visible light and they'll decolor again, or in this case you can apply electricity. You can put a positive voltage in and that spontaneously will drive that reaction back to that colorless state, or in this case that light-yellow state. This means a new technology where you can have transparent electrodes, ITO-coated electrodes for example,

just droplets of polymeric materials sandwiched between those two electrodes. They're radiated to be colored with light. Now you just apply electricity and you can have variable transmission filters, optical filters and films based on this combination of photochromic, electrochromic.

We could talk more about that, but I want to get into really the guts and the heart of the talk, which is a research area where my group has slowly evolved into over the last few years, which is how do you integrate chemical reactivity and photoreactivity,

photochemistry and more chemical traditional chemistry or traditional reactions. It's just modulating chemical reactivity. We've shown several examples of this where we can regulate catalysis either from the boronic acid, the Lewis acid center of the boron and top structure. I'll show you an example of the bottom one in a few minutes.

How we can control stereoselective reactions by making C2 chiral ligands where the isomeric state of the ligand affects how it binds to a metal, affects how that metal acts as a stereoselective catalyst in reactions. And finally the activation of potential therapeutics, again underlining the word potential here.

But this is the one that I want to spend at least a minute on because it's really where the interest of the group is going. It's more into the biochemical aspects. Can we control things in biochemistry? And we were inspired by, like many others, inspired by a set of molecules that all have these enedionine structures I've shown in orange.

Dynamice and klechmycin are two of the many examples. These, as Burkhardt knows very well, were very fashionable and are now very unfashionable. Seems like about 15 years ago if you mentioned enedionine in a grant you would get it. Seems like it's the kiss of death now and if you mention it you will not get it.

But time will tell. I hope that's not true. But all these enedions, they react to form these benzenoid diradicals as the Bergman cyclization and you can imagine how poisonous these are. They just look poisonous, don't they? And these then react. They react, they're anti-cancer, huge anti-cancer potential.

They're very, very toxic. Systemic toxicity is the problem. And so there are many groups when we started looking at this that we're interested in selectively being able to turn on that Bergman cyclization on command. Reducing the toxicity, at least the systemic toxicity until you want it at a certain site to become toxic,

to become that potential therapeutic. So as a proof of principle, glad I didn't send this grant application to Burkhardt. And a proof of principle, we showed this molecule and what David did was he designed a very simple system where you have your enedion up at the top and there are your two thiophenes, there's your hexatrine component.

That is ready to undergo the Bergman cyclization and it does, making this highly reactive diradical. But only when the molecule is in the ring open form. If you enclose it with ultraviolet light, you make this hexatrine or this cyclohexadine

and it removes or at least repositions this double bond so your enedion is no longer there. So that should be stable. That does not undergo the spontaneous Bergman cyclization. So you can think about the ring open form being active and the ring closed form being inactive.

And that would be desirable that you start with something that's inactive, use visible light, which we'll get into the reasons more later. Ring open, activate, spontaneous cyclization, turn on a therapeutic.

It does work in principle. We talked a lot in the early group about principles and almost everything seems like it works in principle, including this one. And we can tell that by just monitoring the degradation of the compounds. There's the ring closed compound degrading spontaneously. There's the ring open compound being perfectly stable over the length of the experiment.

A lot of caveats that I didn't put up on this slide. Working in organic solutions instead of water, the temperature is too high to undergo this Bergman. So a lot of work to do to get this into a real device, a real application. But the point is here. The point is illustrated by this slide. You can turn on spontaneous reactions that have some potential importance.

So the one I promised to tell you about was one that Danielle just made. And it was inspired by biomimetics and inspired by a compound in biology that is really ubiquitous as a cofactor in enzymology. And it's pyridoxal phosphate, very simple structure, catalyzed or helps to catalyze in conjunction with enzymes

a tremendous amount of reactions on amino acids. And they're based on making this imine. They're based on an amino acid condensing with that aldehyde, making this highly reactive imine that has this very acidic hydrogen.

And that hydrogen is acidic, of course, because after you deprotonate and look at the conjugate base, that base is stabilized because it's connected to this pyridinium ring. And you can imagine these electrons delocalizing down into that electronic sink that accepts those electrons to stabilize that charge and you can even draw a quinoidal like structure.

And this is the key step and key intermediate in how pyridoxal phosphate interacts and reacts. And the importance is those two groups, that aldehyde that reacts with the amino acids to make the imine and that pyridinium electron sink have to be electronically connected.

Without that, they have low catalytic activity. Benzaldehyde is some activity, but not very much. So what Danielle did was she designed this molecule where she has the two arms of the diphenyl ethene photo switch. One of them has that pyridinium, one of them has an aldehyde. I've drawn them in two different colors because they are electronically isolated from each other.

They're not connected through bond. But when you undergo ring closing with UV light, once again, I can draw an orange conjugated pathway through the backbone of the molecule. That now connects the pyridinium to the aldehyde and you have something that you can think resembles pyridoxal phosphate,

where it'd be active in one of the forms, inactive in the other, and they're enclosed form after deprotonation, while after condensing with an amino acid and deprotonation, I can even imagine drawing a quinoidal like structure running through the backbone, much like pyridoxal phosphate. So out of the many reactions Danielle decided to look at with amino acids

was racemization. That's one of the common ones that pyridoxal phosphate does. It's also one of the easy ones because you have a lot of analytical techniques, such as NMR spectroscopy, chiral NMR spectroscopy, chiral HPLC, to look at starting with something that's optically pure and making something that's racemic.

So what she's done, she did this first looking at a deuterium, hydrogen-deuterium exchange because of course, if you are going to deprotonate this hydrogen and reprotonate it, if you have deuterium around, you will preferentially react to the deuterium, and it's a very simple way to look at how acidic that proton is in NMR spectroscopy

by just following the disappearance of this signal that corresponds to that hydrogen, as it's been exchanged with a proton. And immediately you can see that in a colorless ring-open form, before and after, after for a set period of time, you see no difference in the NMR signal while in the ring-closed form generated with UV light,

this blue form, you see the signals for that hydrogen decrease in intensity as they're being replaced with the deuterium. And so you can also imagine chirality because you can deprotonate and then upon reprotonation as these electrons are driven back to this imine, which eventually picks up a deuterium, it can pick it up from the top face or the bottom face

of that sp2 hybridized center in that imine. And that's exactly what happens and you can also look at chiral NMR and show that when you start with something optically pure, you end up with a racemic compound. The exchange is fast or faster for the ring-closed form in blue,

in black you see the background, that's the ring-open form, that's not much faster than if you forget to put the molecule in at all and monitor this exchange reaction. But what I really like is that you can turn it off and on at will. You can start the reaction in the ring-open form, minimal to no exchange,

turn on the UV light, ring-close, make the compound blue and all of a sudden you suddenly get exchange. You can then later turn on, turn off that reaction once again by reacting with visible light, which ring-opens, turns it colorless and you have your inactive catalyst, UV light turns it back on and you can just keep doing this.

So here's an in-situ way to turn off and on a biomimetic using two wavelengths of light. So that's the general concept of one of the approaches of how you can integrate chemistry and photochemistry, which is that you modulate chemical reactivity by using light. Each of the forms of the isomers has a different type of reactivity.

That's where the photochemistry gates the chemistry. But you can turn it around, you can think of it the other way, where the chemistry can gate the photochemistry. And this only is possible if prior to, before you have the photochemical reaction,

you have a chemical reaction. Without that chemistry happening, the photochemistry won't work. And that's a very appealing topic to us and an appealing strategy that we've tried to use in several applications. One of them that recently came out was something that Tony and Farnaz did,

looking at a potential way of detecting dangerous compounds, dangerous agents, chemical warfare agents, any kind of nasty that you want to find, conveniently. And so what Tony and Farnaz did was they made a molecule inspired by one that originally was made by Masahiro Irie in Japan.

And we put some different groups on it, but here's the basic structure where this compound is not photoresponsive, despite the fact you have the three double bonds. You have the hexatriene, the compound when you radiate it with ultraviolet light does not undergo that ring closing. And it was suggested by the authors, which we agree with, why not,

that it's because of this hydrogen, this proton transfer reaction involved in the excited state prevents ring closing. That's the fate of the excited state. Well, that means that if you remove that hydrogen, it should work again. Masahiro Irie originally acetylated it. What we did was we phosphorylated it.

And so when you take this compound and react it with this phosphate, this chlorophosphate agent, remove that hydrogen, you now get a photoresponsive compound. That compound now reacts with ultraviolet light, undergoes ring closing, changes its color. You can ring open it again if you want with visible light. So here is the proof of it.

You start with a colorless compound, colorless solution of the compound, react it, this is of the phosphate of course, react it with UV light and you get that blue color. We put these phenyl groups on the molecule because we want it to react with typical office lighting, public lighting, lighting in public spaces, typical fluorescent lighting.

And that does react this way. All we've done here, we've taken some filter papers, we've dipped it into a solution of that compound, dried it, suspended them in vials. At the bottom of the vial is a small ball of cotton wool that's been soaked with this chlorophosphate.

And then we just leave them out in office lights. And you can see only when you have the vapors of this chlorophosphate reacting with the molecule on the filter paper do you get a spontaneous change in color. This case where you don't have any of that phosphate, you don't get a color change. So this is a detection method in ambient conditions

to look at goods or agents that resemble or at least are concurrently being used as mimics for some pretty nasty chemical warfare agents out there now such as sarin and cyclosarin and the other classes of neurotoxic compounds. And so that's our idea.

Is it completely crazy to think that instead of having fancy detectors where you need to have light sources that are special light sources that you can't just use paints and materials and fibers and fabrics that react spontaneously with airborne vapors and then react spontaneously with ambient light and then give you something everybody can see, a visual color.

If you see your white wall turn red, turn blue, run. Another thing we had looked at that we're, I have to say, a bit obsessed about now, not necessarily in a good way, that what we looked at a while ago was can you use these compounds not as molecular switches

but as ways to trigger a spontaneous reaction only once? And it goes back to what I originally said. There are not a lot of compounds out there that react with light to create another isomer so reproducibly that can be decorated so rationally where you can decide what color they're going to be

and synthesize them from stockpile chemicals that you have in hand. The dithionol I think solved that problem. An example I'll show you, there's really two, but I'll talk about one in detail, are these examples where they have the hexatriene here. There's that one in the bottom case. So they undergo this reaction

and the UV reaction does the same thing you've seen. It undergoes this bond forming, makes this conjugated backbone so you can imagine them being colored but I've redrawn or recolored the molecule not to have the orange in the backbone but I've put it up in this six-membered ring. And the reason I put it up there is we designed this system

to be locked and unlocked. Because of this ring, you have, and I'll tell you what it's locked to, a system that's locked to a spontaneous reaction and you unlock it when you make this hexatriene and put this double bond back on that position. That's really the only difference between those two structures

is that double bond. So what is it locked to? The Diels-Alder, the reverse Diels-Alder reaction. This is how we made the molecule in the first place. We took a full-vein, reacted it with a dianophile, made this cyclohexene. This is what we teach undergraduates, don't we? If you see a cyclohexene in retrosynthesis, make it with a Diels-Alder reaction.

That's all we've done here. So here's your cyclohexene made by the Diels-Alder. I don't have that in this compound. A double bond moving has destroyed my cyclohexene, which means that this molecule in the ring-closed form cannot spontaneously fragment and that reverse Diels-Alder.

I have to unlock it first with visible light. Now it creates it and now it fragments. This is so efficient in some of these cases that you rarely see this intermediate compound. This battery is dying. You rarely see this intermediate compound when you start with the ring-closed case, irradiated with visible light, you really only see

the full-vein as it ejects this dianophile. So that's an example of several we have of using light to release. You can see why it's not reversible. I can't drive this reaction from the full-vein back to the ring-closed form because I have to react to the chemical compound first.

So this idea of selective and sequential, you can use different wavelengths of light. This lecture is all wrapping in itself because I originally showed you how you can take these molecules that have different colors, you can irradiate them selectively to ring-close, ring-open them selectively. Well, that's the point of this,

is that you can use a multi-cocktail of compounds, all that absorb different colors, and decide I want to release this one. That's blue. I'll use one wavelength of light. I want to release that one. That's red. I'll use a different wavelength of light. And in this complex mixture, you can select what photochemistry you do

and what you release at what time. So I want to move on. I could have given you some other examples of this idea of release using these compounds, but there's some really important questions that we're starting to address in my group. There's some really fundamental questions. If these are going to be used in practical applications,

there's actually an endless list of questions you have to address. But in the release case, it's great to release. How do you know it's worked? How do you know where it's worked? How do you know when it's worked? How do you know you've released something? And you want a very easy visual way to recognize somewhere in a cell, somewhere in biology,

somewhere in photolithography, somewhere around us, we have done this reaction. So you need something that reports it. Not only releases, it reports. And so what Tony's done also quite recently is designed a relatively complex molecule that undergoes several types of photoreactions.

And they're based on this type of structure. I assume I don't have to show this to people like Sabine who know these kind of caged compounds very well, how they have masked a lot of different types of biologically relevant compounds that I just generalized and insulted the community by calling them a black circle.

And you have these dialcobenzoins linked to these acids, these carbonates, carbonates. And they undergo this photocleavage reaction where they break a bond, they make all these intermediates, and eventually they ring close the aromatic ring onto that oxygen and you get this benzofuran.

And it's that double bond we were interested in. Creating a double bond in my group has really become the bread and butter of what we do and how we can use our molecules. So what Tony's done, inspired by this, all he's done is replaced the benzene ring with another benzofuran, had another benzofuran on the other side,

and now you've got your photochromic, photoresponsive hexatriene that you've seen many times. There aren't thiophenes here. He also has the thiophene version. But in this case, I'm just going to show you the benzofuran case. So that's the molecule he gets it from. So that was the molecule he made originally. Here is, in case you want to release vinegar,

we can do that for you. Here's acetic acid coupled to his molecule. It undergoes a photoreaction, releases the acetic acid, makes, this is now completely dyed, makes this benzofuran intermediate, has that double bond,

and that now undergoes a second photoreaction with another photon, as typical of these hexatrienes to give you a ring-closed form, where now you get all the properties you would imagine of what you've already seen in these dithymal ethenes. And you can ring open those if you want back to their colorless states. So while you start with a colorless,

a relatively colorless form of that protected compound, you can irradiate with ultraviolet light. It generates another colorless form, and then eventually to this red form, as it undergoes this sequential two-step multi-photon reaction. Conveniently, ring closing is very fast,

extremely fast, and that's what we wanted. If you want to have a way of reporting an event, you don't want to be waiting for every time that, waiting and waiting for the event to happen and report back to you. You want every time you have that photo release, you want an immediate or faster cyclization

so you can say the darker the color, the more times it's released and not the reverse. And so luckily in this case, the first step is a slow step, the second step is very fast, and so we can report back on our system how effective this release was. So that's one question,

that question that only applies to the photochemistry in release compounds, but there's a lot of bigger questions. And they all relate to this idea, the concept, the application of these photo switches to biology and then eventually medicine. I mean, can it really be applied?

A lot of people are talking about it, they have to address so many questions, solve so many problems, listed a few here. Can you switch biochemical function? Can you do more than what I've shown you, more than putting this into chloroform and seeing color changes? Can you put it into real systems, under real environments,

and change something in a biochemical system? If you can do that, will any of these compounds be uptaken by living organisms? If you can do that, can you do photochemistry in these living organisms? And if you can do all of that, can you finally turn off and on a biological function? Can you do something to the organism as a whole?

A lot to answer. So a project that came from Burkhardt, from this university, was looking at modulating the activity of carbonic anhydrase, which is a really good model because it has this canyon, this active site that's this canyon. It has two different positions

where you can dock in inhibitors. At the top and the bottom, there's sulfur inhibitor, there's copper complex inhibitor. Both of them have micromolar inhibition. But if you link the two of them by a 10 angstrom bridge, you now have bivalency, you now have titer binding, and you now have much better inhibition, nanomolar inhibition.

So it's a really good model. It's a good model because we can make a molecule like this, which Daniel made, that has the two inhibitor arms linked by that photo switch in the middle that you can ring close with UV light, ring open with visible light. Now I think most people would imagine well you've got something that's flexible, something that's rigid.

If I want to have really good binding in an enzyme pocket, make it rigid. Problem is, this is one of the few times a chem draw actually works. The molecule in the ring open form and closed form are almost identical. In terms of its shape and where the positions of the atoms are, they're very, very similar. So you can't do that. What you have to do is make it too big.

Make the ring closed form, because it's rigid, make it bigger than the 10 angstroms. So you can bind one of the arms, the other arm, but not two of them simultaneously. And that works. You have in the rigid form, the inhibition is micromolar and very similar to what you would see

if you just had one of the arms. But because you have, and this is what I was emphasizing, it's still 11 angstroms in the ring open form, give or take a few point angstroms. But because it's flexible, those two arms can rotate and they can adopt a wider range of conformations and distances. One of them being that magic 10 angstroms.

So now it can rotate around, dock into the enzyme with both arms, lo and behold, you get your nanomolar inhibition. So you can affect biochemistry at least in vitro working environments using this type of photochemistry and these types of molecules. But do they do anything to organisms?

Are they even eaten by organisms? So you can imagine my disgust and surprise when Usama came to me and said that he had worms. And what he meant was that he had fed this compound to a series of worms called C. elegans. We chose this compound because

it's obviously fluorescent. That's a good one. It's water soluble to some level, so it can go into the buffer that the worms are living in. And you can see how the worms have eaten some of this molecule. So you have the fluorescence microscopy at the top showing you after about an hour, the worms have digested some of our molecule.

They're highly fluorescent. In the optimal microscopy, if you ever want to turn a worm blue, we can do that for you. You start with a colorless worm, you use UV light, you turn it blue, you use visible light, you turn the worm colorless again, and you can keep doing that. You don't give it a suntan. It's a very low energy light. So molecules are uptaken.

Photochemistry works. Does it do anything? So here are the worms. They've been fed their molecule. About 15 minutes later, they've been washed. They've been put on their agar dish of bacteria, and they're wiggling around trying to find their food stock. You radiate them with ultraviolet light, and they all fall asleep. So you have complete paralysis of these worms.

You use visible light, wait a few minutes, and they wake up again, and they start crawling. You use UV light, they turn blue, they fall asleep. Visible light, colorless, and they'll wake up again. You can do this four to six times depending on how lucky you are

before the worms eventually die. It shows the proof or the principle that you have simple molecules you can turn off and on biological function. This is not phalamic therapy. This is not using light to create a species that irreversibly does something. This is a species that interacts with biology

in one of its forms, does something, or in this case, prevents something, and in another form, it does the opposite. We have no idea why. We've tried some gene knockout experiments. Long story short, we don't know why it's happening. We have some hypotheses that it involves the cytochromes, electron transfer pathway. It's why we made the molecule.

The ring-open form acts like a peridinium. It's difficult to reduce. In water, it's about minus 1.5 volts to reduce. In the ring-closed form, because you have communication through the backbone of those two peridiniums, it's now about 0.4 volts to reduce. Compounds that are reduced at those voltages interact with the electron transfer process

that's involved in metabolism in organisms such as this. We think it's a circuit breaker. It's taking that electron, preventing the worm from doing what it wants to do. It's going to take a while for us to figure that out, though. I hope that I've satisfied you that you can do some things

in real sightings and answer some of those questions, but the real big question, if you're ever going to imagine biology, is this one. How are you going to get the light there? How are you going to get the compound there? It's relatively easy. You design a compound that looks like it has some solubility. You feed it to some worms or cells.

You cross your fingers, and 9 out of 10 times it's uptaken by the cell. How do you get the light there? How do you get the light deep in the body? Now, you need longer wavelengths of light. We all know that. It doesn't damage tissue. We've all stuck flashlights. Actually, I shouldn't say that. I stuck a flashlight in my mouth with my friends when I was a kid, and the red light comes out.

When you see light that's longer wavelength, it penetrates tissue. But we do know it does less damage. UV light does a lot more damage, much higher energy. Visible light does less. So the answer, of course, use multi-photon absorption. A lot of amazing research coming out with two-photon absorption compounds.

Chromophores use two photons. Big problem is, organic compounds are lousy for this. I mean, there's some really good ones compared to the bad. But having two photons simultaneously arrive and be absorbed by an organic compound is very difficult to do without having highly intense laser light. So it limits the application.

Like I say, great results out there. Really promising. Compounds that are getting better and better. Two-photon cross-sections. But I still think there's a long way to go before this is really universal. So our answer to multi-photon switching, and I really feel like I've come to the Vatican to teach the Pope how to be a Catholic with wolf mice here,

but we're looking at using up-converting nanoparticles. We're looking at using multi-photon approaches. And we're starting with some very simple molecules. Just the simple parent diphenyl-diphenyl ethane. This is the one you've seen dozens of times. Ultraviolet light ring closes. Visible light ring opens.

We don't want that. We want near IR, because as I've already said, the near IR is a better match for biology and medicine. So you can take these nanoparticles. These are these sodiumitrium fluoride nanoparticles. They're dope with some lanthanides. On the left-hand side, you have some thulium. It always has ytterbium in it.

You have some thulium in the left. Erbium on the right. Somebody should have told me that you had a periodic table here. I wouldn't have put one in, because as a scary organic chemist, you have to go really far down on a periodic table to find these. I don't go much down below sulfur, so this was a struggle for me. These have very unique properties when embedded in these sodiumitrium fluoride nanoparticles.

Unlike two-photon absorption in organic compounds, where two photons of light have to arrive and be absorbed simultaneously to take that molecule two steps up to high-level excited states, these have longer-lived real states

where you pump into the ytterbium, energy transfer to the left to the thulium, to the right to the erbium. Those states are lived long enough that you can re-pump light into the ytterbium and then keep energy transfer processes and pumping those energy levels higher and higher in the two lanthanides.

You can just raise the levels, and as they fluoresce, you can see you just have longer and longer wavelengths, or shorter wavelengths, come out of this as you go down and up in that electron transfer process or energy transfer process. Long story short,

if you take the thulium ones, irradiate with 980 laser light, it emits blue light. You can drive it as much as four photons absorbed into the UV, and I'll show you that in a minute, but it has UV and blue light. In the case of the erbium, it has mainly green and red, but because we're more sensitive to the green,

it appears as green. So green and red light are emitted. Either way, you've got ultraviolet to drive your ring-closing reaction, so I can start with a polymer, or I should say that CJ can start with a polymer, and the polymer contains the ring-open form and some of Chris's up-converting nanoparticles.

And you irradiate with a laser, a 980 laser near IR, and wherever the laser light passes through the system is the only place where you get coloring. That's the only place where you're driving with multi-photons, five photons, generating UV light and ring-closing.

Only where that laser light is. Everywhere else, it doesn't absorb. If you don't put in the nanoparticles, no photo switching. It has to have both the nanoparticles and the photo switch. What CJ and Chris also did was they then took another sample, irradiated it in the film with UV light, get the ring closed, form that dark red color,

and now they co-cast this polymer with the erbium-doped nanoparticles. They're the ones that generate visible light, where now, wherever you direct that laser, is where you have fading. That's where you're driving this ring-opening reaction. Once again, without the nanoparticles, these molecules do not react to that light.

So you have remote control photo switching. Nanoparticles are generating the light internally, little light bulbs, and the photo switches are absorbing that and doing their chemistry. What Chris has more recently done is a nice trick where he took a core of the erbium-doped nanoparticle material, he coated it in a shell of the thulium,

and then he coated it in a shell of just sodiumitrium fluoride. The reason for this is depending on the intensity of light, you either get low photon conversion, so the erbium is activated, and you get the visible light, the green and red light. If you increase the power density of your laser light, same wavelength, 980,

you get now the five photon and generate UV light. So all he's doing here, he's taking a sample of the nanoparticles, and he's moving them in and out of the focal point of the laser. And you can see how the closer it gets, the more blue and white, the further away it's green. All he's doing in the bottom case, laser is stable and still,

sample is stable and still, and he's just turning up the power to get blue and UV, turning down the power to get the green and the red. So now using one nanoparticle, one wavelength of light, and just changing the power, you can now control what emitted light you get, which means you control photochemistry. So what CJ did was made this system,

very simple molecule, colorless solution. This is the direct radiation. UV light darkens it, making that new bomb, making it go blue. Visible light opens it. It's got Chris' nanoparticles. If you use high power 980 light, you generate UV and blue, you drive the ring closing reaction to the same state.

You just now turn down the power, make the green and red light. It's visible. Drives the ring opening reaction. So now you can just cycle over and over again by doing nothing other than increasing and decreasing your power, which I think is very, very practical. This is a universal system. We're just generating light

using multi-photon approaches and 980, and then we're just making UV light by little light bulbs in our solution. So the reaction that I originally showed you that Tony did for us, inspired by, for his photo release, we can choose that one too. And that's exactly what CJ and Chris did. They decorated now onto the outside of the nanoparticles attached to them

using this dye acid. They put a very simple model of this Benzoin. Once again, we're releasing vinegar. Simple Benzoin. This has the thulium, so it's got the 980 absorption. It's got the visible light or the UV light emission. So the UV light is what's needed

after it converts to the near IR to drive that photochemistry and we release acetic acid all on the surface of this nanoparticle. It's just a universal way to do photochemistry, but very, very mildly with long wavelengths of light. And finally, the last thing I'll show you is that it does work potentially

in biological systems. So what CJ and Chris now have done is they've taken one of the photo switches, they've clicked it onto the surface of a nanoparticle that was pre-decorated with an azide that had the phosphate linkers, and then you have a peg for biocompatibility for better water dispersibility. So the photo switch is just now

a probe to see if this is turning off and on in a real system. And this is because, as you can guess, by the fact that the laser light is activating the nanoparticles, they're emitting light that's getting absorbed by the photo switches, that means that the emission of the nanoparticles must be reduced.

And they are, you can see how the ring closed form in the dotted line, the spectrum of it overlaps very well with the green emission, and you can cycle it back and forth several times. So you can turn on and off this green emitted light. You can also feed these back to the worms. The worms uptake now the nanoparticles, they're decorated with the photo switch,

the optical microscopy is on the left, fluorescence microscopy in the middle. The only difference in the top and the bottom panel, set of panels, the top panels were not washed of any excess photo switch, while you see some of these nanoparticle spots, and the bottom was washed, which is why the background is nice and dark. Either way, irradiate with UV light,

converts the photo switch from ring open to ring close, ring close absorbs that green light, and you have dark worms. So this is now a way that you can turn off and on imaging and multimodal imaging, since we have different photochromic compounds, they can absorb different wavelengths of light, so we can have green absorbed, red absorbed, blue absorbed,

in a more complex system in a live animal. And these worms are perfectly happy, they continue to live as, I guess, well as a worm must after this treatment. So I've tried to be very clear on who's done the work that I've shown you. I didn't put people in the first part of the talk or the previous group

who's done the bulk of the work that's led up to these more recent projects, but as I say, I try to be very clear as I went along on the latter part of the talk, which of the students in post-talks contributed to what. Great collaborators, again, it's only a partial list for the projects I've shown you, and these are the funding agencies in Vancouver and Canada

that supported this research in part, so I'd like certainly to thank the funding agencies, absolutely to thank the people who did the research, but most importantly, to thank you for your time today.