001 Modern Molecular Science and How is it Changing our Life Dr Ljiljana Fruk

Hi, I am Liliana Frook. I am Associate Professor of Bio-Nano Engineering at the Department of Chemical Engineering and Biotechnology at the University of Cambridge. And I will talk to you today about molecular science, modern molecular science, and how is it changing our life. And this lecture is a part of Cambridge Philosophical Society lecture series. But before I take you down the road of exploring modern chemistry, let me start by telling you a little story. Let's imagine an earth-like planet. This planet has vast amounts of water, it has big oceans, it has continents, and there are settlements of life on this continent. And all of these settlements, they communicate, they work together, they have different traits, and they exchange goods and information. And they live really peacefully together. But then suddenly, one day, a series of environmental catastrophes happen. There are droughts, there is an issue in producing the food, suddenly there is lots of tension between different settlements. And one particular settlement acquires lots of goods and lots of power. And it tries also to dominate other settlements. It becomes more aggressive. And as it has more power, the more aggressive it becomes and engulfs other settlements in its own surrounding. And suddenly, we have the whole continent that is taken over by this aggressive settlement that has ever-expanding need to dominate more. Now, let's stop for a minute, and let's imagine that this earth-like planet is our own body. And these continents are representing our organ. And settlements are nothing else but the settlements of our healthy cells, which are building the tissue. And there is one particular settlement that grows aggressive and dominating. And we can imagine the cancer being this settlement. And this particular cancer that I'm talking about, which is extremely aggressive, and it really disturbs the whole environment around itself, is pancreatic cancer. And this is something we work on. And this is something that we try to develop the strategies for, to find the ways how can we contain this aggressive settlement, this aggressive cancer cell. We actually have strategies in place already. So, we have chemotherapy. We have a range of drugs which we are giving to the cancer patient. And these drugs tend to be very aggressive. They need to be powerful to overcome such a powerful settlement of aggressive cells. The problem with common chemotherapeutics is that although they are very effective, they also impact our healthy cells. So, they can remove the cancer cells, but in the process of treatment, they will also damage our healthy cells. One of the solutions that we are exploring here in the department and within the university as a part of a larger consortium of scientists is to find ways of making these chemotherapeutics a little bit friendlier or a little bit more efficient, so that they impact the cancer cells, but they are less detrimental, less dangerous for healthy cells. And the one way we are doing this is by using nanotechnology. Now, what is nanotechnology? How can we imagine nanoparticles or nanomaterial? Let's imagine that pancreas, pancreas which is a small organ deep within our body, responsible for production of insulin, which is involved in metabolism of glucose. Let's imagine that this pancreas is the size of New York. If we imagine this size, the size of a nanoparticle, a hundred nanometer nanoparticle, will be the size of this small ball. These are relationships that we are talking about when we are talking about nanoparticles and the sizes of our organs and our body. So, how can nanoparticles and nanotechnology help us to design better and more efficient chemotherapeutics? They can do that by enabling us to package the drug molecules inside a drug carrier. The nanotechnology is helping us in design of drug nanocarriers. And these nanocarriers have multiple roles. First of all, they protect the drug from our own organisms so that the drug can really travel where it needs to go. But it also protects our healthy cells from the impact of this drug. And it does that if we design our nanocarriers in such a way that they can target the cancer cells. But this is the biggest problem in the modern molecular science. How do we find the molecules that are specifically binding only to the cancer cell? After all, cancer is nothing but our healthy cells gone wild. So, cancer cells will have the similar set of molecules that our healthy cells have. So, how do we find the ways to target only cancer cells? And this is one of the biggest issues in modern molecular science, which we also try to answer together with a molecular biologist. So, what we do in my group is we explore drug nanocarriers, which are designed from a very bio-friendly materials. So, we were thinking, if we want to design nanocarriers that are good for our body, that can really, that don't cause any kind of toxic effect, then we also need to use materials that are maybe stemming from nature. And the material of interest that we are using is dopamine. You might know dopamine as the hormone of happiness. It's usually produced if you eat a piece of very delicious chocolate, or in my case, if you eat a little bit of ice cream. And it's a very important neurotransmitter. But a lesser known fact about dopamine is that it is also used in nature to produce molecular glutes. It polymerizes, and it creates polymers which are really a tough molecule. So, we were thinking, and lots of other scientists as well, can we use these polymers maybe to design nanocarriers and embed drugs in them? And we can. So, we can take dopamine as a precursor, we can polymerize it into a larger chain, and by using very mild chemistry, we can design spherical nanoparticles. So, they are usually around 100 to 100 nanometers in size. And the beauty of polydopamine is that it can be decorated with various molecules. So, we can decorate their surface of these nanoparticles with various molecules that are maybe specific to cancer cells. Or we can also decorate them with something that is going to help the transport of the nanocarriers into the pancreatic cancer. Another advantage of polydopamine is that it is similar to melanin. And melanin is the pigment we have in our skin, so it gives the different shades of the color. And this, of course, makes polydopamine really biocompatible. This is one of the examples where the modern molecular science is trying to answer or provide answers to. How can we design more intelligent drugs? And designing nanocarriers is one way. Another way is changing slightly the structure of existing drugs so that we make them efficient but less harmful to healthy cells. One example, which is done by my colleagues in Department of Ecology, it's an example shown in this slide of a chemotherapeutic drug called NavitoClax. NavitoClax is used in treatment of many different cancer types, but it has also lots of really detrimental side effects. Well, my colleagues in the Department of Oncology modified slightly the structure of NavitoClax by adding a small sugar molecule to it. My colleagues in the Department of Oncology modified slightly the structure of NavitoClax by adding a small molecule of the sugar. And by addition of this small molecule of the sugar, they have designed a new class of a drug that can eradicate pre-cancerous cells. That means cells which are still not full-fledged cancer but can lead to the cancer. So by using this type of the drug, in the future, we will be able to design drugs by introducing these small modifications to the drug molecule, which will be able to eradicate pre-cancerous cells before a fully fledged cancer is formed. So we work together with the colleagues to really design the strategies that can be really useful in that aspect. But let's go back a little bit to the nanocarriers, because there are different aspects of molecular sciences that we take into account when we are designing the carriers. And one thing we need to think about is the structure of our cells. How does a cell look like? Cell is a self-assembly of many different parts. It has a membrane, it has different organelles, and it's full of floating molecules. So the first nanocarriers that were designed in the mid-1990s and which are still used in the treatment of certain types of cancers are liposomes. Liposomes are nanocarriers which are made of similar molecules that our cell membrane is made of, which makes them biocompatible, but it makes them also easier to enter the cell, so they can take their cargo within the cell itself. We design liposomes in such a way that they can also be decorated on the surface, so they can have different charges, they can have different targeting molecules, and usually the drug, depending on the properties of the drug, can be embedded in the core. And this is an ideal nanocarrier, because it protects the drug. Now the role of a modern nanotechnology and modern molecular science is not only to protect the drug and to get it where it needs to go, but also release it on demand. So once when the drug gets into the cell, we need to find a way of releasing it. And this is where the chemistry comes in. So we can design the molecules which are within the coat of nanocarriers, which can be sensitive to pH changes, to light, or maybe ultrasound, which we can apply externally. What are the nanocarrier materials that we usually use? There are different types of nanocarriers. And before you ask your question, but why didn't I hear about these special new drugs? Maybe because we still have certain issues with targeting of cancer cells. But just to mention, we do have around 50 nanotherapeutics, drugs which are formulated with the help of nanotechnology, already approved by different agencies in US and Europe. So they are used in patients. The only issue is we just need to work a little bit harder to find the right targeting molecule, molecules to prepare really good systems. And here are some materials which can be used for design of nanocarriers. So we can use liposomes, which are made of lipids. We can use different polymeric species. We can use dendrimers, which are a subtype of polymers. We can also use inorganic nanomaterials, although they are not so prominently featured in nanomedicine. And as I showed you a little bit earlier, we also can use these biopolymers, sugar molecules, or elongated dopamines to design nanocarriers as well. The challenges in the field of nanocarriers are few. And one is what are we going to attach on the surface? How do we make them specific? How do we give them the information so that they really can get where we want them to go? And another issue is how do we attach the molecules on the surface of nanocarriers? It's relatively easy to load the nanocarriers with a drug. It's a little bit more difficult to work with the nanocarrier surfaces. Cancer biologists look for different types of molecules that we could use to target when we design nanocarriers. Molecular biologists can give us more information on what types of the drugs can we actually use to target different diseases. And we as chemists, as molecular scientists, we then design the chemistry by which we can attach different molecules to the surface in such a way that we don't impact the function of these molecules. Let me show you some of the examples that we use in my group. So we specialize in biofunctionalization of surfaces, which means that we can attach different molecules to the surfaces as well. And as we are working with very sensitive molecules, we also need to use sensitive and mild chemical procedures. One of the procedures that we specialize in is using light as a trigger. And that means we need to design different chemical moieties, which then we can join together by exposing them to irradiation. And here is one example of this chemistry. As you can see here, we have a nanocarrier, a nanoparticle, which is around 100 nanometers in size, and we modify its surface with a particular chemical moiety. Now, in this particular example, we wanted to attach DNA to the surface of this nanocarrier. And so we modify the DNA with a malamide group shown here, and we irradiated the system with a particular wavelength of light. This kind of strategy not only enabled us the attachment of a DNA on the surface, but it also resulted in the fluorescent product, which means that we could really follow the reaction in the real time. So we could say how many molecules of DNA we have attached on the surface, and we could really say when our reaction is finished. We call this system self-reporting linkers. And it's an interesting tool which can help us to attach not only DNA, but peptides and proteins on the surface of nanomaterial. By using this chemical modification strategy, we overcome a challenge of attaching the things on the surface of nanocarrier. But there are also other challenges, and one particular challenge is how do we tune mechanical properties of a nanocarrier to fit what is happening in our body? And this is something that is kind of becoming more and more interesting in the field of bio-nanotechnology, and it's not only encapsulating the drugs, designing a particular material which can be used for nanocarriers, attaching the molecules on the surface, but also fine-tuning the cores of nanocarriers to suit the mechanical properties of our blood vessels and tissues into which we need to carry the drugs. So for example, here on the slide you can see this is a nanocarrier which has tiny pores. Such porous materials are particularly interesting because they can be mechanically elastic, but we can also embed lots of drugs within the pores, and then we can coat the surface so that the drug doesn't leach out until it actually comes into the tissue where it needs to go. So there is still lots of scope for any chemist working in the field of bio-nanotechnology to get into the field and give his or her own contribution. A subfield of medicine which is concerned with the design of nanocarriers, but also other functional nanomaterials which are useful for biomedical application, is called nanomedicine. And one of the challenges in nanomedicine is not only designing these functional materials, but is also knowing when we need to use them. That means diagnostic tools are still a challenge. One of the issues with cancer, and particularly hard-to-treat cancers such as pancreatic cancer, is that patients usually get symptoms very late in the development of cancer, and often it's too late to undergo any treatment. That means that in nanomedicine we are also trying to develop new diagnostic tools which could diagnose cancer much earlier, as I said, even before the cancer is developed. And tools that can help us in doing this are sensing devices. So modern molecular science has really impacted the way we are designing the sensors. So what are the sensors? Sensors are devices which can transduce some biological interaction into a signal that we can see. So this might be an electrical signal, it might be an optical signal, it might be a colour change. And by transducing some kind of biological interaction into this signal, we can really say that there are certain changes which are happening in our body, and some of them might not be that good. Particularly interesting today are also low-cost sensors which can communicate with our mobile devices. So we have already a kind of sensors, we can use them sometimes which we put on our skin and they can measure the flow rate of our body, they can measure our pressure. But in the future we can imagine also sensors which are going to be embedded within our skin and read out some changes which are happening in our organism. And this is where the modern molecular science comes in. How do we design these materials which need to be embedded within the skin in such a way that they can still give us a kind of optical or electrical readout? Let's have a look at a very simple sensor that benefited largely from developments of nanotechnology. And this is an influenza, a flu biosensor. To contain flu, it's also very important to know that somebody is infected so that we can contain the disease as well. And that means we need very sensitive sensors that can detect small number of viruses which are present in a person. And in this particular case, gold nanoparticles were used to do exactly this. So gold nanoparticles are tiny particles of gold, as you already guessed. They are reddish in colour, so when they are dispersed in the solution they appear red. And we do have lots of chemical strategies by which we can modify these gold nanoparticles with different molecules. In this particular case of design of a flu biosensor, the gold nanoparticle was modified with an antibody which is specific for a protein which is on the flu virus. When we have lots of viral copies present in the patient sample, the gold nanoparticles will bind on the surface of the virus. And as they bind, they will come in the close proximity which will cause the interactions between nanoparticles, the interactions between the plasmons, a collective oscillations of electrons around the nanoparticle. And the colour will ultimately change. And you can see this in slide. If you don't have any virus present, you will have a reddish dispersion of a nanoparticle. But if you have even tiny amount of the viruses, the colour will change. So this is an example of nanotechnology being used for a design of very cheap and easy to use sensors. You don't need any readout instrument. You can really detect the presence of the virus by just looking at the solution. But in the meanwhile, we have more advanced sensing devices that are using electrochemical sensing that are using surface plasmon resonance sensors. And we have the whole subgroup of biosensors which benefited largely from developments of nanotechnology. So nanotechnology helped us not only to improve the signal that we are having in the biosensors, but it can also help us to make smaller biosensors which we can also embed within the skin, for example. What we try to do again with the Department of Oncology here in Cambridge is to design biosensing devices which can tell us a little bit more about the first stages of cancer development. And that means we are designing nanoparticles which can really attach to the cells when they are in pre-cancerous stage. And they light up, so they can really tell us the amounts of these cells in a particular tissue. And when we know how many cells are there, then we can also find the strategies to remove them. And as we remove them, we allow the tissue to regrow and to regenerate. So this is one of the strategies that we are developing together with Munoz's spin lab. And we are hoping that this is going to lead us to a development of new biosensing and diagnostic devices for early detection and early treatment of cancer. But regeneration of tissue is not only relevant when we talk about cancer. It's also relevant when we have different types of diseases or when, in general, something happens that the tissue is injured. Tissue engineering also benefited largely from modern development in science, in particular development of nanostructured materials. If you remember, we did talk about how our cells are built. So our tissues are full of cells which are communicating together. And they are built of nano-sized elements. So having nano-sized tools that can be used to repair the cells or whole tissue would be something remarkable. But in the absence of these tools, we can design strategies to help regeneration of the tissue. We can design materials in which we can grow the cell so that we can then use them to implant them into the patient that have damaged tissue. Here is one example of a nanomaterial that has been used for tissue engineering extensively. These are carbon nanotubes. They are entirely made of carbon. They are nano-sized in diameter, but they can be long. So they can get up to micrometer in length. And the beauty of carbon nanotubes are they are biocompatible. They are also under certain conditions conductive. Therefore, they are particularly well suited for regeneration of neurons which transfer the information through electrical signaling. And here is the example of enabling the communication between two neurons which were not in contact. And this communication was enabled by positioning carbon nanotubes between the two neurons. This is a work done by scientists in Trieste in Italy who have now in the meanwhile really advanced the tissue engineering by creating even larger areas of carbon nanotubes doped materials which can be acting as a bed for growth of very healthy neurons. And they have done extensive experiments in animal models showing they can regenerate neuronal tissue. So this is something where nanotechnology can help us a lot, creating these new functional materials which not only repair the lost function but can introduce new improved functions into our tissue. In general, when we talk about tissue engineering, we have to think how does the tissue look like. There are three components to tissue. We have cells, of course, which are carrier of our information and our signaling and our biomolecular components. Then we have different biomolecular components which are enabling communication between different cells. These are peptides or proteins. And then we have the bed within which the cells are growing, extracellular matrix materials usually composed of collagen and some other structural proteins which enable cells to grow and proliferate. Each of these elements of the tissue can be impacted by chemistry or nanotechnology. For example, extracellular matrices can be designed using some nanotechnological components. We can also have controlled release of some growth elements within extracellular matrix to make tissue grow faster or slower. And we can of course manipulate the cells. We can embed certain materials in extracellular matrix which can also control the growth and development of our tissue and cell. So tissue engineering definitely has benefited largely from modern molecular chemistry. And we will see much more development in the years to come. Here is the example of what we do in my group as well. We are designing some of these extracellular matrices which are made of cellulose. And cellulose is one of the most widely present organic molecules on Earth. It's a polysaccharide made of tiny sugars. And we can use this cellulose and modify it with magnetic nanomaterial or with some other conductive nanomaterial which can then help us to grow neurons and different types of cells on demand within this material. So this is something where we explore nanotechnology together with chemistry to design hybrid materials that can be used for tissue engineering. But modern molecular science is not only present in nanomedicine. We talk so much about nanomedicine because this is of course something that my group is actively involved in. But there are also other aspects of modern molecular science that have really advanced in the past 20 years. Molecular science has also transformed the chemical industry. It has transformed and it's still transforming the way how we produce chemicals. For example, we today also use artificial intelligence in making the decisions on what kind of molecule are we going to make and which kind of route are we going to take. And therefore we save lots of chemicals. We also reduce the production of waste. But we also design new powerful catalysts. And here is where nanotechnology is also playing a big role. Catalysts are the molecular species which are speeding up the reactions. And we have within our body, we have the most efficient biological catalyst and these are proteins known as enzymes. One of the aspects which have really largely benefited from modern molecular practices is taking the information, taking the knowledge that we had from the enzymes and transforming them into modern catalysts which are more robust and more efficient and definitely greener. So for example, you can take an enzyme which has a cofactor known as flavin and you can extract this flavin and combine it with different materials in order to design very powerful photocatalysts. Because flavin is a natural molecule, it's actually present in some of the vitamins. This is a green strategy to make catalytic processes. In this slide you can see one of our approaches. We have taken polydopamine, the same polydopamine that we use for nanocarriers and we modify it with the flavin molecules. Polydopamine is also at a certain condition semiconductor and it can communicate in terms of electron transfer with the flavin. If we now take the nanomaterials which are shown here and we irradiate them with light in the presence of different compounds, we can transform them in a much easier, much faster manner. And in fact, we demonstrated that this catalyst can be used to reduce waste and energy at a certain step of indigo dye production. Lots of dyes which are used today for dyeing clothes are produced using lots of organic waste and also using toxic chemicals. So one of the ways of reducing the toxicity and also improving our environment is by introducing greener catalysts and strategies that are reducing that waste and that can make the compounds in a much easier way. Catalysts are not the only species that we can make. I already mentioned when I talked about nanomedicine that we can design functional materials, but we can also design materials cleverer materials that are changing our life. For example, in architecture there in the meanwhile we have materials which are designed using some nanotechnological principles but can resist earthquakes. They can neutralize seismic waves and therefore stabilize the buildings in the areas where we have lots of earthquakes happening. Or we also have self-cleaning surfaces which are made with the help of titanium dioxide. For example, there are whole buildings which are coated with a particular titanium dioxide functional material and they can be cleaned under the exposure of sunlight. So architecture has benefited tremendously from some of the new functional materials that we are designing. But we are also creating functional clothing. Clothing that can respond to the changes in our temperature or clothing that can self-clean as well because it doesn't attract water and it doesn't attract dirt. So for example, recently there was an article about self-cleaning spacesuits that astronauts are going to wear on Mars. And these spacesuits are made with the help of nanotechnology and they are preventing the attachment of dust. But we also have nano-doped concrete. So this is a concrete that has a cellulose embedded within itself and then it becomes more elastic and more robust. So definitely we are changing materials, we are introducing new functions and we are definitely improving certain aspects of material chemistry with the help of nanotechnology. We are improving the things and we usually improve them by taking inspiration from nature. And the question is, can we also take the inspiration in terms of nanotechnology and modern molecular science? And yes, we can. And let me show you at the end one example of how the nature has solved a particular problem with the help of nanotechnology. This is a Venus flower basket sponge. It's a beautiful organism that lives in oceans. And it has this intricate shield made of silica, which is protecting the soft inner body of the sponge. And for a long biologist thought this shield is acting as a protecting shield. But if we look at the structure of this silica material and we use microscopes, really, really high resolution microscopes to look deep into the structure of this shield, we can see that as we are moving deeper, the structure becomes a little bit more intricate until we come to the last really super resolution structure where we can see tiny nanoparticles of silica being embedded in the bed of different proteins. So this sponge is using the assembly on the nanoscale to assemble materials which give a really lots of strength to the shield that a sponge is having. In the meanwhile, we know that this is not the only role of the silica structures, and that they can also be very useful in communication. They almost act as optical fibers. Optical fibers, which we are using, are also made of silica. So there are similarities here. So the question is, can we use what nature is giving us to really design more functional materials and definitely useful materials? Some examples are already existing. For example, we have lotus leaf mimics, and those materials are used in car industry because they are water repellent. We also have mimics of gecko feet, and those materials are particularly adhesive. If you've ever seen gecko, you will see that it can climb almost every surfaces. And this happens because in a gecko's feet, we have tiny structures. And if we look at them, we will see that they have nanostructured elements, which are enabling this kind of adhesion on different materials. We also take inspiration from frogs. They have particular nanostructures in their toe pads, so we can use them to design, for example, surgical materials, which can be used by surgeons during the operations in medicine. So all of these things are already there, but nature, of course, is hiding much more. There is lots of inspiration we can take from. I hope I could show you a little bit of what we are doing in our lab and what the modern molecular science is about. It's not only about one field. It's not only about chemistry. It's not only about molecular biology. It's about interdisciplinarity. It's about holistic approach, about doing science, but also looking at the nature to take more inspiration, so that we can really, really provide good solutions to the challenges we are faced with. I work in the field of bio-nanotechnology, which means we combine man-made materials with biological elements with the aim to design better tools for nanomedicine, but also, as you have seen, better tools for architecture or clothing or, in general, to improve the way how we are making the things today. But let's go back to that Earth, Earth-like planet from the beginning. Let's go from that planet to our own planet. I think, like never before, it was important to think in terms of interdisciplinarity and in terms of holistic science. We need to rethink the challenges. We need to think, really, what are the challenges today? We need to work together to provide the solutions. And we have seen now, also during the pandemic, how important it is that we remain open and that scientific community works together. And my message to every new fledgling young scientist out there is embrace the molecular science and immerse yourself in discovering what is out there in the nature and what can we use in the lab to improve our lives and really address the challenges we are faced with.