Conquering Cancer: Engineering Solutions to the Problems of Cancer

HAMMOND: Welcome back, everyone. We're entering our second session-- Engineering Solutions to the Problems of Cancer. I'm Paula Hammond. I'm actually a chemical engineering faculty member at MIT, and a member of the Koch Institute for Integrative Cancer Research. And as an engineer, I'm very excited about this session that we're about to enter because it represents how cancer cell biologists, chemists, engineers can get together and actually think differently about the problems of cancer.

Now, in this session-- the session before, we heard about the milestones that have led to significant advances in cancer, and which led to pathways between cancer biologists, engineers, and medical doctors to begin collaborative efforts. In this session, we will address ways in which engineers and scientists from across fields and disciplines come together to address critical challenges in cancer therapy.

Engineers bring a new set of tools, and a new way of looking at problems that are posed by biologists. And these tools and approaches include the ability to design functional materials, from a nanometer length scale, from the very smallest of things, down to the molecular scale, and combine clever and chemistry with physical phenomena, via smart delivery approaches, but they can also design up to micro and macro scopic lane scales to design new kinds of devices that can help us address cancer.

Ultimately, what's interesting is that engineering can also reveal things about biology that would be difficult to uncover without those tools. And we'll also address how modeling and simulation and understanding of engineering systems can help us address cancer solutions. So I decided to use just one very simple example to illustrate this. And this is actually some work that was done as a large collaboration between Mass General Hospital and MIT, and it involves investigators, which were-- who were interested in understanding how they could capture metastatic tumor cells in cancer patients who have already had cancer.

The idea is to be able to find the potential for metastasis, and then address it. However it's very difficult to find that one in a billion cells that is traveling through the bloodstream and is the metastatic cell that is targeted. In this engineering solution, a microchip was developed in which blood could be streamed through the microchip, and when this blood is streamed through, it runs past millions of these tiny posts, these micron scale posts. And these posts are decorated with antibodies that actually recognize a very specific component on the tumor cell surface. So these posts can actually bind to, and ultimately capture, those very few metastatic cells in the microarray.

Now what was interesting about this problem was that it required chemistry to be able to define what's on the surfaces of those posts, and then to determine how we can attach these anti-bodies to those surfaces. It required engineering. It actually required a very careful design of how these microfluidic channels were developed so that we could get fluid through without disrupting those cells, and yet, have a rapid throughput.

And on the other hand, of course, it involved very critical cell biology to understand how we can actually pick up these metastatic cells. Now the development's moving onward, and the team looking at this problem is interested in how they can capture those metastatic cells, and study them, and examine the nature of these metastases in patients.

Finally, a second example. This is simply a slide that I often use to describe how we can understand ways to generate materials that act as this kind of smart bomb for cancer that you saw illustrated in Bob Langer's video. We learned about these things because engineers who listen to cell biologists learned that cancer cells can overrepresent specific molecules on their surfaces, called receptors. And those large protein molecules will bind with or recognize other small proteins.

And we can use that as a way to target these smart bombs. So this is just a micrograph in which a biologist has labeled some of these receptors with these black dots here-- these are gold nanoparticles used to show the presence of these receptors on cancer cell surfaces. If we can understand that, then we can generate particles that are decorated with these receptors. We can understand how they arrange. We can actually use that as a way to address cancer.

Now I'm going to introduce the illustrious panel that we have, which is-- they're actually going to address several examples of how engineering and the life sciences converge to actually create, in some cases, new areas of discipline. Our panel begins with Sangeeta Bhatia. Sangeeta is the John and Dorothy Wilson Professor of Health Science and Technology and Electrical Engineering and Computer Science at MIT and a Howard Hughes medical investigator.

So in this case, we actually see an example of electrical engineering, biomedical engineering, and material science coming together. In this case, Sangeeta Bhatia is particularly interested in micro to nano scale platforms for understanding and diagnosing and treating human disease. She is one of the nation's most promising young professors in science and engineering, as recognized by the David and Lucile Packard Foundation. And she's also, not only worked in industry, but has been involved in two biotechnology startups.

Our second speaker is Dr. Joe DeSimone. And Joe is actually coming from UNC Chapel Hill to join us today. He is the Chancellor's Eminent Professor of Chemistry at UNC, and the Keenan Professor of Chemical Engineering at NC State University. As Bob Langer alluded to earlier today, Joe is actually the director of a center for cancer nanotechnology excellence. One of the very few in the nation that spearheads the efforts of material science toward cancer.

Joe has received several major awards, including the NIH Director's Pioneer Award, and a very critical and important award that we have here at MIT, the Lemelson MIT prize for invention. He's also the founder of the nanobiotech company, Liquidia Technologies. And he's a member of the National Academy of Engineering and the American Academy of the Arts and Sciences.

Finally, we have our own Dr. Doug Lauffenburger. And Doug is the fore professor of bioengineering and the chair of the Department of Biological Engineering at MIT. As the chair, he actually was also one of the founders of this department. And his philosophy about convergence of biology and engineering is one of the reasons that we're here today to be able to talk about how we can pull these disciplines together to address critical diseases such as cancer.

In his work, he has studied the fusion of engineering and molecular cell biology. In particular, systems biology. And he brings the perspective of the power of modeling and systems approaches to address cancer. Doug had served as a consultant as a scientific advisory board member for several companies, including AstraZeneca, and Johnson and Johnson, and Merrimack Pharmaceuticals. And he is also a member of the National Academy of Engineering and the American Academy of Arts and Sciences.

Finally, we have a graduate student represented, who will be addressing our questions. Rebecca Ladewski, who is a member of the Koch Institute for Integrative Cancer Research, and is very excited to help handle your questions today. When you address questions-- this is an interactive session-- so after the talks, we will be taking some of the questions that we've gathered from the audience beforehand.

If you have a question now, raise your hand, and we have graduate students and post-docs from the Koch Institute who will be looking for your index cards. And we'll pick them up. And we'll get them to Becky so that she can ask questions. I'd also like to remind everyone that after the session we will have lunch. And I believe it is in the DuPont Athletic Center. So after we convene, there will be lunch available. It is part of your registration. So I'm going to turn things over to our first speaker, Sangetta Bhatia.

[APPLAUSE]

BHATIA: Hi, everybody. So you may have heard the old adage that getting an education at MIT is like drinking water from a fire hose. One of our favorite educational tools is the pop quiz. So you have five seconds to answer this question. If I can get it up on the screen. Which of the following diseases claimed the most lives in 2002? A. HIV/AIDS, B. Tuberculosis, C. Malaria, D. Cancer. Worldwide. OK.

So in 2002, cancer surpassed all three disease categories combined. Actually, has persisted in claiming human lives. This is what we call a confidence building question. Given the nature of this symposium today. But my point really is that the face of cancer is changing. Over the next 10 or so years, 70% or more of these new cases will be identified in the developing world. You can imagine that the infrastructure that's associated with the diagnosis and treatment of these cancers is enormous. And we're really going to have to change the way we think about diagnosing and treating this disease to meet that challenge.

I would argue today that convergence of engineering and life sciences is one way to approach that. So let's just think about diagnosis for a second. So this is diagnosis here in Boston. This is a virtual colonoscopy suite. So you might imagine that typically diagnosis is done by a blood test, by an imaging test, or by a biopsy. And the infrastructure associated with this is enormous. Not just from the equipment perspective, but also from the trained personnel that have to administer the exams, and also interpret those exams.

So when one starts to think about how might we transform diagnosis for cancer, one attractive idea is to use this road map. So this is a road map of the computer revolution. This is 1 transistor to 100 million over the course of 50 years, of a set of scientists and engineers working together. And this is the revolution of miniaturization. So we and others have been thinking about how one can apply this miniaturization revolution to cancer diagnosis and therapy.

So I want to give you some examples. So here's an example applied to a cervical cancer screening, which is normally done by a pap smear. So what you see here is-- normally a pap smear is a sample of cells from the cervix that's observed under microscopy by a trained pathologist. Just the microscope piece of that whole process is $7,000 or more. One of our alum, an HST alum, Rebecca Richards-Kortum, who is now at Rice, has miniaturized this entire microscope into this $10 part. It fits on the end of a fiber optic. So what she's done by doing this is moved the process from taking patient cells to the microscope from taking the instrument to the patient. And all along the way, reduce the cost enormously.

So when you think about taking this diagnostic paradigm even further, what about the idea that one could do non-diagnostic tests, completely non-diagnostic tests? So this is a dream at the moment. But the dream would go something like this. That we could do urine biomarkers screening for cancer diagnosis. Just want to give you a snapshot of how one can envision that that could be enormously cost effectively done.

This is a new field that's emerging. It's called paper diagnostics. So this is a postage stamp size of paper. This device is three layers of paper. You can see there are channels here that are micro fabricated on double-sided adhesive tape. OK. And the liquid flows in this device by capillary wicking. And it turns out there's a fascinating field of microfluidics just related to how fluids move in paper, in these lateral flow devices. So you can envision that this is a modern cancer-based assay, much like a pregnancy test. OK. So that's a vision of how we might think about transforming diagnosis.

How do we think about therapy? So at the moment what we have at our disposal for therapy, as you've heard, is surgery, chemotherapy, and radiation. And patients need to be hospitalized during this time typically. This Is enormous, economic, and personal hardship as they go through this process. So we start to think about why this is and how one might be able to change it.

One of the reasons that this is is that most of the non-smart drugs that Jackie [? Lee has ?] alluded to this morning, most of the drugs in our cancer armamentarium are actually just poisons. They poison rapidly dividing cells. And, therefore, there are enormous side effects. If you look at quantitatively at what fraction of drug gets into tumors at the moment, it's a less than 1% of the injected dose.

So as you've heard from Bob Langer and others this morning, one notion is that if we could simply take these cytotoxic or poisonous drugs more directly to the tumor, we could increase our therapeutic effect and decrease the side effects. And one way to do that-- to try and do that is to use nanotechnology. So this is an artist's rendition of how this might work. You would administer an intravenous drug to this patient. It needs to be nanoscale for a couple of reasons.

First of all, it needs to escape the filtration organs of the body. So the liver and the spleen and the kidney are the natural filters of the body. And their job is actually to filter things out. So you need to escape those. And furthermore, you'd like to get into the tumor. And it's been shown by Rakesh Jain and many others, that you need-- to get into the tumor, you need things to be at the nanoscale. Smaller than 400 nanometers. Preferably smaller than 50 nanometers. So we need to be quite small.

So one of the things that's important about this process-- about taking the payload deep specifically to the tumor is that one would like to decorate the nanoparticle payload with some kind of molecular zip code. So you might ask how one would identify such a molecular zip code. This is the way we do it in our laboratory. We've been working with many years for scientist named Erkki Ruoslahti, who pioneered this method. He's at the Burnham Institute in California.

And this is a screening approach to identifying molecular zip codes that you would decorate these nanoparticles with that carry that drug payload. And in this approach what you do is you take a mouse. You grow a human tumor in that mouse. And you inject a library of viruses. These viruses are called bacteria phage. You inject a library of 10 billion different bacteria phage. And each bacteria phage has 400 copies of a different peptide sequence, a different zip code on its surface. So you inject these in the mouse, and then you then harvest the bacteria phage, the 55 nanometer bacterial particles now, that have homed in on a tumor.

And then you can just sequence them and find out what the coatings were that conferred homing when they were displayed in multiple copies on a nanoparticle that was about 55 nanometers in size. OK. And when you do this sequence, you can sequence them here-- just a free peptide has been delivered to this mouse. It has a fluorescent molecule on it. You can see that it's homing in on the tumor, and then the excess is coming out here in the mouse bladder. So this is a way to identify molecular zip codes.

What kinds of interesting particles might you put them on? These are particles that we developed with collaborators at UC San Diego. This is Michael Sailor's group. He's a chemist. And these are what we call nanoworms. So these are magnetic nanoworms. They're made of clusters of iron oxide or rust, and decorated encased in a coating of dextrin, a sugar. And on their surface, they carry those molecular zip codes that I just showed you-- the peptide sequences-- as well as a drug payload.

So we were interested in not just exploiting the fact that you could decorate these with a drug payload, but thinking about the fact that the particles are magnetic. They have some interesting properties. So one thing that you can do with a magnetic material is inductively heat it. So we designed these nanoparticles. So this is a cross-section now of that magnetic nanoworm that I showed you on the last slide. And now it's decorated with drug. And the drug is attached to the surface of the magnetic nanoworm with a heat sensitive bond.

And what happens then when you apply about 500 kilohertz of radio frequency electromagnetic energy, that bond melts, and the drug is delivered on demand. So the vision is that these nanoparticles would sit embedded, homed in the tumor, and that you would release the drug of interest at a particular point in the patient's course of cancer therapy. So here is this working in the lab. Here we're pulsing these nanoparticles with power. And you can see the drug is coming off in solution.

For those of you who have molecular biology backgrounds, you might be interested to know that the heat sensitive bond that we used was actually two complimentary strands of DNA. And of course, the temperature sensitive melting of DNA has been well worked out in the fields of microbiology and chemistry. So here are these particles now in a mouse tumor. And you can see, this is another point I'd like to make, that these are actually visible on MRI.

So this is another nice feature of the magnetic nanoparticle is that it can act both as a diagnostic, and here when you-- these are advancing on their-- and when you apply an RF field you can see that you get on demand drug release into the tumor. So this is an emerging field of nanotechnology that people are calling theranostics, therapeutic and diagnostic nanoparticles in one. This is just one of many, many sort of flavors of these that are emerging in the literature. OK.

So one thing that we'd like to do, in addition to release drug on demand, is actually get more payload to the tumor. And we started thinking about ideas for getting much more than 1% to the tumor, which even in the scenario, is actually how much we got there. We came up with this idea that we should cooperate. So here we have two different nanoparticles that have separate jobs. The first nanoparticles job is to act as a beacon, to act as a tumor homer, to have that molecular zip code, to go in and find the tumor, and it has really nothing else to do other than to just send a signal, I found a tumor. Here it is.

And the second nanoparticles job then is to carry the payload. Whether it's the drug or the diagnostic, or multiple different drugs. And so now here they cooperate, where the first nanoparticle is sending a signal, and the second nanoparticle is carrying the payload. What we'd like to do further is to have an amplification system where you have just a few nanoparticles that get in, but then you could recruit lots more nanoparticles with the payload.

So we designed a nanoparticle system that has these attributes. And it has, as the signaler, these nanoparticles here. So these are gold nanomaterials. They have a very interesting property that was first described by El-Sayed at Georgie Tech. And that is that they have shape dependent excitation with light. OK. So these materials have very mobile electrons on their surface. This is called a surface plasmon effect. And depending on the shape of the surface, you can get resonant excitation of that material. OK.

So as they get elongated, you get resonant excitation of these, or they act like antenna, for different colors of light. And in particular, what we want for human tissues is antennas for light in the near infrared. This is what we call the optical window. This is a nice wavelength of light that doesn't scatter and doesn't absorb. And you can all do this sort of experiment at home. Put your remote control right up next to your finger, and you'll see that red light penetrates tissues. OK.

So we'd like these nano antenna to be sensitive to this near infrared light. And they're going to act as our beacons. OK. So this is the scheme. They go into the tumor. We shine light that's near infrared. They trigger an amplification mechanism in the human body. In this case, in the mouse body. The amplification mechanism that we wanted to trigger in this case was to create a little bit of clot, a little bit of injury. This is a whole enzymatic cascade in your blood.

And now this second nanoparticle, its job is to be a clot seeker and carry a payload. So you send a signal within a nanorod. You amplify the signal with the human bodies-- or the mouse bodies' enzymatic cascade, and then you carry a payload with a clot seeking decoration. OK. And when we use these togetherr-- so this is how we envision that. You would inject the gold nanorods. Then you would inject the cargo, the payload particle, and shine the light. And trigger this amplification.

Does this work? So is there mouse experiments now? And so here what you're looking at are nanorods in these two animals. And this is a thermographic image of the nanorod heating in the flank of that animal in the tumor. And if you use a payload, in this case, which is an imaging payload, which are those magnetic nanoworms that I showed you before, you get 150 times more nanoworms in that tumor than you did before.

So for every nanorod that you get in, you get 150 diagnostic nanoparticles. Here we've made them fluorescent so that you can see them. But they're magnetic, so you can see them by MRI. If you use a therapeutic payload, if you use a standard chemotherapeutic drug, like doxorubicin, which is an FDA approved chemotherapeutic, you get 35,000 times more drug than nanorod. So for every nanorod you get in, you get 35,000 drug molecules.

And when you do-- this is a mouse model of breast cancer-- when you do a therapeutic study, you can see that when these nanoparticles communicate, that you can suppress tumor growth as compared to even the same two nanoparticles that are administered when they're not communicating or cooperating. OK.

So this is sort of hopefully a snapshot of our vision for the future. And the last thing I'd like to point out is just that I think that we have to keep in mind this challenge. This is what's called the global accessibility map. This was actually published by the European communities in 2008. And what they've mapped here, worldwide, is access to health care by how long it takes to get to a doctor. And if you just look here, it takes for over 2 billion people in the world, it takes a day or longer to get to a physician. So if one billion of those are in remote regions, and one billion are actually slum dwellers that are in our cities.

So we should start to think about advancing cancer technology and advancing diagnosis and advancing therapy. This is a huge challenge for us for the next generation of scientists and engineers to think about how to make these more affordable and more disseminatable. So I would argue that our future students have lots of work to do. So thanks for your attention.

[APPLAUSE]

MODERATOR: The next speaker is Joseph DeSimone.

DeSIMONE: Great. Thanks very much. It's great to be back up here in Boston. It's not quite golf weather up here yet, but it's good to be back. So our session titled Engineering Solutions to the Problems of Cancer. I thought I would sort of give you an overview-- and that slide's not showing quite like it is on the screen as it is up here. I wander if the guys in a back know that. So the screen up here looks very different than the one we're looking at here. And we can't even do a chalk talk either. Right. Well at least the four of you can see it.

AUDIENCE: Tell some jokes, Joe.

DeSIMONE: Yeah, I'll have to. Yeah.

MODERATOR: They're adjusting [INAUDIBLE].

DeSIMONE: OK. Great. Would you like someone else to go instead? They're working on it. All right. Terrific. OK. Great. So I have looked at thinking about choosing a couple of unmet needs in cancer. Certainly one related to delivery to poorly vascularized tumors as an area. The opportunity and need for preferential delivery and release of chemotherapies in an enhanced dosage range at the site a disease. I think a little about cancer vaccines as well as cancer preventions. And so at very high level, I thought I would just scream through these with you. And let me first start on the poorly vascularized tissue issue.

So certainly we're all very familiar with a variety of different solid tumors. There was a discussion earlier about those that have a terrific highway or access through angiogenesis. But there's a number of other tumors, especially pancreatic cancer, that is poorly vascularized. And so the opportunity for thinking about treating in a focal or local way with device assisted approaches. And thinking about an area of interventional oncology.

And as a little bit of context, I had a great fortune of partnering with Bob Langer, and we developed a fully bioabsorbable drug eluting stent for treating coronary heart disease. This technology, ultimately bought by Guidant, and now it's part of Abbott. And we have about 1,000 people now that have a bioabsorbable stent in them. And we just got CE mark approval in Europe.

But this introduced me to the whole area of interventional cardiology and the opportunities for catheter based delivery of devices. Separately, got involved in a technology using iontophoretic approaches for delivering drugs and particles to poorly vascularized tissues. And it's in the eye.

And a company up here in Massachusetts, EyeGate Technologies, and so thinking about bridging these two very different approaches of interventional oncology and iontophoretic approaches, we are developing a catheter-based approaches in an interdisciplinary approach that develops catheters. This particular catheter is a four lumen catheter electrode that is able to generate electric fields in combination with a counter electrode to use iontophoresis or electrophoresis to drive drugs into poorly vascularized tissues.

In some activity with small molecules, we began looking at pancreatic cancer. And in this particular case-- the animal model is a canine-- where we were driving drugs directly into the pancreas. The counter electrode's placed on like a Bovey patch on the outside of the animal. And we have the ability to drive a huge amount of drug, in this particular case, gemcitabine, directly into the pancreas with current. Then-- and shown in red without current. And this shown in green is the amount of drug that gets in through the standard parenteral delivery approaches.

So we have a massive increase in drug concentration and a key for us is all of the drug that we add is delivered locally. We see no gemcitabine circulating systemically. And so this is the opportunity for focal delivery of drugs. And not only small molecules, but also working on nanoparticles in a really interesting approach for thinking about biologics. And as was stated earlier, there's a very small fraction of biologics that actually get where we want them to go. And the opportunity of infusing a tumor with biologics using catheter-based approaches or fragments of antibodies would be really interesting.

And we've also now moved into small animal studies. And we've miniaturized our device. And we now have these four lumen iontophoretic delivery devices working with a variety of different animal models. Both seen a graph as well as gem models. So we're pretty excited about where this opportunity can go. Beyond just pancreatic cancer, which is our prime focus, we also are working on some transdermal approaches with the triple negative breast cancer as well as melanoma and a whole host of other cancers and a range of drugs that could be delivered focally in this manner.

So looking at some other unmet needs, the opportunity for systemic delivery and nanoparticles is a big opportunity. Our particular focus is-- can we harness the manufacturing tools of the computer industry, using lithography and offshoots of lithography, to make new medicines and new vaccines. And that's a big focus for our lab. And again, a lot of light space in bridging two very disparate fields. This is not to imply we're going to make babies in a clean room, but to bridge a couple of interesting areas.

And so we've developed a particle molding technique. We call PRINT. Particle replication in non-wetting templates. But basically it starts with silicon wafers that are patterned using standard lithographic techniques. We make molds of those. And then we, in a roll-to-roll process, we fill those molds with liquid, shown in red, that are precursors to medicines and vaccines. In a templated manufacturing approach, we're able to harvest those products. This is a classic roll-to-roll or film-based process where we can then isolate individual particles where their size, shape is defined by the template, and then a chemistry is defined by what we put in there.

And so this is very different than a kinetically driven self-assembly approach, where one often has challenges with chemical composition control. And so this has now been extended to a roll-to-roll process and just as important, as we had said, vision without execution is just a hallucination. This is now a GMP manufacturing compliant process. And so this is a nano manufacturing platform. Not a particular drug, but a platform that's now GMP compliant.

And so these are the range of particles that we're able to fabricate, where they are clearly achieving sizes and shapes that are quite unusual relative to kinetically driven objects, but also controlling the chemical composition in some really complex ways by controlling interfacial tension. And some of the things that we're interested in doing is trying to understand the interdependent role that, not only science plays, but shape plays, in a variety of different processes, either cellular uptake processes or bio distribution processes.

Understanding and engineering and antisocial escape, understanding endosomal size and shape based on the size and shape of the particle. In fact, some of these hex knots actually generate toroidal endosomes with a very high surface to volume ratio. We start seeing patterns of how macrophages will take up particles of different shapes to try to avoid the REF's, or both in the airway as well as in perenteral delivery.

So a lot of really interesting opportunities. And then combining that with unique chemistries, we can design chemistries that once particles are in the cell, we can take advantage of a unique cellular chemistry to might, for example, trigger the degradation of the particle to have a Trojan horse. And these are examples of green particles designed to take advantage of the intracellular pH. And that can then fall apart.

And once these particles enter cells-- it sort of looks like Bob's movie, a little bit-- but basically now, we take advantage of the fact that the particles are single molecules, because they're networks. As a network starts breaking down, we create molecules. A colligative property as ismodic pressure, water floods the endosome, ruptures the endosome, and dumps the contents of sitosol. And so we can do that with a range of chemistries.

PRINT is now just a tool to allow us to make particles of any chemistries that we want. And the way we think about things is we have rigid particles made out of materials that are similar to bioobservable stent or bioobservable suture, but now in a nanoparticle. Or we have soft carriers. And let me just walk you through some examples of this. Some PLGA-based particles.

PLGA is probably the most translatable matrix because the FDA has a lot of comfort with it. And these are examples of particles of controlled size and shape made using PRINT that now are loaded up with a chemo agent such as docetaxel. Because of the molding process, we can now adjust the chemical composition of these particles from 0% drug all the way up to 40% drug. So these are solid state solutions of PLGA and docetaxel in ranges of chemical composition that are actually very difficult to get to through other kinetically driven processes. And what that allows us to do then is look at toxicity, or site of toxicity.

These are the anti carriers shown here in black. And then as we increase-- this is plotted against drug concentration-- as we vary the drug concentration, we're getting to the point of almost increasing the IC 50 value-- or decreasing it by a factor of 10. And so dramatic improvements. And then when you go invivo, this is an SKOV xenograph model. We're actually seeing a classic depot effect through the EPR effect of up to 20 times more drug in the tumor relative to the taxotere approach.

And so this is about putting more drug on target using these nanoparticle therapies. And this is a non-targeted particle. So this is just taking advantage of the depot effect of size issues. And we're just beginning now to go into efficacy studies, and this is-- so this is some unpublished data, just for three doses of drug, both taxotere control as well as our PRINT particles. You see the piece scores here. But with taxotere, you can extend the median survival out to six days and then we have dramatic improvement once we start using the nanoparticle approach.

And so we're on to a whole series of studies now using this type of approach. So beyond the rigid carriers, we think a lot about the soft hydrogel carriers. And we're very interested in areas of Mechano biology and Subra Suresh, a former dean of engineering here, was a big proponent of this area and studied this a lot. And these are examples of particles that we've just published and PNA-- apologize-- it slid off the screen here-- but this is where we've systematically varied the modulus of the particles and their ability to deform as a way of navigating biological barriers much in the way that red blood cells do, and much in the way that cancer cells do.

And so these are our red blood cell mimics, same size, same shape, and same deformed ability as a red blood cell. And then we actually then go invivo, and we use intravital microscopy to monitor-- these are large particles. These are six microns. But they are now deformable. And we can look at the biodistribution and elimination half life, and as we drop the modulus down by dropping the amount of cross flanker, we're getting into circulation times that are now getting out to four days for a particle that's six microns. But we achieve this by lowering the modulus, and going very small-- or staying large but going very soft.

And so the strategy now is-- now that we understand the ability to dramatically increase circulation times with softness, we can now begin doing this with particles of different sizes, different shapes, getting down to 80 nanometer by 90 nanometer particles. But they're not rigid like the PLGA particles, but they're, in fact, much softer.

And doing this in combination with targeting, this is example of Herceptin, which is easy to conjugate on to these particles, with HER2 positive cell line. This is 100% isotype control, and then we systematically add Herceptin, and we see really good uptake in these cells, but the isotope controlled barely have any uptake. And then we go to HER2 negative cell line. And again, we have very low uptake.

So the idea is can we start combining these approaches. If you now can conjugate antibodies on the particles, you can now start getting on the order of 10 to fifth chemotherapy molecules per antibody. Very different than a molecular conjugate that might only have six chemo agents per antibody. And that's a great opportunity for doing that. So the challenge is-- these very soft hydrogels don't hold onto chemotherapy agents very well, and so we have to use a pro drug strategy.

And so here we use a silyl ether linkage group that allows us to conjugate molecules like camptothecin. And we can now conjugate these with different linkers depending on these substantial insulin silicon and you get very different release rates. So it's the interplay between kinetics of distribution combined with a kinetics of drug release. And we're working with a whole host of other drugs that we can now, in a plug and play approach, combined drugs deformability and targeting, and this is the direction that we're going.

One of the big holy grails in drug delivery is RNA interference approaches. And when we use rigid particles, we don't have very good bio distribution with some of those relative to the soft ones. This is some intertumeral delivery of SIRNA in a xenograph prostate model, but one of the directions we're going now is that we have a pro drug strategy with SIRNA that only relates to SIRNA in an intracellular environment.

And so we have these disulfide bridges that get cleaved, and you can see there's none of the SIRNA release from particles in PBS, but it presents a little bit glitothyon we can release the SIRNA. And so we can get some really potent ways of delivering SIRNA onto these deformable hydrogen carriers. And this is a direction and combination where we're trying to use some of the chemotherapy agents that might induce DNA damage, and some of the RNA interference that might inhibit DNA repair, for some combination therapies.

And then finally, let me just point to some cancer vaccine approaches for the nanoparticle work. Liquidia, our company, has got a product in a clinic today that's a PLGA based carrier for treating influenza vaccine. And it's basically combining your standard influenza vaccine with our nanoparticles, and we see a huge increase in immune response by using this combination approach.

Well now that we can do this, we're in a focus of adding different adjutants like agonists for TLR4, 7, and 8, and combining those approaches as a cargo with a wide range of tumor associated antigens. And so a combination of these nanoparticles, which are now GMP compliant, and then begin adding a variety of different antigens for addressing different cancers. And so that's a focus for us going forward in cancer vaccines.

And then the last thing I'll point to is inhalation. The PRINT particles themselves can address a number of issues related to inhalation products and aerosols. And we have a big focus now in engineering aerosol characteristics where we can use size and shape to change sedimentation rates, and actually get into particles that are auto rotating in low velocity airstreams, tailoring deposition in the airway, and now these particles are 100% drug. And we're interested in combining these in variety of approaches.

And the two that I'll just point to are some interesting things in the literature, where people are interested in focal delivery to the airway of chemotherapy agents. And so we could do that by combining that with our approach. And then there's even some really interesting things in cancer prevention where people are adding chemo prevention approaches for smokers and adding an anti-inflammatory agents. And so one could start thinking about combining these going forward.

So let me just end there. I think the perspectives that you have in the Koch Center of harnessing all these different disciplines is the real driver for innovation. And it's one that we try to strive for in North Carolina as well, even getting NC State students standing under the old well at Chapel Hill. It's kind of hard to do but they'll do that. And then the other vision, without resources, is a hallucination as well. It's a really privilege to have great funding from NIH Department of Defense, NSF, and our company at Liquidia. Thank you very much.

[APPLAUSE]

LAUFFENBURGER: My contribution will be to illustrate another dimension of convergence. And it's hinted at here in the title, Designing the Biology not merely of the Box. I hope you'll see what that means as we go along the way. You might think of it as looking under the hood and seeing what one can do inside the biology.

So the convergence that most folks are familiar with and has been pioneered by many individuals and many research and academic units here at MIT is taking the basic sciences of math, physics, and chemistry, putting them in the hands of engineers, whether they come from backgrounds in electrical engineering, chemical engineering, mechanical engineering, analyzing that science, making things out of it, and solving problems in medicine.

And outlined on the left here in some photos are some tremendous accomplishments over the past decades. Drug delivery we've heard some things about. Tissue bone implants. The new types of surgery. Artificial organs. These have been wonderful, wonderful examples of convergence of math, physics, and chemistry based engineering, having impact on the world of medicine. And as I said, pioneered by many folks in many places, but including MIT.

Now the dimension I want to add illustration to here is what I'll call an additional new convergence. And that's a new kind of engineering. That's not rooted specifically in math, physics, or chemistry, but, in fact, is rooted in modern biology. Phil Sharp mentioned the molecular biology revolutions and the genomic biology revolutions. These are the two foundational sciences now for a new kind of engineering.

We're still-- analysis is involved, and making things out of it is involved, but there are new scientific substrates here to be the things that engineers use their thinking and develop their tools on. And surely, major applications to medicine, but also has the prospect for impacting other challenges in society, such as environment, energy, and so forth.

So what does this mean? One way to think about it is that engineers are traditionally good at understanding complex systems, machines, circuits. We know how to analyze them, build them, make them behave in the way we want. Well, what we need to do then is get down to the mechanisms of biology, the tissues level, the cell level, the intracellular level, and view them as machines and circuits, but biomolecular complex machines and circuits. Nonetheless, using our same kind of thinking and aiming to develop the same kinds of capabilities.

So I'm going to show you-- today is just some early fruits of thinking about cancer biology in terms of biomolecular machines and circuits in the ways that engineers might think about them under the hood. I'm going to show you three examples, but all about one piece of biology, in order to make it easy. That we don't have to switch all sorts of different systems.

And this has been mentioned earlier, again in Phil's talk, in Tyler's, and Jackie Leese's as well, one major area of challenge in cancer biology is disregulation of a particular receptor kinase signaling system, EGF receptor system involved in many different types of epithelial tumors. And schematically it looks something like this. That this is a cell, and on the cell's surface are a host of different types of receptors that belong to this family. They get activated by a myriad of different ligands that are out in their environment. They set off cascades of biochemical signals inside the cells that regulate transcription of genes, metabolism, cytoskeleton, and all sorts of phenotypes.

So one can look at this, if you're an engineer, and say, this is what we know how to study. This is a highly multivariate circuit. There's multiple components inside the cell, outside the cell, interacting, and this is something to understand this and figure out how to intervene in it. We can bring our engineering systems analysis whether we think in terms of information processing or kinetics.

At the same time, mapped on top of all this circuitry, is another machine that this is another schematic of the cell-- could be the same cell-- and I had shown you these receptor signals around the surface that are activated by growth factors and so forth in their environment, and they regulate transcription and metabolism inside a skeleton. Well they're not just sitting there statically. All that while, they're moving around the cells to different compartments, interacting in different locations, and different molecular partners. This is a cellular machine that's mapped on top of that cellular circuit, and this can be analyzed, whether you want to think of this in terms of kinetics or mechanics or transport, engineers have thinking tools about understanding what's going on here.

So that's the basic background. So what if we take that background in terms of that biological system, and that thinking in terms of machines and circuits, and ask three questions that are important in cancer biology today. One is we have drugs for this system and many other systems, and they work for some patients and not others. Can we understand what patients a particular drug might work for? So in particular, we're going to talk about a drug that inhibits the signaling of this EGF receptor, draws a big x there, and presumably inhibits things downstream.

There's a whole class of these made by many companies. Iressa, you might have heard of. Tarceva, you might have heard of. This-- I'm going to talk about a project that involves many folks here, and also a company, AstraZeneca that makes some of these. And here's the notion that in a particular type of lung cancer, these kind of drugs can work just splendidly. But only in a fraction of patients. And you'd like to know which patients to use it on, because you've got a really good chance of it working, and you don't want to waste it on people that it's not going to work.

In work that was led by Dan Haber, who's with us today at NMGH, what was found was that there is some gene sequence mutations in the receptor that seem to be more associated than not with the drug working. Depending on the study, it might be as many of 90% percent of the patients for whom the drug worked, had the mutations. Might be as few as 30. What we'd like to know who those are, and we'd like to extend it beyond that.

What we brought as an engineering approach was to take the signalling biochemistry and cell biology going on in those tumor cells when treated with drug or not treated with drug and try to compare and say, can we develop a model for all those things going on? All the different growth factor receptor interactions. All the signaling biochemistry. The machinery of the trafficking moving around the cell. And we're going to determine the parameters that characterize the behavior of tumor cells that are sensitive to drug and tumour cells that are resistant, and we're going to find the key differences. And that's going to tell us what's different beyond the gene sequence.