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Doctors are running out of effective antibiotics, as bacteria evolve ways to evade one drug after another. Now DARPA has called for alternatives to conventional antibiotics. Nanotechnologist Chad Mirkin discusses one such weapon—tiny globs of DNA and RNA that can switch off the bugs' antibiotic resistance. Nanotechnologist Chad Mirkin discusses next-generation antibiotics that target a bacterium's DNA.
Copyright © 2011 National Public Radio®. For personal, noncommercial use only. See Terms of Use. For other uses, prior permission required.IRA FLATOW, HOST:
This is SCIENCE FRIDAY. I'm Ira Flatow. In the battle of antibiotics versus bacteria, the bugs are winning. Not only are they evolving resistance to our arsenal of drugs, but we're running out of new antibiotics to launch at them. And antibiotic-resistant bacteria aren't just a problem for hospitals and patients. Think about wounded soldiers on the battlefield, infected with superbugs or a bioterrorism attack using resistant or engineered pathogens.
Would we be able to handle it? That's why DARPA, the research arm of the Defense Department, has called on scientists to develop new, next-generation antibiotics. One promising technology is DNA-based drugs that not only target the superbugs, but they can evolve right along with them, preventing antibiotic resistance.
Chad Mirkin is director of the International Institute for Nanotechnology at Northwestern University in Evanston, Illinois. Welcome back to SCIENCE FRIDAY, Dr. Mirkin.
DR. CHAD MIRKIN: It's a pleasure to be here.
FLATOW: These are little nanoparticle-sort-of-sized things?
MIRKIN: Yeah, they're really interesting structures. In fact, their structure is made out of DNA or RNA that are made on a gold nanoparticle, in fact a variety of different types of particles, but they're strands of DNA that are arranged on the surface of these spherical particles.
And when you make them in this manner, they have properties that are very different from the normal type of DNA that we're all familiar with, duplex, linear type of DNA, and one of those properties is they have the ability to enter cells, including bacterial cells, very, very efficiently.
FLATOW: And when they get in the cell, what do they do?
MIRKIN: Well, the beauty is what we can do. We can design them so that they can go in and flip switches, genetic switches, that either turn off resistance so that a conventional antibiotic will work or, better yet, stop replication and ultimately cause bacterial cell death.
FLATOW: So is there then no need for a standard antibiotic?
MIRKIN: Well, this would be a different route to the standard antibiotics, which are typically small molecules. This would be a genetic-based root, and the beauty of that is that, as you said in your opening, you can move with the bug. As the bug evolves, you can change the sequence and target different genetic components of the bug so that you can constantly battle its response to the new drug.
FLATOW: So as the bug changes, you tailor-make the new stuff to mimic what the bug is doing.
MIRKIN: That's the idea. I mean, this is very early in this whole process. This is actually part of a big platform that we call spherical nucleic acids that we've been developing at Northwestern now for about 15 years and are part of a company that we started called Arosense(ph) that can really go after any sort of genetic disease.
And that's the beauty of it: You can tailor it on a disease-by-disease basis, as long as you have good genetic information about the different types of switches that you have to turn on or off to effect treatment.
FLATOW: If you have - then if you have genetic diseases that are not, you know, antibiotic related, maybe like cancer or something like that, could you not go in and stop the cancers from spreading that way?
MIRKIN: That's exactly right. In fact, we have a very active program in that regard. The beauty of these constructs, they're part of a larger field called gene regulation, which actually has won the Nobel Prize for its promise, the idea that you could use this - a concept of switching off genes or down-regulating genes so that you could adjust protein levels and take effectively a diseased cell and make it healthy, or in the case of a cancer selectively cause it to die.
The problem with conventional approaches is that they often have to have materials to help carry the genetic material into the cells, and they're not very good at targeting. In addition, they cause all sorts of toxic side effects. So you run into the problem where the therapy causes as many problems as the disease originally did.
In this case, these structures, this kind of spherical form of nucleic acid, has this incredible property that it requires no co-carrier. You can treat diseases based upon that genetic information, and you can either locally deliver - for example we have projects with a dermatologist named Amy Paller, where we have the first constructs that can be delivered through the skin to go after things like melanoma and psoriasis.
Or another project involves a guy named Alex Steig(ph), where we're going after brain cancer, and we can systemically deliver these. They go everywhere, but they cause no toxic side effects, and so they accumulate in a lot of cells, including tumor cells in the brain, and you can selectively go after those cells based upon the genetic differences of those cells causing them to selectively die.
FLATOW: So even though they get into the cells, their little genetic pieces don't match up with the wrong cells then?
MIRKIN: That's exactly right. You've got almost a lock-and-key type of shutoff here.
FLATOW: You know, there are a lot of people who were concerned about pumping a bunch of nanoparticles into their body, and I guess they would be concerned about this, too.
MIRKIN: Well, potentially. I mean, the interesting thing about this is, so typically, we will use a gold particle, and we'll arrange the nucleic acid, the DNA or RNA on the surface on the particle. And that itself can be a therapeutic, and we have a lot of therapeutic leads based upon those types of materials.
But we've also figured out ways of what's called cross-linking, attaching the DNA strands on the surface of the particle to each other, and we can dissolve the gold, and we literally can use effectively pure nucleic acid in that case. And those types of constructs work just as well.
FLATOW: All right, now for the $64 question, which I know you knew would be coming, right? You could probably ask it of yourself: When are we going to have a product that is going to be available to try?
MIRKIN: Well, I think the more important question to ask is when are we going to go into trials. So we have incredible in-vivo data in animals, small animals, that suggests that this works and works extremely well. And it can do things that frankly no other gene regulation construct has ever done before, and that is delivery through the skin, very effectively, knock down in animals and also this idea of systemic delivery.
And what's really difficult in this field is getting these big drugs - because they're big particles compared to the small-molecule drugs that we've been talking about - getting them across the blood-brain barrier. And the beautiful thing about these constructs is they show the ability to do that.
And so the real question is how soon will we be into trials? And we're really shooting for next year. So we're hopeful that we're going to be into human trials sometime next year, pushing for the early part but certainly before the end of the year.
FLATOW: And as far as antibiotics are considered, do you consider them old hat now?
MIRKIN: No, I wouldn't consider them old hat. I mean, this may end up being a co-therapy, or it may be a replacement for existing antibiotics. But a lot of work has to be done. So the DARPA program is actually new. It was I think really insightful for them to take this on and to challenge the community to come up with new ways because the world desperately needs these types of constructs.
We have to really go through and validate these in the context of bacteria, like we have in the context of diseases like cancer in small animals. And so what we're going to be doing over the next year on the bacteria side of things is really starting with cells and then moving up through bacteria and then animal studies.
FLATOW: And why is it that DARPA has to jump in here? What's wrong with our own medical system?
MIRKIN: Well, DARPA - I don't know if it's a matter of what's wrong. It's a matter of creating challenges. And so there are business challenges, and one of the problems, of course, in the antibiotic area is that from a drug standpoint, they're not nearly as big a market as, for example, an oncology type of drug.
But there are also just challenges in - grand challenges in terms of chemistry and material science that have to be overcome, and you have to get a lot of different folks together to solve big problems. And DARPA is extremely good at doing that.
They move very rapidly when they recognize you have a big problem. They're able to first of all put together substantial resources, which is needed in this case, to challenge the academic community in this case to come up with alternative solutions and to think outside of the box. And they're one of the best agencies for doing that.
FLATOW: So what you're saying is that the people are willing to spend money on the military to do this where they might not in the civilian case.
MIRKIN: Well, yeah, the military has a different set of drivers, right. So they're not...
FLATOW: So where we used to think of the military as making weapons and transistors and things, they're now making drugs.
MIRKIN: They make a lot of things. They made our GPS, as well. They make a lot of things that positively affect civilians in day-to-day life, and this would be a big one.
FLATOW: All right, thank you very much, Dr. Mirkin, for taking time to be with us. We'll have you back on when you get some results, when the trials begin.
MIRKIN: Thank you.
FLATOW: Chad Mirkin is director of the International Institute for Nanotechnology at Northwestern University in Evanston, Illinois.
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In this Thursday, Oct. 27, 2011 photo, a billboard by switchandquitowensboro.org stands along New Hartford Road in Owensboro, Ky. Dr. Brad Rodu, the director of the organization, and professor and researcher at the University of Louisville, is heading a new campaign for smokers to use smokeless tobacco in order to quit smoking, based on 20 years of research. (AP Photo/Stephen Lance Dennee)
FILE - In this Sept. 28, 2010 file photo, smokeless tobacco products, including Ariva, are displayed in Richmond, Va. In the smoker-heavy state of Kentucky, a cancer center is suggesting something that most health experts won't and the tobacco industry can't: If you really want to quit, switch to smoke-free tobacco. (AP Photo/Steve Helber, File)
Dr. Brad Rodu, the director of switchandquitowensboro.org, and a professor and researcher at the University of Louisville, displays his book "For Smokers Only," written in 1995 at his Louisville, Ky., office. Rodu is heading a new campaign for smokers to use smokeless tobacco in order to quit smoking, based on 20 years of research utilizing billboards, radio, print and other advertising. (AP Photo/Stephen Lance Dennee)
In this Thursday, Oct. 27, 2011 photo, Dr. Donald Miller, director of the James Graham Brown Cancer Center, speaks during a news conference during a Breast Cancer Awareness Month postage stamp unveiling in Louisville, Ky. (AP Photo/Stephen Lance Dennee)
In this Thursday, Oct. 27, 2011 photo, Dr. Brad Rodu, the director of switchandquitowensboro.org and a professor and researcher at the University of Louisville, looks through a microscope at a slide in his Louisville, Ky. Rodu is heading a new campaign for smokers to use smokeless tobacco in order to quit smoking, based on 20 years of research utilizing billboards, radio, print and other advertising. (AP Photo/Stephen Lance Dennee)eval("var currentItemd57851005a80479aaeeb90a12c70b9ff = 1;");eval("var nextd57851005a80479aaeeb90a12c70b9ff = 0;");eval("var previousd57851005a80479aaeeb90a12c70b9ff = 0;"); 
In the smoker-heavy state of Kentucky, a cancer center is suggesting something that most health experts won't and the tobacco industry can't: If you really want to quit, switch to smoke-free tobacco.The James Graham Brown Cancer Center and the University of Louisville are aiming their "Switch and Quit" campaign at the city of Owensboro. It uses print, radio, billboard and other advertising to urge smokers to swap their cigarettes for smokeless tobacco and other products that do not deliver nicotine by smoke.Supporters say smokers who switch are more likely to give up cigarettes than those who use other methods such as nicotine patches, and that smokeless tobacco carries less risk of disease than cigarettes do."We need something that works better than what we have," said Dr. Donald Miller, an oncologist and director of the James Graham Brown Cancer Center, which supports the effort along with the University of Louisville. "This is as reasonable a scientific hypothesis as anybody has come up with and it needs to be tried."The campaign runs counter to the prevailing opinion of the public health community, which holds that there is no safe way to use tobacco. Federal researchers, however, have begun to at least consider the idea that smokers might be better off going smokeless.The National Cancer Institute at the National Institutes of Health says on its website that the use of all tobacco products "should be strongly discouraged," and that there is "no scientific evidence that using smokeless tobacco can help a person quit smoking." But this year it approved funding for a study that might provide some of that very evidence."Switch and Quit" is directed by Brad Rodu, a professor of medicine at the University of Louisville. He analyzed the 2000 National Health Interview Survey and found that male smokers who switched to smokeless tobacco were more likely to quit smoking than those who used nicotine patches or gum."Americans are largely misinformed about the relative risks. ... They think smokeless tobacco is just as dangerous," Rodu said. "This level of misinformation is an enormous barrier to actually accomplishing tobacco-harm reduction because if people believe that the products have equal risk, there's not a real incentive."The program is funded through Rodu's research money, which includes grants from the tobacco industry. Grants through the University of Louisville are unrestricted, which the program says "ensures the scientific independence and integrity of research projects and activities.""There's absolutely no influence whatsoever," Rodu said. "I decide, along with my colleagues, how we use the money, for what projects, and this is entirely the case. I would not have a situation where there was some control over the kind of projects I undertake."Tobacco companies want to market more smokeless tobacco and other cigarette alternatives to make up for falling cigarette sales. Some have introduced "snus" — small pouches like tea bags that users stick between the cheek and gum — and dissolvable tobacco — finely milled tobacco shaped into orbs, sticks and strips.But they're barred by federal law from explicitly marketing them as less risky than cigarettes — at least for now. That means the "Switch and Quit" program can do something the tobacco industry itself cannot: claim that smokeless tobacco has a health benefit when compared to smoking.The program says smoking kills about 220 adults a year in and around Owensboro. The state of Kentucky, a leading tobacco grower, has the nation's highest smoking and lung cancer rates.Owensboro and the surrounding area consume about 3 million cigarettes a week, according to the program. That amounts to well over a pack for every man, woman and child in the community of about 115,000 people.Owensboro resident Vernon Goode had smoked for about 10 years before he recently traded his Marlboros for dissolvable tobacco tablets. The campaign didn't inspire him to quit, but he said he thought it was a good idea."I was just wanting to quit because, you know, I could feel it in my lungs," Goode said. "I'll smoke a cigarette every once in a while, but not very often. I want to quit altogether and I'm just using this right here as I guess what you'd call a stepping stone."The Owensboro program has raised concerns among some in the public health community who say organizers are claiming smokeless tobacco is a healthier alternative to smoking without approval from the Food and Drug Administration.A 2009 law gives the FDA authority to evaluate health risks of tobacco products and approve those that could be marketed as safer than what's currently for sale. None have been given the OK yet. The FDA also plans to regulate electronic cigarettes, battery-powered plastic and metal devices that heat a liquid nicotine solution in a disposable cartridge, creating vapor that users inhale.Matthew Myers, president of the Campaign for Tobacco-Free Kids, called the program "a giant experiment with the people of Owensboro without rules or guidance designed to protect individuals from experimental medicine."Smokeless tobacco isn't a safe alternative to cigarettes, according to the Centers for Disease Control and Prevention. Health warnings on the products required by the FDA state the same thing.However, some studies, including a 2007 report from the Royal College of Physicians in London titled "Harm Reduction in Nicotine Addiction," suggest that some smokeless tobacco products are about 90 percent less harmful than cigarettes."The worst that you can say about smokeless tobacco is that it's the lesser of two evils," said Dr. Randall Thomas, an oncologist with the Owensboro Medical Health System. The health system, the community's largest employer, is going smoke-free in 2013 and is offering Rodu's program as one of a variety of quit-smoking tools for its employees."I don't think we have any problem in telling a person that drinks a six-pack a day that if they could cut it back to two beers a day or two drinks a day that their health risks are greatly reduced," Thomas said. "Finding a way to let people have their nicotine that carries less risk, it's the realistic solution."The Owensboro program doesn't suggest pharmaceutical nicotine replacement gum or patches. That's because they are regulated to provide very small doses of nicotine and are recommended for only a short period of time, while smokeless tobacco can be used as long as a smoker needs, Rodu said.Myers, of the Campaign for Tobacco-Free Kids, said more research is needed before anyone should suggest that the nation's 46 million smokers would be better off using smokeless tobacco. In the meantime, he said, there are a host of FDA-approved products that can help people give up smoking."There's a right way and a wrong way to determine whether smokeless tobacco can and should be marketed as a way to help people quit," Myers said.The National Cancer Institute approved funding earlier this year for a nationwide 1,250-person study to look at whether being given a snus product changes the habits of smokers who are not motivated to quit.The tobacco industry sees smokeless tobacco as its future, said Matthew J. Carpenter, a psychology professor at the Medical University of South Carolina who is conducting the yearlong study.Carpenter said the snus study will examine what smokers do when given smokeless tobacco. He won't look at the health effects, or advise smokers to use the snus to quit."They are probably safer than conventional cigarettes, if for no other reason than you're not burning anything, you're not smoking anything, you're not inhaling any smoke," he said."If you compare it to conventional cigarettes, they're probably a little bit better. If you compare it to quitting, they're absolutely worse."___Michael Felberbaum can be reached at http://www.twitter.com/MLFelberbaum.Associated Press 
