Hi. I’m Lisa Girard, director of scientific communication at the Broad Institute. And welcome to Biologic, the logic behind the science: conversations with Broad researchers exploring what they do and why they do it.
In this episode, we’ll cover antibiotic resistance — when bacteria evolve defenses against the antibiotics designed to kill them and normally treatable infections turn lethal. These resistant bacteria have emerged as a major public health threat around the world.
Broad Institute member Jim Collins, also an MIT professor and a core faculty member at the Wyss Institute for Biologically Inspired Engineering, focuses his research on understanding how antibiotics work and how resistance arises. His team’s ultimate goal is to enhance our antibiotic arsenal and thwart the emergence of resistance.
But how severe is this problem, and how did it develop? And what’s really being done about it? In this episode of Biologic, Jim provides some answers to those questions.
I think antibiotic resistance is one of the major challenges facing the global community. I think it’s on par with climate change. I think it’s on par with our energy challenges. I think it’s on par with our food challenges to feed the planet.
The problem has arisen, I think, largely from overuse of antibiotics. I think the problem has further been coupled with a diminishing pipeline of antibiotics. So on the former we have antibiotics that are being overprescribed, that are too widely available, too easy to find. We’re finding the use of antibiotics both in agriculture and now as well as in consumer products.
And if we don’t kill the bug with the antibiotic, in many cases, the application of the antibiotic can lead to either the emergence and/or the selection of resistance. So we have an increased number of resistant pathogens that are arising around the world.
This problem in the past has been limited largely to hospitals, but now we’re finding increasingly resistant pathogens out in the community — out in childcare centers, in universities, on sports fields, in water supplies, among livestock. And this challenge has been unfortunately coupled with diminished interest from pharmaceutical companies and large biotech to discover, develop, and market new antibiotics.
And there it’s largely an economic decision. The market for antibiotics is still relatively small because most people use antibiotics for only a short time period. And so for the last decade, an increasing and surprising number of biotechs and pharma have gone out of the antibiotic business. So the problem is increasing and yet the supply is decreasing and thus we’re facing a growing challenge.
The media and national governments have been starting to sound the alarm for the last few years. But public perception of the problem is a different story, for a number of reasons.
I think the public underappreciates how large a problem this is. And I think it’s because it’s largely still viewed as this problem that doesn’t necessarily immediately impact them.
They might have a family member that has an infection, they might have a family member that maybe has a resistant infection, but I think the numbers aren’t there yet in the industrialized world at a high enough frequency for somebody to be scared. And as a result, I think that good stewardship, both from the physician side and the patient side, is not at the level that it should be to face the crisis.
My wife’s a primary care doc at Mass General and she’s very concerned about over-prescription of antibiotics and will only prescribe antibiotics for patients who really need it. And yet she, like many doctors, will have patients that demand antibiotics when in many cases it’s not warranted. So antibiotics will not treat a virus, and so if you have a cold or a viral sinus infection, antibiotics won’t make a difference — and yet patients will demand from their doctors that they need it. And I think we need to get a handle on this.
I asked Jim what he thought it would take to make progress on these fronts, and he focused on three broad areas: policy, science, and technology.
On the policy side, I think we need many, many new directions, including incentives for companies to get back in the space.
Congress, coupled with the FDA, has approved a number of bits of legislation and programs that allow one to get faster approval for certain antibiotics. And I think that can help, but I think we need to increase incentive structures, probably from national and federal subsidies or support programs.
We further need to get a handle on the overuse of antibiotics in the agricultural business. So, farmers will use it as a prophylactic for their animals to increase growth and reduce the chance of infection. And I think the U.S., the U.K., and other European countries are beginning to address this at the level they should, but I think we need to get greater buy-in and appreciation of it. We need incentives for good stewardship by doctors and hospitals and patients and consumers.
We need to increase our ability to incentivize young people to go into the field. We, in academia, need to do a better job of recruiting talent into this area. I think we need to excite young people about the tractable and important problems that exist in microbiology and infectious disease, and particularly around antibiotic resistance.
Many young folks interested in biomedicine are flocking to neuroscience problems and cancer problems — two exciting and very important areas that need talent. But we similarly need to excite folks about the challenges that exist in antibiotic resistance and have them begin to commit at least a portion of their career to addressing them.
And we need to just do a broader and much better job of informing the public of what these challenges are.
On the science side, I think we need to do a better job of understanding how the antibiotics act, how the bug responds, both in the dish and in patient settings or host environments. Antibiotics have been around for about 90 years now, and they’ve been in wide use for about 70 years. And I think we have kidded ourselves that we actually understand, well, how they act. I actually think we have a significantly incomplete understanding of what the antibiotics do and how the bug responds, and thus, we need to expand from a basic science and applied science level what’s happening in the bug and what’s happening in the host environment.
I think on the technology side, broadly defined, I think we need to develop new antibiotics and platforms for discovering and developing new antibiotics. I think we need to develop antibiotic potentiators — chemical and other means to boost what we already have. I think we need to develop means to thwart resistance for applied antibiotics and I think we need to develop alternatives to antibiotics using synthetic biology and other means.
In his research lab, Jim is doing exactly this. His team comes at the problem using two approaches. His first is “systems biology,” where his team maps the networks inside living cells to better understand how drugs act and how bacteria respond. The other is “synthetic biology”: developing alternatives to antibiotics by reprogramming other microbes to detect and treat infection.
We’ve been very interested in understanding how do antibiotics act to actually kill bacteria. And the conventional thinking is that the antibiotic will inhibit or corrupt its target, the bacterial target that’s associated with an essential process — and be that DNA replication, or protein synthesis, or cell wall synthesis.
Our lab discovered several years ago that, in addition to the inhibition or corruption of that target, that the application of the antibiotic will lead to a set of stress responses and other physiological responses on the part of the bacterium in response to the corruption of the target.
And around our discovery is this idea that the downstream metabolic processes are critical for how the bug will respond to the drug. We similarly, a few years ago, recognized that you could then stimulate these downstream metabolic processes to potentially enhance the action of certain antibiotics.
And this focuses on this phenomenon known as bacterial persisters. So bacterial persisters are quasi-dormant cells that make up some small fraction of bacterial population. These quasi-dormant cells are highly tolerant, or resistant to antibodies. And it’s now thought that these highly tolerant cells underlie persistent and recurrent infections — be it persistent or recurrent ear infections in kids, persistent or recurrent strep infections in teenagers, persistent or recurrent pneumonia infections and TB infections in adults, as well as pseudomonas lung infections in cystic fibrosis patients.
Several years ago we showed that you could deliver certain metabolites, along with antibiotics, enabling now the antibiotics to kill and eradicate these persistent infections. And we were able to demonstrate that this is due to the stimulation of central metabolism in the bug — and thus, that stimulation in conjunction with the antibiotic makes the antibiotic that much stronger.
In addition to finding ways to make existing and future antibiotics more effective, Jim has turned his attention to making narrow-spectrum antibiotics easier to use. Traditionally, a patient first gets a broad-spectrum antibiotic while doctors work out a more specific diagnosis and treatment plan. He explained some of the history behind the process process.
We got involved in antibiotics about ten years ago, and at the time there was significant interest in developing broad-spectrum antibiotics. The notion was that if you were going to put in all the money and the time needed to develop a new antibiotic, you better be able to have an antibiotic that can kill everything. And the motivation for that was that the ability to diagnose what the patient had wasn’t very effective at the time. And thus, the patient comes in and presents with an infection, you want to apply an antibiotic that’ll get whatever’s there.
In the ensuing decade, we’ve now appreciated the human microbiome, and the fact that our body is populated by hundreds of different bacterial species that play a significant role in health and also a significant role in disease. And there’s been growing interest in thus developing narrow-spectrum antibiotics, so antibiotics who would only go after particular species, a pathogenic species in the case of infection.
But the challenge is that in order to do that, you have to know what the patient has. And point-of-care or companion diagnostics have not developed at the rate that is needed to enable one to meaningfully use a narrow-spectrum antibiotic. Now in a hospital, you’ll take a sample from a patient and it will take typically 2 to 3 days to get the result back from the lab. You may get an intermediate result within a day, as to a general type, but the lab will need to grow out and then run assays to identify what’s there.
Jim is working on a faster diagnostic tool that will enable clinicians to quickly prescribe the right narrow-spectrum antibiotics — which wouldn’t contribute as much to resistance.
Here at the Broad, and as well as in our lab at MIT and in the Wyss Institute as part of Harvard, we’ve developed a platform that enables one to do rapid inexpensive diagnostics of bacterial infections as well as viral infections. We think our platform could give you an output within 30 to 60 minutes.
About two years ago, we recognized you could use synthetic biology outside the cell. We showed that you could take cell-free extracts, so several dozen enzymes, nucleic acids such as DNA and RNA, and molecular machines like ribosomes, and have them function outside a cell. And in particular, we showed you could spot them on paper or other porous media such as plastic, quartz, cloth, or glass, freeze-dry such material as well as spike in engineered DNA and RNA, and then sometime later rehydrate those spots, and they would function as if they’re inside a living cell.
And with this platform we’ve developed now a framework that allows you to readily, within 20 to 25 minutes, identify cellular output associated with antibiotic resistance. We’ve also developed viral detectors, viral diagnostics, for Ebola and Zika.
We’re now looking to see, “Can we use this to develop a rapid antibiotic susceptibility test?” So could one, without the need to grow out the bacterial culture, take a patient sample, apply an antibiotic, take the response of that cell, and quickly assay it using this platform to see, “Did the cell respond in a way that would indicate the antibiotic is working?”
If the bug is susceptible to a given drug that might be narrow-spectrum, it would have a certain response. If the bug was not susceptible, either it was gram-negative and it was a gram-positive antibiotic or it was resistant to the applied antibiotic, it would not have these sets of signatures.
And we’re now excited about how you could use this as a rapid antibiotic susceptibility test that could be used for a broad set of infections, ranging from E. coli, to staph, to pseudomonas, to pneumococcal, to TB.
Jim has more than one personal connection to this field. He grew up in a family of engineers and studied physics as an undergrad, but found a unique challenge in molecular biology.
I was intrigued by biomedical engineering, in part in that my dad had been an electrical engineer who had worked with the aviation industry and the space industry, and his team had, among other things, helped develop the altimeter that was on the Apollo missions, that landed the lunar module on the moon. And I saw — from him, I saw this marvelous technology being used to shoot stuff up into the sky and shoot stuff out of the sky.
And as a kid, I also saw my two grandfathers become disabled. One went blind, and one had a series of strokes. And I saw nothing being done for these guys, these two guys that I loved. And so I became excited even as a young person at what technology could be developed and deployed to help restore function to folks. So when I started as a grad student, I started as an academic then in 1990, my lab primarily focused on medical devices.
But then in the mid 90s, we got intrigued as what was happening in the molecular space, intriguing in molecular biology, that very few bio-engineers were engaged. And I got introduced to Eric Lander and others, and was challenged by Eric and others in the Human Genome Project as to what a control theorist, control theory engineer such as myself, could do in molecular biology. It was a challenge to basically get engaged in what became this field of systems biology.
And after about 5, 6 years, got pulled into antibiotics. We were not an antibiotics lab, but starting about 10 years ago, got excited to see there were very interesting problems and recognized that our understanding was incomplete. And moved into this space and began looking, among other things, at persistent infections.
And interestingly, potentially, that myself, I had a persistent recurring strep infection in college, so I had strep throat maybe 13 times over the course of a year. I was a competitive runner and was unable to compete during that time, and was unable to compete after that, so it almost ended my competitive time.
And once we began working on this, in the midpoint of the last decade, my mom got hit with a persistent staph infection. So there was then personal and family motivation to engage in this — both to better understand how were the bugs protecting themselves against antibiotic treatment and against host attack, and what could we do to better treat these persistent bacteria. And it’s now become a big focus of my effort here at the Broad Institute.
You can read about Jim’s work on rapid diagnostics, bacterial metabolism, and antibiotic resistance at broadinstitute.org. Other episodes of Biologic are also available at broadinstitute.org, or through SoundCloud, iTunes, and Stitcher. For the Broad, I’m Lisa Girard. Thanks for listening!
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