University Place

[gentle music] - Samantha Mulrooney: Hello, everybody.

We'll go ahead and get started.

Thank you all for being here.

Good evening, and welcome to Crossroads of Ideas: When Antibiotics Fail.

My name is Sam Mulrooney.

I'm the Outreach Program Manager here at the Discovery Building and also the director of the Wisconsin Science Festival.

So, thank you all for being here.

And before we get started, just a couple of opening remarks for you all.

Today's event marks the third and final installment of our three-part miniseries on productive failure in science.

Crossroads of Ideas is a program series presented by the Illuminating Discovery Hub here at the Wisconsin Institute for Discovery and developed collaboratively with UW-Madison and other discovery building partners.

Crossroads brings together campus experts and community members to explore thought-provoking topics at the intersection of science, society, and the arts.

Since its launch in 2014, the series has been a cornerstone of public programming at the Discovery Building, fostering dialogue, curiosity, and connection across disciplines.

So, we're delighted to have you all with us for this conversation tonight.

So, throughout this miniseries, we've been exploring the idea that sits at the heart of scientific progress: productive failure.

In science, failure is rarely the end of the story.

Often, it's the moment that reveals something unexpected, challenges assumptions, or points researchers towards a new path.

Tonight's conversation looks at this idea through a pressing global challenge: What happens when antibiotics fail, and how scientists are working to understand and respond to antimicrobial resistance.

So, to help us tonight-- It's a big question.

To help us tonight, we have two of my colleagues here at the Discovery Building, Executive Director of the Tiny Earth Program, Sarah Miller, and Assistant Professor in the Department of Plant Pathology, Dr.

Marc Chevrette.

First, Sarah will explain a bit more about her amazing work with the Tiny Earth program.

And then, Marc will help us explore antimicrobial resistance and what researchers are doing to discover and understand this global challenge.

We'll be sure to save time at the end for Q&A.

So, it is my pleasure to first introduce Sarah, Executive Director of the Tiny Earth Program, and which is an international network of more than 800 instructors across 33 countries that engages roughly 16,000 students each year-- incredible-- in the search for new antibiotics from soil bacteria.

Her work focuses on STEM education, particularly active and inclusive learning, large-scale institutional change, and faculty development.

Sarah is a coauthor of several science education publications, including work in Science magazine, and has received the UW-Madison Teaching Academy Distinguished Teaching Award.

So, without further ado, I welcome Sarah.

[audience applauds] - Sarah Miller: Hi, everyone.

Nice to see you.

I'm Sarah Miller, Executive Director of Tiny Earth, and we are housed here at WID.

As Sam mentioned, Tiny Earth is a global network of college students who are crowdsourcing, or we like to say, student sourcing antibiotics from soil bacteria.

So, we face several pressing global challenges with respect to all kinds of things.

First one is increasing gaps with respect to achievement and access in science in college, increasing antibiotic resistance, and increasing soil erosion.

Each of these constitutes a global crisis, which the Tiny Earth Initiative is designed to address.

Tiny Earth's three goals, therefore, are to inspire students to have access to and to persist in the sciences, to address the dwindling supply of antibiotics, and to protect our precious soils.

I will be unpacking only the first two in this talk.

So, first, let's start with the goal of inspiring diverse students to persist in science.

So, there are two problems here.

Students leave science in college after declaring science majors.

And there is a stubborn gap in performance.

So, first, nearly 600,000 students leave STEM majors every year, citing poor teaching methods as the primary reason.

Worse, women, students of color, and all underrepresented groups leave at higher rates than majority students.

In addition, the gap in performance between underrepresented and overrepresented students, as measured by exams or grades has been called, quote, "one of the most urgent and intractable problems in higher education."

So, in order to have a diverse STEM workforce, students need access to scientific opportunities.

They need environments designed for success, and they need to feel like they belong in science.

Colleges are often falling short, relying largely on didactic lectures despite overwhelming evidence in support of active and inclusive learning strategies.

So, Tiny Earth provides students with access and opportunity to do real scientific research.

So, Tiny Earth is a CURE, which stands for a course-based undergraduate research experience.

Students engage in a full semester of authentic science research, designing their own experiments, working collaboratively, failing, troubleshooting, failing again, collecting and analyzing data, trying again, and all the while building the lab skills needed to be part of the STEM workforce, or simply to be well-informed citizens who are able to think critically about scientific issues by weighing evidence.

CUREs have been shown again and again to promote student learning.

They increase research skills.

They increase project ownership.

They boost confidence, self-efficacy, and belonging in science, and they lead to retention in science.

They focus on relevant problems and they lead to new discoveries.

Students who take a CURE like Tiny Earth in college are less likely to leave science.

In fact, just one CURE in college can increase persistence in science.

And the positive effect is even greater for students who are from groups that have been historically excluded from STEM.

CUREs also provide access to research experiences at scale, because they are taught as courses that enroll tens or hundreds of students simultaneously, rather than a more traditional one-on-one faculty-student research experience in a lab, where the math ain't mathing, right?

Better yet, CUREs can be and are taught at all types of colleges.

Technical colleges, community colleges, tribal colleges, not just research universities.

Okay, so we've established that CUREs provide access to and support for students to engage in research.

But what are the students doing for that research?

In Tiny Earth, the answer is the dwindling supply of antibiotics.

Antibiotics are the medicines, of course, that we take to cure bacterial infections.

They're also used in other applications, like veterinary clinics or farms or on crops.

However, largely due to overuse, bacteria are becoming increasingly resistant to the antibiotics that we have, rendering them useless.

And you can see here that antibiotic resistance has risen sharply this century, especially for seniors.

Scientists worldwide are warning of a looming crisis as antibiotic resistance surges globally, predicting 40 million deaths by 2050.

And yet, pharmaceutical companies have largely abandoned antibiotic discovery.

So, why, you may ask.

Well, it's simply not that lucrative.

It takes a billion or billions of dollars to move a new drug from discovery to market.

But then you, the consumer, only takes it for about five days, seven days, ten days, how long you take an antibiotic, in contrast to other drugs that are taken for much longer, like statins or SSRIs, which you might take for life, and therefore those are much more lucrative.

So, once again, enter Tiny Earth.

So, Tiny Earth students turn to the soil, a rich repository of bacteria where many of our medicines come from.

Tiny Earth students spend a semester working on this problem.

First, they collect a soil sample, just a tablespoon or two from their soil of their choosing.

It could be from their backyard.

It could be from a local park.

It could be from their campus, a field.

It doesn't matter; they get to choose.

They dilute their soil in sterile water.

They inoculate petri plates with those soil dilutions.

They wait a few days to see what grows.

And this is the first discovery in Tiny Earth.

The students see how alive the soil is when their plates are just covered with bacteria.

Next, they choose a few bacteria to screen, so now I'm in module two here, to screen for antibiotic activity by growing them with safe relatives of known pathogens.

We do not use the actual pathogens in the lab, in the class, and the experiments usually result in several bacteria showing a quote, "zone of inhibition" where the soil bacteria, that's what's circled in red up on the slide, where the soil bacteria basically stopped the safe relative of that pathogen in its tracks.

And so, you can see that zone of inhibition, that clearing area on that plate.

And so, discovering that bacteria that is an antibiotic producer, that's the second discovery in Tiny Earth.

So, here we are, only in module two, and the students have already had two pretty major discoveries that literally no one has ever looked at before, because it's the soil of their choosing and the isolates that grew from it.

At this point, the students don't know what their bacteria are, but they're hooked on figuring it out.

So, that leads to countless more discoveries.

They can try a battery of classic microbiology tests.

They can do all kinds of genomic applications to characterize and possibly even identify the soil bacteria that have shown antibiotic activity.

Some Tiny Earth courses even take it a step further, moving into module four, where the students further elucidate the actual molecules that bacteria are making.

Because at the end of the day, antibiotics are, in fact, molecules.

So, that's the gist of Tiny Earth.

The students usually write their results up, you know, lab report or whatever they have in their class.

But they can also present their research findings, at, for example, a symposium.

What you're looking at here is our annual Tiny Earth in Titletown Symposium that we hold at Lambeau Field every December at the end of the semester.

And so, on a dark night, usually on a Friday, about 200 students from Wisconsin convene to present their research, and they invite their family and friends.

This event is attended by about 550 people from the community.

It's pretty remarkable to celebrate the students doing this research.

And these students are coming from UW system schools, technical colleges, the private colleges, you name it.

Sometimes, we get others from outside the state, but mostly, that particular event is for the state of Wisconsin.

We also hold an international symposium here at WID in the summer.

All right, here's our map.

So, I have some, from even what Sam said, we have some new numbers.

The problem of antibiotic resistance is so massive that it requires a massive crowdsourced effort.

So, we have trained actually more than 900 instructors now, mostly college faculty, to teach Tiny Earth.

And estimating conservatively, if you imagine that each of those is teaching, on average, 20 students per year, that means 18,000 students have access to the Tiny Earth CURE research experience every single year.

And this is where I think Tiny Earth is really clever and how we get around the overwhelming numbers game.

Our main expansion tool is the Tiny Earth partner instructor.

We call them TEPIs, T-E-P-I.

The TEPI training, it's a week-long immersive summer camp.

We hold it here in the Discovery Building, and we teach faculty how to teach Tiny Earth.

It's based on evidence-based pedagogical and peer mentoring practices.

And during the week, the TEPIs work in facilitated groups to adapt the curriculum for their particular students and their particular version of Tiny Earth.

They learn scientific teaching principles such as course design, active learning, inclusive learning, and they apply them all to the development of their Tiny Earth course.

And they go through all the lab protocols along the way, just as if they were students while thinking about the course that they're building.

So, bringing this all together, Tiny Earth is an antibiotic discovery pipeline that starts with training instructors, but really focuses on students engaging in authentic research for a full semester.

Students enter their data into the Tiny Earth database, and they can send any interesting isolates they find here to WID to our Tiny Earth chemistry hub, which is upstairs in Professor Jo Handelsman's lab.

Today, we have more than 4,300 isolates in the collection and several of interest that we're pursuing further.

So, I just wanna thank you all for coming and thank our sponsors for Tiny Earth, in a particular, Dr.

Jo Handelsman, who is the founder of Tiny Earth.

All right, and with that, I get the pleasure of introducing Marc Chevrette.

He is a relatively new assistant professor of plant pathology.

He is a Discovery Fellow here at WID.

He was hired as part of the Wisconsin RISE-EARTH initiative, and is one of those rare scientists who did both his PhD and his postdoc here at UW.

The PhD was in bacteriology in the Currie Lab, and the postdoc was here at WID in the Handelsman Lab.

Previously, Marc was an assistant, [clears throat] excuse me, professor at the University of Florida, and before grad school, he was head of the experimental genomics at Warp Drive Bio, now Ginkgo Bioworks, where he was one of the lead developers of the ubiquitous software called antiSMASH, which identifies and annotates genes in bacteria and fungi.

According to Marc, quote, "Microbes are the best chemists in the world, "and their metabolites are the language of microbial interactions."

He is an incredibly interdisciplinary scientist, drawing from fields as broad as genomics, chemistry, microbiology, data science, plant pathology, and ecology, with impacts bleeding into medicine and public health, agriculture and the environment.

His lab uses both computational and experimental approaches to study the ecology and evolution of bacterial genes and how bacteria interact using compounds encoded in those genes.

He has 75 peer-reviewed publications in systems ranging from natural products, discovery and bacteria to drug resistance and fungi and antimicrobial potential and insect biomes, biofilms, and even Tiny Earth.

I've had the pleasure of working with Marc for almost seven years now in his role as Tiny Earth genomics director, and he is, at heart, a Renaissance man who loves to solve wicked problems.

We share this, and thank goodness, because as you've already learned, antibiotic resistance is in fact one of those wicked problems that requires us all to draw on all of these disciplines to address it.

So, without further ado, Marc Chevrette.

[audience applauds] - Marc Chevrette: Thank you, Sarah.

That was a very warm and friendly introduction to a rather unfriendly topic that I'm gonna be talking about, which is what happens when antibiotics fail and what types of strategies we as researchers are using to try and overcome that failure.

So, firstly, what are antibiotics?

As Sarah introduced, antibiotics are chemicals that are made by bacteria and fungi, just living their everyday lives in nature that we as humans have discovered and found uses for them to treat infections.

So, there are two main flavors of these antibiotics.

Those that are bacteriocidal, think of those as kill switches.

They're actively going and killing bacterial infections or things that are bacteriostatic.

So, these are arresting the growth of bacteria so that other mechanisms can help you overcome the infection.

So, think like stopping their growth so that your immune system can then go fight off the disease.

One of the more famous antibiotics that I'll use to introduce this is penicillin.

This is a molecule whose discovery was born of failure.

Some of you may already know the story, but in 1928, Alexander Fleming left to go to a conference.

His lab, in charge of-- All of the grad students in charge basically took the week off and left all of their bacterial plates out.

And when he came back, a few of them were contaminated.

One of those contaminations had one of those zones of inhibition that Sarah introduced that's part of the Tiny Earth curriculum.

He found one of those on his plates just by accident.

And over the course of the next couple of years, he tried to understand what was actually being produced and how that zone was happening.

And that, to cut the story short, was penicillin.

Penicillin is one of the more famous drugs, because it's one of the ones that has had a massive impact in human health.

How it works is it enters the bacterial cell and targets an enzyme that's responsible for building up the cell wall of that bacteria.

So, you're not able to build your cell wall, you're not able to reproduce, and the bacteria die.

So, think of these as kind of lock and key type interactions.

The antibiotic needs to go into the cell, find its cellular target, and interact with it in a way that disrupts the bacteria so it either dies or stops growing.

So, these are very specialized tools.

They're not used as all-purpose medicines.

And so, what that means is that different infections are gonna require different keys to unlock different locks.

Antibiotics, as a very general term, can be these molecules that target either bacteria or fungi.

So, the ones that target bacteria are antibacterial, antifungal for the ones that target fungi.

And you'll notice that I didn't mention viruses because antibiotics do nothing against viruses.

So, everything that we know about antibiotics and how they work are them disrupting cellular processes.

And viruses operate in a completely different biology.

So, they're not active against viruses.

So, antibiotics are very important.

But not too long ago, we were in a world before antibiotics were widely used.

This picture here is of Calvin Coolidge's son, Calvin Coolidge Jr, who was in 1924 playing tennis on the White House lawn and developed a relatively minor cut on his hand that turned into an infection.

That infection, over the course of the next four days, led to his death.

So, even just about 100 years ago, people who were the sons of world leaders that had access to top medical care were still in very life or death situations from bacterial infections.

Now, this is an ad from Listerine from 1930.

Basically, just minor cuts that men were facing with their razor blades could end them in the hospital or even death.

So, one of the major primary uses for Listerine in the early days in the 1930s was to guard against these bacterial infections.

And penicillin that I mentioned before, it's credited with, in part, the reason why the Allied troops in World War II were able to get an advantage on the battlefield.

So, battlefield injuries were not as much of a problem for the U.S.

and U.K.

forces because we had access to penicillin that was getting our soldiers out from underneath the infectious disease that they could pick up in the battlefield.

So, how do we use antibiotics?

Typically, we're using them to treat infections in humans, in us that are caused by either bacteria or fungi.

And in parallel, though, I think something that isn't as well noticed is that antibiotics are the reason why we're able to have so many other breakthroughs across medicine.

So, when you're getting treatments for cancer, or you undergo an organ transplantation or surgeries or even relatively routine things like dental cleanings, antibiotics enable us to be able to not worry about infections.

So, they're very, very important.

Aside from human health, they're also very important in agriculture.

And so, crop and livestock bacterial and fungal diseases are combated with antibiotics the same way that we combat diseases in humans, but we also use them as prophylactics.

So, to prevent infectious disease from even occurring within our food.

Different countries have different regulations on this.

But I think what's very telling is that in the United States, at least, 80% of the antibiotics that are sold go directly to agriculture.

So, even though we think of these as very human-centric medicinal molecules, we're using them across the food chain.

So, how do they work?

They work, like I mentioned before, by disrupting key cellular processes that the bacteria are needing to survive.

This could be interacting with the cell wall, the things that biosynthesize the cell wall and build it as they're replicating.

They interfere with those.

They can interfere with the membranes, how they make proteins, different types of key metabolic pathways, and how they reproduce and copy their genetic information.

And so, again, kind of think of this as a lock and key mechanism.

Different bacteria are gonna have different strategies to live their lives and be fit in their environment.

And so, antibiotics that are active against one bacterium may not be active against another.

So, different tools for different jobs.

Now, what happens when antibiotics fail?

This typically is thought of in through the lens of resistance.

Bacteria, over the course of evolution, have figured out ways to deal with antibiotics so that they're no longer susceptible to them.

This could be by using pumps to actively remove them outside of the cell.

So, they get in and they get right back out before they can do their job.

They can modify those cellular targets so the antibiotics can no longer fit the lock that they used to.

They can get degraded by specialized enzymes.

So, breaking down the antibiotic before it has a chance to act.

They can modify their cell wall basically to put up a fence so the antibiotic doesn't get in in the first place.

And, of course, they can crowdsource the problem by talking to their neighbors and potentially taking on new genetic material to do all these different types of things.

And so, evolution is a real driving force here.

And the way that we use antibiotics contributes to the evolution of resistance.

So, one of the core key concepts of bacterial evolution is that the more fit will survive.

And if we're changing the environment that they live in by bombarding them with antibiotics, there's a really large pressure on these bacteria to evolve in these different ways to circumvent that antibiotic treatment.

And this is how resistance develops.

And so, if you have an infection, realize that that infection is gonna contain many, many different bacteria, not just one.

Some of those will be drug resistant.

You apply an antibiotic, that antibiotic will kill the ones that are susceptible, and the ones that are resistant will stay alive, multiply, and then potentially transfer that resistance to others.

And so, this is a major problem.

And mechanisms like Tiny Earth and some of the research going on here at UW-Madison is directed at this problem to try and find new ways to stay ahead of resistance.

So, what are the major causes here?

One is overprescribing of antibiotics.

I think the United States, Canada, and the U.K.

have done a really good job in their policy over the last 20 years to make medical doctors aware and educated about antibiotic use and in stewardship.

However, in many other countries, developed and underdeveloped alike, those policies are not in place, meaning that prescription of antibiotics or just over-the-counter use of antibiotics for things that are not bacterial infections still commonly occurs in the world.

So, for example, I'm sure everyone here is familiar with having a cold or COVID-19.

These are viral infections.

So, antibiotics will not be useful against those infections.

Yet in some countries, they're available over the counter and people are taking them anyway.

So, this is one way that antimicrobial resistance, that extra evolutionary pressure to have this resistance rise up is due to taking antibiotics when you're not supposed to.

We also use them quite ubiquitously in livestock and fish farming.

So, I mentioned that on an earlier slide, 80% of the antibiotics that are sold in the U.S.

go right into agriculture.

So, perhaps we can be smarter about use in agriculture as well.

And one of the major problems that I'm gonna highlight for the rest of my time with you is the lack of new antibiotics being developed.

So, Sarah introduced this topic as kind of a divestment in Big Pharma because the money wasn't there.

The economics don't work.

If you're spending $1 billion, $2 billion to get a drug developed and you only make half a billion dollars back for something that patients are not taking over the course of their lifetime.

And so, that's where really, I think, academia and our student-sourcing Tiny Earth can come in to really address this goal and challenge.

So, resistance is a major problem both across the world and locally here in Wisconsin.

In the U.S.

alone, 2 million infections are caused by resistant bacteria that cost about $20 billion every year.

What I'm showing you here on the bottom is a heat map of resistant bacteria for the antibiotics ampicillin and ciprofloxacin.

You can see that the hotter colors, the ones that are more red are where there's more cases of resistance.

The greener colors are where our antibiotics are working well.

So, in different population densities across the state, as infection can spread, you get these kind of dynamics that are somewhat scary.

They require us to find new ways to address these bacterial infections.

We are getting good at this in some ways.

And we still have a lot of room to run in others.

And so, that's what I'm showing you here on the right.

The green bars are where we were at for the number of deaths per year in 1990.

And the blue bars are where we're at for the deaths per year in 2021.

And as we go up the page, you can see the different age groups that are being affected.

So, early on in life, there was, there used to be a major problem with bacterial infections that we've basically have-- We have 50% of the incidence rates in deaths that we did about 30 years ago.

However, the problem is worsening in older age groups.

Forty years of age and up, you can see that the blue bars are bigger than the green bars.

And so, resistance is really affecting these different age groups in different ways.

And it's estimated that by 2050, if there's no interventions, one person every three seconds could die from antimicrobial resistant or related complications.

So, it's a very dire problem.

I mentioned agriculture is a big focus for antibiotics.

And that's because plant pathogens cause big economic issues as well.

So, 40% loss in yield and $220 billion annually are the cost of plant pathogens that are infecting our crops.

What I'm showing you in the world map at the top is where we at for the abundance of plant pathogens in 2020.

And by 2050, if nothing changes, we're expected to have extremely high incidence rates across the globe.

So, what do we do?

We need to find better ways to use antibiotics and practice stewardship.

We need to discover new antibiotics that work in new ways.

And we need to develop new ways of thinking about treating infections that are maybe outside the box of antibiotics.

And what I'm gonna focus on now is what my lab does, which is the one in the middle.

Discovering new antibiotics.

Where do we go and find them and how do we look for them?

So, as Sarah mentioned, bacteria are a major source of antibiotics.

Nature has the most promising routes for these new antibiotic discoveries.

Bacteria and fungi, over millions of years, are evolving to live in competitive environments.

And so, even though some bacteria and fungi cause disease, and that's been the topic that I've talked about so far, many or most microbes are beneficial to their hosts, so they live on and with humans and contribute to their health on and with plants on and with other organisms.

And often, they're making their own antibiotics to compete with other bacteria or members of their environment.

So, that gives them a survival advantage.

And we can study how they make them, what they're making, and maybe get some inspiration to bring into medicine and crop management practices.

And so, interactions between species are really shaping all of the diversity of life that we see across the planet.

And so, this is pretty obvious, I think, at the macro scale.

You can have predator-prey dynamics.

You can have, you know, different fish and their schooling behavior and how that's contributing to their fitness as a species.

We farm crops for food.

Ants also farm crops for food.

And, you know, the intricate interactions between insects and pollen and how they pollinate plants also contributes to all of this lifestyle.

This is something that I think we're very familiar with because we can see that at the macro level.

But at the micro level, all of this is happening in large part due to their chemistry.

And the way that they're interacting with their environment, competing with others, signaling to others is through their chemistry.

And it's very, very diverse.

So, I don't mean for you to take home all of these structures and memorize them.

I just want to impress upon you that it's very, very different across the tree of life.

And there's a lot of capacity for new molecules.

All of these molecules have functions in their natural environment.

And some of the things I have listed on the left are how we've kind of co-opted these molecules and used them for human purposes.

So, either as antibacterials, antifungals, or manipulating host-microbe interactions.

This is where most of our drugs come from.

So, on the left, I'm showing you a pie chart where all of the colors are antibiotic or anticancer drugs approved by the FDA that have been either directly sourced from nature or inspired by these bacterially-produced compounds.

And on the right, what I'm showing you are the very important key access antibiotics that the World Health Organization holds in the highest regard.

These are largely from nature or nature derived.

Very few of them are thought up by chemists in a lab and are purely synthetic.

So, where have we looked for new antibiotics?

Sarah introduced this well.

We can start in soil, isolate bacteria, screen them for activity.

Who's killing who?

And then, hopefully, we make a discovery.

And this has been relatively successful.

So, since that 1928 discovery of penicillin, there have been many, many new classes of antibiotics discovered where kind of the heyday, the golden age of which was between 1940 and 1960.

Streptomycin was discovered in 1943, and as soon as that was used in the clinic to treat tuberculosis, mortality decreased by over 85%.

Before streptomycin was discovered, people that were suffering from tuberculosis had their beds moved out of the hospital and onto the street, because the standard of care was for them to get fresh air.

That was the only way that this infectious disease was treated.

But introduced streptomycin, and 85% mortality decrease within just 20 years.

But recently, we've been kind of striking out in finding new antibiotics.

Like I mentioned, 1940 to 1960, where we were getting a lot of success looking in soil in the bacteria that are found there and seeing what they could produce.

But since about 1987, there has been a void in discovery of new classes of antibiotics.

And that's largely in part due to the problem of rediscovery.

So, when you do these kind of isolations of bacteria and looking for activity, you can find streptomycin over and over and over again.

So, one of the strategies that our lab and what Tiny Earth is doing is to try and be smarter about where we're looking for these antibiotics.

What are the different types of bacteria that we can exploit, or the different types of environments where we haven't looked in the past?

So, my lab tackles this not through soil, but looking at host-microbe interactions and the microbiome.

In particular, microbiomes that are associated with hosts that have to deal with disease.

So, plants and crops, we already talked about, they have to fight off infectious disease all the time.

They're microbes that are either in the soil or on their leaves are helping fight off that infection.

And so, we're taking that kind of discovery approach to see what type of molecules they're producing.

And maybe we can use those to develop new antibiotics.

Frogs, salamanders and snakes are also a major focus of our lab.

So, looking for frogs and salamanders out in the environment, swabbing them for their bacteria, and seeing what kind of chemistry that bacteria might provide to help combat against their infectious diseases.

So, we integrate new methods in this too.

Getting this big culture collections from various hosts, diverse hosts, seeing how these bacteria interact, who's killing who, and then bringing in some kind of new technologies like transcriptomics, genomics, and metabolomics to make this a high throughput discovery exercise.

Sarah impressed upon you the massive numbers of Tiny Earth students that are taking the course every year.

That, to be able to screen all of the isolates from all of those students would be impossible without these high throughput methods.

So, we're both actively involved in running them, but also developing new ones.

And yeah, new methods lead to new discoveries.

So, this involves integrating all different types of genomic and metabolomic information.

Also screening them against organisms that we haven't tried to kill before.

Acinetobacter baumannii is a major priority of the U.S.

Army right now, because infections that are getting picked up by soldiers in the battlefield tend to be resistant if they're caused by this organism.

And we only really knew about this organism in around 1990 to 1995.

So, it was not part of the screening methods from Big Pharma that were pretty much over by 1980.

So, looking in new places, but also screening for new targets.

Integrating all these different high throughput data sets can be very challenging.

And so, one of the things that our lab is doing as well is trying to integrate machine learning and artificial intelligence to make sense of all this data, to point us towards the new antibiotics.

So, these are the major challenges that we're going after.

Finding new and useful molecules and using high throughput and new school omics methods to try and mine that chemistry.

Getting the bacteria that make these molecules to actually produce them can be a major challenge as well, because most bacterial chemistry is going to be not produced under lab conditions.

They're used to being living out in nature in very different environments.

When we bring them into the lab, sometimes they don't behave in the same way.

And so, synthetic biology and high-throughput elicitation is a major focus of our group as well.

And then, of course, we don't really know much about what antibiotics are actually doing in nature.

And if we did, then we might be smarter about where to look for the next ones.

So, understanding these ecological roles is a major frontier that our lab is very interested in studying further.

And so, just to wrap up, antibiotics are the cornerstone of modern medicine and our major defense against bacterial and fungal diseases, not just for our diseases, but the diseases that affect us through the food chain.

So, the diseases of our crops as well.

Most antibiotics that we know about are made by bacteria and fungi themselves.

And resistance is a major threat to their effectiveness.

So, both in my lab and at research across the globe, we're aimed at developing new strategies for combating this resistance and to find new antibiotics that work in new ways.

And with that, I just want to acknowledge my team.

Some of them are pictured here.

Others are not.

We need to take a new picture soon.

And then, our funding sources at the bottom.

And thank you for your attention.

[audience applauds] So, Sarah, I'll invite you up and we can have a conversation.

– Sarah: A little chat.

– Marc: Yeah.

– Sarah: All right, thanks, Marc.

– Marc: Yeah.

[Sarah chuckles] - I always learn something from you.

So, let's start with soil.

– Marc: Okay.

– Sarah: What makes soil such a powerful place to look for new antibiotics?

– Marc: Well, it's all comes back to the microbes that are there.

And so, both soil and seawater are the two most diverse environments that we know about on Earth in terms of the different types of bacteria and fungi that you might find there.

And so, the more diverse a environment is, the more diverse its interactions are gonna be.

And like I mentioned in the talk, those interactions are largely driven by chemistry.

So, if we wanna find new and exciting things that have activity against stuff that humans are interested in, it follows that you wanna look in the most diverse places on Earth.

And so, soil has been extremely fruitful in the past.

I would-- I don't have an exact number for you, but I'd say probably around three quarters of all of the antibiotics that we use right now are not just from bacteria, but bacteria that are from the soil.

– Sarah: Yeah.

– Marc: So, that's the major source.

- Yeah, let's talk a little about those conversations, those chemical conversations that bacteria are having.

How can understanding those interactions help us discover new medicines like antibiotics?

- Mm-hmm.

Well, I think one of the things to keep in mind there is that medicine is a very human topic, a very human-centric way of thinking.

And the bacteria and other microbes that are making antibiotics in the soil, for example, may not be using them in the same ways, and maybe almost surely not the same concentrations that we use them when we try and combat disease.

So, if we can better understand what these molecules are actually being used for in their natural environments, then we can take those principles and apply them forward to finding new ones.

Yeah, so in terms of, in terms of medicine, I think it's helpful to separate those two ways of thinking.

It's us kind of stealing the ideas of bacteria and really applying them for human problems.

But how they're evolving and found naturally distributed is a very different context.

– Sarah: Mm-hmm.

So, it sounds like... ...this type of research really requires interdisciplinary thinking, right?

I know you in particular draw on multiple disciplines.

I do as well.

How important is that kind of interdisciplinary thinking when we're addressing antimicrobial resistance?

And what types of skills would you say the next generation of scientists needs to be honing now in order to be helping us to solve the antibiotic resistance crisis or keep ahead of it?

- Yeah.

I'd say it's not just important, but it's necessary.

I think inherent to this problem of resistance is approaches that come from different angles that complement each other really well.

And so, we're definitely in the information and omics era right now.

And to be able to understand and utilize the crazy amounts of information that we're generating about resistance rates, about the mechanisms of resistance, that requires people to be very well trained in the data sciences.

It also requires people to be trained in the basic biology and microbiology of these organisms, to really understand the mechanisms through which antibiotics are working or not working in the case of resistance.

And there's a huge gray area in between with newly evolving fields that weren't there five years ago.

So, I'm thinking in particular about the recent advances of genomics and metabolomics that, you know, just 20 years ago would have been a pipe dream to generate the data that we have now.

Now it's relatively commonplace, and the challenge is making sense of all that data.

– Sarah: Yeah.

- So that's where I would put-- I would point the next generation of scientists to is, you know, really trying to find a way to integrate new methods in ways that doesn't pigeonhole you into one discipline or another, because it's reaching across disciplines that, I think, is where the hard problems in biology are going, which antimicrobial resistance is one of them.

– Sarah: Absolutely.

Let's shift gears a little bit to policy, stewardship, things like that.

So, what role do systems like health care, agriculture, policy play in protecting the antibiotics that we already have?

- Mm-hmm, yeah, and I think, you know, something that you brought up in your portion of the talk makes sense to bring up again here in that, you know, if you are taking a successful round of antibiotics, it's not a lifelong endeavor.

It's going to be a week or a couple of weeks.

And so, because of that, I think we need to expand and keep safe the medicine cabinet that we can reach for.

– Sarah: Mm-hmm.

- So, that has two angles to it.

One is finding new antibiotics, which was not your question, but I think it's very important.

And the second is deploying them in ways that are rational and smart so that we don't encourage resistance.

I mentioned the United Kingdom, Canada, and the U.S.

during my talk as being kind of the global leaders in shaping policy around proper use of antibiotics, but there's still a long way to go.

And I don't mean that just globally, I mean within the United States as well.

So, this takes place at many different levels.

It's at the level of policy.

It's at the level of insurance companies and best practices.

And it's at the level of patient-doctor relationships and how they're actually understanding what diseases might be treated with what.

- So, is, so public awareness is playing a role in this as well.

- Yeah, and I think I'll call out Canada in particular of taking a really firm stance on this and training all of their MDs with cutting-edge science that is recently peer reviewed that they may not have gotten 20, 30, 40 years ago when they were in medical school.

And so, I think the rest of the world is catching up.

The U.S.

definitely has a little bit of progress to go before we reach the level of Canada and the U.K., but we can see that these stewardship practices actually work.

So, the rates of infection for places that have these kind of principles in place versus those that don't are very drastically different.

– Sarah: Mm-hmm.

- And so, so yeah, I think it's more of a public awareness issue at all levels.

So, not just the general public, but those that are going to be making these policies, those that are in politics.

- Yep, yeah, one of the things I didn't mention in my talk, I mentioned the symposium that we do in Green Bay, here, and other institutions do them too.

We also have our students doing social media campaigns, for example, during World Antibiotic Awareness Week to help get the message out with the tools and the concepts that they've learned in the Tiny Earth curriculum, yeah.

Well, since the theme here is productive failure, how about we talk about the role of failure in science as something that helps us to advance discoveries, but also in terms of the next generation learning how to fail productively.

- Sure.

- Yeah, what are your thoughts on that?

- Well, it's an interesting phrasing because I think failure is science.

So, like, the scientific method and the way that we approach designing experiments is you have an idea, you think you know how it works, but you're not really sure.

And then, you try your damndest to disprove that idea, right?

And so, failure or being wrong about your hypothesis is inherent to the scientific process.

I guess another way to interpret failure is, you know, unexpected results or something that you didn't, you weren't necessarily looking for.

But it's difficult to explain and you're not sure yet how it works.

For me, I see that as extremely exciting.

And that's where the frontiers of science are.

If you don't know how something works, then it's our job as scientists to try and figure out how it works, even if we were wrong about that initial guess.

- So, are you optimistic that we can stay ahead of antimicrobial resistance, and what breakthroughs or discoveries would make the biggest difference in the next decade or two?

- So, I'm very optimistic.

I think, over the last 20 years, we've really accelerated the development of new technologies that are just in the last five years now getting implemented for this problem of antimicrobial resistance.

And so, we're kind of, I think, at a, not a golden age of antibiotic discovery, but a golden age of data integration.

And so, you know, all of the different breakthroughs to generate lots of data, but also using artificial intelligence to make sense of all of that data, we're really at the cusp of right now.

And so, that's, you know, continued funding and breakthroughs in those areas, I think, are where the major discoveries are gonna come from.

- Right, very exciting.

Do you have any suggestions for our audience members about what further reading they might do and popular science to explore this topic further?

- Sure.

Let's see.

So, one that comes to mind immediately is a book called Plucked, which is a nonfiction account of antibiotic use and misuse in the poultry, food industry.

It's a really interesting story that kind of layers in the topics that you had just brought up.

And so, how-- What is the role of policy makers?

What is the role of the different stakeholders?

What is the role of the public?

And so, that's one that kind of brings that agricultural, livestock focus into it.

I think another that I would recommend is Everything is Tuberculosis.

So, that's a book that kind of takes the perspective of a bacterial-centric view of the world that I think is really useful to think of when we're trying to solve problems at that scale.

– Sarah: Yeah, yeah, one-- I know one that I've read is called Perfect Predator by Steffanie Strathdee, I think, and that one is the story of an infection her husband got, Acinetobacter, that was resistant to every drug we have.

And I think it's an interesting example of when they started to look at alternative therapies, in particular, they were looking at what's called phage therapy, basically using viruses to treat the infection, the bacterial infection.

It's a rippin' read.

[laughs] - Yeah.

- It's very-- Yeah.

You're not sure how it's gonna end.

But it's, yeah.

All of these are nonfiction.

- Yeah, and that disease was extremely fast progressing too, If I remember right, they were just on vacation in Egypt and he was wearing the wrong kind of sandals and some sand got into an open cut, and the bacteria came along for the ride, and it was completely unfazed by antibiotics.

So, they had to engineer some viruses that selectively go after the bacteria to be able to actually treat that disease.

– Sarah: Yeah.

- So, that's one example that I didn't talk about, but, like, how we're kind of thinking as a community to get outside the box of antibiotics when they fail.

- Yep, yep, great, thank you.

I wanna thank you, Marc.

Thanks for coming.

- Thank you all.

[audience applauds]