Ending the Arms Race with Infectious Diseases
“It is now time to close the book on infectious diseases and declare the war against pestilence won.” It’s something that we all want. We all want to live in a world free of infectious diseases. Think about when you watch movies like Contagion or Outbreak, or when you watch the news coverage on the Ebola virus, or more recently the Zika virus.
How did seeing those things make you feel? They freaked you out, right? Infectious diseases invoke legitimate feelings of fear in every single one of us, because none of us are free from the threat of contracting an infection.
The quote that I began with is from the US Surgeon General from the 1960s. He made this statement in response to the success of early antibiotics. It’s a statement that accurately reflects the overall sentiment of the time, which is that, because we had such great success with the early generation antibiotics, infectious diseases were soon going to become a worry of the past.
I want to tell you about one person’s war against an infection that took place just last year, and that’s my dad’s. In January of 2015, my dad became very sick. It took the doctors a few weeks to figure it out, but they realized that he had gallstones, and that he would need to have his gallbladder removed.
That diagnosis was a relief to all of us, because gallstones are very common in the United States. Gallbladder removal surgery is one of the most commonly performed surgeries in the country. This was standard operating procedure for his doctors. We couldn’t imagine that anything serious could possibly go wrong.
Actually, nothing serious did go wrong with his surgery. It went quite well. He was discharged from the hospital. But 12 hours after his discharge, my mom sent me a text. It said, “He can’t walk. I have to call an ambulance. I don’t know what’s wrong.” My family is up in the Bay Area. I was down here in San Diego when this happened.
My sister was communicating to me from the ICU my dad’s symptoms. I’m the only biologist in my family, so you can imagine how confused they were. How could, 12 hours ago my dad be perfectly healthy and discharged from the hospital, and now he’s laying paralyzed in a bed in the intensive care unit?
After I heard his symptoms, I knew exactly what had happened. My dad had sepsis. If you don’t know what sepsis is, this is a life-threatening condition that occurs when your body’s response to an infection is so powerful that it begins damaging its own tissues and organs. It’s pretty much a death sentence. It has mortality rates greater than 80%. I dropped everything. I had to rush home. I had to get to the hospital to be with him and talk with his doctors.
It felt like I couldn’t get there fast enough. First, my flight was delayed. Then I had to battle Bay Area traffic for over two hours. I was certain that he was going to be gone by the time that I got to the hospital. But he wasn’t. When I walked into his room in the ICU, my dad waved to me. He gave me one of his classic thumbs up that I had seen 1,000 times growing up.
The doctors confirmed that he did have sepsis. His gallstones went undetected for so long that his gallbladder became infected. From there, the bacteria spread into his bloodstream, and then infected his vertebrae. That caused his paralysis. It was his body’s response to the bacteria being in the blood that caused him to have sepsis.
The treatment strategy proposed by his doctors was really the only option they had available. To administer broad spectrum antibiotics and to hope for the best. I sat there for a week with my dad. I can remember obsessively watching his vital monitors, hoping that the next blood pressure read was going to be higher or the next ventilator read was going to be lower. I was looking for any indication that the infection was responding to the antibiotics.
But the numbers never got better because he had an antibiotic-resistant infection, making the only strategy that was available to him completely useless. After nine days, my dad lost his war against an infection and he passed away. It’s because of the global spread of antibiotic resistance and our current strategies for treating infectious diseases that my dad died, and that we’re further away than ever from closing the book on infectious diseases.
But why? If we really had such great success with the early generation antibiotics, how is it possible that we screwed things up so badly, that we’re now in far worse condition than we were 50 years ago? The main issue is our perspective on how we should be dealing with problems.
When we’re faced with a challenge, we think that, in order to solve that challenge, we have to annihilate the source of the problem. If you have a mouse in your house, you set traps to try to kill that mouse. If you have a weed in your yard, you spray toxic chemicals all over your yard to try to kill that weed and prevent new ones from coming in.
Infectious diseases are no exception to this mentality. All of our current strategies to fight infectious diseases are based on the question, how do we fight infections? As a result, we’ve declared a war against infectious diseases. We’ve put all our efforts into developing weapons in the form of antibiotics and antivirals in order to win this war.
But bacteria and viruses are incredibly slippery targets. They can evolve so quickly resistance to our weapons, making them obsolete. So what do we do? Our solution has been to make more weapons. Make more antibiotics. Make more antivirals. It’s not surprising that the microbes have evolved resistance to our new weapons.
Our perspective is fueling an ever-escalating arms race between us and infectious diseases. The scary fact is, it’s an arms race that we can never win. The second issue, in addition to driving drug resistance, is that there is a fundamental issue with this perspective if we want to develop therapies that will enable a patient to survive an infectious disease.
To help you understand what I mean by this, I want to continue with the war analogy. In an actual war, there is combat between soldiers. But that combat does not occur in isolation. Something that can happen is what’s called collateral damage of war, which is the unintentional or incidental damage that can occur to civilians, property, economy and the society.
The same principle can be applied to an infection that’s occurring in a patient’s body. If we have a septic patient, there is going to be bacteria, virus or even fungus that has entered their bloodstream. Their immune system is going to recognize that foreign invader. It’s going to mount a killing response to try to fight that infection.
But that fight is not occurring in isolation. What happens is, every other physiological system in the patient’s body becomes damaged. The liver, the kidneys, the intestines, lungs, cardiovascular system all get damaged. You can give a septic patient antimicrobials and they might be effective at killing the infection, but you’re left with a patient that has suffered extreme collateral damage to their body.
For my dad, even if his infection was sensitive to the antibiotics, the likelihood of him surviving was very low because he suffered so much physiological damage from the infection. What he needed were therapies that would fix that physiological damage, but he wasn’t given any drugs that do that, because those drugs don’t exist. This is because we haven’t been approaching infectious diseases from the right perspective.
If we’ve been asking the wrong question, what is the question that we should be asking? Instead of asking, “How do we fight infections?” we should be asking, “How do we survive infections?” I know that single word change from “fight” to “survive” seems simple. But by making that single change, we’ve completely changed the meaning of the question.
If we can understand the answer to this question, we will completely change the way we treat infectious diseases. We will be able to develop drugs, therapies and strategies that will enable a patient to survive an infection without driving drug resistance in the microbial populations. These drugs will be fixing the collateral damage that’s happened in the patient’s body rather than targeting the microbe that’s causing the infection.
I became very interested in this question, how do we survive infections, when I was getting my PhD at Stanford about 10 years ago. We all know that our bodies have an immune system. This immune system is important for recognizing microbes that are invading our body. It’s important for mounting a killing response against these microbes to fight the infection.
We found that, in addition to our immune system, our bodies encode a distinct defense system that we call the Tolerance Defense System. This Tolerance Defense System is absolutely necessary for our ability to survive infections. It protects us from mortality by preventing and fixing the collateral damage that happens to our bodies during infectious diseases.
This is really exciting. It means, if we can find out how this Tolerance Defense System is working in our bodies, we can change the way we treat infectious diseases. We will be able to develop therapies that overcome the limitations of current strategies that are available. We can develop strategies that promote survival without driving drug resistance.
How do we go about doing this? This is a main goal of my team at the Salk Institute. We’re committing to understanding this Tolerance Defense System so that we can make this a reality. We take a variety of approaches to address this goal.
One of our main approaches that we’re really excited about, and that we’ve already been successful with, is leveraging our interactions with beneficial microbes. Right now, all of you have about three pounds of bacteria that are living on your body surfaces exposed to the environment. If we sprinkle in some viruses and fungus, now you have your microbiome. Your microbiome is absolutely essential for your health.
We have evolutionary theory that has led us to predict that the microbiome has evolved mechanisms to turn on our Tolerance Defense System. It can effectively manipulate this defense system to promote our health. We’re using the microbiome to teach us how to turn tolerance defenses on, to teach us what they are, and how to manipulate them to promote health. We’re using these microbes as platforms for drug design so that we can move this into the clinic.
For example, we’ve recently identified an e. Coli that lives in the intestines of healthy individuals. This e. Coli has taught us that we can cure infectious diseases by mediating communication between our immune system, fat tissue and skeletal muscle, by preventing collateral damage in the form of skeletal muscle wasting.
In pre-clinical trials, by orally administering this e. Coli to model patients, we can cure sepsis, bacterial pneumonia, typhoid fever and infectious diarrhea without the need for a single antibiotic. I think that’s amazing. I think it’s exciting. I think it opens up a promising future for our ability to treat and cure infectious diseases.
My lab will continue to do this. We’re committed to it. But we can’t do it alone. We’re all vulnerable to the threat of contracting an infectious disease. We’re all terrified of that threat.
But if you leave here with one thing today, I want you to leave here believing that there’s hope to get us out of the mess that we got ourselves into. The first step to this is changing our perspective and going from, how do we fight infections, to how do we survive infections. All of you, doctors, scientists, healthcare officials, drug companies, need to make that perspective shift. We have the technology and knowledge to do it. We have to make that shift. Only then will we truly be able to close the door on infectious diseases and end the war against pestilence. Thank you.