It’s a Dangerous Business, Going into the Laboratory | Paul B. Savage | 2022
It's a real honor to be with you this morning. Thank you for being here. I get a chance to share with you some of my experiences that I've had here at BYU, but I have a minor concern, and that is that many of you may be anticipating a highly scientific lecture punctuated by unintelligible slides of charts and molecular structures. And you know I get to give those types of lectures often, but today instead I'm going to talk about multiple different subjects with a minimum of scientific jargon. So if something I'm talking
about is not immediately appealing to you, I ask for you to be patient. I'll switch to something far more interesting shortly. The title of our discussion today is, “It's a dangerous business, going into the laboratory." A few weeks ago I told my research group this title and i was really pleased that at least one of them understood the reference and this is a reference to a quote from the lord of the rings so in the lord of the rings trilogy bilbo tells his nephew frodo it's a dangerous business frodo going out your door you step onto the road and if you don't keep your feet there's no knowing where you might be swept off to now of course frodo does leave his home steps onto the road and is swept off to these wonderful and heroic adventures now the same dangers exist when one steps into a laboratory by following the directions which simple ideas lead and simple discoveries lead one can be swept off into all sorts of adventures similarly by stepping into a classroom one can be swept off into adventures in new and unfamiliar paths my purpose in talking with you today is to share some of the adventures that i've been swept off to while at byu and to encourage you to think about the places to which you've been swept and also to be willing to take those first steps out your door into a laboratory or a classroom or wherever it may be that will allow you to be swept off to adventures in front of you now in describing these adventures i need to first introduce fellow adventurers and my dear wife valerie has taken to heart the charge to climb every mountain from the musical the sound of music consequently as was mentioned we've climbed most of the high peaks in utah and it's very fortunate that there are many high peaks in utah or by now we would have moved on to fording every stream the last the rest of the cast of savage adventurers is shown here and now before getting into the adventures i'd like to describe the scene and location in which these adventures have occurred what a blessing it is to be here at byu i've been here for nearly 27 years so i know a lot about the institution and the people here i've come to understand the care concern and wisdom that go into the decisions that are made here and i appreciate the selfless work of those in the administration and in staff positions i love my professor colleagues and i see their efforts to teach nurture and mentor students and i'm so very grateful for my association with these good people most of all i'm blessed to interact with the students at byu one of my greatest joys comes from seeing students with faith determination and hard work succeed in life now on to just a very simple adventure it's an early and memorable one came at byu in teaching my very first class i was a beginning assistant professor and i had only helped teach a couple of very small classes while in graduate school but now i was stepping into this huge classroom to teach 300 students organic chemistry and of course i was nervous now where should i turn for advice and comfort well my dear parents are both educators my mother taught at loop public school on the navajo nation for 25 years and my father was a professor at northern arizona university go lumberjacks for even longer than that and he served as chair of his department for years he worked with new faculty that were also learning to teach so of course i went to him with my concerns his response was rather blunt ah don't worry about it you'll be either really good or really bad wow thanks dad believe it or not that comment did take some pressure off and i successfully made it through that first class and at the end i hoped that i was at least headed toward the really good side of my father's binary teaching scale over the years i've had many pleasant and very very few unpleasant adventures teaching students from these experiences i would like to think i've become a better teacher and from these and also from observing the teaching of other professors i've learned some important lessons one of those is that there is no right way to teach there are many teaching styles that i've seen and methods that can be used effectively however i've learned that one of the most important aspects of teaching is establishment of proper motives for teaching and from my experience there are two the first is simply a love for students individually and collectively unfortunately byu students are really easy to love the second is a conviction that it what is being taught is essential for the happiness well-being and future success of the students now i'm very fortunate that i get to teach organic chemistry and chemical biology now you may be saying to yourself whoa these topics are not essential for anything in my life i would of course beg to differ let me try and convince you please think about your five senses sight smell taste touch and hearing these are of course the ways in which we experience the world and we'll consider a few of these let's start with smell we have receptors in our nasal cavities that can stick to or associate with small molecules that we find in our environment and in our food these molecules have to get up into the air to get into our noses and some of these are recognized based on their chemical structures when a molecule is recognized the signal is sent to our brain indicating the type of molecule and we interpret the signal as smell so i get to teach students why vomit smells like vomit and why bananas smell like bananas similarly we have taste buds on our tongues that associate and recognize specific molecules leading to sweet sour salty bitter and umami tastes unlike the molecules we smell molecules we taste don't have to get into the air instead they are in the food we eat and in the liquids we drink i get to teach students the types of molecules that are sweet which are bitter which are sour and so on and then my students become those people that in response to someone saying this tastes like an apple will respond it doesn't taste like an apple it smells like an apple apple is the smell not a taste they may even add that apple's smell comes from a collection of ester containing molecules now contrary to my promise some heavy scientific jargon see if you can catch any of this our ability to see comes from quantum mechanical phenomena involving filled and empty molecular orbitals absorption of photons and differences in stability of cis and trans isomers of retinaldehyde all right if you didn't get all of that it's okay but just know that i get to teach how and why our vision works even and even though the process seems complex most students are able to understand how it works and it is hard to describe the joy that comes from seeing pun intended a student start to understand how their eyes work all right finally most of the materials around us are made up of or at least coated with organic or carbon containing molecules in the form of polymers from the clothes we wear to the cushions on your seats to the finish on the floor so if you've been keeping track i get to teach about smell taste sight and the things we touch and my dear colleagues in our department get to teach about the same things now in addition we are kept alive through beautiful processes by which we digest food then metabolize the breakdown products that give us molecules that are used for all sorts of important things like muscle contraction even thinking these are improv these are processes involving organic molecules and are considered part of chemical biology now learning about these things helps us understand and appreciate the world around us and how our bodies work and i am convinced that this understanding and appreciation adds to the joy that we can feel now you may be thinking whoa this information sounds very complicated and difficult to understand turns out that most of this information is fairly simple and in one semester i get to watch students go from almost no understanding of these concepts to where they're so excited by them that they rush to tell others about what they've learned so next time you are washing your hands in a public setting don't be surprised when one of my students can't help but explain to you how soap works i hope you can understand the enjoyment that i find in teaching now let's step out of the classroom and into the laboratory where we've been swept off into wonderful paths that i would never have dreamed i would follow when i began work as an independent scientist my training through graduate school and postdoctoral research was in organic chemistry but i've been swept into immunology microbiology development of medical devices chemical manufacturing and even patent law these fields are as different as the shire is to gondor that's another lord of the rings reference if you're keeping track and if not please note that these fields are very different from one another i'd like to tell you briefly about a few of these adventures that have come because we've been swept off into these fields and when i say we i need to introduce additional fellow adventurers this is a picture of my research my current research group is comprised of graduate students working on master's and phd degrees post-doctoral researchers they already have their phds and a fulbright fellow technicians and undergraduate researchers these are truly great people and great scientists we also collaborate with great scientists at other institutions this slide shows institutions with which we actively collaborate and those with which we've collaborated in the past so i'm going to be using the pronoun we a lot but it's not the royal we it represents a large group of talented scientists all right on to the adventure let's start with a simple question what do bacteria look like and how can we kill them in other words how can the features on the outer surfaces of bacteria be used to selectively target them now you may ask why is killing bacteria important there are multiple reasons but one is simply a numbers game our bodies are made up of trillions of cells and for every cell of you you carry in and on you about 10 bacteria now bacteria are small organisms that play important roles in our health most of them that we carry are in our lower gastrointestinal tract but others are on our skin in our mouths and even in our lungs most of the time these bacteria behave themselves and help to make us healthy and possibly even happy believe it or not but that's a subject for another day but at times these bacteria that we nurture grow where they're not supposed to be and in numbers that are far beyond those they should reach at other times bacteria from our local environment start growing in and on us where they shouldn't we commonly call these processes infection and all of us have been and are likely infected to some degree so the bottom line is that it is important to be able to get rid of bacteria when necessary now we are not defenseless against bacteria our bodies make molecules that can be considered antibiotics in most of our tissues these molecules either kill bacteria or at least slow their growth they are part of our innate immune system now innate immunity is the part of the immune system that is always functioning and provides the first line of defense against bacteria fungi and viruses an important part of the innate immune system is molecules called antimicrobial peptides i know that's a big phrase but we're going to use an acronym for it amp so amp is how we'll refer to antibiotics that our bodies make now the best studied of these is called ll-37 and to give you some idea of how important ll-37 is if you do an internet search for ll-37 you will get more than 7 billion hits that's more than if you search for kim kardashian now your body makes the most ll-37 in places in which you are likely to encounter bacteria your skin your mouth your intestines your lungs even the surface of your eyes and if you didn't make ll-37 your teeth would have rotted out within a few years in some cases we don't make enough ll-37 with many injuries such as burns ll-37 is deficient and we become susceptible to infection as and with some diseases such as eczema ll-37 is not produced in normal amounts and so bacteria grow in the accompanying lesions now as an aside let me explain how ll-37 kills bacteria bacteria generally have minus or negative charges on their surfaces ll-37 as an amp has plus or positive charges as we know opposite charges attract so ll-37 sticks to bacteria but that's not all ll-37 has a shape here represented by a cylinder that causes defects to form in the membranes of bacteria those defects are enough to kill bacteria should be noted that our cells have a mixture of positive and negative charges so ll-37 does not stick to them as well as i've all mentioned we've experienced infection to some extent an infection may be considered a failure of the innate immune system so the obvious question is how can we help the innate immune system overcome potential failures a simple answer is that we could provide artificially extra ll-37 this approach has attracted some interest but it comes with challenges first making ll-37 for use as a medicine is very expensive the second challenge comes from bacteria themselves bacteria have their own defenses against ll-37 bacteria release enzymes which are active molecules that destroy ll-37 all right food for thought bacteria in your mouth regardless of your oral hygiene are releasing enzymes to destroy ll-37 right now so you make ll-37 which is in your saliva to help kill bacteria in your mouth bacteria in your mouth are fighting back by releasing enzymes they get rid of ll-37 this is chemical warfare so because bacteria fight back ll-37 doesn't uh survive very long in some important arenas for fighting one additional thought on amps we're not unique in that we make ll-37 but other organisms make amps too in fact all higher organisms do they were first discovered and studied well in frogs than in insects and then in us and there are thousands of examples all right this is all background here's where we come into the picture and where our adventure begins some years ago we looked at all of these amps including ll-37 from all of these different organisms and thought you know amps aren't that complicated we can make smaller molecules that have the same shape as amps this is one of the fun things about being a chemist we can make pretty much anything so we made molecules that have the same overall shape as amps except they're much smaller easier to make and they're not destroyed by the enzymes released by bacteria and we call this class of molecules serogenins we including many collaborators have studied the properties of serogenins for years and we find that they do the same or similar things to bacteria as amps that is they kill bacteria quickly but as an added bonus they reduce inflammation around infection sites and they accelerate healing of tissue and bones all right now you have serogenes what do you do with them how can they be used to help people how can they augment or replace innate immune responses that may be faltering to answer these questions we needed help and ultimately we needed help from experts that could develop the technology for clinical and commercial applications all right a quick sub story which doesn't paint me in a very good light soon after our first efforts with sarah jennings one of my colleagues professor morris robbins stopped by my office and asked how research was progressing i told him about our work with sarah jennings and he asked if i had talked with the technology transfer office at byu about patenting our work naively i told him that i wanted our work to be used by anyone without worry of infringing on a patent he informed me correctly that if our work was not patented no one would ever use it he explained that for our work to be helpful to people companies would need to raise and expend very large sums of money to develop the serogenin technology and only if the technology was patented would companies be willing to undertake the effort now byu has a great technology transfer office and i told the director about the serogenin technology and he agreed to file patents to protect it this costs money which came in initially from the university which owns the patents technology transfer offices at byu and at other universities advertise the technologies developed at their institutions and companies can license the technology for use and development multiple companies have licensed the serogenin technology from byu reimbursed byu for patent costs and have been developing the technology to help people and animals now multiple different avenues of development have occurred but i'd like to just share one example as i described our tissues produce amps like ll-37 as part of innate immunity to control bacterial growth however if a foreign object is placed in or on us it won't have an innate immune defense that is it doesn't make amps medical care often involves placing foreign objects in or on a patient for example with major surgery if a patient is in or if a patient is incapacitated they may be placed on a ventilator which assists and regulates breathing the ventilator machine is attached to a tube called an endotracheal tube that extends from outside the patient's mouth to into the patient's trachea as soon as this tube is placed in the patient bacteria begin to grow on the tube its surface provides a near ideal home with plenty of food and warmth and as bacteria grow on the tube they form communities called biofilms and biofilm communities grow and expand and portions are sloughed off to lead to infection elsewhere including the lungs endotracheal tubes removed from patients that have been ventilated for extended periods are typically colored green or pinkish brown by the large populations of bacteria that are growing on the tubes these populations can be above 100 million bacteria per square centimeter the problem with the tubes they have no protection they have no innate immune system the solution give them an innate immune system as protection what is the best approach use the serogenin on endotracheal tubes as an artificial innate immune system so we put a serogenin in a very thin coating on endotracheal tubes to give them their very own innate immune system now on the right here is an image of the stained coating on an endotracheal tube which is thinner than a human hair and this protects the tube for days shown in in the next slide is biofilm that forms on an endotracheal tube when it's exposed to bacteria for more than a day over the same course of time and under the same conditions the tube with the serogenin on the right shows no bacterial growth and this coating has been termed seroshield to be able to use serous shield endotracheal tubes in people they first had to be evaluated in animals i won't take you through all of the necessary testing i'll only show one image these are the ends of endotracheal tubes that were in the trachea of pigs for three days one of these is from a normal uncoated endotracheal tube the other is from a seroshield endotracheal tube can you see a difference which would you prefer to have in you in human studies performed in canada we showed that seroshield endotracheal tubes reduced bacterial colonization dramatically the bars on the left show the amounts of bacteria that grow on normal uncoated endotracheal tubes and on the right is the amount on a serous shield endotracheal tubes these tubes have been approved for use in multiple countries and further studies are underway including those necessary for approvals for use of the cereshield endotracheal tubes in the u.s and that's all i have to say about that and now for something completely different the molecules that make up the outer surfaces of bacteria are telltale signs of the presence of bacteria that is these molecules are unique to bacteria and our bodies have very well designed ways of watching for the presence of these molecules because they indicate that bacteria are present these molecules are commonly called endotoxins and when our bodies encounter endotoxins figurative alarms go off resulting in inflammation think about when you've had an infected injury the redness and pain are in part due to the response to bacterial endotoxin so not too long ago a particular type of cell from our immune system was identified that responds to endotoxin-like molecules the cell is called a natural killer t cell which is a cool name for a cell this cell type nkt cell plays a central role in the interface between the innate immune system and its counterpart the adaptive immune system i'll tell you more about the adaptive immune system in a few minutes because we were interested in the surfaces of bacteria and endotoxins we became interested in nkt cells and it turned out we were interested in nkt cells at the right time and we were swept into a collaboration with the right people groups of brilliant immunologists when nkt cells gained our interest they were only known to watch for molecules that came from marine sponges it was well recognized that these nkt cells are not in us to protect us against marine sponges so the race was on to discover the reason that all of us have these nkt cells in us and what they're watching for now i use the term race deliberately here some aspects of science are highly competitive that is there are multiple research groups working on similar projects and the race is to be the first to make discoveries to be competitive we have to have good ideas and great scientists in this race to discover why we have nkt cells we were very fortunate to have multiple full-time researchers in my group and in my collaborative collaborators groups that help us compete against other groups at byu i've worked with many graduate students and postdoctoral researchers and dr xia dang has worked on this and related projects for multiple years and made substantial contributions to work at byu and also within the immunology community around the world he's one of the most talented chemists in the world and his efforts has have pushed us to the front of this and related races on multiple occasions the race in this area began us look began with us looking for the real molecules that that these nkt cells look for we found them at about the same time as a prominent group in this in this area found them so it was a tie we published back to back papers describing our findings in the journal nature so i tell that to you as an introduction for additional work that we did we started working on optimizing molecules to stimulate nkt cells we were after a way to stimulate nkt cells using only very very small amounts of an optimized or designer synthetic molecule and to do this we performed structure activity studies let me explain how they work imagine you wanted to make the very best chocolate chip cookie and to do this you make many many different batches of cookies and for each new batch you change one ingredient slightly maybe one as an extra egg one as an extra tablespoon of flour after you make all of these batches you taste them all and identify the best recipe we do something similar with molecules called structure activity studies we make many many different molecules that are varied slightly and then we test them all and find the best one we did structure activity studies with molecules that stimulate nkt cells and found an optimized molecule that stimulates nkt cells at extremely small amounts of material this molecule has been given the name abx-196 and if you had the the amount of this molecule equivalent to a medium-sized apple you could stimulate the nkt cells to their maximum level in over 1 billion people so a small bag of apple equivalents of this molecule could dose everyone on the planet so now what do you do with a super potent molecule that stimulates nkt cells it turns out that nkt cells can be very useful in fighting cancer i won't go into all the details of how this works it's a lot of immunology but this molecule abx-196 was shown to be exceptional at treating cancer models in ant in animals so abx 196 was licensed from byu university of chicago and scripps research institute by a company called abbyvox this company has taken abx-196 into human clinical trials for the treatment of liver cancer and results were recently reported reported they're highly favorable and the company is working on getting approvals for this compound to be used to treat cancer in patients in the us and in europe all right now for something else completely different first a short primer on adaptive immunity remember that we have innate immunity amps ll-37 we also have adaptive immunity and as the name suggests it's able to adapt to the types of disease we may have for example if we get a coronavirus innate immunity is supposed to blunt the infection while adaptive immunity builds the tools to rid us of the virus and it takes time for adaptive immunity to adapt to the virus sometimes days this is why when we get sick with a respiratory virus we start to feel better after a few days that's because adaptive immunity is kicked in adaptive immunity produces among other things molecules called antibodies that help inactivate viruses and antibodies mark viruses for destruction by other parts of our immune system the very best antibodies stick very tightly and selectively to the virus that they target a primary purpose of vaccines is to induce our adaptive immune system to make good antibodies for a virus without us having to become infected with the virus adaptive immunity can also work against bacteria but it typically doesn't work very well let me explain why bacteria have evolved subtle ways to avoid allowing the adaptive immune system to generate good antibodies against them and i'll use an analogy of a matador to explain why i'm not promoting bull fighting it's only an analogy you know how this works and bullfighting the matador uses a red cape the bull charges and eventually runs at the red cape passing under the red cape and missing the matador in this analogy bacteria are the matador the red cape is a collection of molecules that bacteria produce on their surfaces and our immune system is the misdirected bowl our adaptive immune system attacks the molecules on the surface of the bacteria that is the red cape but can never really hold on they just it just runs right past so bacteria the matador remain unscathed these molecules on the surface the red cape are called capsular polysaccharides i'll use cps as the acronym and that so cps equals red cape in our analogy working with a great group of scientists we've found a way to get our adaptive immune system to get more focused in essence what we've done is to talk to we've taught our immune system the bowl not to focus on the entire cape but rather only a small portion of the cape and instead of running right through the cape to grab onto a small portion of the cape and hold on tightly once this happened friends of the bowl that is other aspects of our immune system see the bowl holding on to the matadors cape and the matador is eliminated so let's take a closer look at a bacterium and it's cps or red cape this is an image of a bacterium showing the cps molecules extending from its surface these hair-like projections are the cps and they're what keep our adaptive immune system from tower getting bacteria well so how can we effectively train the bowl not to run through the red cape that is how do we get our immune system to bind to the cps made by bacteria well we do the following step one we make a small part of the cps or the red cape instead of sewing the whole thing just a small portion we have to do this in the laboratory and it's very challenging step two is we attach that small piece of the cape or cps to a bigger molecule that looks like a virus step three we add a molecule similar to abx-196 to stimulate nkt cells step four we inject this combination which is a vaccine into mice and let their adaptive immune systems go to work the result great stunning unprecedented antibodies that bind to the cps of bacteria that is the bulk quits running through the cape holds on tighter than has ever been seen before now the challenge with this approach different types of bacteria produce different types of cps in other words different matadors hold up different kinds of cape so we have to train the adaptive immune system to hold on to these different types of cps or capes this means a lot of work and a lot of fun in this image i'm showing in in this slide i'm showing you the image of an antibody that is binding to the cps of a type of bacteria that causes pneumonia in humans the cps part is represented by the yellow and red tubes and the antibody is the great part we have learned now that we can target the cps of any type of bacteria that is we can train the bowl to hold on to the cape of any matador now the intent of this research is to generate ways of treating bacterial infections without having to use broad spectrum antibiotics if a patient has an infection the type of bacteria causing the infection can be quickly determined and then antibodies that specifically bind to the infectious bacteria will be administered these antibodies target only the infectious bacteria and leave the other bacteria in the patient alone we believe that this approach is how infections will be treated in the near future all right today i've described some of the adventures that i've been swept off to by stepping into the laboratory or classroom as a beginning and nervous assistant professor just starting at byu and trained only in organic chemistry i would have never dreamed of the opportunities i've had in chemistry microbiology immunology and drug development and i am excited about where our work is going and through all of these adventures i've had the chance to work with groups of wonderful talented and creative people by watching countless students here at byu use their education to be swept into great adventures and from my own experience i'm convinced that our father in heaven has planned adventures for each of us through no worthiness of my own i have felt guided and encouraged many many times as i've been swept into new areas of inquiry these experiences have strengthened my faith that our father lives is aware of us and he gives us purpose in our lives he loves us so much that he sent his son to live and atone for us so that even when our adventures don't work out the way we want from struggling in a class to not having a grant proposal funded to more serious challenges that we all face our savior provides comfort and guidance thank you for letting me share some of my adventures with you and i wish the best as you're swept off into your own adventures i'm pleased to share this message with you in the name of jesus christ thank you you
2022-05-28 17:07
