It’s a Dangerous Business, Going into the Laboratory | Paul B. Savage | 2022

It’s a Dangerous Business, Going into the Laboratory | Paul B. Savage | 2022

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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

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