GOOD AFTERNOON. WELCOME TO ETHICS GRAND ROUNDS. I'M THE CHIEF OF THE DEPARTMENT OF BIOETHICS HERE AT THE CLINICAL CENTER. I'M HERE TO TELL YOU THAT THIS IS A SPECIAL ETHICS GRAND GROUNDS FOUR TWO VERY IMPORTANCE REASONS. FIRST, TODAY IS OUR SECOND ZEK EMANUEL GRAND ROUNDS. HE WAS WITH US FOR OVER A DECADE, WHEN HE LEFT THE NIH, WE DECIDED TO NAME AN ANNUAL ETHICS GRAND ROUNDS IN HIS HONOR. ERNIEALTHOUGH ALL OUR ETHICS GRAND ROUNDS ARE SENSATIONAL, THE EMANUEL ETHICS GRAND ROUSE IS MEANT TO HIGHLIGHT AN INVITED SPEAKER ON PRESSING ISSUES IN BIOETHICS. HENCE, THE SECOND REASON THAT THIS ETHICS GRAND ROUNDS IS THIS SPILL IS BECAUSE OF OUR INVITED SPEAK ERR. WE ARE HONORED TO HAVE DR. HOWARD HOGAN. THE PRESIDENT OF THE INNOOHOURVY FEINBERG. HE WAS SOON COMPLETE HIS SECOND VERY SUCCESSFUL TERM AS IOM PRESIDENT. AND NEXT YEAR WILL BE PRESIDENTIAL CHAIR AT UCSF FOCUSING ON GLOBAL HEALTH. DR. FEINBERG RECEIVED HESS MD AND Ph.D. IN PUBLIC POLICY FROM HARVARD. HE WAS FORMALLY THE DEAN OF THE SCHOOL OF PUBLIC HEALTH AND PRO HOST AT HARVARD. HIS CAREER HAS BEEN DEVOTED TO HEALTH POLICY AND MEDICAL DECISION MAKING. DR. FEINBERG HAS PLAYED AN IMPORTANT AND INFLUENTIAL ROLE IN AMERICAN HEALTH POLICY, ESPECIALLY FOCUSING ON ISSUES OF VACCINE USE, AIDS PREVENTION, PANDEMIC PREPAREDNESS, CLINICAL DECISION MAKES AND THE USES OF MEDICAL TECHNOLOGY. HE AUTHORED AN IMPORTANT BOOK ABOUT THE SWINE FLU IMMUNIZATION PROGRAM OF 1976 AND CHAIR ADD COMMITTEE THAT EXAMINED THE WORLD LEGITIMATE ORGANIZATION HANDLING OF THE 2009 H1N1 SWINE FLU EPIDEMIC. HE HAS A RECENT PAPER IN APRIL, 2014 IN THE "NEW ENGLAND JOURNAL OF MEDICINE" ON PANDEMIC PREPAREDNESS AND LESSONS LEARNED FROM THE H1N1 PANDEMIC. IT'S A SEMINAL PAPER WE SHOULD ALL READ. IN 2012 HE CHAIRED AN INTERNATIONAL CONSULTATION ON THE CONTROVERSIAL H5N1 AVIAN FLU GAIN OF FUNCTION STUDIES, AND IMPORTANT CONSULTATION WHICH INFORMED NIH AND DHHS POLICIES ON DUAL USE RESEARCH OF CONCERN. WE ARE HONORED AND GRATEFUL TO DR. FEINBERG FOR TALKING WITH US TODAY ABOUT DUAL USE IN A SLIGHTLY DIFFERENT WAY, DUAL USE RESEARCH ETHICAL CHALLENGES OF ACADEMIC MEDICINAL CHEMISTRY. NOW I'M GOING TO TURN IT OVER TO DAVID WENDLER 450 ORGANIZES OUR ETHNICS GRAND ROUNDS. -- ETHICS GRAND ROUNDS. >> THANK YOU. SO JUST A COUPLE OF REMINDERS ABOUT THE WAY ETHICS GRAND ROUNDS WORKS. ONE, THESE ARE SESSIONS STREAMED ON TO THE WEB. WE RECENTLY GOT DATA THAT ABOUT 125 TO 150 PEOPLE WATCH THESE LIVE. THEY DO MUCH BETTER IF THEY CAN HEAR THE QUESTIONS ALONG WITH THE ANSWERS, SO WHEN WE GET TO THE QUESTION SESSION, IF WE -- WE ENCOURAGE QUESTIONS, GOOD QUESTIONS ARE WHAT MAKE THESE SESSIONS GO AND INTERESTING. IF YOU CAN GET TO ONE OF THE AISLE MICROPHONES BEFORE YOU ASK THEM, THAT WOULD BE GREAT. IF YOU PAUSE FOR A SECOND, ONE OF US WILL REPEAT THE QUESTION BEFORE IT GETS ANSWERED. THESE ARE ALSO ACTUAL CASES. FOR PEOPLE WHO HAVE BEEN COMING TO THESE FOR A WHILE, REALIZE, BUT THE VIEWS EXPRESS RESIDENT THE VIEWS OF THE INDIVIDUALS WHO EXPRESS THEM, NOT THE VIEWS OF ME, NOT THE VIEWS OF CHRISTINE. NOT VIEWS OF OUR DEPARTMENT, THE CLINICAL CENTER, OR THE NIH. IN GENERAL. LAST THING IS THAT THIS IS THE FINAL ETHICS GRAND ROUNDS FOR THE SPRING. WE START UP AGAIN IN THE FALL. AND FOR TODAY'S SESSION, WE'RE GOING TO TALK ABOUT HOW TO PUBLISH, HOW NOT TO PUBLISH WHAT, THE CONDITIONS ON PUBLISHING SHOULD BE. AND WHAT SHOULD I ASSUME BE RELATIVELY OBVIOUS AND STRAIGHT FORWARD IS THAT 2 THE VALUE OF THE MEDICAL AND SCIENTIFIC LITERATURE PRESENTATIONS, DISCUSSIONS, DEPENDS CRUCIALLY ON THE COMPLETENESS AND THE ACCURACY OF THEM. SO IF WE PUBLISH THINGS IN MEDICAL JOURNALS THAT AREN'T COMPLETE, THAT LACK IMPORTANT DETAILS, IMPORTANT PROCESSES, OR IF THEY'RE IN INACCURATE AND THEY DESCRIBE THINGS IN INCORRECT WAYS, COULD HAVE EXTREMELY DELETERIOUS CONSEQUENCES. THERE IS AN ENORMOUS FOR GOOD REASON EMPHASIS ON BEING COMPLETE AND ACCURATE. NOW, IF THAT'S ALL THERE WERE TO IT IT WOULD BE RELATIVELY STRAIGHT FORWARD. BIOETHICS, YOU COULD SAY BEGINS -- THE REASON TO HAVE A DEPARTMENT OF BIOETHICS AT THE NIH CLINICAL CENTER, BEGINS BECAUSE THERE IS MORE THAN ONE THING THAT TENDS TO BE IMPORTANT IN A LOT OF CASES. ACCURACY AND COMPLETENESS IS ONE THING, IT IS AIMPORTANT -- THERE ARE OTHER THINGS THAT ARE IMPORTANT. SO FOR PEOPLE THAT KNOW, WE TRY TO PUBLISH A NUMBER OF THESE GRAND ROUNDS AND WHAT WE TEND TO DO AS PEOPLE WHO HAVE BEEN HERE KNOW, IS WE'LL MASK THE CASES IN VARIOUS WAYS FOR THE SAKE OF CONFIDENTIALLY. SO I'LL CHANGE A WOMAN TO A MAN WHEN IT DOESN'T MATTER. I'LL CHANGE JOE TO FRANK, GIVE SOMEBODY THREE SIBLINGS RATHER THAN FOUR. WHEN IT DOESN'T MATTER, JUST TO MASK THE PERSON'S IDENTITY AND FOR REASONS OF CONFIDENTIALLY. BUT OUR PURPOSES -- THAT TENDS TO MAKE SENSE. WHEN I SUMMIT THAT TO MEDICAL JOURNALS, THEY DON'T LIKE THAT. THAT'S NOT ACCURATE. THAT'S MAKING THINGS UP, GIVING INACCURATE DETAILS. THEY DON'T LIKE TO PUBLISH THINGS WITH INACCURATE DETAILS SO THEY TEND TO REQUIRE THAT WE GIVE AN ACCURATE ACCOUNT. WE SAY THE PERSON'S REAL NAME, WHERE THEY REALLY CAME FROM, HOW MANY SIBLINGS THEY READ HAD. SO THAT'S ACCURATE BUT UNDERMINES TO A VERY SMALL EXTENT THE PERSON'S CONFIDENTIALLY, ALSO, MAYBE FOR FUTURE ETHICS GRAND ROUNDS MAKES IT HASHEDER TO DO ETHICS GRAND ROUNDS ON BAD CASES. YOU HAVE THE PERSON THAT DOESN'T LOOK SO G YOU WANT TO GET THEIR PERMISSION TO PUBLISH THE CASE. THEY'RE NOT ENTHUSIASTIC ABOUT THAT. SO THAT'S ONE OF THE WAYS THERE CAN BE CONFLICTING INTERESTS OR CONCERNS OR VALUES WITH COMPLETENESS AND ACCURACY. ANOTHER ONE IS WHAT WE'RE GOING TO DISCUSS TODAY WHAT, PEOPLE CALLED DUAL USE RESEARCH. CASES WHERE WHAT YOU PUBLISH MAY HAVE THE POTENTIAL FOR SOMEBODY ELSE TO TAKE THOSE RESULTS, IF THEY'RE COMPLETE AND ACCURATE, USE THEM FOR MALIGN OR NEFARIOUS PURPOSES. THE QUESTION IS, WHAT TO DO TO TRY TO REDUCE THAT POTENTIAL. DO YOU TRY TO CHANGE WHAT YOU REPORT? TRY TO CHANGE HOW MUCH YOU REPORT? SHOULD SCIENTISTS WHO GIVE PRESENTATIONS CHANGE THEIR PRESENTATIONS TO JOURNALS CHANGE WHAT THEY PUBLISH? THAT'S THE QUESTION FOR TODAY, AND TO LEAD US WITH A CASE IS AIDAN H.MSON. HE HAS WORKED FOR A FARM CUTICLE COMPANY, HE HAS WORKED AS A MARINE BIOLOGIST AND TOXICOLOGIST, AND HAS WORKED IN JULIE AXELROD'S LAB AT NIH, CANNABINOIDS AS ANTIOXIDANT AND NEURO PROTECTANTS. HE CAN AREA GOING TO START US OFF TODAY SO WELCOME AIDAN. [APPLAUSE] I'M GOING TO RUSH THROUGH THE FIRST FEW SLIDES, WE DON'T HAVE MUCH TIME AND THERE ARE PEOPLE THAT GOMORE THAN I DO. THESE ARE MY OPINIONS, NOT THE OPINIONS OF THE NATIONAL [INDISCERNIBLE] ON DRUG ABUSE. THESE ARE THE GOALS. THE NATIONAL SCIENCE ADVISORY BOARD IS A FEDERAL COMMITMENT THAT LOOKS AT DUAL USE RESEARCH AND SEEKS TO PROVIDE GUIDANCE. THEY DEFINE IT AS BIOLOGICAL RESEARCH WITH LEGITIMATE PURPOSES THAT CAN BE MISUSED AND WITH PROBLEMS TO PUBLIC HEALTH AND NATIONAL SECURITY. AND OR NATIONAL SECURITY. IN 2007 THIS CATEGORIZED A LOT OF RESEARCH UNDER THIS DUAL USE RESEARCH HERE. IT WAS MAINLY FOCUSED ON BIOLOGICAL AGENTS AND TOXINS. NOBODY HAS REALLY TALKED ABOUT SMALL MOLECULARS, GENERALLY NOT CONSIDERED IN THE REALM OF DUAL USE RESEARCH. I'D LIKE TO ADDRESS THAT. AS WE KNOW, THE -- IN 2011 THE RESULTS CAME OUT ABOUT THE H5N1 FLU VIRUS. THERE WERE A COUPLE RESEARCHERS THAT WANTED TO PUBLISH AT THIS TIME ABOUT MUTATIONS THAT COULD IMPROVE TRANSMISSION. THIS IS VERY IMPORTANT FOR UNDERSTANDING PANDEMICS BUT IT HAS POTENTIAL MISUSE. ONE OF THE PAPERS WAS PUBLISHED IN FULL, CONSIDERED THAT IT WASN'T IMMEDIATELY ENABLING. INITIALLY, THE CONCERN WAS THE SECOND ONE, THAT IT MIGHT BE MORE IMMEDIATELY ENABLING AND MIGHT CAUSE -- IT DIED IMMEDIATELY. THAT WASN'T ENTIRELY DIED BUT HE HAD TO ADJUST WHAT HE PUBLISHED. THE ROYALTY OF NIDA, GETTING BACK TO WHAT WE DO HERE S CONDUCTING RESEARCH IN THE FIELD OF DRUG ABUSE. AND OUR MISSION TO ENSURE EFFECTIVE AND RAPID DISSEMINATION OF RESEARCH RESULTS WITH REGARDS TO DRUG USE AND THE MECHANISMS UNDERLYING THAT. SO THERE IN COMES INTO THE STORY THAT I'M GOING TO TELL. I'M GOING TO GIVE OWN EXAMPLE HOW ONE PAPER WAS PUBLISHED. MEDICINAL CHEMISTRY. TWO CAB NOWED RECEPTORS EXIT. ONE FOUND IN THE BRAIN, CONTROLS MEMORY, WHICH PEOPLE TAKE THC, SMOKE MARIJUANA TO GET HIGH. THE SECOND ONE IS MAINLY PREFERERAL, NOT INVOLVED IN GETTING YOU HIGH. SO ONE GROUP WAS ASKING WHAT DOES IT DO? HOW CAN WE DEVELOP PROBES FOR THEIR SYSTEM? AND SOME THEY WANTED TO DO A PROBE FOR A DRUG SPECIFIC FOR CB2. IS TO TART WITH THEY STARTED WITH A LEAD COMPOUND, A COMPOUND THAT BINDS TO CANNABINOID RECEPTORS, AND THIS WAS THE COMPOUND THEY STARTED WITH. NEXT YOU NEED TO SAY WHAT IS IT WE WANT TO IMPROVE TO GET AT TO THE GOAL, IN OTHER WORDS, DRUG SPECIFIC TO CB2. THE WISH LIST INCLUDED REDICE INTERACTION, INCREASE WATER SOLUBILITY. INCREASE THE LENGTH OF TIME IT STAYS IN THE BODY, NO POINT IN HAVING SOMETHING THAT IS THERE AND GONE. AND IMPROVE DERATES AT WHICH IT'S TAKEN UP FROM THE GI AND GETS TO THE SITE OF INTEREST, IN THIS CASE, INTO THE BRAIN. THAT'S WHAT CB1 IS AND THEY'RE AIMING FOR CB2. THESE WERE THE SPECIFIC THINGS THAT THEY LOOKED AT INITIALLY TO TRY TO INCREASE THE SPECIFICITY FOR CB2 AND ENCLOSE WATER SOLUBILITY. THEY STARTED WITH A MOLECULE. AND THEY HAVE TWO AREAS WHICH THEY'RE AIMING AT ALTERING TO TRY TO INCREASE WATER SOLUBILITY AND INCREASE SPECIFICITY. TO TO THAT, THEY DEVELOPED A BUNCH OF DIFFERENT DERIVATIVES WHICH EITHER HAVE DIFFERENT MOLECULE ATTACHED TO X OR R1 THERE. AND THE CATEGORIES HERE'S SEEING HERE, THE FOUR CATEGORIES. NOW, THEY HAD THIS ANTAGONIST WHICH WAS AROUND BUT IT'S REALLY INSOLUBLE, SO THEY WERE TRYING TO IMPROVE ON THAT. AND THEY CAME OUT WITH THREE MOLECULES THAT LOOKED PROMISING. THEY GOT GOOD AREA FINTY, BETTER WATER SOLUBILITY, THIS ONE WHICH IS THE BEST ONE HAS GOT WORST WATER SOLUBILITY. THIS IS A STUDY THAT THEY DID. THEY PUBLISHED THIS. THIS INFORMATION AS TO WHAT THEY HAD ACHIEVED AND -- IN THE NEW PROBE TO CB2. CHEMISTRY PUBLICATIONS SUCH AS THIS DESCRIBE THE CHEMICAL STRUCTURE, DESCRIBE HOW TO SYNTHESIZE THEM. EVEN DESCRIBE THE STRUCTURE ACTIVITY RELATIONSHIP, THAT THAT'S TABLE I JUST SHOWED YOU AROUND THE LEAD COMPOUND. OCCASIONALLY THEY MAY INCLUDE SOME BEHAVIOR, A READOUT OF THE ACTIVITY, THE RECEPTOR THEY'RE INTERESTED IN. WHAT THEY DON'T COVER IS THE TOXICOLOGY, THE OFF TARGETS EFFECTS, HOW TO THEY INTERACT WITH OTHER DRUGS THAT YOU TAKE AT THE SAME TIME? OBVIOUSLY, THESE WERE DEVELOPING A PROBE FOR THIS CB2 RECEPTOR. THEY DON'T ADDRESS ANY OF THESE THINGS. WHY WOULD THEY. >> WELL, THAT WAS THE THEORY, UNTIL 2008 WHEN A NEW BUSINESS MODEL CAME OUT AS WE CAN SEE HERE, BLOOMBERG BUSINESS WEEK. FAKE POT, REAL PROFITS. MEDICAL RESEARCH WAS BEING USED BY LESS THAN LEGITIMATE INDIVIDUALS TO MAKE A DOLLAR. AND THE POINTS OF THIS BUSINESS MODEL, TO USE THE CHEMISTRY LITERATURE. THE STUFF WE'RE PUTTING OUT THERE IN TERMS OF LEGITIMATE SCIENCE TO PROVIDE NEW MARKETABLE RECREATIONAL DRUGS, THEY WANT SOMETHING THAT'S HIGHLY POTENT, NOT READILY DETECTED IN NORMAL EUROPEAN AREA SAYS. ONE -- EUROPEAN ASSAYS. SO THIS IS ANOTHER ATTRACTION FOR PEOPLE WANTING TO TAKE SYNTHETIC MARIJUANA. IT CAN'T NECESSARILY BE IDENTIFIED EASILY. IT'S NICE IF YOU HAVE COMPOUNDS NOT EXPLICITLY SCHEDULE ONE, THERE THEREFORE YOU DON'T HAVE THE THEM BANGING ON YOUR DOOR WHEN THEY KNOW YOU HAVE IT. BECAUSE OF THE PAPERS PUBLISHED, YOU CAN MOVE FROM COMPOUND TO COMPOUND FAIRLY RAPIDLY, WHILE THE SAME IS NOT REALLY TRUE OF THE LESS OLEGISLATION. THIS SYNTHETIC MARIJUANA EXPORTED TO THE U.S. AND EUROPE IN 55-GALLON DRUMS. THEN SPRAYED ON TO ANY BASIC PLANT MATERIAL. AND MARKETED AS K2 SPICE. OWNED YOU CAN BUY THESE OVER THE WEB, YOU CAN BUY THEM AT GAS STATIONS. NOW, THE DEA IS HAVING A PROBLEM WITH THIS. THIS IS ALL OF THE COMPOUNDS THAT THEY HAVE BANNED IN THE LAST THREE YEARS. THERE IS 11 OF THEM. AS YOU CAN GUESS FROM THE TABLES I WAS JUST SHOWING YOU, YOU CAN EASILY STAY AHEAD OF THIS. THIS IS A BIG CONCERN FOR THE DEA. THEY CAN'T KEEP UP, ALWAYS CHASING TO CATCH UP HERE. NOW, THESE SITES THAT SOLELY STAY LEGAL BY SAYING THEY'RE NOT INTENDED FOR HUMAN CONCEPTION. THEY MARKET THEM AS INNOCENCE. HERBAL INNOCENCE. HERE IS ONE -- INNOCENCE. BECAUSE THEY'RE NOT MARKETED FOR HUMAN CONSUMPTION, YOU CAN'T SAY HOW POTENT THEY ARE. THEY TALK ABOUT COLLECTING EXPERIENCE, A MEDIUM POTENCY COLLECTING EXPERIENCE IN THIS CASE WITH THIS DRUG. NOW, THIS USE OF SYNTHETIC MARIJUANA IS VERY, VERY COMMON. AND YOUNG MARIJUANA USERS IN PARTICULAR, IF YOU LOOK AT -- THIS IS 2013 RESULTS, OF THOSE THAT USED MARIJUANA IN 89-12 GRACIOUS I SEE 25% ARE USING THIS SYNTHETIC MARIJUANA. AND THE COMPOUNDS IN THERE ARE NOT TESTED FOR TOXICITY. NOT SUBJECT TO ANY FDA CONTROLS IN THE MANUFACTURE. AND SO THAT THEY BECOME A REAL PROBLEM. BUT MARIJUANA, SYNTHETIC MARIJUANA IS NOT THE ONLY TIME WHERE WE'VE HAD THE ISSUES OF LEGITIMATE RESEARCH ENDING UP IN DRUGS THAT ARE ON THE MARKET LANDAUSING HARM. DAVID NICKELS, WHO IS AN MDMA RESEARCHER. PRODUCED AN EDITORIAL IN 2011 IN WHICH HE PUBLISHED IN NATURE LOOKING AT ONE OF THE COMPOUNDS THAT THEY HAVE BEEN LOOKING AT, TREATMENTS OF DEPRESSION. AND HE SAID HERE, MD WILL TA WAS SYNTHESIZED. SOME OF THE BEAM THAT TOOK IT DIED. HE WAS STUNNED AND DISTURBED THAT PEOPLE DIED. ANOTHER FAMOUS CASE, THE FROZEN ADDICT. THIS WAS 1982, SOME DEMEROL, AN ANLING OF DEMEROL WAS MADE, AND THE COMPOUND WAS CALLED MPPP. WITHIN A FEW DAILIES, ALL THESE FOUR USERS TELEPHONED PARKINSON DISEASE -- DEVELOPED PARKINSON DISEASE. THE COOK HAD NOT CLEANED UP PROPERLY AND IT CONTAINED A DERIVATIVE CALLED MPTP, WHICH WAS TAKEN INTO THE NERVE CELLS, AND DESTROYED THEM. ULTIMATELY THE CDC FOUND 300 PEOPLE THAT HAS TAKEN THIS SUBSTANCE. 150 DEVELOPED PARKINSON DISEASE. WE WERE LUCKY IT HAD OWN EFFECT SO RAPIDLY. CAN YOU IMAGINE WHAT WOULD HAPPEN IF THIS CAUSED CANCER? 3, 4, 5 YEARS DOWN THE LINE? BY THE TIME -- THERE WAS NO WAY YOU WOULD BE ABLE TO IDENTIFY HOW THESE PEOPLE HAD GOT CANCER. SO IN SUMMARY, WE'VE GOT PUBLICATION OF SAR STUDIES. THEY'RE ABSOLUTELY REQUIRED FOR THE FIELD AS DRUG ABUSE RESEARCH. NECESSARY TO PRODUCE MEDICATIONS OWNED ALSO RESEARCH TOOLS, AND TO ADVANCE THE SCIENTIFIC CAREERS OF THE CHEMISTS THAT DO THIS WORK. HOWEVER, WE HAVE RESULTED IN UNTESTED DRUGS BEING IN HUMANS NO, KNOWLEDGE OF THOSE LONG TERM CONSEQUENCES NO, QUALITY CONTROL BECAUSE THEY WERE NEVER INTENDED TO BE IN HUMANS. POISON CENTER CONTROL DATA INDICATING THAT WE ARE HAVING HARM CAUSED BY THIS. THE NUMBER OF CALLS TO POISON CENTER CONTROLS HAVE DROPPED OVER THE LAST COUPLE YEARS BUT THEY'RE FLOATING ALONG AROUND 200 PER MONTH. THAT'S BECAUSE PEOPLE KNOW HOW TO DEAL WITH THESE, RATHER THAN BECAUSE THEY NO LONGER CAUSE A PROBLEM. WHEN YOU SEE IN THE PAPERS THAT PEOPLE ARE HAVING HEART ATTACKS, THAT SORT OF THING, IT'S PROBABLY CAUSED BY THE CONTAMINANTS IN THERE AS WELL. YOU HAVE NO CONTROL OVER THE QUALITY OF THESE THINGS. SO THE QUESTION IS SHOULD WE RECOGNIZE PSYCHO ACTIVE MED CHEM. IS IT POSSIBLE TO PUBLISH THESE STUDIES AND MINIMIZE THE CONSEQUENCES? AND CAN WE LIMIT INFORMATION IN ANY WAY WITHOUT UNDERMINING SCIENTIFIC ADVANCEMENT? IS IT EVEN POSSIBLE TO LIMIT INFORMATION ACCESS IN THE DAYS WHERE PATENTS ARE AVAILABLE ONLINE? AND THEN FINALLY, JUST WANTED TO DRAW ATTENTION TO THE FACT THAT THE NSABB, THEIR ANSWER TO THIS HAS BEEN DEVELOPING A CULTURE OF RESPONSIBILITY. THIS IS WHAT PEOPLE HAVE HAD FOR YEARS IN THE NUCLEAR PHYSICS, WOULD,ING WITH THESE ISSUES FOR 60 YEARS. INVIROLOGY HAS BEEN WORKING WITH THESE ISSUES FOR MANY YEARS, PHARMACOLOGY, TO WE TEACH OUR STUDENTS THE CONSEQUENCES OF WHAT THEY'RE DOING. SHOULD THEY BE DEVELOPING MOLECULES IN THESE LINES, CONSIDERING THESE THINGS? THAT'S WHAT I'D LIKE TO PUT UP. [APPLAUSE] >> BEFORE WE GO ON TO DISCUSS THE ETHICAL ISSUES RACED BY THIS CASE AND OTHER EXAMPLES OF DIAL USE RESEARCH, THERE ARE ONE OR TWO QUESTIONS FOR AIDAN ABOUT THE FACT PRESENTED THAT PEOPLE MIGHT BE -- THINK MIGHT BE HELPFUL? OR WAS IT CLEAR ENOUGH FOR EVERYBODY. >> OKAY. >> THE CANNABINOID RECEPTOR BLOCKING LIGANDS ARE ONE OF THE IMPORTANT [INDISCERNIBLE] THANK HAS GOOD EFFECTS, IN ADDITION, ALL THE BAD EFFECTS THAT HAVE BEEN [INDISCERNIBLE]. HAVING AN EFFECT ON THE YOUNG GENERATION. SO WHY NOT STUDY? WE KNOW OF ALL THE [INDISCERNIBLE] AND OTHER TYPES OF DRUGS. WHY NOT CANNABINOIDS? >> YOU'RE POINT IN GENERAL IS REALLY THE CRUX OF THE MATTER, THE AGENTS HAVE BOTH LEGITIMATE AND ILLEGITIMATE VALUE. IN THE PARTICULAR CASE YOU'RE TALKING ABOUT. CANNABINOID AN TAGNISTS ARE NOT IN SYNTHETIC MARIJUANA. PEOPLE WANT THINGS THAT WILL GET THEM HIGH, NOT THINGS THAT WILL BLOCK THE RECEPTOR. >> THANK YOU. >> NOW DO HELP US THINK THROUGH THESE VERY INTERESTING ISSUES, HARRY FEINBERG FROM THE OIM. HARVEY. >> THANK YOU VERY MUCH. THANK YOU CHRISTINE FOR THAT GENEROUS INTRODUCTION, AND INTRODUCTION TO ALL OF US TO THE ZOOM EMANUEL LECTURE. I WAS SO IMPRESSED WITH YOUR SUCCEED SINK SUMMARY AND LAYING OUT AN CRITICAL ISSUE FOR ALL OF US. AS I WAS THINKING ABOUT THIS CASE IN ADVANCE OF OUR GETTING TOGETHER, I COULDN'T HELP BUT REFLECT ON THE FACT THAT THIS PARTICULAR CASE, AND THE QUESTIONS YOU POSE ABOUT MEDICINAL CHEMISTRY AND PHARMACOLOGY, REALLY APPLY IN MY MIND, TO EVERY IMAGINABLE LINE OF RESEARCH. I THINK THE QUESTION YOU POSED AND THE EXAMPLE YOU GAVE US COULD WE REPLICATED TIME AND TIME AND TIME AGAIN IN A RANGE OF SCIENTIFIC ENDEAVORS IN EVERY RESEARCH HABIT THAT WE WOULD VISIT AT THE NIH, AND AT ANY UNIVERSITY OR ANY COMPANY. THE QUESTIONS ARE VERY FUNDAMENTAL. AND I THINK THE QUESTIONS ACTUALLY GO BACK TO THE VERY BEGINNING OF TIME. I WANT TO POSE THE QUESTION TO START, IS ANY KNOWLEDGE RISK FREE? EVERY TIME WE OBTAIN NEW KNOWLEDGE WE SIMULTANEOUSLY HAVE DO THINK ABOUT WHAT BENEFIT ARE WE SEEKING, AND WHAT IS THE POTENTIAL RISK THAT WE ARE FACING WHEN WE DEAL WITH THAT KNOWLEDGE? IS ANY KNOWLEDGE FREE OF POTENTIAL MALEVOLENT USE? I THINK SO IT'S VERY HARD TO DRAW FIRM LINE BETWEEN INFORMATION AND KNOWLEDGE, SCIENTIFIC FINDINGS THAT HAVE A PURELY OR CERTAINLY BENEVOLENT USE AS CONTRASTED WITH THOSE ELEMENTS OF KNOWLEDGE WHICH MAY HAVE A MALEVOLENT USE. ONE OF THE QUESTIONS THAT I THINK THIS OPENS UP FOR US IS HOW DO WE THINK ABOUT THE ISSUES OF BALANCING THE RISK AND BENEFIT IN OUR RESEARCH, AND REALLY IN ALMOST ANY ELEMENT OF USE OF KNOWLEDGE THAT WE CAN IMAGINE? ALL OF THESE QUESTIONS COME BACK TO A BASIC MATTER OF OUR STRATEGY, OUR WAY OF DEALING WITH RISK VERSUS BENEFIT. AND I WANT TO LAY OUT TWO CONTRASTING APPROACHES TO THINKING ABOUT THE LIVING AND BENEFIT BALANCE AND BRING IT BACK TO THE APPLICATION OF OUR RESEARCH. ONE OF THESE IS SOMETIMES CALLED THE KEHOE PRINCIPLE. THE OTHER IS CALLED THE PRECAUTIONARY PRINCIPLE. AND THESE PRINCIPLES BASICALLY DEAL WITH THE QUESTIONS OF WHAT IS YOUR STARTING POINT? WHAT IS YOUR DEFAULT ACTION? ARE YOU CONDUCTING THE RESEARCH? ARE YOU NOT CONDUCTING THE RESEARCH? ARE YOU ENGAGING IN A PROGRAM, NOT ENGAGING, TAKING ACTION, NOT TAKING ACTION? WHAT'S THE DEFEAT STARTING POINT. WHO HAS THE BURDEN OF PROOF TO TELL YOU THAT THE RISKS ARE EITHER WORTH OR NOT WORTH TAKING? DEPENDING ON WHAT YOU'RE CONTEMPLATING TO DO. NOW, KEY HOE, THE PRINCIPLE IS NAMED AFTER A PHYSICIAN PATHOLOGIST THAT WORKED WITH GENERAL MOTORS AND DEALT WITH THE QUESTION OF TETROETHAL LED. AS AN ADDITIVE TO GASOLINE. THE ARGUMENT THAT KEY HO MADE, WE'RE USING THE LEAD IN GASOLINE FOR A LONG TIME, UNTIL YOU CAN PROVE IT'S DANGEROUS WE SHOULD BE ABLE TO CONTINUE TO USE IT. THE PRECAUTIONARY PRINCIPLE IS DIFFERENT, BUT BEFORE WE LEAVE THE KEY HOE PRINCIPLE, LET'S JUST SAY THAT BASICALLY, KEY LOW ARGUED IN THE ABSENCE OF EVIDENCE OF CLEAR RISK YOU SHOULD STAY ON COURSE. PROCEED UNTIL THE DOUBTERS PROVE THAT THE ACTION IS UNSAFE. THE BURDEN IS ON THOSE WHO WANT YOU TO STOP BLOOD PRESSURE THE PRECAUTIONARY PRINCIPLE TYPICALLY START AT THE OTHER END. THE PRECAUTIONARY PRINCIPLE ARGUES THAT UNLESS YOU KNOW SOMETHING WILL BE SAFE DON'T UNDERTAKE IT. DON'TDITEDITE UNLESS YOU'RE SURE IT WILL BE SAFE. HERE, THE BURDEN OF PROOF IS ON THOSE WHO WANT TO ARGUE THAT THE ACTION IS SAFE. NOW, I WANT TO MAKE AN INTERESTING -- I THINK A VERY INTERESTING OBSERVATION. BOTH THE KEHOE PRINCIPLE FOR DECIDING ABOUT RISK AND THE PRECAUTIONARY PRINCIPLE FOR DECIDING ABOUT RISK HAVE IN COMMON A CERTAIN PRIVILEGING OF CURRENT STATE OF BEHAVIOR. IF YOU'RE NOT DOING SOMETHING, TAKE THE PRECAUTION. IF YOU'RE ALREADY DOING SOMETHING, INSIST ON PROOF BEFORE YOU STOP. SO IN THAT SENSE, I WANT TO POSE THE QUESTION IN GENERAL, SHOULD WE AND DO WE WANT TO PRIVILEGE EITHER A STATE OF ACTION OR A STATE OF INACTION AS REQUIRING THE BURDEN OF PROOF BEFORE WE DECIDE WHAT WE DO. AND I WOULD SUBMIT WHEN IT COMES TO RESEARCH, AND THE CONDUCT OF RESEARCH, WE OUGHT TO HAVE A BALANCED VIEW ABOUT THE MERIT ON THE BENEFIT, THE RISK ON THE NEGATIVE SIDE, AND KEEP BOTH OF THOSE EQUALLY IN MIND REGARDLESS OF WHETHER WE'RE ANTICIPATING DOING THE RESEARCH, OR HAVE ALREADY DONE IT AND ARE THINKING ABOUT DISSEMINATION. IN BOTH INSTANCES, I WOULD SUBMIT THE BURDENS I BELIEVE SHOULD BE BOTH ON THOSE WHO WANT TO PROPOSE ACTION AS WELL AS INACTION, BECAUSE THEY BOTH ENTAIL MANAGING AND BALANCING BENEFITS AGAINST RISKS. NOW, THIS IS NOT ALWAYS AN EASY TASK. EVEN THINKING ABOUT IT AND COMMUNICATING ABOUT IT IS NO, SIR ALWAYS A SIMPLE THING TO DO. I WOULD LIKE TO TURN UP THE LIGHTS IF I COULD, AND I'D LIKE TO ASK YOU TO HOOK AT THE PAGE THAT WAS HANDED OUT TO YOU, JUST AT THE BOTTOM AT THE OPTIONS. EVERY ONE I THINK GOT ONE PAGE, HOW MANY PEOPLE GOT A PAGE THAT GIVES OPTIONS A OR B? HOW MANY PEOPLE GOT THAT, COULD YOU RAISE YOUR LANDS? HOW MANY GOT ONE THAT SAYS OPTION C OR D? OKAY. HOW MANY PEOPLE HAVE LAD A CHANCE TO LOOK AT THIS PAGE? ALMOST EVERY ONE MUCH I'LL GIVE 30 SECONDS TO THE REST TO READ OVER THE QUESTION. ANYBODY NOT READY TO TELL ME WHAT THEIR CHOICE IS? WE'LL GIVE THAT PERSON TEN SECONDS. LET ME ASK THE OTHERS. ALL THOSE WHO HAD A OR B AS YOUR CHOICES, RAISE YOUR HANDS. A OR B AS CHOICES. OKAY. HOW MANY OF YOU PREFER A OVER B? KEEP YOUR HANDS UP. HOW MANY OF YOU PREFER B OR A? I WOULD SAY ABOUT 60/40A OVER B. OWE THIRD ARE NOT YET SAYING. OKAY. THOSE WHO HAD C AND D. HOW MANY PEOPLE PREFER C? KEEP YOUR LANDS UP. HOW MANY PEOPLE PREFERRED D? ABOUT 80% I WOULD SAY PREFER D OR C. OKAY. SO.HAD A SLIGHT MAJORITY OVER B, 60/40. D HAD A STRONG MAJORITY OVER C OF 80/20. LET'S LOOK AT THESE TWO QUESTIONS. THIS IS THE AB PROGRAM. IT SAYS THAT THERE IS AN OUTBREAK OF AN UNUSUAL ASIAN DISEASE. THIS WAS AN ACTUAL EXAMPLE PUBLISHED IN 1981. THERE ARE TWO PROGRAMS. ASSUME THE EXACT SCIENTIFIC ESTIMATE OF THE CONSEQUENCES ARE AS FOLLOWS. PROGRAM A IS ADOPTED, 200 PEOPLE SAVED. IF B IS ADOPTED THERE IS A 1/3 PROBABILITY 600 SAVED, 2/3 PROBABILITY NO ONE SAVED. IN THIS CASE THE MAJORITY OF US FAVORED A OR B. EVERYBODY WITH ME SO FAR? NOW WE'LL LOOK AT THE OTHER QUESTION. THE PARIS THE SAME. THE SITUATION IS EXACTLY THE SAME. HERE IS THE DESCRIPTION, IF C IS ADOPT 9, 400 DIE. AND IF D IS ADOPTED, A ONE-THIRD PROBABILITY, NO ONE DIES, TWO-THIRDS PROBABILITY 600 DIE. HERE, A STRONG MAJORITY FAVORED D OVER C. NOW, HERE IS THE PROBLEM. A AND C ARE THE SAME. 200 LIVING, 400 DYING, SAME THING. B AND D ARE THE SAME. AS YOU'LL SEE BY LOOKING AT THE PROBABILITIES. SO IF.IS EQUIVALENT TO B AND C EQUIVALENT TO D, WHY DID THE GROUPS COME TO DIFFERENT COLLABORATIONS? THEY'RE FRAMED AT GAINS OR PRESERVING A GAIN. C AND D FRAMED AT LOSSES, AVOIDING A LOSS. BASICALLY, IF YOU ARE GIVEN A CHOICE OF PRESERVING OR ACQUIRING A GAIN YOU TEND TO BE CONSERVATIVE. AND KEEP THE GAIN YOU HAVE FOR SURE. WHEREAS YOU'RE FACED WITH A QUESTION OF A LOSS, YOUR TENDENCY IS TO TAKE A CHANCE TO AVOID THE LOSS. YOU'RE MUCH MORE WILLING TO TAKE RISKS TO AVOID A LOSS. IF THIS SIMPLE PROBLEM CAN REVEAL THESE KIND OF DIFFERENCES IN OUR TENDENCIES ON AN IDENTICAL PROBLEM, SELLING DEPENDING WHETHER IT'S -- SALE DEPENDING WHETHER IT'S A GAIN OR HOSPITAL, IMAGINE HOW DIFFICULT TO HAVE AN HONEST, OPEN, INFORMED, COMPLETE AND MEANINGFUL CONVERSATION ABOUT THE TRADE OFFS IN BENEFITS AND RISKS WHEN WE'RE CONSIDERING RESEARCH CHOICES. AND YET THAT'S THE TASK THAT WE'RE BEING ASKED TO DO. NOW, I'M GOING TO JUMP TOWARD THE END BECAUSE I WANT TO LEAVE AMPLE TIME FOR US TO HAVE A DISCUSSION AND TO CONSIDER THE PROBLEMS TOGETHER AND PARTICULARLY, HOW THEY WOULD RELATE TO THE CASE THAT WE HEARD TODAY. ONE IMPORTANT QUESTION AS RESEARCHERS, I WOULD SAY, WE ARE NOT MAKING DECISIONS FOR OURSELVES. WE MAY THINK WE ARE MAKING DECISIONS ABOUT OUR OWN CHOICE OF RESEARCH BUT WE ARE ACTUALLY MAKING DECISIONS ABOUT GENERATING KNOWLEDGE THAT CAN EFFECT MULTITUDES OF OTHERS. AND THAT PUTS THAT BURDEN OF RESPONSIBILITY OR AS THE NSABB DESCRIBED, A CULTURE OF RESPONSIBILITY AS A COMMON THEME, I WOULD SUBMIT, FOR ALL RESEARCH. AND WE CAN ANTICIPATE IN SOME INSTANCES, ATTRIBUTES OF RESEARCH THAT MAKE IT ESPECIALLY MEANINGFUL FOR DUAL USE CONCERN. ESPECIALLY RAISING QUESTIONS. DOES IT ALTER THE WAY IN WHICH THE NATURAL ORDER OF THINGS IN CHEMISTRY, IN BIOLOGY, ARE TRANSMITTED? APPLIED, UTILIZED, IS THE RESEARCH DOING SOMETHING THAT WOULD CREATE A CHANGE FROM WHAT IS IN NATURE? WHAT IS THE SCALE OF THE POTENTIAL HARM? WHAT IS THE BALANCE OF KNOWN GAINS AND RISKS KEEPING IN MIND THE IMPORTANCE OF NOT BURDENING EITHER ACTION OR INACTION WITH SPECIAL RESPONSIBILITY, NOR WITH FRAMING AS GAINS OR LOSSES, DISTORTING OUR THINKING. HOW IMPORTANT DO WE WANT TO MAINTAIN AND HOW DO WE PROTECT BOTH FREEDOM OF INQUIRY AND FREEDOM OF COMMUNICATION, IN SCIENCE. AND IN ALL OF THESE INSTANCES, THESE ARE NOT SIMPLY QUESTIONS FOR A SINGLE LAB OR SINGLE COUNTRY BUT THEY ALMOST ALWAYS ENTAIL ALSO RELATIONS POSSIBILITIES AND ACTIONS THAT MAY BE TAKEN IN COUNTRIES AROUND THE WORLD, AND THEY ULTIMATELY COME BACK TO THE RIGHTS AND RESPONSIBILITIES OF THE INVESTIGATOR AS AN INDIVIDUAL, AND THE USER AS AN INDIVIDUAL, IN ANY SOCIETY. SO WHEN WE COME BACK TO THINK ABOUT THE QUESTIONS, ABOUT DOES DUAL USE OF -- DUAL USE OF CONCERN APPLY TO MEDICINAL CHEMISTRY, TO ME, THE ANSWER IS IT HAS ALL THE ATTRIBUTES THAT WOULD RAISE THESE QUESTIONS FOR US. DOES A CULTURE OF RESPONSIBILITY, THEREFORE, APPLY IN MEDICINAL CHEMISTRY? THE ANSWER TO ME IS YES, IT DOES APPLY. DOES THE BENEFIT OUTWEIGH THE RISK IS A QUESTION WE HAVE TO ASK ON EVERY RESEARCH ENTERPRISE, AND THAT REQUIRES US TO COME AT IT, I WOULD SUBMIT, WITH A BALANCE OF BURDEN OFF PROOF. ON THOSE WHO WOULD GO FORWARD AND THOSE WHO WOULD REFRAIN. ONE LESSON I WOULD FINALLY ADD FROM THE REVIEWS OF PREVIOUS EXPERIENCE, IS THAT IF YOU FOCUS ONLY ON THE QUESTION OF PUBLICATION, YOU ARE NOT ANALYZING THE PROBLEM WITH SUFFICIENT COMPREHENSION. THESE CHALLENGES REQUIRE US TO THINK FROM THE VERY BEGINNING ABOUT WHETHER TO UNDERTAKE WHAT STUDIES AS WELL AS THE CONDUCT OF THE STUDIES, AS WELL AS THE NATURE OF REPORTING OF THE STUDIES, AND THE DEGREE OF DISSEMINATION. AND I HOPE THAT WE CAN BEGIN AND INITIATE A MUCH MORE WIDESPREAD CONSIDERATION OF THESE CRITICAL ISSUES AS INTRODUCED BY AIDAN AND SO AMPLY DEMONSTRATED IN EVERY LINE OF BIOMEDICAL RESEARCH. THANK YOU ALL VERY MUCH. [APPLAUSE] >> SO QUESTIONS, SUGGESTIONS, COMMENTS? CONCERNS? SO IF YOU GO -- IF YOU GO TO THE MIC, WE CAN PICK UP THE QUESTION ON THE MIC. >> HARD TO GET TO A MIC. >> THAT'S FINE, TOO. YEAH. QUESTIONS FOR EITHER SPEAKER? >> OKAY. IN TERMS OF THE CONCEPT OF EXPECTED VALUE, IN YOUR CHOICE OF A OR B, OR THE CHOICE OF C OR D, THEY ALL HAD THE SAME EXPECTED VALUE. DO YOU KNOW WHAT THAT MEANS? >> OF COURSE. THAT'S WHAT MAKES IT AN INTERESTING PROBLEM. >> OKAY. >> A AND B HAVE THE SAME EXPECTED VALUE, BUT ONE IS CERTAIN AND THE OTHER IS PROBLEMISTIC. C AND D HAVE THE IDENTICAL EXPECTED VALUE BUT ONE IS CERTAIN AND THE OTHER IS PROBABLISTIC. WHAT'S INTERESTING WITHOUT THAT PROBLEM ISN'T THAT A AND B HAVE THE SAME EXPECTED VALUE AS C AND D. IT'S THAT A IS IDENTICAL TO C, JUST FRAMED DIFFERENTLY. 200 LIVE VERSES 400 DIE. AND C AND -- I'M SORRY OWNED B AND D ARE IDENTICAL IN PROBLEMISTIC TERMS, AND -- PROBABLISTIC TERMS. WHEN WE ONLY SEE HALF OF THE PROBLEM FRAMED AS A GAIN OR LOSS, ON AVERAGE, OUR TENDENCY IS TO HAVE DIFFERENT PREFERENCES. THAT'S WHAT MAKES IT A PROVOCATIVE, VERY IMPORTANT STUDY. I THINK AN IMPORTANT LESSON FOR US IN FRAMING QUESTIONS FOR OURSELVES, FOR OUR COLLEAGUES, FOR OUR PATIENTS, FOR OUR POLICYMAKERS, AND EVERY INSTANCE BEING MINDFUL THAT THIS DIFFERENCE IS REALLY EFFECT THE WAY PEOPLE APPREHEND THE PROBLEM. >> I WAS LUCKY, I GUESS, THAT I WORKED IN COULD HAVE CARDIOVASCULAR DISEAS E WHERE THERE WERE NOT MANY CONTROVERSIES, THIS IS AN INTERESTING DRUG, MARIJUANA, AND USED, PROVED IN COLORADO AND MAYBE SOMETIMES IT WILL BE COMING OUT IN OTHER STATES. SO HOW MUCH WE KNOW ABOUT CANNABINOID AND HOW MUCH WE SHOULD KNOW MORE. I DON'T SEE SEE ANY HARM IN KNOWING IT. BASICALLY WE ARE DEALING WITH IT. WHY NOT KNOWING IT. >> I'LL LET AIDEN START WITH THAT QUESTION. >> WELL, THERE IS QUITE A LOT KNOWN ABOUT -- THAT'S A WHOLE FIELD THAT YOU'RE ASKING ABOUT. IT CAN'T BE ADDRESSED IN A COUPLE SENTENCES, BUT WHAT WE'RE TALKING ABOUT HERE IS PROBE LIGAND, THINGS DESIGNED FOR MAINLY JUST IN VITRO STUDIES, BUT THE CONSEQUENCES OF THOSE PEOPLE NOW USED IN A BUSINESS MODEL ARE GREATER THAN THE ORIGINAL SMALL QUESTION THAT PEOPLE WERE ASKING. THAT'S WHAT IT COMES DOWN TO. RESEARCH IS -- WE'RE ALL RESEARCHERS, ALL BEEN RESEARCHERS, THOSE WHO HAVE BEEN RESEARCHERS AT THE BENCH WILL OFTEN FOCUS VERY CLOSELY ON OUR AREA RIGHT THERE. SOMETIMES PERHAPS WE NEED TO STEP BACK AND LOOK AND SEE WHAT ARE THE BIG, BIG CONSEQUENCES OF THE THINGS THAT WE'RE DOING? SO YOU'RE ASKING ABOUT WHAT DO WE KNOW ABOUT MARIJUANA, WHAT DO WE KNOW ABOUT CANNABIS, AND YOU'RE TALKING ABOUT WHERE IT'S RECREATIONALLY USE THE. AT NIDA WE'RE VERY INTERESTED IN LEARNING MORE, INVESTIGATING, TRYING TO ADVISE THE POLICY ON THOSE ISSUES. BUT THE POINT IS YOU CAN'T JUST LOOK AT THE SMALL WHAT I'M DOING RIGHT NOW. I'M TRYING TO DECREASE DIVINITY FOR CB2. I HAVE TO ASK WHETHER THIS MOLECULE HAS A REAL TOXIC POTENTIAL. OTHER WAYS TO PROCEED? MAYBE THIS CULTURE OF RESPONSIBILITY IS WHAT WE'RE TALKING ABOUT THERE RATHER THAN FOCUSING ON ONE SMALL AREA F WE HAD -- HOW ARE YOU GOING TO WORK? [INDISCERNIBLE] >> A BIGGER QUESTION TO ANSWER IN A YES OR NO. THAT'S WHY WE'RE HERE. >> WHY NOT. I'M HEARING THERE IS AN ANSWER. >> YOU WANT TO KNOW THE ANSWER TO THE QUESTION, ARE THESE DRUGS HEALTH AS MEDICINAL USE AGENTS. >> YES. >> WE MAY EACH HAVE AN INDIVIDUAL OPINION, SO IT GOES BACK TO THE DISCLAIMERS DESCRIBED SINCE I'M NOT PART OF NIH, AND SOON WON'T BE IN MY OFFICE AT THE IOM I'M WILLING TO ANSWER YOUR QUESTION. [LAUGHTER] AND MY ANSWER IS THAT I DO BELIEVE THAT THEY HAVE LEGITIMATE MEDICINAL PURPOSES, AND ARE APPROPRIATE AS PRESCRIBED AGENTS FOR APPROPRIATE PATIENTS, LIKE ANY PRESCRIPTION AGENT. BUT THAT'S MY PERSONAL OPINION. THAT'S DIFFERENT TO THE QUESTION YOU ASKED ABOUT IS MORE RESEARCH NEEDED TO WHICH MY ANSWER IS YES, MORE RESEARCH IS NEEDED DO CLARIFY UNDER WHAT CIRCUMSTANCES AND IN WHAT SPECIFIC INSTANCES THESE AGENTS CAN BE USEFUL. OWNED I WOULD STILL DRAW A DISTINCTION BETWEEN THAT AND THE LINE OF RESEARCH THAT AIDAN WAS DESCRIBING, WHICH IS LOOKING AT SYNTHETIC CHEMICAL CONSTITUENTS THAT HAVE SIMILAR PROPERTIES, BUT ARE NOT CANNABIS ITSELF. >> CONGRATULATIONS. [INAUDIBLE] >> THANK YOU. THESE ARE VERY INTERESTING TALKS. SO I WAS INTERESTED FOR DR. FEINBERG TO EXPLAIN MORE HOW YOU WOULD USE THE CONCEPT OF BURDEN OF PROOF. IN THE LAW YOU IMAGINE AN ADVERSARIAL BROKE SAYS, TWO SIDES. ONE SIDE HAS TO PUT ON THE EVIDENCE TO SHOW THAT THEY CAN GO FORWARD, MEET A CERTAIN THRESHOLD, OR CROSS A CERTAIN THRESHOLD. SO I GUESS WHAT I'M CONFUSED, HOW DOES IT APPLY TO DIAL USE RESEARCH. FOR ONE THING, YOU WOULD WANT RESEARCHERS TO THINK ABOUT THESE ISSUES FROM THE VERY BEGINNINGS WHEN THERE IS NO ADVERSARIAL PROCESS GOING ON. SECOND I'M NOT SURE HOW WE SHOULD THINK ABOUT WHAT THE NSBPB ISING TO, WHETHER IT'S TWO SIDES PRESENTING EVIDENCE OR SOMETHING MORE LIKE A COLLABORATIVE EFFORT? SO I GUESS I'M CURIOUS FOR YOU TO EXPLAIN MORE. I THINK THE CONCEPT OF BURDEN OF PROOF COULD BE USEFUL BUT I'M NOT SURE HOW IT PLAYS OUT. >> THANK YOU FOR THE COMMENT AND QUESTION. I THINK IT'S A VERY IMPORTANT PRINCIPAL BECAUSE I THINK WE SOMETIMES ACTUALLY DON'T FRAME THE PROBLEM AS WHO HAS THE BURDEN OF PROOF. WHAT IS THE STANDARD THAT HAS TO BE MET IN EACH INSTANCE. I THINK IT'S A VERY USEFUL WAY TO THINK ABOUT THE CORE PROBLEM. WHEN YOU BEGIN TO LOOK AT PARTICULAR AREAS OF RESEARCH, ONE OF THE THINGS THAT BECOMES VERY EVIDENT IS THAT THE GENERAL PRINCIPLES CAN TAKE YOU SO FAR. THEN YOU'VE GOT TO LOOK AT THE DETAILS AND SPECIFICS OF THAT LINE OF WORK. AND UNDERSTAND IN DETAIL WHAT ARE THE NATURE OF THOSE RISKS AND BENEFITS? WHEN IT COMES TO A QUESTION ABOUT REGULATION, AND IMPLICATIONS FOR REGULATION, I THINK THAT THE THRESHOLD FOR YOUR ABILITY TO START AND THE STANDARD BY WHICH IT EXCEEDED YOU SHOULD STOP, OUGHT TO BE THE SAME. THAT IS, IF YOU'RE DOING SOMETHING THAT IS ABOVE A CERTAIN THRESHOLD OF RISK TO BENEFIT, I WOULD SAY THAT YOU SHOULD BE AS LIABLE TO STOPPING TO IT AS IF SOMEONE WHO WAS THINKING OF DOING IT HAS TO MEET THAT STASHED IN ORDER TO -- STANDARD IN ORDER TO START. WHAT I CAN IS NOT FOR MYSELF APPROPRIATE WHEN MAKING DECISIONS FOR OTHERS, IS TO HAVE A DIFFERENT STANDARD REQUIRED FOR A THRESHOLD TO ALLOW ACTION AS FOR A THRESHOLD TO REQUIRE STOPPING ACTION. I THINK THOSE OUGHT TO BE FRAMED IN A VERY, VERY SIMILAR WAY. >> HI. YOU GUYS BOTH BROUGHT UP SOME VERY INTERESTING POINTS ABOUT MEDICAL RESEARCH IN GENERAL, AND EVEN BROUGHT IT TO RESEARCH IN GENERAL. ONE OF YOU ACTUALLY SAID, WHAT IS THE VALUE OF KNOWLEDGE AND RESEARCH. SHOULD WE GO FORWARD WITH ANYTHING BECAUSE IT COULD BE USED FOR BAD PURPOSES? >> P ALSO THE IDEA OF PHYSICS WAS BROUGHT UP. PHYSICISTS ARE THE MOST OBVIOUS EXAMPLE. THESE GUYS TRY TO FIGURE OUT HOW THE WORLD WORKS, WHEN WE CAN FIGURE IT OUT WE CAN MAKE ATOM BOMBS AND KILL PEOPLE. WHEN WE DON'T FIGURE IT OUT WE CAN'T SAVE PEOPLE. SO I THINK THAT THE QUESTION CAN GO FROM THE MICROSCOPIC OF IF WE FIND SOME LIGAND THAT HELPS US UNDERSTAND CANNABINOIDS BETTER, ANTHONY WE CAN ALSO HURT PEOPLE WITH THAT DRUG. SO THAT QUESTION IS COMPLETELY FROM MICROSCOPIC ALL THE WAY TO THE COSMIC UNIVERSAL QUESTION. THE REALLY IS JUST VERY SIMPLE. SHOULD WE KNOW STUFF? IF WE KNOW STUFF, BAD THINGS WILL DO BAD THINGS WITH IT. IF WE BELIEVE IT'S IMPORTANT TO KNOW STUFF, WE HAVE TO DEAL WITH THE CONSEQUENCES OF THE KNOWLEDGE. IS THERE ANY REASON TO SAY IT'S BETTER TO NOT KNOW STUFF? >> WELL, I'LL START WITH THAT. AIDAN CAN FOLLOW. PERSONALLY, I THINK THAT IT IS -- WOULD BE A WRONG MINDED CONCLUSION TO SAY WE SHOULD STOP KNOWING THINGS. I THINK THAT OUR QUEST, CURIOSITY AS HUMAN BEINGS TO UNDERSTAND NATURE, TO UNDERSTAND THE WORLD IN WHICH WE LIVE, HAS SERVED US WELL, WILL CAPITOL CONTINUE DO SERVE US WELL. THE FACT THAT KNOWLEDGE AND I CONCUR, ANY KNOWLEDGE CAN BE APPLIED TO MISUSE. NEVERTHELESS, DOESN'T RELIEVE US FROM DRAWING DISTINCTIONS BETWEEN CERTAIN CLASSES OF RESEARCH, AND CERTAIN TYPES OF KNOWLEDGE, WHICH MAY HAVE A CLOSER PROXIMITY TO VERY MAJOR RISKS THAN WHOLE ANOTHER MAJOR CLASSES OF RESEARCH. SO OUR ATTITUDE TOWARD CONDUCTING THAT WORK, TOWARD MANAGING THAT WORK, TOWARD SECURE THAT WORK, TOWARD REPORTING THAT WORK, AS IT MOVES CLOSER TOWARD THAT END OF THE SPECTRUM, WHERE IT HAS POTENTIAL SEVERE CONSEQUENCES, THAT ARE READILY ANTICIPATABLE, SOMETIMES EMBEDDED IN THE PURPOSE OF THE RESEARCH AS IN GAIN OF FUNCTION RESEARCH, AS AN EXAMPLE, OR NUCLEAR RESEARCH, AS ANOTHER EXAMPLE, AND WHERE IT IS RELATIVELY EASY TO BE ADOPTED, TRUE FOR GAIN OF FUNCTION, NOT SO TRUE FOR NUCLEAR RESEARCH WHICH REQUIRES LOTS OF SIGNIFICANT INVESTMENTS AND EQUIPMENT. AND WHERE THE CONSEQUENCES ARE LARGE AND IMPORTANT, ALL OF THOSE SIGNALS LEAD US TO WANT TO DRAW CERTAIN STANDARDS. AND NORMS OF BEHAVIOR IN OURSELVES AS SCIENTISTS, IN OUR COMMUNITY AS A COMMUNITY OF CURIOSITY SEEKERS, AND DESIRES OF LEARNING ABOUT THE WORLD, RESPONSIBLE CLINICIANS, OR POLICYMAKERS, WHO LOOK AT THE AVAILABILITY OF MISUSE AND WANT TO PROTECT AGAINST THOSE POTENTIAL MIDST USES, SO THE ANSWER IS NO NOT AS YOUR RHETORICAL QUESTION, I KNOW, POSED, THEREFORE, DON'T SEEK TO KNOW. I THINK THE ANSWER IS THAT WE NEED TO DRAW MUCH MORE REFINED CONSTANTLY RENEWED UNDERSTANDING OF WHAT CONSTITUTES RISK AND HOW WE BALANCE BENEFITED RISK, AND WHAT WE CAN DO APPROPRIATELY AT DIFFERENT STAGES WITH DIFFERENT TYPES OF RESEARCH TO MANAGE THAT RISK. >> THANK YOU. >> COULD I ADD A LITTLE THING TO THAT AS WELL. I THINK HARVEY REALLY TOOK YOUR SORT OF GLOBAL QUESTION WHICH IN ITS GLOBAL CAN'T WE ANSWERED, RHETORICAL, COVERED HOW WE SHOULD DEVELOP SYSTEMS TO INVESTIGATE THAT. YOU WENT DOWN TO THE PEOPLE SHOULD BE LOOKING AT INDIVIDUAL PROJECTS. BECAUSE I'M BASED AT THE INDIVIDUAL PROJECT LEVEL, DON'T HAVE THE BENEFIT OF THE WISDOM OR WORKING OUGHT 20,000 FEET, THE ANSWER HAS TO BE DOWN TO THE INDIVIDUALS. YOU HAVE TO BE CONTRACT OF WHAT YOU'RE COOG -- CONSIDERATE OF WHAT YOU'RE DOING, WHAT YOU'RE TEACHING STUDENTS TO LOOK FOR. NOT JUST THE SMALL AREA, BUT CONSIDER WHAT THE CONSEQUENCES ARE. AND IF THE DIRECTION THAT YOU'RE MOVING -- IF WE MAKE THESE LIGANDS, THEY COULD BE PROBLEMATIC, IS THERE OTHER WAY OFF APPROACHING IT? DO YOU HAVE TO MAKE LIGANDS LIKE THAT. JULIE ALAL ROD TAUGHT ME, SHOCKING WHEN HE FIRST SAID TO ME IT TAKES AS MUCH WORK EVERY DAY TO DO UNIMPORTANT RESEARCH AS IT DOES TO DO IMPORTANT RESEARCH. SO MAKE SURE WHAT YOU DO IS IMPORTANT. I THOUGHT THAT WAS SHOCKING, BECAUSE THIS IS WHAT I -- I'M INTERESTED IN THIS. IT'S INCREDIBLY IMPORTANT. THAT DOESN'T MAKE IT IMPORTANT. ALSO BECAUSE YOU'RE INTERESTED IN IT DOESN'T MAKE IT RISK FREE AND MAKE IT WORTHY OF DOING. YOU HAVE TO COME BACK AND ACTUALLY ASK THOSE QUESTIONS, IS IT IMPORTANT. IS IT ESSENTIAL I APPROACH IT THIS WAY. DEVELOP RESPONSIBILITY AT THE INDIVIDUAL LEVEL. >> THANK YOU. >> SO THANKS FOR THIS PRESENTATION. I THINK THESE ARE REALLY FASCINATING, VERY LARGE ISSUES. SO WHAT I WANTED TO ASK YOU ABOUT IS DIFFERENT TYPES OF RISK AND RESEARCH. SO WHAT IS IT A THAT MAKES THIS SORT OF DUAL USE RISK DIFFERENT OR POTENTIALLY EXCEPTIONAL, WHEN WE COMPARE IT TO OTHER RISKS WE UNDERTAKE ALL THE TIME, LIKE RISKS TO INDIVIDUAL SUBJECTS, AND STOPPING ROLES THAT WE HAVE FOR PHASE ONE TRIALS, THINGS LIKE THAT. HOW -- BASICALLY I'M REALLY INTERESTED IN WHAT PLACKS THIS SORT OF -- MAKES THIS RISK, THIS CULTURAL DIFFUSED WIDESPREAD, MAYBE LESS WELL UNDERSTOOD RISK DIFFERENT FROM THESE INDIVIDUAL RESEARCH RISKS THAT WE HAVE THIS WHOLE STRUCTURE FOR REGULATING THROUGH IRBs AND DSMBs, THINGS LIKE THAT. >> WELL, THANK YOU VERY MUCH FOR REALLY THOUGHTFUL QUESTION. RISK DOES COME IN DIFFERENT FLAVORS. AS YOU DESCRIBE WHEN ONE IS CONDUCTING RESEARCH, THE ACTUAL RESEARCH PROCESS ITSELF COULD ENTAIL RISK TO THE INVESTIGATOR, TO THE SUBJECTS, TO THE INSTITUTIONS THAT ARE INVOLVED PLAINTIFF SO THAT THERE MAY BE -- THERE MAY BE INTRINSIC ELEMENTS THAT ARE RISKY IN CHARACTER. WHEN IT INVOLVED THE SUBJECTS, THAT'S WHEN ALL THE MACHINERY ABOUT THE APPROPRIATE REVIEW OF THE RESEARCH, AND MAKING SURE THAT IT PASSES STANDARDS OF DESIGN AND QUALITY CONTROL TO ALLOW INFORMED CONSENT TO BE GIVEN FOR THE SUBJECTS IN RESEARCH, ALL OFF THAT COMES INTO PLAY. WHENEVER RESEARCH IF IT MEDICINAL CHEMISTRY PRODUCES A NEW DRUG, THE DECISIONS ABOUT THE USE OF THAT DRUG, THE MARKETING OF THAT DRUG, THE APPROVAL OF THAT DRUG, ALSO ENTAIL A QUESTION OF BENEFIT VERSUS RISK. WHAT IS SPECIAL ABOUT THIS CATEGORY OF DUAL USE RESEARCH OF CONCERN IS THAT IT IS NOT THE INTRINSIC TO THE RESEARCH ITSELF, ALTHOUGH IT MAY OR MAY NOT BE RISKY, I'D NOT IN THE PRODUCT THAT IMMEDIATELY MAY FOLLOW FROM THE RESEARCH THAT IS -- MAY BE MARKETED OR NOT MARKETED, APPROVED OR NOT APPROVED, REGULATED OR NOT. RATHER, IT'S IN THE KNOWLEDGE THAT IS GENERATED BY THE RESEARCH, THE POTENTIAL FOR THAT KNOWLEDGE TO BE MISUSED. MISAPPROPRIATED, APPLIED IN A WAY THAT WOULD CREATE SIGNIFICANT HARM TO THE PUBLIC HEALTH OR RISK TO THE POPULATION. SO IT'S PARTLY ABOUT THE RISK ENTAILED NOT JUST IN THE CONDUCT OF THE STUDY, BULSE, IN THE USED OF THE KNOWLEDGE AND PARTLY, THE SCALE OF THE RISK WHICH ARE THE DISTINGUISHING ATTRIBUTES OF THIS DUAL USE RESEARCH OF CONCERN. >> OKAY. I WAS GOING TO TAKE A CHANCE, NOW THAT WE CAN PUT YOU ON THE SPOT. I REALLY LIKE YOUR POINT ABOUT THE FACT WE SHOULDN'T JUST FOCUS ON PUBLICATION. OF CERTAIN TYPES OF RESEARCH. WE THEY'D TO LOOK AT THE WHOLE PROGRAM FROM WHAT YOUR QUESTIONS ARE, HOW YOU'RE TRYING TO APPROACH THIS, WHETHER YOU BUILD LIGANDS ARE NOT. HOW YOU PRESENT THAT, HOW YOU DISCUSS IT, PUBLISH IT. THAT SEEMS TO BE REALLY CRUCIAL. WHAT I THOUGHT WAS INTERESTING IS THAT WHAT YOU DO AND WHAT DECISIONS YOU MAKE AT ONE POINT IS DEPENDING ON WHAT THE NORMS ARE AT ANOTHER ONE. I WAS GOING TO GIVE YOU ONE EXAMPLE TO TRY TO FUTURE YOU ON THE -- PUT YOU ON THE SPOT, IT STRIKES ME MOST SCIENTIFIC AND MEDICAL JOURNALS HAVE THIS POLICY WHICH INITIALLY SEEMS LIKE THE RIGHT ONE, WHICH IS THAT THEY SHOULD ONLY PUBLISH REPORTS THAT ARE ESSENTIALLY COMPLETE IN THE IMPORTANT DETAILS, AND ARE ACCURATE. AND NOW IT SEEMS TO ME THAT IF THAT'S GOING TO BE THEIR POLICY, IT'S IMPORTANT TO GET THINGS PUBLISHED, THAT MIGHT EFFECT WHAT AIDAN DECIDES TO DO UP FRONT, WHAT APPROACHES HE DECIDES TO TAKE. HE THINKS WELL, THIS IS GOING TO BE OKAY, AS LONG AS I CAN LEAVE OUT THIS LITTLE BIT OR PART OF THE MOLECULE. I DON'T HAVE TO DESCRIBE THAT STEP IN THE PROCESS. DO YOU THINK THAT THAT POLICY OF JOURNALIST IS RIGHT, WE SHOULD -- THEY SHOULD HAVE THAT AND WE SHOULD MAKE DECISIONS IN LIGHT OF THAT NORM OR SHOULD THAT CHANGE AS WELL. OR BE CONSIDERED? >> WELL, I THINK THE PREDISPOSITION, THAT IS, THE INTENT TO DO RESEARCH THAT IS GOING TO BE ABLE TO BE DESCRIBED COMPLETELY, IS THE RIGHT STARTING POINT IN CHOOSING RESEARCH. IF ONE STARTS ON A LINE OF RESEARCH, SOMETIMES THERE COULD BE FINDINGS THAT WERE NOT THE INTENTION OF THE RESEARCH, THAT WERE UNEXPECTED. THAT ARE NEVERTHELESS SIGNIFICANT SCIENTIFICALLY. AND THEY MAY ALSO RAISE A SIMILAR SET OF QUESTIONS ABOUT HAD I KNOWN THIS WOULD FOLLOW, WHAT WOULD I HAVE DONE, AND WHAT SHOULD I NOW DO ABOUT DESCRIBING IT? I THINK THAT THE PREDISPOSITION TO BE COMPLETE AND ACCURATE IS THE RIGHT PREDISPOSITION, AND IT HAS TO BE CONDITIONED ON THE REALITIES OF THE RISK AND BENEFIT THAT ARE ENTAILED IN THAT INFORMATION. IN THE WORLD OF IF YOU SEICS, THE SCIENCE COMMUNITY IS VERY ACCUSTOMED TO UNDERTAKING RESEARCH IN A MUCH MORE RESTRICTED, FOCUSED, SECURE AND NON DISTRIBUTED WAY. WHEN THEY'RE DOING ESSENTIAL RESEARCH RELATED TO NATIONAL SECURITY, FOR EXAMPLE. A BIG DIFFERENCE TO BIOLOGICAL IS VERY OFTEN YOU DON'T NEED THE SAME DEGREE OF COMPLICATEED FACILITIES, EQUIPMENT, AND VERY, VERY SPECIFICALLY DESIGNED TOOLS IN ORDER TO CONDUCT THAT RESEARCH. SO IN BIOLOGY, WE HAVE TO BE VERY MINDFUL OF THE REP PLIABILITY OF THE FINDINGS WHICH IS MUCH MORE READILY ACCOMPLISHED IN MANY INSTANCES THAN IT IS, FOR EXAMPLE, IN A WORLD OF PHYSICS AS WAS RAISED IN AN EARLIER QUESTION. SO MY ANSWER IS THE PREDISPOSITION IS CORRECT, CONDITIONED AS ALWAYS ON A BALANCING OF BENEFITS AND RISKS IN THE SPECIFIC INSTANCES. >> ONE OF THE WAYS OF ADDRESSING YOUR POINT THERE WAS -- IN 2011, THE NSABB CONCLUSION WITH LARD TO H5N1, A REDACTION OF INFORMATION WAS NOT A VIABLE STRATEGY AT THAT TIME. BUT THERE IS ANOTHER BIOLOGICAL SCENARIO THAT -- WHERE SUCH INFORMATION IS CONTROLLED. P THERE IS A LOT OF GENETIC INFORMATION AVAILABLE. INFORMATION HELD BY THE NATIONAL LIBRARY OF MEDICINE. PEOPLE WILL ANALYZE THIS DATA AND THEY WILL PUBLISH THE FINDINGS ON VARIOUS SNIPS, POLYMORPHISM THAT SAID THEY FIND IT THERE. PARTLY PAUSE OF THE BLASIVENESS OF THE DATABASE THEY CAN'T PUBLISH ALL THE DATA OUT THIS. SO PUBLICATIONS ARE NOT AUTOMATICALLY PUBLISHING EVERYTHING THAT'S IN THERE. AND PEOPLE THAT HAVE ACCESS TO THE DB GAB, THE DATABASE, THE RESEARCHERS, ARE AUTHICATED RESEARCHERS THAT WORK IN LATHS THAT ARE AUTHENTIC THED WITH REGARD TO SECURITY AND ACCESS TO TERMINALS, THAT SORT OF THING. I DON'T THINK THAT THE IDEA OF PUBLISHING INACCURATE INFORMATION IS A GOOD ONE. IT DOESN'T NECESSARILY MEAN THAT THERE -- THERE IS ALREADY SITUATIONS WHERE NOT EVERYBODY GET THE SAME LEVEL OF INFORMATION. FOR EXAMPLE, YOU COULD IMAGINE, AND I'M JUST SUGGESTING, THAT BEHAVIORISTS DON'T REALLY KNOW OR CARE WHAT THE GAU OF THE MOLECULE IS. THEY NEED TO KNOW IT'S THIS MOLECULE. THEY DON'T -- WOULDN'T KNOW WHAT TO DO WITH THE FACT THAT IT'S GOT A HERE AS OPPOSED TO ALCOHOL. THEY DON'T NEED TO KNOW THE CHEMICAL SYNTHESIS BUT THEY NEED BEHAVIOR INFORMATION. ECONOMIST MIGHT NEED TO KNOW -- CHEMIST MIGHT NEED TO KNOW MORE. SO THIS IS A POSSIBILITY YOU HAVE TO HEAR INFORMATION ABOUT A CERTAIN SUBJECT. >> THIS IS GREAT. MAYBE JUST ADD THAT IN TODAY'S WORLDIS OF OPEN COMMUNICATION, TRADITIONAL PROFESSIONAL JOURNALS ARE NOT REALLY THE OBSTACLE TO GETTING INFORMATION OUT. AND SO IT COMES BACK TO THE RESPONSIBILITY OF INDIVIDUAL INVESTIGATORS AND THIS CULTURE OF RESPONSIBILITY THAT AIDAN WAS TALKING ABOUT FROM THE BEGINNING. >> ALL RIGHT. JOIN ME IN THANKING --