articles on sex

>> at this time ann rancourt, communications director office of women's health will introduce our next keynote speaker. >> hi, everyone.

articles on sex

articles on sex, welcome back. i'm thrilled to introduce our second keynote speaker dr. londa schiebinger, she's the john h.

heims professor of history of science at stanford university an directs the eu uf gendered innovations in science health and medicine, engineering and environment project. she is leading international expert on gender in science and technology and over the past 30

years her work is devoted the teasing 'part three analytically distinct but interlocking pieces of the gender in science puzzle. the history of women's participation in science, the structure of the scientific institutions and the gendering of human knowledge.

she has twice addressed the united nations on topic of gender science and technology and has worked with the european commission on a number of projects. she's also authored numerous prize winning books on women and gender and her research is

featured in the new york times, new yorker, on npr and numerous international publications. her talk is gendered innovations analyzing gender and pre-clinical research. thank you for being with us. [applause] >> thank you, pleasure to be

here. and as a professional historian i think i i can say we are making history at this moment. so let's do a good job. doing research wrong, cost lives and money. you all know this, for example ten drugs eventually withdrawn

from the u.s. market because of life threatening health effects and eight pose greater threats in women. not only do that he cost billions of dollars to develop but when they fail they cause human death and suffering so we can't afford to get it wrong.

doing research right saves lives and money and analysis of the women's health initiative hormone therapy trial, found for ef dollar spent 140 were returned. and the study also saved lives and 76,000 fewer case of regard co-vascular disease, 126,000

fewer breast cancers, 145 more quality adjusted years, and the only down side was more osteoporotic fractures. so we know this already. but i want to advocate very strongly that nih developed metric metrics for understanding the

cost in dollars and in lives to integrating sex as a variable in we started looking at the economics at stanford, we had a workshop a couple of weeks ago and people were involved and this is just the beginning but this is what we hashed out after a couple of weeks on email.

after our meeting. so the question is, will analyzing sex as a variable cost more more money. people tend to consider this only in relation to their own lab. we knee to look at it from a u.s. and perhaps even

international point of view. developing a new drug costs $5 billion. and the cost is so high because it factor it is failure rate of drug candidates estimated at 95% with most failing in phase 2. so the cost of sex inclusion in pre-clinical research is small

by comparison. so back to the question, will more money? we found or we are going to do a larger study, but i think nih should take this on because we aren't going to do it all, there are two things to look at, the effect on sample size and we

discussed this this morning, adopting a strategy of 50/50 female an male animal cells instead of 100% of one sex seems likely to allow detection of at least some sex influences namely the largest ones that presumably researchers would first want to detect with not much impact on

sample size. in some cases this is called additional sample size to study section differences in finer detail. studying variants such as age or reproductive phase for example in males an females with the same power.

and even in this latter case, sample size may not need to be doubled. so the second effect is on study costs, many costs of running studies are fixed such as basic lab operations. and would not vary with the sex of epicolluded animals or cells.

some cause costs maybe expected to decliner, for example housing female animals maybe cheaper than housing male animals. additional statistical analysis reporting may have some cost but this is likely to be minimal. so in general adding considerations of sex difference

would often have small effects on overall costs though some situation cost might increase and others might decrease. even when costs increase, they should be weighed against additional cost, so any additional cost should be weigh ed against possibility of

new insights improve therapies and reduce risk of subsequent problems. and recognizing this issue of cost, the nih in 2014 distributed $10.1 million to support sex inclusion research and anticipated i hope janine we can say, additional support will

be provided going forward. so we may need new legislation being a historian i went back to 1993 nih health revitalization act public law 103-3 subtitle b and applied to women and minorities in clinical trials. i had anytime my brain it applied to females.

in research biomedical research, maybe we need a law that states this latter case. we can see it's crucially important to get research right and that's the goal of this gendered innovation project that i directed, it developed state-of-the-art methods for sex

and gender analysis. and it provides case studies or examples of where if you actually use sex and gender analysis, you get something new. so we took examples of things that had already been developed to get people 23 examples how that is true.

in a globally accessible website so you can see it. so let me go there just for a second and show you this is a good resource for students or for anyone who has not thought about sex and gender. since it's not included in the curriculum we need a starting

point for people. so over a period of four years, this project was funded by european commission, the national science foundation and also stanford and we worked with 60 basic scientists engineers, technical people virginia heller was part of our team for --

where did we meet? i forgot where we met, all these wonderful places. we hammered out methods or questions for people to put to their projects if they don't know where to start. system of these are important. for example, rethinking

priorities and outcomes. we have to think what our priorities are, why are we putting pub look funds in research a particular thing. another interest for us is analyzing sex, analyzing gender analyzing how those two interact, i will say more about

that. analyzing the other factors that intersect with sex an gender, these include socio economic status, lifestyle in cells and animals, comorbidities, cell type, type of disease treated animal strain and kay june practices and so forth.

-- caging practices. you can see case studies in different buckets. someone was mentioning osteoporosis instance men had been left out of the research so we delved into that one. so i would like to reinforce here just one point from our

method analyzing section, this was touched upon this morning, that is reporting null findings, this is very important journal editors need to hold the line on this. so marsha mcnut, editor in chief of science tells me that in the first week of november we will

have guidelines. for researchers i hope they're really good. let me give a quick example from stanford, our center for sex research is getting seed grants to researchers so whatever they're doing in that research if they add the sex or gender

dimension, we will give them some funning to do that. so the first round of funding is coming in now, and one lab was panicking we don't have a result to give you. the pi simply didn't recognize the absence of a different as the result.

so we have much more education to do. people have to recognize that and your honors need to publish -- journals need to publish it. >> just a second. i want to go back here for a second. now i want to open discussion to

gender. sex refers to biological characteristics and gender refers to socio cultural process es. authors in peer reviewed journals use gender because they don't know what it means when they mean sex.

my point here is word sex and gender are not interchangeable, preaching before the choir, we have to get on to colleagues. eached precisely. peer review journals must hole line on direct terminology. careful use of these terms enable meta 'nalsis of archive

data which is not possible. >> so we as research community really are smarter than that, we shouldn't be confusing these because it's not that hard and we can get it right. on to gender in animal research so gender is a constellation of socio cultural processes than

interact that and influenced biology, that's why we care. the danger is p,s confound sex with gender and i don't mean here, just using the terms encorrectly, but that we see secretaries or buy -- sex or biological trait when we are looking at gender in the lab or

environmental conditions. so gender influences sex an vice versa. animal research i will use the term gender for subset of care management and environmental processes that may impact male and female animals differently. such as caging or differential

handling of male versus female animals. gender will be those characteristics that could be mistaken for sex so subset of the environmental factors. i don't want to call it the environmental factors. so again we don't want people to

see sex or biological trait when they're really looking at gender or an environmental condition. the reason i call this gender and not just environmental factors is these gender differences are precisely the ones that we might mistake for sex differences.

that's the challenge. i would argue analyzing gender in addition to analyzing sex will be increaseing value of animal models. let's have a look. verbalization guy at stanford start working with me on this and i would be happy to get your

responses. so animal research includes what is in the animal here analyzing sex, those are the biological traits and then how these interact with -- what i'm going to call gender, i have an example for each of these that i will talk about too.

and double ended arrow interaction between the two. so in general applied to humans, however it might influence animal research as follows. i want to make three distinctions here. so gender norms, you have to learn this, i'm sorry.

i'm putting a quiz afterward. you have to learn this. so gender norms refer to researchers attitudes toward and handling of male an female researchers may act on gender stereotypes concerning the behavior of male an female animals, so gender males are the

forces for humans the social forces acting i don't know you to make you follow the rules and for animal research they're the forces the gender norms are the forces from if researchers. the researchers attitudes an behaviors acting upon the animal that trigger gears stress or

behavior in the animal. so look at an example of that in a moment. gender relations refers to the interactions between male and female animals, on one hand and between men researchers an women researchers an male and female animals so between researchers

an animals on the other hand. there's also gender identities, this is what you're most familiar with, undergraduates will think of when they're thinking of gender. and gender identity refers to how individuals perceive and present themselves how they're

perceived and presented by others whether behavior is masculine or feminine, straight transerosives, facebook last year released 51 categories of genders, we can't be binary now. i'm saying i don't believe gender identities applies in the animal lab.

i do not believe that little mice and rats have gender identities. virginia primate mice, i think some of the other animals might but not these animals so i'm interested in the first two, the gender norms an relations. here is another -- visuals are

helpful, here is an image how sex an gender interact over the course of the lifetime. so you have in the germ cell you have both coming together and then you have the biology happening interacting at the same time at every stage of the life, to influence the -- well,

adult animal or animal as long as it may live. so let's look at it in a couple of examples how gender might be con founded with sex. and some of these have come out of i think interestingly come out of canada because canada sense 2010 had a policy for

integrating sex and gender in to their baying is research, it doesn't have teeth because you can still get funding even if you don't do -- but i think it has sparked a lot of research. caging environmental effect and animal. so importance of caging

practices shouldn't be mistaken for biological sex differences. you know males are often caged alope buzz they fight and females are typically caged three to four in a group because that saves money. its et al in canada shows when animals are housed alone hay

they pen more energy maintaining body temperature which causes differences in caloric entake, muscle activity, metabolic rate, fat distribution or body size and then a plethora of potential downstream effects on bodily and cellular activity. animals housed together by

contrast cruster together to sleep. and as a result they spend less energy just to stay warm. the danger is if we don't analyze gender sex difference maybe identified where in fact differences result from housing conditions.

it's important here not to see a sex difference when what we're looking at is influenceed by cages difference. we know this but pendergast et al in 2014 meta analysis found half the studies of mice failed to specify the number of animals per cage.

so there's a lot to be said about caging but you get the point. so i want to go on now to the re search staff with a second example this example mentioned this morning but i want to >> into it in more depth. this is an example about the sex

of the researcher and the response of the animal. so it's not about the gender of the researcher. it's not about the attitude or behavior of the of the researcher but about their pheromones. and the gender in this example

is then the relationship between the researcher and the animals response. so it's in that interaction that i was talking about before. so here is the study, experiment or sex maybe a confounding variable in rerodent research where stress is a significant

factor. floor et al out of (inaudible) lab earlier this year found rats and mice demonstrated reduce pain response in the presence of a male experimenter as compared with empty room. whereas presence femaleer experimenter produced no

both male an female rodents show response but the affect was in females. researchers identified male observe very effect as stress response to male pheromonepheromones found at higher concentration in men than women. stress can effect the release of

god inial steroids and sex deferences in behavior an physiology. so researchers were specifically measuring pain response in the in this case we found the sex of the researcher matters but it's an example of gender relations that needs to be taken into

account. animal had specific responses to men an women researchers. and according to mogul this throws into question all prior results from pain research. so let me conclude with just a few comments about policy. i'm very interested in the

policy we are developing here. on our website we also we also give information about policy. we have policy of measure major granting agencies an peer reviewed journals. i want three interrelated areas. granting agencies are very important.

granting agencies can ask applicants to explain sex and gender analysis and how this is relevant in their proposed research as a requirement of funding. and i have to say that u.s. is a bit mind in this. we were ahead in 1993 when nih

asked for women to be included in phase 3 clinical trials but now european commission has move aid head in december 2013, they launched horizon 2020 and designated 137 subfields of science health an science engineering that must include gender an sex analysis.

horizon 2020 is the next seven year funding framework for the european union. as i already mentioned since 2010, canadian ta's institutes of health research request all granting applicants include section and genre in their research design.

eu, ec has more teeth than canada but canada is important these policies from nih are very important, we need to keep our place in the world and we need to do research right. among other things i recommend nih develop some compendium of sex differences, i draw your

attention to belynn institute of gender and medicine, on their website. they have a database of vetted articles on sex difference in humans and animals and we shall take this opportunity to think up -- sync up with international groups already doing this work.

the carol linska institute in stockholm has resources. so that's major granting agencies, on this website or this page we have given policies of the granting agencies that we know about and that we think are i mention peer reviewed journals.

this page we give all the policies of journals that we know of, i would be happy to add more journals to this. so the second area of policy important to implementing sex and gender analysis is the peer editorial boards peer reviewed journals can require

sophisticated sex and gender analysis when selecting papers for publication. and i think the very best policy right now is from the clinical ortho pee dick and related research, this journal in january of this year, they did a wonderful editorial, if your

journal is thinking about this, i think you can adopt it to your particular area of research, it's useful. finally, we need to integrate the knowledge of sex and gender differences in the medical curriculum. i think it might be criminal if

we don't. aren't people going to do you know dye if medical students don't have the right information we nova have miller work on this there,s a consortium of 7 medical schools working on we certainly need to donor. thank you very much.

>> we'll entertain any questions. >> when jeff was the editor. adopted the rule, that the title must state if it's male or female leading the charge, the bigger journals i interacted with don't go there but e certainly hope they understand

that they need to go there sooner or later. >> i want to make sure credit is given where credit is due. the major driving force for change in crick almost has come from the women's health in gender collaborative with spearheaded by marjorie jenkins

and her materials go live soon. she's going to put out an rfa for medical schools to actually pay to at this their materials so she'll offer grant money for them to incorporate those materials in to crick hum in the spring. analysis of that success --

curriculum for that in the organizing jointly with aamc and there will be more information on that. (inaudible) start asking the right questions, that will be facilitated. in the meantime comprehensive material that she has -- go

across specialties including pharmacists and nursing and health science as well as medical schools is going to be transformative. all the materials have been vetted through experts and it's going to be -- a great web material and definitely

compliment gendered innovations that led the way in terms of providing international re resources. >> that's good to know. i can't move stanford on this point, i just can't move them. i want to add to that, besides medical curriculum there has it

shall a move to get that into the graduate curriculum as well. , we have the requirements for responsible conduct of research every grad student at nih has to take. this should be a (inaudible). >> we have to train the next generation.

it's absolutely crucial. >> this is a curiosity question but maybe it will -- why is it that both canada and europe have been so much further out front on this issue than we have? >> united states of america after all. we invented gender analysis,

north america did. canada and the us. we don't have any stomach for policy and everyone says we don't want to do things top down and i think that's really where europe gets its strength so europe tried to do this in 2003 they require people to integrate sex and

gender into research design, they got push back because people didn't know how to do it. so they arrived in my office an offered me money. how good is that. right? they wanted to develop tools for so now i told them the next step

is to have big training workshops. i think nih, i don't know if that's a model but training workshops to get the current generation of researchers up to speed. the things i mean, it's not rocket science but we have to do

it right. and i can't believe such smart people don't get it right. >> congratulations on this talk about work, can you update us on what's happening at the un, update on testimony and what's happening on the horizon there. >> don't think -- the un is not

really the agency to take this on. they have large issues but the year that i worked with them they took gender and seen and technology as a theme for the women's unit. we did a physician paper, globally which is really hard.

then last year they had an update what happened. i was happen myopy to report on the european commission, a lot had happened there. so we have a lot more to do in the us. i think -- so now nih is on board and assess needs to get on board, i have great hopes

with france, used to be my colleague at penn state p and she gets it completely and i don't know how -- so all the life sciences at nsf, it's very important and for any engineering that has a human end these issues are extremely >> i'm a program director at

nigms and i want to say we put out a funding announcement for institutions to come up with training modules. for incorporating sex differences as a biological variable. >> oh. so can you just say a little bit

more what this is. >> it depends what the institution comes up with so put in an application and get reviewed. we (inaudible) maybe a month and a half ago. >> okay. you have to get your --

>> yeah. yeah. i would like to get your card, i would love to get more details. >> thank you. we'll move on to session 3. >> if i can invite all the speakers from session 3 to to come forward please.

>> welcome to session 3. we had a lot of interesting presentations today that really point out the importance of conducting a sex gender analysis of data and while the focus has been on pre-clinical research, we have heard it's also important in clinical research

as well. so we're going to be moving to session 3 which is entitled practical methods to integrate the biological variable sex and research projects. so if you had an earlier version of the agenda you may have been expecting gary churchhill here,

i'm not gary churchhill, i'm the moderator cora lee wetherington from the national institute of drug abuse. this has been one nida has been advocating for a number of years. we had program announcement in this area and have continued

since 1992 but it's really hard not to crack -- nut to crack as you know. but the clayton collins article is just a major turning point for us. so we have been advocating for looking at sex differences in pre-clinical research and then

clinical research in all areas of drug abuse and analyze sex gender in all areas and also to recognize that when difference is found you done leave it there as an interesting observation but you do something about it you take it to the next level which maybe an application level

or if you're talking about basic pre-clinical research, it maybe what's the mechanism, what's going on here, when you sea a male female difference you have a free tool there, telling you if you can fine out what's causing the difference between males an females you're learning

about the subject matter you're studying. we also recognize that when there is no sex difference, no gender difference, that doesn't mean sex or gender does not matter in that particular subject matter, so males and females get to the same end

point but by different mechanisms, that's really important point to drive home finding no difference doesn't mean being male or being female does not matter. another point is that just simply not finding a male female difference in pre-clinical

research if you throw in another variable that may change the whole thing, may reveal the male female differences so these are the issues that we have been advocating for research to recognize for a number of years so in this session we have three speakers and i'm going to take

some time now to tell you a little bit about all three of them and their talk. and then they will speak one after another. so first speaker is dr. susan makris from the environmental protection agency where she's been working in various

capacities for 23 years, her regulatory work focuses on toxicology assessment and risk guidelines guidance a and policy, developmental reproductive toxicology an risk. initially at epa she was in the office of pesticide programs where she evaluated hazard and

risk characterization for numerous pesticides. since 2004 she's been with epa national center for environmental assess where she's a senior staff toxicologist in the area of human health risk assessment. she's authored numerous journal

publications nci and book chapters in this field and is a long standing member of u.s. and european considertology societies, behavior teartology society society of toxicology an risk assessment. and her talk today dr. makris will discuss the toxicology

guidelines that the e pa uses in pre-clinical research with particular emphasis on methods and techniques for integrating that research. so she will conclude with a discussion of the importance of sex based approach. the second speaker will be

dr. art arnold who is a distinguished professor of integrative biology and physiology and director of the laboratory neuroendocrinology at ucla. editor and chief of the buy lodge of sex difference, the official journal of the

organization of study of sex differences, a publication of society of women's health research. he's also the inaugural president of society of behavioral neuroendocrinology from 1997 to 1999. and he's a aaae of -- he's long

studied biological factors that make males an females difference. what he calls the sex objectionme. which she describes the sum of all sex based influences on gene networks and cell systems studieded globally.

his talk will highlight the fact for two prevalent serious health conditions, obesity an hart disease, research has not asked the fundamental question whether our sex chromosomes play a role apart from our god inial hormones. he'll describe core genotype

model to tease apart the two factors, it's a spoiler alert to women, you may not be happy with all his results. remember a comment made by jill becker that biology is not destiny. a final speaker is dr. jillian einstein, faculty member in the

department of -- department of psychology and public health sciences at university of toronto. director of the new collaborative program in women's health. she's currently treasurer of the organization for the study of

sex differences an serves on the advisory board of the institute of gender an help which is canadian institutes of health her book sex and the brain reader published by mit press is a compilation of with critical introductions to each chapter. dr. einstein's research program

focuses on women health research sex difference in the brain and empirical explanation of whole body exploration of mind. her work is based on the premise of brainplastity and she use as variety of methodologies incruding standards psych logical test of memory and pain

response psychophysiological task, fmri and qualitative interviewing. her talk today will center three topics. first, what clinical researchers need in order for animal experiments to be relevant. secondly we will hear more about

integrating the idea of gender in pre-clinical studies. and finally she will tell us about approaches from canada. our firstlaf.a speaker. thanks for the nice introduction. thank you for inviting me to the wonful workshop, impressed with

everything i heard today. with initiatives ongoing, there's really astounding a lot of work, a lot of thoughtful conclusions people are coming to so i had the intend of talking about toxicology testing guidelines, actually glp pre-clinical testing guidelines.

in a way it's a little bit a little off track what you guys are doing in your life and in your jobs but there is a lot of overlap as well. so hopefully i can write bring that to your attention today. there we go. so testing guidelines are

standardized testing protocols. i don't know if you have really had a lot of time to look at testing guidelines, probably not. most of you seem to be researchers and you're making your own protocols. these are standardized testing

protocols. and they're developed for regulatory agencies throughout peer review and public comment processes and they're published, publicly available on regulatory web sites. it's not just epa, not just fda, there's a lot of different

agencies that have testing guidelines but i'm just going to focus today on epa and fda, fda also harmonizes with the international committee on harmonization and epa harmonizes with the organization for economic collaboration an development which is a global

group based in paris so these guidelines are broadly applied, across a number of different agencies an offices within the agencies. and there are a lot of different guidelines, categories of guidelines listed here for epa and and fda but a couple i

highlighted focusing for the most part on the toxicology studies. the pre-clinical toxicology studies that we're interested in today. so for e pa there's the health sex test guideline, fda the safety guidelines.

i mentioned glp, that was one of the things i was asked to talk about a little bit, good laboratory practice regulations are intended to assure -- to as much as they can the quality and integrity of data for regulatory decision making, so these guidelines include specification

on lots of different aspects of study conduct. on how studies are organized, the actual organization of the laboratory and the personnel the facilities and equipment and animal care and standard operating procedure it is laboratory has to have on hand,

how the tests in control an reference substances are handled , the study director and what the roles an responsibilities are, glps require that every study be conducted with quality assurance unit, that's based in that laboratory that looks at both

conduct in the study, protocol for the study and the reports that are done for the study as well. glp documenting the data recording it, archiving it and reporting it. so even reports are reviewed by the qa unit.

that can give you a lot of confidence in the way that the studies are conducted. and also reports from the glp study. they actually."rdz don't addressthe adequacy of the study design or how appropriate the end points are being collected.

so it serves as one very important function you enup with a good study when done under glp generally. it really doesn't say have we looked at that time right end another thing that needs to be talked about in terms of guidelines, one thing that isn't

addressed by guidelines is when you actually do the study. for different regulatory agencies that can be based upon different attributes guidelines or guidance or decision making. toxicology testing requirements for office of pesticides and law under fifra.

might be applicable in some agencies, we need this particular study in a registrant to provide test rules can be set up through negotiated processes and very formal processes. from can be published recommendations or guidelines, there can be negotiated

agreements that happen between industry and regulatory agencies and sometimes the studies that are conducted might be actually non-guideline studies. though they very lookly be conducted in a glp laboratory. this is an example of the tox testing requirements for foodies

pesticides where there are a number of studies required acute subchronic, immunogenicity an special testing. and some of the studies lived there are required it would be based upon the data you have on the chemical. there might be strategies used

in the toxicology testing frothiest pre-clinical studies. there are differences between environmental agents are approached and pharmaceuticals would be approached. so for the environmental agents these are actually broad screening studies.

the purpose is identify hazard dose response for use and ultimately risk assessment, a lot of times these study there's lack of important information for example mechanistic information mode of action or adverse pathways, toxicokinetic data are not available.

so that would lead you to an approach you need to more rigidly adhere to the guidelines to the study protocols that are out there. there's not a lot known on human exposure, sometimes the pesticides or the chemical substances that are being

tested, we don't really have a lot of information about human exposure. it might be assumptions that we're using to try and estimate how people might be exposed. we might know what the use is for a pesticide we might know what's showing up in the

environment and we i'll make some assumptions but human biomonitorring data aren't available so in general, the purpose of the risk assessment for environmental chemicals is to avoid or limit human so for pharmaceuticals it's different because the studies

are generally designed to focus on specific questions regarding target organ toxicity, and and assess safety. there ooh usually extensive database of information available for incoming pharmaceutical being assessed. all the good stuff that's

missing for environmental chemicals. mode of action perhaps certainly pharmacokinetic data so that leads to an approach where there's more flexibility in study design. and of course for pharmaceuticals the human

exposure is going to be intentional, not accidental. so tox testing guidelines are designed to evaluate a range of issues, not talking just within one study those these are within a study but also across studies in general the whole scheme of testing so different life stages

are looked at, different duration race exposure and roots of exposure. there are multiple treatment levels looking for dose response in these studies, looking at species differences, number of difference species used in the testing.

gender differences and multiple target organs structural an functional, by that i mean the different between pathology, and doing some functional aspect reproduction or immunotox. and also mechanistic data and kinetic data. so these are the regulatory

testing guidelines listed for fda and ich under the safety guidelines. and i p not going through them in any manner. one thing i want to point out here is within the list of various testing guidelines, there are some of them that are

actually guidance documents, they're not specifying who you do the study so much as the saying when do you do the study. what would be the reason to do a study like this. and basic principles for doing the testing. that is a different kind of

approach than what's used for environmental chemicals. and allows more flexibility in the application of these guidelines to test them. whereas for the regulatory testing guidelines for epa as health effects guidelines, as you see a whole list of various

studies by title, in each guideline will have detailed recommendations that go into all aspects of study design, every end point that's looked at, and i have included here a couple of endocrine disrupter guidelines at the end as well, not part of the health effects guideline,

different group endocrine studies but i included them because they illustrate a point in just a bit. , that's here where i pulled out all of the for fda and epa guidelines, pulled out repeated dose mammalian toxicity studies, this doesn't include

immunogenicity studies which are more mechanistic orientation and doesn't include in vitro studies in some of the endocrine assays for epa. what i looked at, do these guidelines say treat and evaluate males and females. as you will see here, most of

the guidelines do specify evaluation of both sexes. a few don't a few say you could use either sex. some there's a blank because they don't mention that sex. and there's reasons. in some cases. i want to mention necessary

these are not the only guidelines out there. fda has red book guidelines for safety assessment of food ingredients and they're a lot more like the epa guidelines. and on their website they include general guideline for toxicity studies which does say

both males and females should be tested in guideline studies. so there's a general approach in these studies to looking at both males and females because it sort of up front screening for assessments of environmental chemicals and pharmaceuticals as test test test test test test

thank you. >> the fundamental difference, the genetic deference plays out in god inial difference that sets up hormonal action that accounts for most differences but the genetic imbalance happens in all cells of the body, to cause unequal

expression of x and y genes which cause chromosome effects which we're trying the study. the main problem is how do you dissociate the hormonal effects. we like to take a female and give her a y chromosome to see if it makes a difference, if you give y chromosome testes

behavior hormones too, those genes in the y chromosome, the first -- it's two major mouse models and other mice too downstream from that and the four core genotypes model was pioneered by fullberg and this makes determination independent of sex chromosome compliment, in

other words, giving a female a y chromosome without making her male, if that's okay. so in this model, the y chromosome which has the testes -- y deleted for soy and it's put into chromosome 3 expressed and now this animal instead of making x spermnd y sperm it

makes x with -- it makes y sperm with x or y or not making forty babies. so we -- for babies. so we study four not two. they're xx or xy animals with ovaries lacking or they're have testes and therefore male hormones so it's two by two x

versus xy on one access and male versus female or god inial male versus god inial female. we study a phenotype. mice, male mice weigh more than female mice, about 25% more. in this model we can study the force sex difference and if this difference in body weight is

result in hormone we expected two animals with testes to weigh more than the two animals with ovaries. or if the model works another way we would expect if it's not hormones, the compliment of sex chromosomes the two xy animals will weigh more than the two xx

animals, that is an effect of sex chromosome compliment. so we have obesity, the studies of karen rubin and colleague and the team in genetics she's an expert in obesity and metabolism, and (inaudible) have been working with us on this issue.

so here is a graph just simple body weight. the two god inial male groups and two -- and then we say okay looks like it's sorting out that it's hormones doing this causing this sex difference in body weight. if it's hormones take out the

gonads to see if the sex difference goes away, if it does after about a month, the males stopped increasing the be body weight and females caught up and after a month there is no group difference in body weight. so that shows that it was in fact the hormones from coming

from the gonads that caused this sex difference in body weight but if you wait another seven months here, it turns out that the two xx animals whether they used to have ovaries or used to have testes are heavier than the two xy animal showing underlying effect of sex chromosome as well

as hormonal. you say wait a second. these two xx animals larger, they always have the sex chromosome, when you go back to the beginning, even when they had gonads, the animals that had two x chromosomes weighed 7 or 8% more than animals with xy in

both god in groups so you have a combination of a larger hormonal effect and smaller sex chromosome effect in opposition because male hormones make them bigger female x chromosomes make them bigger so they're canceling each other out partially and you can see the effects under

different conditions. weight is due -- the sex chromosome effect is due to fact so if you take out gonads and wait ten months and body fat the two x chromosome animals are almost twice as bad as animals with one x chromosome though it depends on whether they used to

have ovaries or testes. going on so that's one model before genotype, it really shows there's an x versus xy difference and the second model which we call -- which is called xy star is another set of genotypes and wish the number of x chromosomes in the presence of

y chromosome are independent of each other. so the animals god inial males or females, one or two x chromosomes so is males have a y and comparing the two columns one x versus 2 x chromosome but god inial males compared to the females y chromosome, it's

different model, in the model same experiment, take out the gonads, wait a few months and the animals with two x chromosomes weigh more than -- have more body fat than the animals with one x chromosome. this shows sex chromosome effects on the x chromosome

we're making progress here, first chromosome effect, and now what we're trying to do is find genes on the x chromosome that are causing this effect and we have in fact found two genes, not going to talk about it two genes escape activation which make a difference in body weight

one adiposity. so we're -- the real goal is to find new genes to control metabolism in a second specific manner. the geness capitalling act vague are particularly interesting because both x chromosomes express in females

and one in males, constitutively as a matter of sex chromosome compliment these are higher in xx than xy and they're particularly interesting in one class sex chromosome effect. we collaborated with (indiscernible) in ucla department of anesthesiologists

and she's expert in cardiovascular disease and pulmonary disease and we found sex chromosome effects in a cardiac ischemia reprofusion model and model of pulmonary hypertension. so if you take the heart out of the animal and profuse it, allow

stabilize for a while, give ischemic event to turn off oxygenated for half an hour, and brief per fuse 15 minutes you can measure how this ischemic event was in the groups, we find the xx animals are -- so here is the heart beat, pressure, trace in the hearts beating and x vivo

experiment. showed off the oxygen supply for half an hour an allow the animal to recover. it turns out if the animal has two x chromosomes it recovers more poorly than one x chromosome it's x chromosome effects measure, one of the

measures of infarct size, white hair has damage tissue in the heart. and you can measure the infarct size and show that xx animals are worse than xy and as i said before the second model xy star model comparing one x versus 2 x animals with two x chromosomes

whether they have a y chromosome or not. worse off in recovery than animals with one x chromosome, so x chromosome effect having a second puts female at risk here in a god in he can tomized we're focused on trying to find the x genes that do this, and

our focus is on these specific genes a handful of genes higher in xx and xy because they escape xx activation. so we are indebted to number of nih institutes for supporting this research, so thanks very much. while the slides are being

switched over i first of all thank janine collator very much for inviting me to participate -- clayton very much for inviting me today, amazing set of talks so far and i expect the rest will be fantastic. i have learned so much and gotten so excited.

and i also want to thank her for the initiative because it means a lot to the world when the nih does this and makes a strong statement. it also want to say i really appreciate the lovely enterduction but i think i need to update my website.

because first i was the first treasurer of the ossd but rita is the current treasurer so it's her problem now and i'm now chair of institute of gender and health advisory board. by which i'm honored to be and gives me an opportunity to talk about the strategic plan in this

talk. i also like the say i modified my soon activic goals a bit and decreased them to just studying oo freaktomy studying cognition for oo freaktomy prior to menopause. i wanted to bring you up to date a little bit and myself.

oofectomy. and myself as well. i want to say that my -- i want to call my talk and go out on a limb thinking gender and so i'm taking off where londa left off intersecting and year lapping. we will see where it goes.

the prelude is like many others like larry in fact, i started off as a basic scientist, i injected single cells, i traced synaptic input, and i moved into pre-clinical research in humans looking at the effects of oofrectomy on women who carry the braca mutation.

i can say it's easier than studying how human beings are messy creatures. second of all, i feel like i'm giving this talk a little bit from the perspective of somebody who is p trying to go back and forth between animal research and the clinical case and so i

think a lot about what i might need to know in the modeling of also want to say it's sex and gender because the world is right on everybody including animal bodies. gender isn't just self-reflective, as londa pointed out, it has to do with

your power and place in a higher archie which animals have, it has to do with how you're treated on the basis of your phenotype. and environment. so in these ways gender is relevant to pre-clinical models so what i wanted to talk about

is what i as clinical researcher would like to see or need from animal experiments to be relevant to a large extent to what i think about and i would like to talk about translating gender to pre-clinical models three examples and then some approaches to canada.

so gender is like this psychology elusion. it's either sometimes gender and sex it's a vase, sometimes it's a face, two faces facing each other. they're flickering demand out. that's how i see them. we sometimes separate them for

purposes of an experiment but it's really hard to dissociate them. and what we need are models that match the human condition because they're not reductionist. human conditions are complicated.

so we need what i would call a situated science, the intersection of sex age time of day, all the things we have been talking about and i talk about on the paper in a chapter on a study called situated neuroscience. so we need to think about

co-morbid conditions because most humans have are not just one condition. many go together for example in pain, there's hardly anybody who has temporal mandibular joint problems, they have chronic pelvic pain with it, they might have addiction treated with

opioid, et cetera. we need environment because environment affects the progression and the etiology of conditions social conditions for the same reason, as developmental background make as huge difference in how conditions play out you need to

think a little bit more about whole body effects. i'm a neuroscientist by training so i think about the brain but there's a lot in the body that affects the brain. so the immune system reflects the brain, the reproductive system affects the brain so

whole body effects are going to be very important i think when we're making these models. at least the give a nod to the fact that we can't just study one system in'slation. in thinking gender and pre-clinical models i think it's important to first situate your

model. you want to think about this species, this cell type under these conditions. because your species can make a difference in what the outcome of the experiment is. we want generalizable principle principles.

it's important to be clear about all conditions. i would like us to think about the whole model, not the single animals because their effects of a complex biology and issue of co-morbid conditions. i would like to step out to think about gender an animal

models, pre-clinical animal models because i think that gender for (inaudible) is like memory in a sea slug. so memory is a very human phenomenon and eric kandel said to himselfs this human phenomenon in to pieces to talk about it in a sea slug.

i think in a way we want to do the same thing to gender, it won't be applicable to human condition but there's ideas we can take from that that will take us in a fruitful direction. again we want to think about environment as being the social world for animal models.

of course as has been pointed out now, scientists have gender too, we have gendered expectations about what we're going to see in the materials, we have expectations ability what we should study if male or female. and also we have gender as well

that affects the experiment. first example i want to talk about is situated in a particular model. this wasn't a ground breaking study by any mean, it was about a hundred years ago with kristina williams and graduate student.

and we looked at aged female denty granule cells deprived of god inial steroids long term, we saw in females that females deprived estrogen long term had decreased spine density and the age males did not. it was different between males an females for sure.

you don't have to be an anatomist in this difference. in this particular species sprague-dawley rats, there aren't differences in granule cells, in this cell type denote granule cells, we didn't see -- and enders these conditions long term deprivation and i will tell

you something else about the condition which was when we gave females estrogen back in long term fashion by implants and synaptic tubes we didn't see any difference in the granule cells spine density so it didn't change because we gave them estradiol long term.

but when we gave them 17 beta estradiol short term or in a bolus, we saw that the denty granule spine density went up in females and in the males it went down. so we saw sex difference but the way it was administered makes a this takes you back to health

initiative and makes you think what hormone were they delivering, who was it being delivered. how hold were the participants? how old? it makes you need to situate what the out i don't mean of studies were in terms of detail

of the study themselves, that's important insight pre-clinical models can give us. then i think we can also think about the whole model and not just a single animal. so what is your model that you're looking at so jane danska asked about type 1 diabetes, why

more common in women than men. one thing she noticed in her animal was that when males an females were raised in in pathogen specific pathogen free specific environments the males had a very different microbiome than the females did. and when they were raised in a

germ free environment there wasn't a difference. so the environment made a big difference in what was seen. and she also saw in the specific pathogen free environment testosterone in between germ free and specific pathogen free environment testosterone levels

were different in both sets of animals and in both between the environments. so she saw this correspondence now between testosterone levels and the microbiome which is really incredible. so she went on to look at immune system function and model for

type 1 diabetes f they were raised in this specific pathogen free environment. whereas females were not so she concluded the higher tees to roane made a difference. if she transplanted, if she transplanted the the male microbiome to the females, she

found a decrease in the incidence of type one diabetes. this is an amay z egg people, it's complicated but it is what it is to be in a complex human world and it's an animal model. another animal model to metaphor using environment instead of self-reflected nothing of gender

another ole experiment done by (inaudible) lab jerry and jew death stern probably judith steps idea to look at the representation of somatosensory cortex of lactateing female rodents. what they found was that in the females who were not lactating

the representation of the ventrum was the same size as -- quite small. in the lactating female, the -- it was increased two times. this is a really interesting experiment, it speaks to a particular female condition of pregnancy and lactation.

and it tells you about experience of lactation. i makes you wonner how hormones play into this, how does hormone change after pregnancy approximate lactation, does it potentiate this expansion? does it reduce the expansion? does it influence the expansion

at all,? so it opens new questions whether what's it like for human t-cells. turns out there is not a model. there's not a map of the female body and the female brain so pen field mapped the mail brain but he did map the female brain he

mapped ten women, he only reported on one. and there is no map that was generated. so it raises all kinds of interesting questions. but also shows if you take the environment as a met for for the gender world you begin to learn

things and raise questions about being engendered female, this is experiment that everybody is talking about already now. at least twice. thinking antigen defer pre-clinical models where scientists have a gender too, amazing experiment jeff mogul's

lab, showing that whether male researcher sitting in the room, the pain thresholds of rodents was lower male rodents was lower than female observer sitting in the room and h he correlated with increase in stress hormone in the males which reduced the pain threshold.

this is another complicated kind of model that also talks about really what philosophers call the second person interaction, it's the interaction between the environment and the subject, it's something that i think is really important, i don't think about we can think about it any

longer. talk about the model existing in isolation. from the investigator. so to talk a little bit about approaches in canada, londa raised the point that in canada we have had a mandatory reporting of sex and gender

questions in our grant application since 2010 which does include pre-clinical animals, pre-clinical models as well as humans. how successful or not that's been, had a report, written up, and what we're hoping to take it to now is the level of actually

having this question count in a review process. and we will see how successful we are. but director of our institute joy johnson is working hard on having this become part of the we also have strategic plans 2017 going forward which is our

key goal to bring the social together with the biological. while at cehr if you look at the total funding for biomedical grants as opposed to psychosocial grants, the money is really going into the bio medical grants there what the kind of funding igh, institute

of gendered health looks at is the kind that is integrating the psychosocial and what we need to do now is to bring the biomedical into what the institute of gender an health is already strong in. we also had an igh sponsored workshop in 2013 for bench

scientists on inclusion of inclusion an sex which resulted in stacy it's paper cited here. so there are things that have been -- being done at the institute of gender and health. we have an emphasis on something we call capacity building in canada.

so training. and we have had for three years an institute, gender an health summer institute for graduate students post docs. that tries to bring the biologic together with social trying to unite sex and gender. we brought a lot of qualitative

interviews, qualitative work together with more quantitative work and tried to help students think about how you would do this is a specific stream training initiative from british columbia looking at effects of sex and gender on addiction. and it also also has worked hard

bringing students from the bi medical quantitative sciences together with those doing more qualitative research and the training program includes monthly web exseminars where people began to integrate what they're doing. there is a collaborative program

in women's health it is a graduate program that tries to bring together sex and gender. we have two key elements in this program, it doesn't affect every graduate student but it does effect those interested in women's health, those interested in doing this multi-disciplinary

research since 2007, which runs every single month. the goal of both of these is to juxtapose biomedical with the theoretical so the course when we read about say autoimmune disease being common in women and men and the students read eleanor fish's paper on on

auto-immunity which is extremely interesting paper. we also have faculty from different disciplines respond to the students work. the last thing is the canadian consortium on neurodegeneration aging a brand new initiative out of canada.

we have three themes, 8 platforms cross cutting programs , and myself and mary proposed a cross cutting program on women and dementia. we are now faced with the task of integrating gender sex across all of these platforms teams an themes with dementia, it is

exciting we're developing principles an procedures for this initiative, and be happy to share with them later. in thinking about gender and pre-clinical models best practices. are the same conditions difference for male females an

male? we should get rid of the notion either or binary. this is come up today. we talk core lap and plurality, we need to provide individual data points so we can see the overlap. need to acknowledge recognize

difference without redefine be open to similarities, circumspected interpretation an determine which differences matter. we need to do a piece of pr teaching people that difference is just a difference, it's not better or worse.

and i just want to say sex and gender matter and to quote the iga 2017 strategic plan has have you considered the possibilities. >> so at this point i would like to invite the three speakers as well as our keynote speaker up. and the floor is now open for

questions to all of these speakers as well as comments. >> wonderful job each and every one of you, i want to make one comment, so that the nih inclusion policy applies to all nih defined clinical research, not just phase 3 clinical the 1993 one applies to all nih

funding clinical research, clinical, not just phase 3 clinical trials. so i want to correct that. there's additional requirements for phase 3 clinical trials in addition to women being included studies have to be designed such that valid analysis for sex

difference can be performed. so that's the difference additional requirement for phase 3 clinical trials. >> could you speak how canada manages for the basic sciences all model organisms so mouse an rats monkeys, maybe fairly obvious but what are the

mandates or the suggestions recommendations for canadian basic science using zebrafish, xenopus or other model organs c elegance, what's the thinking in -- c elegans, what's the thinking in canada? >> that's a great question. whenever somebody says great

question it means they don't have an answer. we put the policy out there on the grant applications. wanting people to answer it. there is, there are training materials being developed and there are some written documents that joy (inaudible) an herself

as authored. but i will say they don't go into the granularity of how you do this. at the level of cells an non- mammalian animal models, again i think we push the idea that people need to think about this and metaphorrize and

imagine. i think they do but there's no actual policy on it. >> metaphorrize? do you think of animals that have mammals, is that metaphorrization boundary condition? maybe to londa as well.

how far do we metaphorrize given two different given the two definitions that you provided us which have to do with environmental interactioninteractions, zebrafish has -- where are the metaphor boundary conditions. >> (off mic)

>> i want to say first of all, there are fish that definitely have genders that change so the (inaudible) their sex changes but there must be something in the interaction, the fact this is no male. >> i really think that they have gender in the sense that there

is an environment in which there -- >> interaction that that is under. i think that's a good (inaudible) >> the sex changes in reaction to the gender interaction. >> finally this topic as well,

so chromosomes begin to matter to biology as we go up towards humans. i wonner if you and your colleagues have thought about alligator sex is imposed by temperature. so maybe you're identifying genes that will ultimately be

those temperature regulated genes, how do you think maybe in this context of sex chromosomes or parts of chromosomes as they reflect what were now calling sex sry in the case of the four how do we broaden that thinking? >> first research on non-mammals is enormously informative when

you get into evolution of genomes and sex specific evolution of genomes. i spent time working on birds and i want to say i got more bright ideas from studying birds than studying animals, sex chromosomes might make a that's just me but the whole

concept of the evolution of sex chromosomes an this dosage compensation issue which is a major part of the evolving sex differences, if you look beyond mammals you see difference patterns of dosage compensation and how genomes handle sex differences in gene dose an

birds don't at some level don't look like they handle it well just fine but races questions about compensation. so there's a place for this non-mammalian research, of course money on mammalian research diseases must bear in a mouse than alligator.

genetically manipulated them. but i'm a big fan of comparative research because it helps define gives us a real place to stand and view mammals including ourselves. and see how mammals differ an why they differ. i don't know if that answers

your question, but put in a plug for birds. >> endocrine disrupters, animals are often non-mamammalian. >> does the epa start to understand that sex differences and pharmacokinetics and pharmacodynamics are really large?

i was just just concerned when i saw the immunotoxicity as category where there's no sex and then also a question about you had this table gender differences versus sex differences -- you were looking at but also the same level as the effect of where you are in

your life span or wondering is the sex differences going down the chart of all the different things you're looking at? or is it only at one stage? say for example life span? >> well, i think sex differences are generally evaluated in the guidelines the epa guidelines.

so it's a standard component at the testing that's done. rather than thinking of it outside as well, should we do this comparison or not. it's the exceptions,'s a few exceptions where it's not looked at. and but i think in general the

major tox testing that's done to screen a chemical includes both sexes. >> i have a general comment that comes from hearing a lot of the lectures today. quite often we are reminded that when et comes to sex influences there is overlap.

it's presented, i learned apologetic kind of way, there's overlap, and whenever you present the results in your sex influences you have someone say but not true for every man, not true for every woman. and i just wanted to take the opportunity to say that comment

makes no sense. there's overlap between schizophrenics and controls. alzheimer's patients and controls, if fact there's overlap means nothing about the general importance of sex issue and when people say this to me i ask them do you think aspirin

reduce pain? and they say yes, and i say what? you think all doses of aspirin reduce all pain for people at all times no matter the pain? no, no, no i never say said that, be you said aspirin reduces pain.

so there's this strange thing i want to say applies selectively or disproportionately to the sex influence issue where you have to be apologetic about the nature are like those in the entire rest of biology not so much a question as a tirade but i felt the need to comment on

that before this thing is all over. >> i would like to say something about that. >> i'm going to tirade right back at him. only a man could say what you just said. oh, wow.

only a man doesn't know the discrimination that women have put up with in every realm of life for so long and how we are so trained first to apologize for anything, but also we have to be so careful about sex differences research being abused and misused and

misinterpreted, why a woman should be shouldn't be president because they're hormonal and weak an et cetera. it made a woman not being schizophrenic not having alzheimer's disease, not having pain is a biological category. so your argument doesn't hold.

i just -- >> it doesn't diminish it, it accurately reflects it. no it doesn't you're an extremist. you are a convert that's your problem. you are extremist as a convert. >> i would like to say that when

i say there's overlap i don't see it as a apology, e say it actually an interesting finding. because for example, i know men who have carrologist whose have had heart atakes in the same way women present and they haven't recognized it. in themselves and as a result in

fact they have died. so that, in that case it's really important to understand that it -- women don't all get heart attacks in one way and men don't in another way. i think in a clinical realm, so i don't think i wouldn't say it apologetically at all.

it's an interesting fact. need to be acknowledged. >> for those viewing online, we'll reconvene at 2:45. my name is lee alekel from national center for national septemberer for alternative medicine. what is someone from ncamm cog

at this meeting. we do a lot of human based research, i was a human researcher for many years but i'm very interested in this issue of sex differences an extremely interested in women's i think there's a lot those of us from the clinical arena can

learn from basic mechanistic work and vice versa that we have seen today so this cross talk is wonderful, it's excellent. so i will outline what the purpose is and provide some of the questions today. this session is cultivating a culture of sex matters across

multiple didisciplines an purpose is threefold. one to discuss when sex matters and when biological variable of sex should be considered in science. two, two determine where gender fits the research realm and three determine if there is a

research space for single studies and if such studies result in no harm. i may go through these slides very quickly and skip through them just in the sake of time, because i really would like to turn it over the you are speaker s.

to our speakers. but first discuss sex mattersen when biological variable of sex shower considered in science. i would say sex should always be considered in scientific always always always. not that you always contrast males versus female bus you

always have to consider it. so i have a quote from one of dr. milner's articles from the american physiological society. i will leave it to you the read yourself but essentially this is just demonstrating how important it is. so we heard this many times sex

chromosomes are in every cell and they certainly play non-god inial functions at sex hormones and sex differences as well as in terms of god inial function. i won't belabor -- g god inial. sex should be considered in sign toughic research. i can give you lots of example

but will leave to it you are speakers. i want to give you one example that was raised at this north american menopause society meeting that i attend t ed. there was a wheel session one day, it was opt basic underlying mechanisms, absolutely

fascinating so one issue that was raised is why we study motor system instability in women, men have it as well with deficiency. so the time has come to think about basic underlying mechanism s that we thought study it in women. its would be very illustrative.

pheromone neutral zone. meaning that they can with stands temperature fluctuations much better i won't belabor this, we heard about this reiterates what we have been talking about as far as the difference between gender an sex.

and we know what that is. we talked about this, this is the liability of going in afternoon but it's also the advantage because you can move quickly, but the point depends upon the questions being asked, your experimental design and each investigator has to decide

how am i going to include sex in my research paradigm. that's a very important question. we will answer these questions today mind you. so certainly when we think about space for single sex studies with pregnancy, a single sex

study might be appropriate. an there are other really good examples in terms of non-reproductive function, it really depends upon question being asked. providing examples for year here those are the references. now i would like to welcome

dr. miller who is no stranger to this group, i know. i just want to say a few things about her. she's a professor of physiology in surgery, also research director in the building interdisciplinary research careers in women's health at

mayo clinic. and i want to mention a couple of things about her. her current research focus is on preeclampsia of pregnancy and as well as examining sex steroid effects and change changes on accelerating the atherosclerotic process in cardiovascular

disease. for sake of time i'll do both introductions at once then turn it over to our speakers. so the questions dr. miller has been charged with, though i understand you may have questions of your own, working address disease states what role

do they play and how they interact with regard to comorbidities. also we want to welcome dr. katherine sandberg from georgetown, director stuff study of health health -- pref professor of nephrology and hypertension, department of

medicine as well as a ph.d. program director. so we have questions for dr. sandberg, when approaching a new research question, what methodology can be used to determine whether or not sex should be considered and are there circumstances to justify

studying a single sex. so i will say a couple of things about dr. sandbag's research. it is also in the god inial -- so cardiovascular disease and so their research areas actually seem to overlap a bit. without saying any more, i will turn this over.

once we get up the slides. >> thank you very much, this is such a stimulating conference, thank you for inviting me. i will like to 'know ledge funding through the score program which is co-funded by the national institutes of aiming, i wouldn't be here today

if i hadn't participated in this particular activity. as we mentioned, i was charged with discussing culture sectors address disciplines. i will do that by addressing three questions that i was charged with. is it acceptable to exclude sex

as variable experiencal design. i turned it around a bit. can a specific criteria be developed for excluding consideration of sex and experimental design. and what tools can be acquired to work across disciplines understanding animal models of

complex human disease. this is key and has been brought up a couple of times and hope to leave you with rereally definitive questions that you might be able to ask to direct the answer to your own research. first question, is it acceptable to exclude sex as a variable and

experimental design? you already know the answer to lee answered it. and i'm going to answer it again every cell has affects. so a fact of life is sex always a buy logical variable of animal derived material. i put animal derived material

and not hour to put vertebrates when we talk amoebas and paraplease yum, i don't want want to go there but talking vertebrate animal you have sex as variable and it needs to be identified. i needs to be identified in the methods.

when i was in graduate school we were taught write writhe meths so somebody can we produce your experiment which is details. and i think the whole impact factor thing has deterred us from that. because typically the methods are shortened, put into the

supplemental material and who knows what everybody has done. we have to get back to being presize in science telling each other the exact parameters of our experimental design. sex is key to that. so second question, can specific criteria be developed for

excluding consideration of effects and experiment design. i told you we have to think as a this leads us to the question, is it appropriate to study single sex -- single sex experiment experiment that doesn't do no harm, i was put out by the donor harm we'll

frame this differently, it's not an issue. when we think about sex differences, we think of -- i used to say three categories but i want them -- i lump them into two categories. first you have to consider that when we talk about sex, it

affects every system of the body. so we have to get back to thinking integrated physiology, if we're going to advance pre-clinical studies to translational level then think about it in two ways. we can think about it as sex

specific versus sex different. so what are sex specific can bees? these are conditions which are unique to one sex. they clearly, we can't study prostate cancer testicular dysfunction, ovarian or uterine things in the pop sit sex

because the organs just aren't there. so that takes care of a whole group of studies which has to be sex specific. in order to understand the mechanisms of the disease associated with those organ systems.

the second step because we're thinking integrated physiologists are conditions or diseases which occur more frequently in one sex or the other, present differently in one sex compared to the other. for those of you who are physicians, in here, think about

one disease that doesn't fit the second category. i don't think there is one. so when we break into two separate categories whether it's sex specific or sex different in terms of presentation morbidity, mortality, you have to think that it fits into the realm of

you have to study the sex differences. now i'm going to use our arnold special phrase of sex biasing factors across the life span. i love this picture. for a variety of reasons. first of all i think it's very sweet that it shows the life

stages, but particularly i want you to focus on our woman right the female body is designed to support pregnancy. so pregnancy comes and goes. it's not a -- fortunately it's not a permanent state. and so you have to accept if the female body adapt tots this

condition, will there has to be underlying physiological mechanisms that allow adaptation. if this is sex chromosomes, or hormones or combination across the life span. and others today have provided significant evidence to say that

it is a combination of the two, you may start with sex biasing factors or chromosomal dictated, but that's going to change across the life span as the hormonal environment modifies. so we talk parameters that influences conditions we can talk about sex we can talk about

gender which i'm not going to say, but critically we have to talk about hormonal status and age so when we think these key variables that are going to affect the outcome of the experiment, the sex differences may depend on whether you have the appropriate age and

appropriate hormonal environment. so we are thinking about this in an integrated way, sex biasing factors across the life span, sex chromosomes underlying them all. so the sex specific conditions reproductive neurological organs

processes. i didn't know what to do with the establish cell lines here because they have a sex. you should identify the sex in your paper, it shouldn't be given that everybody understands a certain cell line comes from a particular source.

we should say that. we are at the stage of scientific investigation where we should say there are data needed from cell lines on previously unrepresented sex. so if the cell line has a lot of information comes from those, i'm not going to try tophi my

niche those discoveries or on variation bus in time to say what will happen if we use a cancer cell drug from male. or pulmonary carcinoma from another cell, whatever particular cell lines maybe. i think we need to start exploring the other sex.

so what about the sex difference? how can you use what we know about the underlying physiology that's going to be different across the life span to help you design your experiment so thinking about this, i would like to propose these questions

for the investigator tick off in their head when they start to write their application an designer experiment. the first one, is there evidence of a sex difference and disease incidence prevalence morbidity mortality in humans, if so, what is it?

if we are translating our findings to the human condition improving human health we need to understand what that condition is in humans first. many basic sciences do not. that may get started thinking. we have to keep in mind this is brought up many times today if

there is a difference in the literature, you have to ask the question has it been studied. or if there is a difference, it has been studied, has it been reported. so these are conditional questions that you have to put on that, because it's not in the

literature there must be no if you look at that time clinical outcome data you will see version differences in any disease you look at. prevalence incidence morbidity mortality, or treatment options. second you need to think, is there an experimental model of

the condition or the disease. we have experimental model, i don't like the word model but emperimental animal to investigate what you want. more importantly we have to analyze was that actually represents in an accurate way the condition observed in

this is again come up several times today. one of our scholars applied for the condition for their thing osteoarthritis. using a male model of disease. and i said osteoarthritis, there's a female prevalence, have you considered the females

in experiments and her answer was no. i'm thinking okay, this is a program women's health, and prepare better for the interview but anyway she's not in our program, but this is what we have to change what the model is actually going to tell us

something about the human finally our data lacking from emperimental model in one sex compared to the other, this is brought up we need to have equal number males and females going forward and i will put forward the fact that we have a huge body of data on male animals.

it's pervasive in the literature we don't know if there's sex differences, should we require every investigator going forward to look at that exact same condition when it's published. so even in those physiological differences between men an women there would be a place for

single sex studies if they are providing a database which is missing. which is information about that we see meta analysis all the time of literature december looking at the same experimental design as much as you can get adequate, you design that

experiment in the opposite sex, that data should have some value and actually be able to formulate or inform further hypothesis generation in terms of investigators, same sex so the question what tools are required across disciplines towards understanding animal

models of complex diseases. i'm integrative anesthesiologist so this is easy way to think but not everyone has been and was trained in the idea you have to develop the tools to get the answer, not the other way around. so i think what we have to put

forward is encourage people to think differently about how they design their experiments. not only how they design their experiments but how they develop their teams and who they work with. so we hear this all the time at mayo because we have to save

money an adjust to the healthcare reformats. we have to think differently out of the box. so why not in research as well. we can. so here is some things to consider. do we work in silos or networks?

do we have limited resourcesorr"kax share those resources and how can we -- if we have unlimited resources how we can better share them. not necessarily, even within your laboratory lab down the hall, can we take a programmatic approach to our ones that are

individually investigator driven. i would think this is a way to think out of box, in terms of we want people to do translational research, we want people to do interdisciplinary research but we still fund single pi program, within that paradigm can we

think of it differently, we have multiple pi kinds of grants, so on, but is there another model that can be developed? for example, if the score project, we have to have human component and molecular -- animal based component, so on, i have used this from our own

study how we look at either sex specific, we look at sex specific conditions of pregnancy and menopause. but i think we can also design this approach more broadly. think of the sex specific or sex difference condition that you want to study.

can you study in terms of the whole animal or whole individual. are there molecular cellular mechanisms that could be obtained from that same particular animal model applied to really understanding what's going on in the oregon structure

in terms of function. so if we take this question here, we -- even when you do clinical trials, although the question related to cardiovascular effects of the hormones an early menopausal women we design eight ancillary studies with those women without

extended burden to obtain a variety of information. so our resource, our volunteers was pulled resource with several investigators, when we went to mayo we did vascular work on dogs who were expensive. we had a pool dog. we called around to everybody

that was interested in doing some vessel or brain or eye or ear, whatever, we pulled those resources and said if we buy the dog this week will you next week and so on. we didn't have to put together some nih thing or score project, investigators saying i only have

this amount of money, i need need to have this animal, do you want the share it. i think we have to encourage sharing limited -- limitation of this way of thinking we can see how easily a shared resource like experimental animal or a -- within an institution could be

shared for physiological studies, molecular testing, other kinds of conditions or other organs that might be available and really develop a network. what's limiting this? i think the tools have to be different, we have to think

network instead of silos. i may get in trouble for this but i hope larry will bail me out because he initially startedded the program talking about brain networks and connectivity in terms of matrixes and brain and networks and female brain.

i'm thinking do we in art brought this up too, same data be interpreted the same way, between a man and a woman depending on their point of view, how they process that information. not better or worse but difference and perhaps time to

think net work than matrices in terms of cross disciplinary in terms of programs. so the next thing we need to think about is how to clearly maximize the limited resources, clearly without compromising precision, scientist want precision and want control, want

to be control with those variables we have to think how they can share resources without compromising precision. within the individual ro-1 laboratories. and really think creatively, i would like to challenge nih as alternative funding models for

how we do they can mechanistic work of sex differences. nih has been around since almost as ole as me and review process, hasn't changed a lot over that time, it's time to take a deep breath and say in this new world we heard today about the cancer society -- or cancer institute

sharing databases on the cloud. is there some way that we can do that also with the animal >> i want to reiterate the questions an close today and leaf you with the answers. so you can go off and be success ful. as a variable in experimental

design? i'm going to say no, lee said that too, we have to for all experiments using vertebrate sex is only the reportable reportable variable. so we have to report it. can sex specific criteria be developed for excluding sex and

emperimental design and i think is here we have to really consider is it sex specific or sex different, and what are the characteristics that you can -- criteria that you can apply to those excluding things. and most importantly can the model be justified on the basis

of disease or outcomes in and i think depending on what the answer to these two questions might be or to these two considerations you get the answer should you even develop specific criteria, rather than having justification for what you are actually doing.

finally what tools can be acquired to work across disciplines to understanding animal model of complex diseases. i think that you have to think defendantly. in terms of network, resource sparing and alternative funding

models. with that i will leave you to go forward and develop your enter disciplinary programs. thanks very much. >> i don't know if we have time for one more question. just one. we'll have time after at the

end. but often situations happen where for example (inaudible) irritable bowel syndrome (inaudible) some of the dominant models in that (inaudible) don't work only knows. isn't it time to see that as hanging fruit and start to say

that is not acceptable? >> yes. absolutely. that's directly to my point. we have all these data out there in terms of irritable bowel syndrome, let's study the female is that justification for (inaudible).

is that an example of the animal model not recapitulating what might in the happen in women or human population? >> to me it's not. you bring it up in study section when the program comes up and people around the table go there's that sex person talking.

but it's -- i don't think it's acceptable. it's not accessible and i her we're not treating patients with cutting edge or the men, with that procedure that won't work, it's unethical. >> on that note i'll turn it over to katherine.

i'll address that question. it's a presure to be here today and thank you very much dr. clayton for putting this together and for organizing our session, fantastic. what i thought i would do for the last talk in this session is not talk about what virginia

just talked about, as you know the session purpose discuss sex matters and when the biological variable of sex should be considered in science. i think i don't need to say what what's already been said. it matters an determine when gender to research realm and

julie jill gave an excellent talk on that. and third topic which is the last topic which is something else to determine if there's research space for single sex studies and it's such studies that result in no harm. couple of examples from my own

research and make my case. first i want to point out this article -- is a pointer here? so there's an article that is written by david harrison's lab in 2007, in emperimental medicine on the role of t-cell an genesis of angiotensin induced hypertension and

vascular dysfunction. you can see by looking here at the total downloads that it is a very popular article andesines citation classic by now. and paper in my field causes a lot of lapse to start studying immune modulation of nowhere in this article did they

mention the sex of the animals and i searched, this is what they showed but no mention of the sex of the animals. so y axis is blood pressure, the x axis is days an this is is a common model in my feel. we have used angiotensin increases blood pressure, it's

model of hypertension because it's a good model of hypertension that clinically we treat hypertension with inhibitors of the synthesis of this peptide or inhibitors of receptor. so you can see when you influence angiotensin brood

pressure goes up that's the black line, just a regular mouse and in a mouse no t cells, the purple line t blood pressure doesn't go up as much. so this is a first indication the immune system play a role without t-cells blood pressure is lower.

ite a green line you can restore the mag did of hypertension. so the author concluded that t-cells are contributing to hypertension so there's immune modulation of hypertension. i told you, there was no indication of the sex of the animals or t-cells in this

paper. whatsoever. if you try to reproduce this study, what happened? why is it going away? i hope that's not a problem. ashame. i'll have to tell you. if you reproduce this study

using male t-cells, and you do adoptive transfer you will restore the hypertension in the male mouse. and you want to reproduce the study you would be successful and not waste money and time and resources and say yes, it's that bind i can reproduce it and i

can study the mechanism. if you use female t-cells in the same male mouse, you would not reproduce the hypertension. in fact if you used cd4 for the confertel 8 t cells you lower the blood pressure. so if you give female t-cells, you cannot drive the

hypertension and if anything you protect the mouse from the so if you're trying reproducibility, here is classic example, we had tried -- somebody tried to do this study in females, they have not been able to to reproduce findings and wasted a lot of resources.

so the wreck you can't see, must be an anti-mac thing. we can reproduce the study using male t-cells but not female t-cells, the only difference in the hypertensive mouse and the norm intensive mouse is the sex of the t-cell. here is another example.

this is another model of hypertension where you take out the right kidney and the left kidney you tie in a figure 8 configuration the kidney so you cause constriction and damage the kidney. if you look at the male kidney after after six to 8 weeks you

see a lot of damage to the kidney. you see chance amount of -- if you look at the female there's no pathology. so here are two examples of how i would say it would be irrelevant to study the male but not the female.

because if i look at the mechanism of this renal rap induced hypertension and what's causing it there's no point to include the females because i can't get any pathology. i would be including animals looking at mechanisms an learn nothing except wasting, i would

be wasting money because this in this model does not develop renal pathology or hypertension. the same in the model. by looking at immune modulation hypertension that's no point to use the female model. there's no immune modulation of women get chronic kidney disease

and they get immune mediated hypertension so we need to study those conditions, we just need the models. what i can say is these models are good models to look at resilience, not susceptibility of disease resilience. so in that case we're going to

try to figure what's protecting the female and the design of those is inherently different in looking at what's causing at susceptibility, i'm thinking this is a good argument for why these studies should be different but conducted in both sexes the billion one and the

resilience in another. that's why i will recommend that nih balance their portfolio by having models, there aren't models available to study chronic kidney disease, put put out rfas to get investigators to come up with new models looking at chronic kidney

disease in females or at least appreciate the fact that this is a great model for looking at resilience to renal rap induced hypertension, the same with the immune modulate of hypertension. so here is counter. this is my colleague mic ryan university of mississippi,

interested in lieu pus, interested in the hypertension, associated with the autoimmune disease, you can see these mice, blood pressure goes up when they develop the lupus at the ncb wf-1 mouse. they get high blood pressure we can see the black bar, if you

compare that to the control. this is true for the female. there's no point to include male in this model. male mouse because the male mouse does not develop any of the lupus type pathology until very end of life. there's no point, it would be a

waist of dollars. however, when you that justifies we study lupus in male animal models in the disease as well. i think there is space to do single sex studies, and you can think of it in terms of susceptibility or resilience to disease, those are good reasons

but i think that we have to be careful because this could be turned around and used as an argument for why business as usual because there are no good models of chronic kidney disease in females an immune modulation of hypertension in the female is also we don't have good models

for that either. we have to be careful in how we look at this do think there is a need for single sex studies because they are different mechanisms susceptibility and resilience. so i thought since i have to go back to what the session title

is, how we cultivate a culture of sex matters. i like -- i was looking for a something comic because the end of the day i saw this little comic strip and i thought you might enjoy it. so we must change our culture cynicism and negativism you two

will be happiness, come up with ideas to improve morale. so far we have got raises, nude fridays. i feel cynicism building away already. so i use this as a way to talk about how do we change culture and in the business world they

are thinking about this. and we don't do it as much in science and here is an image of how we see culture change that is tremendous activation energy to change thecle chu but we can. we can change the culture and i thought i would go look at the business model of how they have

done it and one -- there are lots of different books written about this, changing the culture of an organization and they're very similar, one model is define align manage and begin with an end in mine, team work, working together toward common vision and manage culture

discipline principle greatness and i think dr. clayton an office of research and women's health is going through these steps. except one thing i think has been left out of the discussion that i think is absolutely critical.

that is how are we going to measure success, if we don't measure success we will not know if we need to change what we're doing or if we succeeded. so how do we measure it? so the last part of my talk is metrics, suggested metrics. i think we need to are have more

conversation what these metrics should be. so for short term, one could easily measure a number of applications and grant awards that are proposing single sex studies in males an those in that's the metric we can measure.

what about the number of applications and grants proposing dual sex studies we can measure that too and then look at ratios of these and of the single sex studies, look at the male, female ratio and dual sex we can look at ratio of male female animals proposed for

amplycation or grant award, we can do that because thanks to the vertebrate animal section required on all nih grants involving animals, you have to describe animals in terms of species, strains, ages an sex and numbers. this is required.

it's not enforced but it is required and nih does say they can use this as historical point and withdrawn administratively if you don't address this and it can affect your score. so we can measure this, that's short term metrics so what about midterm metrics?

i would say some midterm metrics can be valuable indicator, would be the number of published papers on a single sex study. again, we can only do what is decided by nih support, we can know the number of quantitate the number of papers on a single sex study in male and those in

female and we can look at number reporting on both seconds and ratios, dual to single sex an single sex studies, mr. richbourg: yes of male to female, much like this table we have seen cited earlier today did, where they hook at 2009, number of articles, in 2009,

gray is where second was not specified purple is where they specified both. red specified female, and blue is male only, you can see there's a lot of blue here we could quantitate we continue whether these numbers improve with all the initiatives that

the nih is going to do. we can see this 75% investigators who don't report the sex of their cells this number would go down 75% there's a lot of room here for improvement we can do that because it's nots anything new, we have to up load our papers in

to pubmed funned by nih right improve science and human health, nih makes peer reviewed article, funds publicly available. we already have to submit our papers online, there's no reason why we couldn't modify this and capture the number of papers

that are published. that are on males only or females only. or in both sexes. and i would like to think that in the future what would happen is that this is again from the same bare ron paper, look at the number of articles over time and

the blue bar, the blue circles the male only, i like to think if we're successful, this number is going to come down of single sex female studies go up an number of dual sex studies will go up, and number of studies that don't report the sex go that's a measurable metric we

can capture and we would know we're doing what we need to do. we can also of those studies that are looking at both sexes we can look at what of those papers how many were actually pose the sex difference. so i did a quick survey i use key words sex differences gender

differences and this is a number of papers published on that year. so 1940 those terms were not used in pubmed. but look at 2010, this number is going up, that's great. that's good. i think we could expect to see

this number go up higher if we are successful with these initiatives that we are going to introduce. what about the long term metrics why does it matter? why does it care? i think that the long term metrics are things that number

of clinical studies an trials whose design exclusively addresses sex specific hypotheses that are revealed by pre-clinical studies or propose study in full analyses in male and females due to a lack because we don't have the pre-clinical sex differences in

a study proposed to do that. the number establish newly developed drugs with specific specific labeling by the fda, like we're starting to see in the field of sleep, with am bee yen and we will see more of those if we are successful. we might see the number of

consensus statements and clinical guidelines recommending sex specific therapeutic strategies for treating dis orders and diseases, because of sex disorder, and lastly reductions in sex specific skewing adverse event reporting we heard earlier, this is the

ten drugs that many of you know were pulled off the market with eight having worse adverse consequences in women. that hopefully would go down. so when when i was thinking culture change what can i point to that would be a great model. it is the 50th anniversary

of our anti-smoking campaign, outthought this is it. this is the perfect analogy because we could have stopped smokeing if we said it's illegal, you can't smoke. but we didn't say that. and that's not what i gather we're prepared to do here, not

like we did with the nih revitalization act and we require women to be included in clinical research what we're doing here is we're going to motivate investigators basic scientists to do sex based biology and think about sex. so that's kind of like the

anti-smoking campaign, it was not required they tried a lot of things, one -- but i want to make the point they were measuring the number of cigarettes that were smoked, number of people that were smoking all along this 50 year campaign and we have to do the

same thing. because if you look at the kinds of things they did, they did a lot of things, look at this red line, the first thing is put warning labels on cigarette packs that was in 1966. and in '75 they no longer provided cigarette rations to

troops. the number of cigarettes being smoked still going up so i say if they stop there, we wouldn't be where we are now today. which is 18%, great. we have 18% of the people in this country smoke. we can get that number down

lower. compare that to something over 50% when we started out. that's progress. that's exciting. that's why i believe that we can do this we can change the culture. we have to measure because if we

don't measure we're not going to know we need to keep doing things. you can sigh all the different things that the anti-smoking campaign, things that were tried, it's kind of -- it's cumulative, there's no one -- i -- i thought it would be

preventing people smokening public places, i thought that would be give you the biggest drop, educational initiatives and making more difficult to smoke, there's a lot of different things that we have done to try to get people to stop smoking.

what dr. clayton an office of research women's health is perfect. using educational initiatives and using -- trying to encourage investigators to in the grant review process to address and think about sex. and i think that this putting

everything together will hopefully have an effect but we have to measure it. we have to measure it, otherwise we really won't know if we have been successful and if we have to add another component. so with that, i just want to thank dr. clayton again for

putting this excellent workshop together and it's been real exciting for me to hear all this great science and policy and thoughts. >> thank you, dr. sandberg and dr. miller. i think we have about nine, eight, nine minutes for

for our speakers. and hopefully the mic will work, if not you can come up here and ask. >> thanks, so two terrific talks and very thought provoking, i wanted to come back with a couple also strategically oriented questions.

one point you made i don't think we should overlook is some circumstances we do not have the right models to go after the questions that we want. virginia, you also mention tools i hope that would be one of the areas that collectively as a group get our recommendations

because with the pressure that most scientists are under an most scientific entities are under, having the tools to go forward would be enormous. to second comment i want to make and then i will toss it back to you is that what you're telling us is that cultureing strategy

for every day and we know that. culture moving forward, virginia, a lot of things you were talking about culture also silos versus networks, et cetera, what would be in your view the most important thing we might do to be able the change that culture.

i think there's a lot of resistance in the community, if we mandate that one has to do x versus y, i can be wrong. we had culturally where do you think the best bang for the buck so to speak would be. >> people change behaviors the incentives is high.

so i think a good example of that was in the early '90s when there was rfas out to look at the estrogen cardiovascular disease, it drove a lot of investigators into that field. the rfa number was -- amount was limited but what resulted after

that on study section where all the unsucksisful applications ended up -- unsuccessful applications came in to different study sections and there was a plethora that came forth from that initiative. so i think money is limited, whatever but i think

strategically placing some of that into these initiatives with alternative animal models. we learned a lot from cellular studies and we learned from general it cannily altered please from all kinds of animal models but another place we need to consider is alternative

models for disease other than mice. we're looking at complex traits. how much can we really learn more by knocking out single genes and a lot of these animals are modifying them or turning them on or off when we heard from art's work that we're

looking at sexome and clusters of gene and gene networks. so i think we have to have some education in terms of encouraging and investigators to look at something that works. so those are two areas i would put forward where there might be helping to change the culture.

katherine what do you suggest? >> i was in a meeting in brazil, i was impressed how many investigators there were interested in the influences of biological sex. in their studies. they're all young and i think of you -- if you educate the young

people that this is an important area, that you'll probably have the most effective change in couldture. one of the things that i was thinking about, i meant to mention in my talk and i didn't, we view, i'm starting to view sex differences as a health

disparity. there's a lot of driving force to reduce disparities in healthcare. if we consider sex as a health disparity, there is incentive to investigate those differences from a variety of -- we have expanded the pool of influence

in terms of pressures to reduce those disparities. catch words are fine but in reality they are health disparities and these are a primary target for reduction in terms of healthcare delivery and the purpose of nih. so i think thinking about these

things in health disparity, we had a conversation with -- before we started about leadership in research centers and whether the sex bias and leadership at research institutes, in terms of not being diverse and having diverse mix of sexes really biases

agendas. >> other questions? >> i have a question about how you might see from the outside looking in to nih. because i think if you look at nih it's really hard not to see the silos. and we at nih talk about this,

and struggle with it. but from the outside looking in, how would you envision us to be able to move forward to break down some of those silo? do you have any real pearls of wisdom where you think nihers could make a difference? >> i think if we have

initiatives across institutes so that you have request for applications in different areas that are crossing institutes, like the nhlbi, niddk for example, i think that can help break down barriers where there's cost sharing and so that would be one way of -- in one

sense one institute would only be responsible for half the amount of money and be able to claim that as part of that research as part of that portfolio. so i'm a strong believer in team science and i think that it could be one way, as virginia

said, creating these networks is really important in especially looking at the influence of biological sex and gender. >> the structure of the study sections also could be better integrated to have interdisciplinary program, that happens on program project

reviews but not necessarily one review or k reviews typically individuals with siloed interests and so on without understanding the integration and be able to provide quality of review for proposal that may integrate multiple systems into a sex difference through some

resource sharing model. >> actually i sat on rank and tenure and they have a category for collaborative science and they value it so some institutions are have heard that message. and hopefully others will follow suit but it's actually one of --

we have to address how much collaborative science we have done in rank -- when we go up for tenure or promotion. >> i want to discuss a little bit the silo issue at nih, it's more of a i don't have any solutions because i think it's a fundamental deep seeded problem.

the study of section differences is a discipline by itself. there are animal models and procedures and understanding of hormones and sex chromosomes. that discipline is not actually represented to my knowledge in any nih admission statement so no one institute will embrace

if you want to have t-32 to train across disciplines, cardiovascular neuroscience, immunology, on how to go about studying section and gender issues where would you tack your 1332? what institute could you go to? so those are just questions i'm

asking, certainly when one applies for a research grant on sex and gender, influences on a disease, study sections are great experts on the disease, but they're really naive about sex and gender issue, it's very difficult to -- yet for example cath reason's study where the

section of the t-cells that you're infusing into the animal, that discovery is interesting not only in hypertension but it's interesting across disciplines because there's immune component of so many diseases so knowledge of that sex bias an t-cells is of great

interest yet it's not well represented. sure you already know this, what's already obvious but it is i think deeply seeded issue organization of the nih. quote unquote few nci way i say it, nih wants (inaudible) to cure somebody's else's disease.

especially the reduction of funding and research, each institute is focused on a very specific set of diseases. these broad issues such as sex are kind of lost in the shuffle. >> we do have another question. i think that might be the last one we can take for the day but

these are excellent questions and responses as well. >> this isn't a question, it's a response to art's question, but i think it's a really important point which is as people begin to generate these new ideas and these breaking down silos annette works and looking at

multiple body systems, there's going to need to be a review process. that we'll be able to meet that, that problem. a hundred years ago i was a scientific review administrator at csr. one of the values of csr is that

it's not aligned so it has study sections and study sections have cultures. if i'm still correct about that. but it's not aligned. so if there were a way to this initiative to include ensuring that there was expertise in sex and gender, on the multiple

study sections for example, and also to ensure a way of reviewing multi-disciplinary, which is always a challenge, when i was csr they called them complex applications. thack talk how you review there is a mechanism to bring on other experts for those

applications. so i think some kind of explicit conversation about this with suggestions to from expertise and sex and gender represented on study sections right actually be helpful. >> excellent point. i see dr. clayton is taking all

kinds of notes too. so i think that wraps it up for now. we have a break, is that right? how many minutes? 10 minutes. no more. >> good afternoon, everyone. we're almost finished but we're

not quite done yet, so if you could please take your seats, i'd like to reconvene the meeting. we'll get on with our last few discussion points. this will be the last song and dance of the meeting, so get prepared, get your cameras out.

this will be a youtube event. [laughter] so for this session, what we're going to do is, this is really your opportunity and all the people in the audience, all the people in our video audience and anyone who's listenng, this is is your opportunity to weigh in,

all right? you have heard a tremendous amount of information today. i've learned several things myself, and i'm afraid to admit i've done this research in the past. i should know this. but i learn something every day,

and every day i work at the office, i learn something new with regard to sex differences and women's health. so, we have at the front of the room here the moderators from the sessions today. my name is susan maier. i am the deputy director of the

office of research on on women's i come to this methods and techniques issue because i am -- okay, i'm a methodologist, i'm sorry, i admit it. but i'm not embarrassed about it. because methodology is where it's at.

knowing how to do something, knowing how to structure your experiments, your study, your clinical study, knowing how to analyze the data, what's the appropriate type of thing to do, and how to interpret your data. those are all things that are very, very important to any

field of study, i think we can all agree with that, we can agree that methodology techniques, statistics, are all very, very important. we've heard about some things that are lacking, maybe there are models that aren't appropriate for some of the

things we want to do, maybe males and females aren't necessary, maybe they are necessary for very specifi types of things that individuals are looking at. so this is your opportunity to weigh in. we do have a bit of a structured

discussion, and what i'd like to do is i have two -- let's see if i can get them. i can't get to them. we had two comments come in in the mailbox, and one comment was a comment on the doubling of the n, all right? and this comment came in from a

viewer in israel. and this person suggested that at some point, you know, we can't just double n. i'm paraphrasing from them. you can't just double the n, all it might not be possible to do so. scarce resources, you have --

you didn't do it that way in the beginning. so what you can do is certainly try your experiment, you can use it with -- if you had an n of 8 in each cell or each group, you might try four males and four females, and then if you don't detect a difference,

you're not powered to do so but you may get a glimmer of something, then you can move on and say, look, i really need toto power this to do so. then you use the same experiment to design the same methods and you can power it up so you can detect whether sex has an

influence or whethe there is a difference or not. so i think this is a very thoughtful comment from this person. and i think we've heard that a few other times today, is that, you know, sometimes understanding if there's a sex

difference may lead to more research on sex difference, or it may tell us something about an underlying mechanism, about something, a method about a pathology that might not ip voflinvolve sex differences anymore but certainly led to new discovery, and nih is all about discovery.

okay? so those were most of the comments that came in. what was the other one? sorry. my outlook wasn't working. so here are more questions that came in. these would certainly be very

good for our discussion. so the question would be, then should sex specifications be required for cellular and molecular studies, and one step further, should the field require that both sexes be -- and how do we bridge the gap between preclinical and sex

effects in humans. so those are the questions that also came in with the other one that i just stated. so we're going to use these as fodder, if you will. i'm going to have the moderators weigh in as they want to. i'm not going to drive this

whole song and dance, but i do have a few things that i'll jump in with. i'd like to go through and do a little exercise with everyone. i think it will start the discussion. and then i would like to go to the actual call to action, and i

want you to tell us how we can because you're going to suggest what we need to do, how we need to do it and what's our implementation plan. so, i have a question for everyone. answer this question. you have to start your answer

with this. sex matter its. we've heard everyone talk about so by using both sexes in preclinical research, dot, dot, dot, dot, dot, dot, dot. go. what do we gain? what do we lose?

what is it that's a problem? what's the barrier? yes, please. i'll take the first leap here. i was struck listening to all the panelists that the -- eve talked a great deal at nih about personalized medicine. i think i've said to several

people in my institute, nci, we call it precision medicine, we can never be the same as everyone else. however, when i think about the difference between whatever we learn in the research setting and actually observing physicians who are taking care

of us, that, to me, is the model of personalized medicine. maybe i've been lucky, but it seems to me that very many physicians take into account the holistic approach to what a patient is, who's sitting in his or her office. so what i was hearing here today

has to do with i think the major opportunity which is to somehow do the research in a manner that really enables in the clinical setting physicians to have at their fingertips the kinds of information that does enable them to provide personalized medicine that is at the state of

the art. and i'm not sure exactly how we convey or how readily or how well we convey what we're learning in basic science to the clinical world. certainly in the cancer side, we have a very difficult time, it takes a very long time to change

the practice. nawsso i, having listened allday, really wonder how we could, using this kind of discussion about sex differences as a springboard to improve how we convey what we're learning about the basic science and the differences in the sexes to the

clinical side so that we really can realize this goal of personalized mode sin. it isn't a matter of sequencing someone's genome. it's really linking the biology, and this, i wonder sometimes at nih if we do a really good job of that.

so first of all, thank you for your comment, but we know that you're from nci because you didn't follow the rules. okay >> we never do. my director certainly doesn't. >> i know. i know.

so let me just rephrase it then. preclinical research, we need to be able to develop information at the basic science preclinical level that will eventually transform into information that we could disseminate to clinicians. that's the ultimate big goal.

okay. because we can't serve the patient population which is more than likely half female by only studying one sex or 25% of one sex in the experimental realm. >> i'll just finish that sentence. i think that you originally gave

us sex patter matters inpreclinical research and it was to fill in the blank. i think i'll just summarize some of the stuff i've heard here t >> sure. >> try to do it in a nutshell. and that is to say up front that

it's a matter of doing a good the reason it's a matter of doing good science is because if there's basic -- if there's differences between males and females in preclinical research, and they're not detected, we're going to draw conclusion arrows, and there could be a finding

that is true only for males or only for females, that's a specific finding, and if it's generalized -- if it exists and it's not studied so as to be detected, well, then generalization is made incorrectly to the other sex. so -- and this is true for human

research as well. it's not just in the preclinical realm. so i guess i can speak more generally, in the human realm as well, and of course at nih, all human research has to include females, but gender analysis of data is not always done.

and if there's an underlying difference and it's not detected, there will be conclusion errors. so as i was saying sex may occur only in males or only in females and they're incorrectly generali the other gender, and then there may be cases in

which -- we heard some today in which effects are opposite in males and females and if the data are not analyzed so as to determine, as to detect those opposite effects, they can simply wash each other out and then we have incorrect conclusion errors, the data were

not analyzed to detect it, the conclusion would be there was no effect. so rampant conclusion errors is a big problem if we do not include both males and females and do the appropriate analysis. so that is not good science, and it costs us.

it costs us in terms of the research that unfolds, that cascades from studies like that that has incorrect conclusion errors. that's the quick answer. >> no, that's great, because it encapsulates using both sections in preclinical research helps

generate better science. better science through appropriate interpretation, better science through a generalize ability of the results and better science to an understanding of the baid baste ik biology of males and females, and then the difference between

them when those sex-specific or sex analyses to compare the two are performed. >> and of course adding to that, we often hear about the concern about perhaps added financial costs that changes might create, but we also have to keep in mind that that does have to be

balanced or considered in the context of the cost of doing bad >> right. so when does the cost make the most difference? what is the difference between the cost of not including males and females in your experiments or your studies at the

beginning, but then finding out later in your translation or in your clinical work that you need to or should have versus the cost of now having to include males and females in your early preclinical studies and then deciding at some point there is no effect in one or it doesn't

make a difference or the it difference is not relevant to the disease or condition under so when should the cost be borne, and wa is the relative cost? i think for some of the drugs that have been -- ambien as an example, we know what the cost

was in the end. so that's a consideration. >> i don't think basic scientists necessarily see themselves as part of the pipeline in its entirety, so i think the attractive that we need is cash, i'm convinced when people start doing the

experiments and find discovery, basic scientists and translational scientists will get hooked on the euphoria of new discovery. so i think a at the outset, andi really love the analogy that kathryn had to the fight for tobacco reduction and all the

little incremental things that happened. i would advocate for -- i think that costs are not going to be too rampant, in fact, but i think that's the per accepting. so i think one thing that could be done is that all grants that include both sexes and an

analysis of that sex would be increased by one module. that puts an atrack tant in the water, people all of a sudden want to do this because they think that will actually fund some of their research in a more provocative way. i also think rfas are a good

way across all the ics that each ic gets on board and has an rfa that is from each institute, i think the notion of inter-institute funding as we had for the road map was wonderful, i happened to have one of those common fund grants, it was fantastic, but it's just

cumbersome. so i think we need to have each ic, and in fact one of my notes says "educate nih institute directors, they need to be the champion ares for the best most reproducible science and encourage notes about their enthusiasm for this award

together with a link to an rfa from each of them. so those costs then become a neutral -- we need to neutralize that as part of the argument right now, because as long as the big hand is up, no, i can't do it because of cost, even though the analysis as wanda

presented today is ongoing and the costs are unlikely to be enormous, we still have to combat a perception. and so i think those two tactics -- three tack it tics, increase modular budget by one, put an rfa out from every individual institute, and get

our institute leadership on board with this, i think could go a long way towards getting us towards that first couple of it steps along the pathway that we saw for smoking cessation. i would neutralize the cost discussion up front. >> you realize i can't write a

check, right? but i'd gladly take your suggestion for it. >> i think sex differences matter in preclinical research because they really can teach us something about mechanisms that one would otherwise not be able to really ferret out, and that,

then, becomes instructive for doing the clinical research. and as a recoveing academic who did clinical work myself for years and i didn't do very much of the basic mechanistic work, i think i have a ground to stand on, just as having a man in the room speak up for wanting to do

sex differences, so i think i can speak for the clinical side of it and say how important it is to it do this basic work examining sex differences. and i also want to say something about rfas in this day and age at nih where we have such stringent and stretched budgets.

so what i would say is that, you know, we shouldn't let the perfect be the enemy of the good in that if funding opportunity announcements come out and their pars or pas, that's a good thing too. it's okay of the doesn't have to be a setaside.

some questions from the audience, please. go ahead. >> so you asked us a while ago what we would have to suggest to nih to sort of restructure, encourage this. i would like you in there. do you have insight as to what

you could do within the structure of nih or restructure it to improve the interdisciplinary translational sex differences approach? i mean, you want us to fit into your paradigm, maybe you all need to fit into our paradigm. so i just throw out a teaser and

i don't know if this is being recorded, but i would probably -- if i was, you know, queen of nih for a couple of years, i'd probably want to restructure nih entirely, because i think it's very disease-focused, and i would like for us to be much more

health-focused, and one of the ways that i've thought we might do that is by actually organizing a new institute, some institutes would have to go away probably, but organize it according to what some of us call in the health field as a three legged stool, so sleep,

physical activity, and nutrition. and i think that sex differences work into that paradigm very, very well. but i also think there are other areas a a that work into thatvery, it really becomes so difficult to study a number of

health-related outcomes in our current structure, because even though we try to reach out to other ics, institutes and centers, we still live in silos. so i would want to restructure entirely. >> so in the absence of restructuring, of course i'm not

intramural, i mean, i'm on your side, but i think we also have this notion of us versus them, and i do think that as we're putting these notions in the water, we have to appreciate the intramura science and extramural science all have to be singing the same song,

although it seems to me that intermural science can be converted now, and perhaps there's some structural reasons why not, but again, just trying to figure out what the soft underbelly of this issue might be, and if collins can immediately say to intramural

scientists, we're working with the extramural grantees because there is a grant relationship that is a contractual one that has to be set up associated with study sections, and so i have a lot of recommendations on that front that i hope we can get to, but right now, we could turn the

switch on intramural science and say to all the members of working in this building, neuroscientists most of them, you're now going to include sex as one of the biological variables. now you're not going to have additional funding because

appropriations has already occurred, but begin to think about how it to integrate sex and reporting sex and report to us the noll data, the same sort of thing we're talking about in the extramural environment, it seems to me can happen today with leadership from the top.

and i think that that would go a long way towards starting to think about what are some of the issues that come up in a pragmatic way, so i do hope this is recorded because i think that would be a really smart thing to turn the switch on. we're not doing it for october

this year, which we thought we were, but having a very, i think, good and authentic discussion with extramural grantees to try and convert hearts and minds, intramural, i think that's ready to go. that may not be structuring nih but that uses nih in a very

positive way to move the agenda forward quickly. >> good comment. >> i wanted to go back to this issue of it costing more money. which it may well cost more money but i was also quite taken with landa's point that there's a lot of infrastructure already

in place, it may not cost that much more money and if you measure it against the money lost by drugs that have to be taken off the market and that sort of thing. so i'm wondering if one of our metrics might not be actually to track the money.

and see if it really does cost more money. i mean, if we, for example, compare -- i don't know, maybe this isn't accurate exactly because there's probably studying slightly different things, but let's say we compared larry cahill's program

on a motion to hanna manderson's program on a motion. would one cost more than the other? and one looks at sex differences and one doesn't. so i think that would be a really interesting project and also maybe part of a metric that

would be useful. >> i think there are certainly ways that we can run numbers, and i think anyone could do anyone who has extramural research, intramural researchers, extramural administrators can certainly run numbers on this.

as a p.i. myself with rats and mice and sheep and goats and cats, you know, you always were being cost conscious. how do i make sure that i maximize what i have by not putting in -- not spending all of my money just on that one resource, and that's where

pooling data, pooling resources, i believe the doctor has benefited from that in past years, because my pregnant rats that i used for my studies to generate pups, when they become 12 months old, they're now reproductively he? senescent, so i

say i'm going to transfer them to dr. strodke, he's going to work on repro it ducktive senescence. so pooling, sharing and being collaborative certainly helps with that. but yes, it will not be difficult to run numberses on

i think as we start to explore, today a point was brought up of alter animal model. as we start to explore them, faith just went on my favorite, but otherwise flat worm, things like this, there may be an opportunity to reduce costs >> i just wanted to speak to

very much agreeing with her on we don't need to compare apples and apples as far as programs. you can model that very readily, it would cost you very little to do it. the other thing that wouldn't cost a whole lot would be really to put out -- we've talked about

education, about culture, but this is an issue of what are the best practices in this area? you heard all day long about how people do their science, how they use their animals, how they construct their cells, how they put their programs together and those best practices for people

who have been working in this field a long time could be extremely helpful for people that want to get on board with this or feel they should or whatever and that's something from the nih that wouldn't cost a whole lot of money, much less than program announcement but

highly effective, i would guess. >> i think that's a great idea. and i think one of the questions i had for our actual call for recommendations and it's related is how do we get people to learn about this? how do they know, how do they kw what to do?

we all know what to do pretty i think we're all -- many of us are experts in the field. but how do we teach others? how do we get that information across? nih can do different types of activities to promote and to put out information, but i think all

of you have the same responsibility to do so whether you have graduate students, whether you have medical students and whether you have younger -- i'm sorry -- newer faculty in your departments that you do also have that particular resource, so developing content

and making sure that it is something that can be disseminated by everyone, not just by nih but by everyone, it's not our dictum, it's not you will learn this, it's a -- this is a collective understanding of how we do work. and this is how you might try to

but no, great idea. >> i'm going to take a contrary view, surprising, because i think we're sitting in a room amongst -- we're in the choir, this is obviously an extremely collaborative group where there's a rather strong sex ratio in the room, but out there

in the wild, there is a whole lot of people who are really angry and upset about this, and they're going to do everything they can to avoid it and they're going to throw up the cost card constantly, and i know all of us, i have heard it from our colleagues, were they going to

give me twice the amount of money, that kind of thing. what teresa said, i think she's absolutely spot on. we've got to put the money issue it to rest immediately, and i think it can be done with a relatively small a money but it can't be a lot of hand waving

of, oh, this isn't going to cost you anything, because we can bring those horses to water but we can't make them drink. we have to make them want to drink. there has to be some kind of incentive that says that this is a good thing for me to do.

a single module that is not a lot of money but it is more than enough to make them drink. then we train them how to do it. the one thing i wanted to ask, i know trees ii -- if we do makesomething that is actually paid for, then it has to be a review criteria, so how are we going to deal with

that? >> i think it should be a review criteria, and i do think that many people in the room are on the transnih committee, janine, that are working on this, so i think this is part of your call to action, and it seems to me that threation there's a numberof

things -- is this my kau to start reading my list? >> please. >> i think we have to require researchers to report sex by subject and outcomes by sex and include both sections in their this is for intramural and extramural scients, and i've

already talked about turning the switch on the intramural now, convert them now because that can be done. i do think that we're talking about sex at this point and i think that curve for smoking cessation is one of the things that eventually gender or as we

begin to define what environmental impact or gender will be defined as invertebrate animals can be described, invertebrate animals and cell line sex must be reported, test sex differences and one part of your experiment and then if no difference, include male and

females in future design to be sex inclusive, and adequately justify this and report this. i'll come down to some tactics for that, and so create model systems as a shared resource, i think that's an rfa that could come out. i mentioned the cost.

i think we have to train researchers on an experimental design that includes sex variables and require that ars part of the reprodility models already being built, so i don't think we have to build differently than that. i think that's going to come as

part of the responsible conduct of training so i think sex comes right in line with that. i think we have to encourage the report of null data. journals are disincentivized to do this because many of them are run by societies and organizations that need to make

money from every single page, so this needs to come in to nih and there needs to be some thought on how ni nih is going to dothat. i think we have to educate the nih directors, i mentioned they should be our champions, we with have to crete ate some rfas that model -- for people who may

not be within the enclosed circles who have already done this who might have some ideas, and i think all those rfas mentioned earlier create grants and those grants eventually come back in the system, so every rfa is like the 1 dollar equals $140 in biomedical advances.

i think you always get 100 fold impact on rfas. then we have to create a sex outcome website with experimental evidence of sex differences, sex equality and good experimental design and create a template based on field leaders, i think we've seen some

of those excellent examples here, and we know them and we've heard each other's talks, but i think we have to put that into a format that then can be used didactically, and i think that can be accomplished fairly readily and should be done with some alacrity.

i think we have to educate proposal rea viewers and sros on sex inclusion design elements required, and i suggest there's one study section member who is assigned to review the sex inclusion element for the next year, so that there can be some examples of how this should be

done. it's similar to when women first came on to study sections, there was one each on each of the study sections aft nih was sued just to see how it would work, and i think that this could be accomplished here. i think we have to monitor

inclusion policy compliance both through grantee reporting but also by -- of published papers so we can roll up the data at the end at the end of the grant but i think published papers also have to it be evaluated. i think we have to get the vice presidents for research at all

the grantee ins tawtions. there should be a video meeting required for all vps that have nih dollars. and this sounds very punitive, but i think that they should be required to listen to the issues on reproducibility because their institutions directly benefit

from the nih dollars, particularly the way we've talked about, how tenure is structured and we're putting it on us but really institutions have structured salary based on how nih budgets. usually 80% in clinical departments are requires from

nih budget. so i think they can be incentivized by fairly strong language, but we have to do that because then we've got another pain point, and some are going to be chemo atrack tants some are going to be pain points and all are going to eventually keep

us from smoking too much. we have to encourage institutional research center cores to identify services that focus on sex variables. two times ago in the office, there was a discussion on institutional cores. if cores start having these

kinds of activities, that, again, is a little pressure point that then each individual scientist who is feeling so under the weather over everything that's happened from sequester and not knowing if people care about them, scientists needy goa stroking

all the time, you know, at least this is a place that we can go and find information, and we can get information out to those cores, i think relatively quickly rather than kind of the hand to hand combat. the fda, nsf, pharma, biotech, all the agencies really need to

get on board with this, and that has to come from collins, journal editors we've already talked about, and i think as i mentioned elier, all nih press releases must include the sex of animals in studies, so nih has to start reporting on the variable that they think is

important and if there is no sex reported, the nih doesn't do a press release. even if it's a big deal. so that starts to incentivize nih to actually think that this is important. medical school and graduate school curriculum, pro

figuressal societies are the ones that develop the clinical guidelines bu that then the physicians use so many people in the room help with those guidelines that then go to the patients. we're encouraging through our public advocacy for patients to

come and say was that drug tested in a sex-specific way. that's a mouthful so we need a clipier way of saying that. even though that physician is sitting down and talking with you one on one for your 10 minutes, it doesn't mean that they know whether or not the

sex-specific guidelines have been followed, and i think that's a real gap. so the consumers increase awareness of the importance of sex and medical research to consumers, but not in a way that's punishing. we can't con flate sex inclues

with cost, we talked about that, and journals need to accept sex inclusion data as authentic at not boutique. everything can't go to the women's health journal, even though we love it, but that's just not the right way for science to continue.

so those of us on editorial boards, we've really got to get on board with figuring out how to get these things there as you a then then ticauthenticscience, which it absolutely is. my final thing to say, our end goal is that we should ee limb nat the office of research in

women's health because we have done such a good job of inculcating all of these kinds of metrics for women, for minorities, so that these kind of health antecedents developed through basic science pipeline are all so there, janine, that we don't need to be there.

that's our goal. our end goal is to have a party to eliminate ourselves. so those would be my recommendations as i've sat listening to this. does anyone have anything additional to add to dr. woodruff's list?

>> the use of the word chemo attractant, the extra money, i keep coming back to this issue -- >> it's too pejorative. i apologize for that. >> well, it also suggests that this is a sugar coating on a bitter pill, and we have to get

away from the idea that this is a bitter pill. >> no, no, it also could be a sex -- >> i think the messaging has to be very, very positive. >> and it is positive. yes. >> that it's going to be

important, i agree with the idea that we need to actually see what the increase will actually cost. i mean, some of this is -- may just being in people's head because they envision doing everything over twice with two pairs of -- four pairs of hands

now to do all of this, whereas in reality, you can very strategically incorporate it. so i think the messaging needs to be very positive and it needs to also not mainly speak about how women were disadvantaged by this but also how both sexes are disadvantaged by it.

>> important point. >> i just wanted to make one comment, that is sort of an additional thing that program directors could do at nih. if we are in the process of developing funding opportunity announcements that are not, you know, specifically on sex

so just funding opportunity announcements in general, i think we need to be including in those foas the language and be being able to really frame the issue so that in each one of these foas that come out, that we really want to examine sex and so i'm trying to think of a

way i can do this for an upcoming seer eaves funding opportunity announcements, and i think i might talk to jeneane and figure out if i could even have her come and talk to some of the other program officers as >> yes, sir. >> i may have missed it but in

the various recommendations and suggestions here, it did anybody talk about having program officers review their portfolios to see if the portfolio as a whole was improving on this on this dimension or some metric of inclusion of both sexes? >> i don't recall the program

actually portfolio analysis itself, but certainly a review of what it is that's available, what's out there, what have we done and how does it -- interestingly, how does it vary by institute and center? >> well, that sounds a little different than like having each

program officer, th be measuringin some way their portfolio with regard to this topic. and i think there's at least some program officers out there that are going to be quite interested in doing this, if they are released to do this by their superior officers.

>> i can try to address that a little bit. at ncam, we just went through almost a year's worth of portfolio analyses whereby each one of our program directors had at least one portfolio analysis to conduct, and tha dictated by-- i don't mean that in a negative

sense, but it really -- we were told what type of analysis was wanted from above. and i think that if that -- if w you're talking about could work, i think it would have to come from above, because -- and i cannot tell you the amount of time these analyses took.

they came out of our hyde. we weren't released from doing anything else in our job description, so it was weekends and evenings and it's a lot of hand picking of picking through the journal articles, it is -- it's enormously time-consuming. so i'm not saying we couldn't or

shouldn't do it, but i think it has to be thought of really in a very logical way from above, and with a lot of discussion. it's a good point. >> i echo that on behalf of the -- of my colleagues in the nci. we were asked to do the same

thing, and just as you said, we have the progress reports rarely have any information like that accept in the cases in which someone is studying on the basic side an animal model or a if he nophenomenon that we know hasbeen shown in the clinic to be a sex difference, and the other was

having to go through publications. now, we weren't asked to look at our entire portfolio, at least in my division of the institute with 2600 grants, that's a lot of work to do. but i can also tell you that we are looking at on this committee

that we have now at how would hewe will be asking researcher, applicants in the future, to define how they are going to do their research with sex differences or sex in mind in the research design, we are talking about ways in which we might be able to automate the process of

scanning the reports so that, in fact, we could report on an annual basis how many grants had, in fact, adopted a sex type of experiment design so that we have both sexes. but that is not a trivial thing but one of the things they said was, i think across the

institutes, most program directors would quit. we have enough trouble getting compliance with putting the publications into pubmed. >> could you not just ask that be part of the progress report, require that it be part of the progress report?

>> we can in the future. >> right, not in the past, but going forward -- >> not just retrospectively. it takes us a couple years to change anything in these forms because of the offic of management and budget, but -- but many of those things were

started a couple of years ago. trust me. >> so to just echo that concern about the laboriousness of getting that information if it's done by hand, so the problem is, is the lack of an automated system, whatever that tem mightsystem might be.

of course whatever form it would take would be the ideal solution, so that this could be tracked and unfortunately, it's non-existent right now, but maybe moving forward, we can think about doing things differently. >> are there other questions or

issues you would like to bring up before i start on my list? no? this is the song and dance part. so i'm going to give you in a nutshell basically what we talked about today. just to give you a refresher, try to pull you back to where we

are, i know it's late but bear with me for five minutes. so i started out by asking, by using both sexes in preclinical research, what is it? what's the benefit? i think we heard today, we heard that you may be able it to decrease variaby, you can

account for variability associated with using both males and females, you have the potential to see an interaction of sex with variable interests. you can't do that if you don't include both sexes and if you don't design your experiment you have the opportunity to

decrease sample size. we know that may not be possible for every single condition or disease, but you have the opportunity to do so and as the literature builds up and you know what your effect size is, start to reduce your sample size.

so you have the opportunity now also to interpret your -- and it's meaningful, so what does your out come mean if you just have treatment and control if you don't know if it's male/female, young old, something something, red, blue, black or green?

you have an opportunity to increase power by your sample if you're using five males right now as your. n in each cell and you add five females, then you've got an n of 10 in each cell instead of an n of 5. how do you do that?

how do you control that variability? you can control the variability by knowing females have an es truss cycle, i can monitor it and know how many females are in which portion of that estrus cycle. i can use my 2 by 2 design to be

able to account for the variability from the estrus cycle and build that into my analysis. i can include both males and females in my studies. i might only want to use one sex. there may be a time when there is only one sex to use.

why would you do this? well, we h we know studying both sexes helps understand the biology of both sexes. we know that there could be a difference, males and females are different on something. studying one sex can certainly help us understand that sex.

that sounds trivial. but if you think about drug development, if you think about diseases that are very fast moving, contagious, if we know that one sex is involved and we know that we have to develop something quickly, using only that one sex is a time that's

justified and it's allowed to you cut down on the times through to drug development discovery and hopefully treatments for sex-specific so that's a sex-specific type of we can only study sex differences or the differences between males and females when

we collect data on males and so this is part of leveraging, so we're leverages resources. we talked about it cost so much, it might not cost so much, we're not sure what it costs, but if i don't have females and males in my initial study and then i decide that i want to do another

study, i need to be able to know whether there's an effect on the males and females from the original study. i can't do a study all in females and then a year from now, do it all in males. you're going to have issues with compound and with different

cohorts, how you compare those cohorts, what if a male experimenter tests your mice in the first experiment and now females test your female mice in the second experiment. it's all rolling into experimental design and thinking about the questions you're going

to ask. you might only use one sex in the case of very, very scarce engineered animals, primates, large animals. animals that are very difficult to generate, anything that's embryo lethal, you can't generate those.

or it's very difficult to get the outcome you need to get sufficient sample size. we have the opportunity by studying both sexes in preclinical research to understand the mechanisms of pathology, physiology and function at a very, very early

stage. so by using cell cultures, by using in vitro work, by using e plants, by using all types of tissue culture techniques in which we know the sex that the tissue came from, we have that opportunity to build that in. we can move faster by

understanding that there is a sex difference, there is not a sex difference, or it's important to look at both sexes when i move from my cell culture to my animal work. and on. the outcomes in sex segregated cultures can lead to precision

we need tmay need to better identification and appropriate development of our targets. appropriate view of what is it that's happening out there and what should i look for because my cell cultures are very specific. they're not ideal, they're not

perfect, they have their own issues, but combined with knowing the limb nations of what your model system is, whether it's in vitro, in vivo or other, you answer that question by doing your studies, doing your experiments. we can actually use both sexes

to understa each sex, so we can use, we can vary the hormonal cycles, we understand what females are -- what cycle females have, we can control those cycles, we can also manipulate those cycles to understand questions of relevance.

so ultimately, using both males and females in our preclinical research leads to better i think we all agree on that. there's no disagreement i'm hearing from the audience. the interpretation of our outcome when we include both sexes is clear.

there is is a difference, there is a difference or i'm not sure yet, but i'm going to pursue using both sexes in our studies leads to better science because even if we don't find a sex difference or we find a sex similarity, there's no difference, we might discover

something else. and that's all about science, is how we move forward in the discovery, the discovery leads to better science through the use of multiple creative and innovative experimental designs, repeated measures within subjects' designs.

we can redweus the number of creatures that we use by employing these designs and then applying the appropriate statistics to determine whether there is a difference, whether there isn't a difference, or whether there's a similarity or we can answer a question at a

reduced effort, reduced cost perhaps. and we end up with an understanding of these mechanisms as i mentioned earlier, if we start to study them earlier. so we don't study whether females and males differ in

phase iii clinical trials. we want to step back and take a back to the very, very early studies, even starting with cell so i think all of this, as everyone has archaic lated in it rhyme and those in the audience and video audience, everyone believes that sex matters.

and i think for lack of a better tag line, and since i'm running out of time, we can do this. we can do this and we can tell others how to do it and we it help them. through whatever means we do, whether we issue money, whether we provide extra funds

incentive, whether we show people how to do it, whether we develop educational materials, we can do this. yes, ma'am, please. >> susan, that was terrific. that was an outstanding summary. two things since it's being recorded for utility down the

line that i want to just state the first thing you mentioned that we talked about estrus cycles but didn't talk about them in terms of having to do them as you suggested and i would urge janine to get a podcast with herb zucker so they can describe to the scientific

community about these pesky hor noans moans second only to cost in why people's minds about why they shouldn't do this is the that paper helps you definitively understand in general biology, we can study males and females independent of the cycle, once you find a

difference you're going to want to go down that path, but i wanted to clarify that, susan, in your comments and i would urge the office to get irv or brian to do this. the second thing you that mentioned, as was mentioned here was, earlier today, the issue of

the individuals who are handling the animals as part of this gendered part of the equation and i also think that's going to be third on the list of why people are going to be concerned about this issue. i want to point out that i suspect that if jeffrey mogul

were here, he would also say that was one study with one end point that had to be about pain. that has not been replicated in another lab and it has not been replicated in any other biology. and so the biology of pain receptors we know is touch-sensitive, so there's all

these things he is uncovering in that paper which was hard fought for to even get published, so i think we don't want to generalize about the issues of management of the animals in our report as you listed, it is something to be aware of but it is not something that i think we

want to have as a generalizable part of the dialogue at this point in time. those are two things i wanted to bring up. >> thank you very much. does anyone else have any other comments before i turn this over to dr. clayton to close the

meeting? last time. the song and dance time. that's it, dr. clayton, please. >> this has been an absolutely fafantastic day. i am really so grateful to each and every one of you for your participation, in particular,

folks up here, but i have to begin my remarks by acknowledging dr. maier and dr. miller, who worked incredibly hard along with team orwh to achieve this meeting without support from contractors. so please join me in giving them

a round of applause. dr. maier said everything i was going to say, much better than i could say it, so i'm going to say two things. and she's doing a dance back there so that's a good sign. i'm going to talk about two things which are near and dear

to me as a physician and why i'm here rather than at the national eye institute where i started out. do no harm is the it tenant of physicians and i want to talk about first things it first and beginning with the end in mind. so beginning with the end in

mind, that just makes sense, i think somebody had it on their slide. first things first and beginning with the end in mind. what are we trying to achieve? so you refer to the nih mission. so often the first slide of all of our talks is the nih mission.

what do we do here? well, i usually say the h in nih is for health, unlike some other the mission of nih as you all know is to enhance understanding of basic living systems, and apply that knowledge to improve human health, minimize suffering, minimize disability

and enhance quality of life. if that's what we are doing, that's our goal, when we begin, with need to design our experiments, select -- actually first, we need to select our research question with that in mind. human health.

humans come in two basic types. at the most basic level, when you're born, the first thing they say is it's a girl or it's a boy. that's the first thing. so you've got to start with first things -- with that in and if we are to do that, we

think about it, you consider it when you're developing your research question. if you're developing a research question on a disease that affects men and women, you need to consider that there might be similarities and there might be you need to use the power of a

comparative approach to get the most out of every single experiment you do. every dollar is so precious right now. we have to do as much as we can with every single experiment, and we could do more if we thought about this in advance,

if we took on a different mindset. that's the other word i wanted to leave with you. culture change we definitely need. i have to say when i talk to scientists when i start talking about culture change, think they

zone out, just to be honest. we need a change in mind set. scientists are thinkers. that's what we are at our core. we look, we try to understand, we look again. if we have a mindful purposeful beginning, why am i doing this, what is my research question?

let me design my experiment to test that. w could learn so much more, because that's why we are here at nih. so i left ophthalmology to do this because i thought there was a chance to do something more than a very circumscribed highly

specialized subspecialty and -- and this is so exciting to me because we could make a very big change, and while i was -- she stabbed me in the heart a little bit there, saying -- i'm just teasing. of course, the ultimate success if i were queen of nih for a

day, ultimate success should be that everyone does this automatically. so of course it would be that we're not needed because this is part of science. and i agree, the next generation, the early stage investigators, they should be

the change agents. they are amazing. you guys work with them all the time. they are incredible. they should be the -- we do need champions in our leadership, absolutely, and i'd be happy to continue meeting with them and

talk about this. but i hope that i can count on every single one of you to be with us in this challenge and in this fight, i think we still have a fight. i think we need to be very thoughtful and strategic about how we move forward, and i think

we need to understand how the game is played, how life works, the realities of what the pressures are and people in academia, the realities of what nih can do, the realities and opportunities of partnering. we cannot do this, none of us can do this alone.

we need new partnerships, and you're talking about a multidisciplinary team versus an interdisciplinary team versus a real team versus combining some ingredients and putting them together thinking you're making a cake. we know the reality.

we know what collaboration is, we know what sharing is, we know what cooperation is, we know what getting together just to put something together and call yourself a team is. that's not what we need. a team means everyone is interdependent and you're

working together for a common goal. we can do this, i agree with dr. maier, we can do this together. thank you very, very much for being here. thank also the communications staff who have been tweeting and

doing interviews in the back, and all the speakers and moderator, we are so appreciative of all of your time and effort.


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