always be viewed through the social, ethical legal and political prism. In fact, not too long ago Darwin's revolutionary theories on natural selection and the evolution of species that sparked so many wonderful scientific advances and led to a greater understanding of mankind's place in the natural world was dreadfully misapplied through the prism of bigoted notions of the underlying causes of class, social and biological differences bringing us the legitimized atrocities of the eugenics movement. Science can be easily corrupted, experts are often wrong and governments sometimes traffic and cruelty and ignorance and what is interesting to me is that whether or not the scientific community is mobilized to derive something as junk science or voodoo genetics may ultimately not matter. Sometimes public opinion and market forces prevail regardless of whether something is scientifically rational or not. As the science of genetics explodes and the technology becomes more accessible the issue of how society protects its workers from the misuse of genetic information will become more important and while I certainly applaud the emergence of new genetic technologies my fear and a fear that is shared by others is that employers will attempt to exclude qualified workers from employment due to real or perceived genetic predispositions or their carrier status. Now this concern applies to those who either have a predisposition to or who are carriers of markers for both rare and common disorders alike. I think that those that the particular risk of discrimination is higher for people with genetic disabilities because of the stigma attached to such disorders. Genetic discrimination in my mind concerns an employer taking an adverse employment action based upon an asymptomatic genetic predisposition to a disease or a medical condition. What we're talking about is the increasing ability due to advances in genetics of predicting who may become ill in the future. Most genetic markers cannot predict that an individual will in fact get sick in most instances only that there is a greater likelihood that he or she will actually fall ill. I believe that to exclude qualified employees or applicants from employment opportunities due to such a genetic marker indicating a potential medical condition constitutes illegal discrimination. Now it's difficult to know precisely how prevalent the use of genetic testing or genetic discrimination in the workplace is today. There have been studies that have provided anecdotal evidence of instances of genetic information and yet in my mind even if such evidence does not point to a widespread problem today, I believe that as the cost of genetic testing decreases and the practice becomes more commonplace, the potential for real discrimination will dramatically increase. Moreover, the mere fear of discrimination may cause people to become reluctant to take advantage of the growing array of genetic tests that can identify vulnerability to specific diseases and may in fact hamper one's willingness to get involved in being genetically tested for research purposes. Genetic discrimination though I think it's important is a new application of an old violation of law. The entire body of American workplace anti-discrimination law is based upon the premise that applicants and employees must be selected and evaluated based upon their ability to do the job and not based upon the myths or fears or stereotypes made about that person due to his or her race or gender or age or religion or disability. Society faces the question of whether employers should be able to consider genetic predisposition information in making employment decisions and if so how the law should protect workers from the misuse or the potential misuse of such information. While some, including my agency, the EEOC have argued that the Americans with Disabilities Act, the law which prohibits discrimination on the base of disability protects people from employment discrimination based upon one's genetic predispositions. There are those who are concerned that the courts will find that the ADA does not cover genetic predisposition discrimination. Others believe that genetic discrimination is so different from traditional disability discrimination that the ADA does not provide a satisfactory framework and no court has yet ruled on this issue. Nonetheless, the principle of genetic non-discrimination in employment enjoys wide bipartisan support. Legislation has been introduced in both Houses of Congress by both Republican and Democratic members which specifically prohibit discrimination based upon genetic information by employers. Moreover, President Bush has expressed his support for the principle of genetic non-discrimination. However, as those of you who travel in Washington know, the devil is in the details. And as of yet, the Republican and Democratic sides have not gotten together and reached an agreement as to how to craft and how to draft such a genetic discrimination bill. However, I am hopeful, I am still hopeful that Congress may pass a new genetic non-discrimination law, in fact, this term. And I also want to note that towards the end of his term President Clinton signed an executive order which banned the use of genetic information and employment decisions in the federal government. Now, the first and only lawsuit alleging genetic employment discrimination was filed by the EEOC against a company called Burlington Northern and Santa Fe Railroad. And because it was settled before a trial on the merits, no court ruled on the applicability of our theory. And the facts of the case are simple and it got a lot of press and you might have heard of it. And the facts of the case are such, the EEOC alleged that Burlington Northern or BNSF, the railroad subjected its employees to surreptitious genetic testing. BNSF was testing to identify a genetic marker for carpal tunnel syndrome to address the high incidence of repetitive stress injuries among its employees. The EEOC further alleged that at least one employee was threatened with discipline and possible termination for refusing to take the genetic test once it was discovered. Now, shortly after filing the case, the EEOC and Burlington Northern announced a mediated settlement in the amount of $2.2 million. The railroad also agreed to halt any genetic testing that may or may not have been going on at the company. While the result was overwhelmingly positive in that the EEOC achieved everything that it sought in its lawsuit, by resolving the lawsuit informally, which was the right thing to do, it was never necessary for a court to rule formally on our legal theory in the case. But what was most particularly reassuring about this Burlington Northern case was that no one, not the business groups, not the employer groups, not the scientists, not the press, not the politicians, not even the talking heads on Fox News Channel, nobody thought that surreptitious genetic testing of employees and taking adverse actions against those who had the wrong genetic marker should be allowed. In closing, let me say that with advances in genetic technology, we will soon realize that everyone has genetic predispositions for one genetic condition or another. Mapping the human genome changes the way we understand who is quote normal and who is quote disabled. If we all have genetic misspellings, how do we now define who is healthy and who is not? If we all have genetic conditions that are just waiting to express themselves sometimes in the future, aren't we all in some ways truly disabled? As we will have the knowledge of the potential genetic disorder that each of us harbors, disabled people may no longer remain stigmatized as the other within society. Thank you very much. Our final speaker for this session is Dr. Robert Schaler, who is the director of forensic biology at the office of the chief medical examiner of the city of New York, which is the largest public forensic DNA laboratory in the U.S. today about forensic DNA testing and human identification. Thank you very much. I have to say that it's a privilege and an honor to be able to take part in the celebration. I had to think back when the first time I had a chance to take a look at DNA, and that was in June of 1964, my first day of graduate school and it was quite exciting, I have to say. And so I spent the next four years working with DNA in graduate school and I didn't go back to it again until 1986 when forensic science began to think about DNA as something that might be important. The world of forensic science the world of forensic sciences is clearly a world that's a little different than we've been talking about the last few days. Forensic DNA analysis had its origins about the same time as the discussions about sequencing the human genome were taking place. I didn't realize that until yesterday but it dawned on me that that's about true. Alec Jeffries in the mid 1980s coined the term DNA fingerprinting and so to speak with respect to law enforcement that's the starting point and once the prosecutors and the police jumped on board it was up to the scientists to keep the ball rolling so to speak and we had a tumultuous time of it as well. We had a lot of court decisions. Eric Lander we put another hat on his head from yesterday was one of the defense experts and one of the first famous cases the Castro case in New York City when he was a forensic expert and now he's also forensic scientist as well as a well-known geneticist and genome person and I was talking to him last night about that and we had a little bit of a chuckle over it because I was on the other side of the fence. The Castro case was an important one and Judge Jerry Shindlin whom you probably have seen on TV is Judge Jerry his wife is Judge Judy was the presiding judge and he came up with an interesting decision which basically said the work that was done by Life Codes Corporation could not be used to include anybody but it could be used to exclude someone and what he also said was that there was a science of DNA technology forensic DNA technology that could be used to make identifications and that was critical. In New York a few weeks ago at the 50th celebration Dr. Watson made a statement that one of the things he's most proud of is the application of DNA to law enforcement and although Dr. Watson is not here today I would like to say that this is for him. Law enforcement with respect to DNA testing we're involved in rapes and homicides and burglaries and property crimes as you know we're involved in mass fatality identification the victim identification and the re-association remains and I'm going to talk a little bit more specifically about these in a few minutes and then of course we're also concerned with identification from parentage testing and more specifically I'm more concerned with the identification of rapes as a result of identifying from the products of conception and in those instances the husband is not really a husband he's in a salient. Dr. Charles Hirsch who's the chief medical examiner for the city of New York described forensic DNA testing as the single most important law enforcement tool in the 20th century and I think he's correct and I think from all the newspaper hype and everything that you hear about it on television I don't think there's in any law enforcement tool that you've heard more about on March and in May in 1994 two 15 year old girls were raped September 11th 1997 Joe Halis Castro who was 19 was raped murdered and set on fire on a rooftop in April 19th the 13 year old girl was coming home from the skating rink and she was attacked at knife point and raped and her rape has said be quiet and take it like a woman on June 2nd 1998 Rashida Washington was 18 years old she was raped sodomized strangled and dumped in a stairwell on September 25th 1998 a 15 year old girl was abducted at knife point and her rape has said you're lucky to be raped by such a good looking guy September 16th 1998 a 14 year old girl was raped and sodomized and he said to her act like you love me and then we go all the way back to 1991 in May Jonathan Hayes was conducting an autopsy of a young woman who was 13 years old who had been stabbed in the left breast strangled and dumped on the street the police had no knowledge that any of these cases were connected they just didn't know they had some theories that several of them were linked together by at least and they thought maybe there was as many as three people committing these crimes in the April 19th 1998 case there was a composite drawing of the person who attacked her and the murder of June 1998 there was a sweatshirt that was found at the scene this is the CSI stuff by the way and Jonathan Hayes removed a pubicare from the vagina of Payola Ilarra who was 13 years old but still the police had no idea who committed these crimes and again still believing that there was more than one person on the sweatshirt there was a laundry tag and the police followed the trail of the laundry tag because it went back to one particular laundry and although there was a long list of people who had the tag they were able to identify the mother or a woman who had that laundry tag about a half an hour before they about the same time as they got the information on the laundry tag there was an anonymous tip from the composite drawing where a woman said that there was a guy who lived in her apartment building who matched the assailants description and the laundry tag belonged came from a woman named Key who lived in that same apartment building and the guy who lived in the apartment building had the name Ace and he was in apartment 1910 it's a good looking guy this statement comes from the lady in my laboratory who testified against him I think something happened here but he was non-threatening appearing and it was someone your daughter might date so we have all of these rapes and we have suspicions that this one person was at least involved in one perhaps two of them but science has to come to the rescue as you know the murder of in 1998 the June 2nd 1998 murder and the September 28th, 25th 1998 murder rape case were linked by DNA testing and so that was the first clue that other cases were involved in these cases what is interesting is in the murder case three suspects and a boyfriend were eliminated the suspects were under intense investigation by the police in the April 19th 1998 case two suspects were eliminated by DNA testing in the September 25th 1998 case a man by the name of Daniel Simmons was two weeks away from going to trial for that rape and DNA eliminated him the prosecutors were so convinced that if he didn't do it someone in his family must have that they had four of his brothers tested and we were using YSTR testing to eliminate them the Johalis Castro who was the 1997 murder victim had not yet been identified her body had been burned beyond recognition but there were suspicions of who she might be and so she was identified by doing parents testing by DNA testing on the March 1994 case the rape kit had been discarded by this time there were suspicions that maybe this one guy had done all of these and so we were going back and looking at all of the evidence trying to piece it all together but the rape kit had been discarded but the hospital had made a slide that had the sperm on it so we were able to get a DNA type from the sperm there was no evidence in the 1991 case except the vaginal pubicare that was removed by Jonathan Hayes in the New York City Medical Examiner's office and this was eventually subjected to mitochondrial DNA sequencing we still had to prove the case we had the guy we thought we had the guy but we had to get his DNA to make the comparisons and this is a smart guy he didn't want us to test his DNA so the police at one point the police had actually tried to trick him into giving a blood sample for TB testing and he said he's a Jehovah's Witness but he can't give his blood and he refused to do it so they gave him a cup of coffee and the cup of coffee came back and it wasn't his it was quite a surprise turns out that he had exchanged the coffee the coffee matched the rape pattern and the murder pattern but the coffee cup came from the cell mark because this Aaron Key was the guy's name and he had exchanged the coffee cup with his roommate so the police had to go and get other other examples to try to get his DNA in another way so they ended up going more cups of coffee they finally gave a cup of coffee to the cell mate and they knew it was his cup of coffee and so we had to match his DNA to that which means that Aaron Key's DNA was on the other coffee cup one DNA series matched the coffee vendor that they got the coffee from which means he was probably taking sips out of cups of coffee that he was giving out to people during the trial he was convicted he got 200 plus years in prison so he'll be in jail for the rest of his life and during the prosecutor's summation Aaron Key said he didn't want to listen to what the prosecutor had to say about him and the judge told him to be quiet and take it like a man now there's no DNA index at this time which we call CODIS combined DNA indexing system which is established by the FBI and it's a nationwide system right now two of those murders wouldn't have happened and three of those rapes would not have happened because Aaron Key had been put in jail in 1992 and his DNA would have been taken and so we would have known right away who it came from but the system works pretty well my laboratory were uploading cases twice a week the system is something like this if we take a look at New York State for example New York City is considered a local database we upload our DNA profiles from crime scenes to Albany which is the state system it's called the S-DIS and then from there it goes to Washington DC and so we can search locally within the city itself we can search statewide and we can search nationally and we've had hits nationally as well as internationally and we're identifying people behind bars just as importantly we're identifying people who do not commit crimes and we're able to release them as I showed in the example of the Aaron Key case so we were happily going along at this point in time doing rape cases and doing homicide cases doing some crime scene work and I was feeling very much like a forensic scientist and then this happened in case you didn't know the chief medical examiner in any jurisdiction has the responsibility of making the identifications in any mass disaster whether it's an airplane crash or a fire or in this instance where two airplanes crash into two buildings and the buildings fall down this perhaps is the most complex use of DNA for human identification that I know of we had 2,792 missing people and about 19,930 remains and some of these have gone up because we had to go back to the remains and try to find where we have co-mingling and we have been able to separate out a number of those we originally thought were from one person but now we know they're from more than one person at that time it was pretty chaotic as you can well imagine we had to reorganize the laboratory and because the chief medical examiner is responsible for making identifications that put me in responsible for making the identifications using DNA so we had to reorganize the laboratory in fact we had to reorganize the way we think about doing business and a number of things came to light pretty early one of we had no idea how many samples we were going to be getting but we certainly knew that we weren't going to be able to do all the work ourselves so we began to think about how we could get other people to help us to do this work the New York state police came on board on September 14th and we split the responsibilities of them they took the DNA responsibilities for the family samples and we took the DNA responsibilities for the samples coming from the World Trade Center site on September 12th I got a phone call from Craig Venter and he offered the services to do mitochondrial sequencing you have to understand we were looking for ways to do a lot of DNA analysis in a short of time as possible we were looking for high throughput capabilities the New York state police had an existing contract with myriad and myriad had a high throughput capability of doing STR analysis which is the typical forensic test that is used for the CODIS system as well as all forensic laboratories pretty much throughout the world and so this became the way we set things up originally we had a lot of help we had a help from the national institute of health and I thank everyone here who was I know people here in the audience who have helped us tremendous help the national institute of justice set up a committee to help us convene 30 scientists and these 30 scientists were able to help us in various areas we needed help in certain aspects initially and one aspect we needed was we had no way to make identifications we didn't have the software tools to do it number one and number two if you can make an identification using STR the paradigm at that time was 13 loci makes an identification what if you don't have 13 loci what are your statistical barriers so you know that typically what happened to those matching anti-mortem DNA profiles with post-mortem DNA profiles gives you a match and then you have your kinship analysis which is basically a paternity test and then of course you have to make the notifications so the families can have closure the preset statistical barriers were set up by the NIJ committee which is called the kinship and data analysis panel which is affectionately known as the KADAP we had a number of challenges I don't know why those pictures don't stay up there but what happened was we were getting all things and all kinds of samples preserved samples, baked samples decomposed samples, bones, bone splinters mummified samples samples which looked like they had just been buried for a short period of time chunks, small pieces and what faced us most was the fact that degradation was occurring we had the possibility that this process would take over a year to recover the samples it actually took about nine months but as you can well imagine human tissue doesn't like to stick around in the normal environment for that long and so by the time the end of September came around we realized that at least 25% of the samples were giving no DNA test results at all and another 25% were giving partial DNA test results so we had to figure out a way to deal with decomposing tissue and what was happening was this we were having PCR reaction failure for a number of reasons we had a lot of co-mingling remains so a lot of our samples were mixed samples because of degradation and the extent of degradation we were getting limited target DNA so we were getting stochastic sampling and we were getting strange effects the typical DNA degradation looks something like this where you begin to lose signal eventually you lose low size sometimes you lose alleles and sometimes you lose alleles that they're not in a very predictable way the typical mass disaster testing paradigm is do the typical forensic STR test maybe go back and do some reanalysis and do selective mitochondrial DNA testing and this was done in the American Airlines Flight 587 which fell in New York at the same time we were doing the World Trade Center and so we did that TWA, Flight 800 Swiss Air and Alaska Air we changed the world for this process because of the World Trade Center we did the forensic STR testing we had really aggressive, we had to re-do re-learn how to extract DNA from degrading tissue we set up mini-plex STR reactions we did massive mitochondrial DNA testing and we're still in the process of doing SNP testing I'm going to give you an example this is the number of DNA identifications we've made you can see how they've fallen off over time but we're still doing it we've created samples something like this this is the original testing on the bones and this is not working basically what you're seeing here is a sequence of using mini-STR mini-plexes where we've reduced the primers so that we get a smaller amplicon size and we're able to fill in the blanks of some missing loci that way and then we can match it up to a toothbrush which is the top line and you can see by making a virtual profile from all the original testing we're able to show that the STR profiles are the same and can therefore make the identification and the statistics fall within the guidelines of the cadap which basically, like I said, helped us out a lot we're also using mitochondrial sequencing to help us sort through the large numbers of samples that have bad data and we can choose a name basically every person who died has an RM number which is a reported missing number we can select a disaster sample we can look at the DNA, the mitochondrial sequencing on that sample and then we can check the STR see whether or not we have a match and you can see here we have a potential match but we're missing a lot of alleles we can also check the against the personal effect with the original electrophereograms to see whether or not we have alleles that should have been called that weren't called because of some threshold barriers and we can also look at the mitochondrial sequencing and you can see here that we're missing a number of positions where calls were made so we have to go back and try to re-sequence this anyways, this last example is one which is in progress we have not made the identification we believe we know who it is but this requires more analysis and probably another year before we're able to get it all completed and I thank you for your time and I think that's it I don't think I have time to talk about SNPs I can just show you, we kind of look at SNPs in a little different way I will that's it, thank you don't go down I'd like to invite our speakers up here for questions and answers from the audience with the rich amount of material that's been discussed in the last hour plus that we'll have plenty of questions I do regret that we're only going to have 14 minutes left for questions so well, so please keep your questions brief do you have a question? Please I wanted to ask Paul Miller examples are often given in this discussion about the workplace where testing for predisposition may be a benefit, the example that's often used is if a particular gene predisposes for sudden cardiac arrest wouldn't a airline want to test its pilots for such a test, also the Department of Energy currently has experiment going on in testing for those who might have a predisposition working with beryllium for beryllium of this disease how do you handle in your context those kinds of situations where there might be a benefit where predisposition would show that's a really important question an important issue I think that is important is first that the individual worker have the flexibility that becomes the worker's choice and that their their decision forced and consent whether to be tested or not I think that people have the right to engage in sort of activities that may not be healthy for them being a cop for example may not be a particularly non-threatening job but people need to do that I think that where we get into trouble is to use predisposition information that is some likelihood that they may get sick as an opportunity or to screen people out of jobs that they're qualified for in the law we have something called the direct threat standard and that is if somebody poses a direct threat to others or to themselves now under the law that an employer may have an argument not to not to have to hire them and I think that that direct threat standard will probably apply here in the instance of genetic predisposition testing but what I think is really important about genetic predisposition testing is that in most instances genetic predisposition information doesn't tell somebody that they are going to get sick, that they are going to have a heart attack just that they may have a higher likelihood from other people from the general population in having a heart attack and I don't think that that is should be enough to exclude people from opportunities in employment the gentleman up in the balcony has a question for Dr. Schaller DNA evidence was subjected to a great deal of scientific validation before it was fully accepted by the courts some people have been arguing recently that other forms of forensic evidence should have similar kinds of scientific examination and validation including fingerprints and I'm wondering what your reaction is to that proposal and why I agree I think that you know we take fingerprints for granted because they've been around for so long but nobody's really ever done an exhaustive study by the same token I don't think we have any indications that fingerprint analysis if done correctly gives wrong identifications but I think what we're dealing with is a situation in which we have people doing fingerprint analysis and I do know that a lot of fingerprint analyses are challenged and some of these have been found to be errant simply because the examiner either didn't utilize enough points of comparison to make come to a conclusion or maybe the field itself needs more clarification as to what constitutes an identification with safest semi-automated fingerprint analysis there's imaging which matches things up and that does a database type of function but then a person takes the matches that are brought to the top and then does a comparison with them so once again you're back in the realm of a person doing that kind of comparison and by and large these people are not scientists yet. Yes ma'am. Hi, Leah Hardy from Pfizer. I have a question for Dr. Freeman. First I'd like to thank you and all the speakers for very thoughtful and thought-provoking presentations. My question is this. As you describe race as a very crude variable for categorizing people for scientific study and one alternative that's been proposed to self-describe race is the use of genetic markers that are exclusively or at very high frequencies in certain sub-populations and in light of your comments and given that the world is increasingly becoming a smaller place and people are increasingly mingling with each other and populations are becoming less distinct I'd be interested in your thoughts about the use of these markers in scientific research. A good question. I think that the issue of using markers in scientific research for outcomes that are designed to help people is perfectly perfectly good. The danger is though I think in defining who the populations really are from a genetic perspective and the danger also is been brought out in my colleagues concerned about if you do find something what does it mean with respect to the rights of that person. I believe that we should look down deeper into populations from crude levels of understanding now to refine our understanding genetically of populations of people who are subject to increase the risk for certain problems and there should be nothing to stop us from doing that but it has to be done with the sensitivity that I mentioned and in particular I don't believe there's any evidence that if you do that analysis that the groups that you will finally discover with respect to some particular measure that you're trying to understand say from a medical point of view those categories will be much different from what we call race. Yes. Hello, today Hamilton University Pennsylvania School of Ethics. This question is for Dr. Schaler. I was wondering if you could speak to how the FBI's DNA database impacts racial profiling. Have there been conversations in the law enforcement community on if there's a positive or negative impact on racial profiling? The National DNA Index CODIS utilizes markers which specifically do not affect racial profiling and so when samples are put into the National DNA Index there's no indication of race at all so it doesn't impact it at all. I guess I'm speaking more from a societal perspective in the black community you often hear conversations that maybe African-American men are targeted more often and some of this is hype but some of it is also reality so I guess more from a societal perspective have there been conversations with relationships with African-American men or women, African-Americans in general in the law enforcement community. Have you been privy to those conversations or do you know if those conversations are going on in the law enforcement community? I personally have not been privy to those conversations but I do know that there are efforts out there by scientists, forensic scientists to try to get more information from the human genome that we're using right now. People will be talking about. Up in the balcony. My name is Eric Ornman from Applied Biosystems I had a question for Dr. Scheer. I'm most curious about with all the successes of CODIS they're still quite small compared to the successes in the UK in terms of number of cold hits per day or per week. Can you comment about the likelihood of the US getting more serious about forensics the CODIS is rapidly expanding right now the limiting number of profiles that is keeping us back from getting more hits are the number of crime scene samples that are in the index we have a lot of convicted felons who have their DNA profiles in the index right now thousands and thousands of them tens of thousands of them we have relatively few crime scene samples to compare them against and so that's really what limits you in my laboratory we upload several hundred profiles a month and we're getting approximately a hundred hits a month and we have a relatively small number of samples in there so I think you'll see as we get tens of thousands of crime scene samples in there you're going to see some dramatic numbers Hi, I'm Will Fitzhugh from Solera the question is about patents I was wondering I wanted to make sure I understood what you said about EST patents they weren't enforceable or weren't invalid is that what you said and the follow up question is then if there's quite a continuum between ESTs and complete accurate gene sequences so what are the standards for enforcing patents with slight errors and polymorphisms and things like that Yes, I was talking historically on the filing of the EST patents and the guidelines of the PTO as you all know them as well as I do I went into the news this morning and one of the anchorman said I'm sure that after the break I'll have something thoughtful to tell you so stick around let me think about what I need to say about that and that's sort of the reply because you're absolutely right there is a continuum there and the utility of course keeps getting is something that needs to be associated with it it is an interesting observation and I think for those who are interested in this field we will see how these patents eventually are issued and how the guidelines are implemented so right now you and I can speculate I think all we want but the proof is going to be in the pudding and then it's going to be more important as to what the courts are going to say I hope you all will join me in thanking these wonderful presenters this afternoon our final presentation today I think is really fitting today's investigators from around the world as we've talked about the development of the human genome sequence and we've heard today about the importance of thinking about genetic variations that contributes to disease around the world both from Doctors Hill and Dr. Freer this afternoon and so it is fitting that our final speaker is Sir David Weatherall the Regius Professor of Medicine Emeritus from the University of Oxford University who is going to speak to us now about genomics and world health Well thanks very much indeed for inviting me to what's been an enormously exciting few days I'm a little bit nervous about speaking as the last speaker I've had one or two bad experiences over the years when I was a very young man I was in a position like this and the hall emptied except for a group of old ladies and I thought well good pro as I am I better give them their talk and after about ten minutes two of them got up and I could see they were carrying buckets and I realised that I was lecturing to a group of people who were in there to clean the hall so if you're feel like getting up just keep your buckets on there quietly I'm also archaic I hate anything modern and so I'm using good old fashioned slides and the two little men at the back I hope who are going to put them on for me could I see the first slide please I think the reason I was asked to give this talk was because for reasons best known to herself the director of the general of the world health organisation asked me years back if I would be the lead writer that's the person who does all the work on a report and genomics and the world health and this has been published now in a fairly massive report so I strongly advise you not to read it but you can actually buy the summary and I found it quite honestly one of the most difficult things I've ever done although I've actually worked quite a lot in the banking world and we have a big group of people in Oxford who do that and the reasons that it's so difficult I think are shown on the next slide this is a picture of the state of disease really in 1990 or 1992 and shows disease in what are called Dali's disability adjusted life years I think health demographers are not terribly interested in whether we're dead or alive but whether we're the nuisance we are when we're alive but it gives you a very good idea of the I think it gives you a good idea of the frequency of death and disease in the community and the red shaded areas are the diseases of sub-Saharan Africa malaria diarrheal illness perinatal deaths HIV and the sad thing is that same diagram compared with the disease pattern in the established market economies because to be very similar right across the richer world hasn't really changed since the 1960s or 1970s it's changed a little and it certainly hasn't changed over the last 10 years HIV would have come shooting over tuberculosis would certainly be back in this list probably the most frightening statistic and the kind of thing I think any of us who have been in clinical practice would go to bed every night with a bad conscience about the figures from 1998 of infection and the analysis of deaths in childhood from infection of about 12 million deaths indicated that about 5 million of those were due to diseases where we have vaccines or easy methods of prevention so when you actually go into the world public health and against this frightful situation of gross poverty and dysfunctional health care systems and you look at the kind of things we've been talking about for the last 2 days they seem almost irrelevant and that was really the problem that I had if we look at the next slide the other problem is that if you're really kind of honest with yourself and you ask what has been the impact of genomics on world health so far the answer is it's been very limited it undoubtedly has altered practice in single gene disorders and in clinical genetics but in communicable disease malignant disease it's given us huge insights into mechanisms, quite extraordinary and to some degree in the other common diseases of western society but if you took day-to-day clinical practice because these diseases make up a very small part it's not yet fulfilled its promises so it's against that background that we have to kind of think now should we what should we be doing about thinking about the future for not just our own countries but the developing countries and I'd like to take just two issues really this evening can we see the next slide please one is the approach to the analysis of genetic disease and also the second point is can we look at genomics and ask the question is some of it already ready for transportation and can that act as a kind of future model if we look at the approaches to determine of the genetic component of disease we've talked over the last two days about two major approaches the kind of genome down the kind of genome to phenotype approach which has been so successful in the diseases where we knew absolutely nothing about the kind of cause and path of physiology then there's the genome up approach the phenotype down approach which seems to me to be of so critical importance and I think so many of our younger people coming into this field now don't really realize the importance and I'd like to show that by one or two examples particularly in my own field and then the other approach which again we've neglected in many directions we've looked at twins for common disease but we're now about to spend hundreds of thousands maybe millions of dollars analyzing monogenic disease for modifiers where we haven't got one good twin study and we've totally neglected the kind of classical approach of epidemiology the analysis of genetic disease in a changing environment so let's ask the question can we look at an up-down approach and can we apply any of these approaches as models in the developing countries we'll see the next slide I'm going to just briefly remind you about the hemoglobin disorders because they're monogenic diseases which are now completely forgotten in the kind of western genetics but they are the commonest ones in the world population and the WHO reckons about 7% of the world population are carriers they're either genetic diseases of the synthesis of hemoglobin or of the structure of hemoglobin and I'd just like to focus on these two here at the alpha and beta thalassemia just for one minute if we could see the next slide this is the world distribution of these diseases and these are the estimated births of new cases each year and all this data is completely wrong it's inaccurate what is fault particularly is WHO data but what we know now is that if you go into these countries and you micro-map for these disorders you find that the distribution is grossly uneven right across all these regions so these bland figures from one center or two centers don't give any idea of the frequency we've recently been micro-mapping this whole region with our Indonesian colleagues and the heterogeneity is extraordinary but the overall data suggests that we tell the Indonesian government that to treat these children over the next 20 years they will require about 1.8 million bottles of bloody year and currently in Thailand it's estimated about nearly 3 quarters of a million of these kids so that's a monogenic disease in a setting of a developing country now the central question and problem for this disease and like all monogenic diseases is the following if we could see the next slide this is a child who's got the very worst clinical pattern of beta thalassemia he was born well profoundly anemic within six months in a country where they didn't have enough blood to give him to keep his blood up and frightful deformities of the bones, numerable fractures his hands over his painful liver he's got a huge painful spleen under this and it's a kind of living death it's not that bad if he's adequately treated and this child is homozygous for beta thalassemia and so is the next child who comes from a few miles away and both these children are homozygous for the same mutation and it's this level of heterogeneity of all monogenic disease which again you step back and you say really are we ready yet for putting this kind of information into a kind of a simple population like many of the developing countries well if we look at the next slide which tells us in very simple terms and pre-genomic terms of about 30 years ago the value really of having some at least primitif idea of the pathophysiology of a disease when one is looking for genetic complexity these diseases are diseases of hemoglobin and humans have two alpha chains and two beta chains as adults so that boy is born fine he switches over to make beta globin he can't and this disease is not a disease of hemoglobin production but it's an imbalanced globin production because these excess chains precipitate damage the red cell precursors I was talking about this disease in Washington a few months back and I pointed out that what happens to these bone marrow of these poor kids they're a bit like a committee and I just likened it unwisely to an NIH committee where there's enormous input and enormous proliferation but no output and that's the problem now if you understood just the outlines of this pathophysiology you could sit back and say well I could understand the heterogeneity of this disease difference defects at this locus of different severity maybe children who inherited a defect in alpha production would be better off if you got two forms of thalassemia they might be better than one or maybe children who were able to make a little more fetal hemoglobin after birth and so one already had a clear view of what the genetic identifiers might be and if you take this old picture and you then transfer it to 19 or to 2000 wherever we are in the next slide what genomics has done for us it's not changed our kind of overall views of the principle of these sick kids it's just added of some levels of complexity so here we are with our excess alpha chains and our inclusions we now know that there are about 250 mutations here of varying severity those two children have the same mutations so we can't account for the differences here but we now know that there's enormous diversity in the human alpha globin genes you and I have four hundreds of millions of people in the world population are missing either two or one alpha thalassemia is by far the commonest mild genetic disorder so again some populations have more alpha genes so just up here this combination and this combination enormous diversity we now know that there are genes which make it more likely or less likely to make fetal hemoglobin after birth and that's heterogeneous we also know that there's another layer of complexity that the complications which the anemia causes for these poor kids, their bone disease their loading iron their jaundice are all under genetic variability even infection because of co-selection different populations have different back genetic setups now you might argue so what we know there's going to be genetic fine tuning but if we just take one example jaundice when I went to Sri Lanka a couple of years back I saw mild cases of this disease but the kids were all deep yellow and had never seen this before and there was no good reason for this when we knew about that there were promoter variants in this gene which is involved glucuronidization and the handling of bilirubin and any child with this kind of disease makes a little bit more bilirubin we looked at the promoter polymorphisms in Sri Lanka we found remarkably that about 30% of Sri Lankans are homozygous for the long polymorphism in this gene which actually makes them handle bilirubin less effectively now this is an extremely distressing symptom and these kids are deep yellow, they're almost green if they're homozygous for this polymorphism with this disease now the two messages here if you are looking for monogenic diseases in different parts, in populations you do need to know the frequency of these modifiers and in this case it did occur to me that if we knew nothing about the cause of this disease and we'd done a genome search for these mildly anemic children we might have picked up the beta-globin genes the one thing we certainly would have picked up would have been this gene and if we'd done that and we thought that this was the cause of this disease or even related to the cause we'd have set the field back about 70 years because the early people who investigated these diseases oh yeah, they may be pigment disorders now can you take this complexity into the developing world well I think you can you don't need to know a lot you need to know the mutations and it turns out that every country with these diseases has a different set of mutations you need to have a rough idea of the frequency of the major modifiers and so what's happened over the last 10 years or so who see the next slide is that programs have been developed as partnerships between universities in the richer and poorer countries and they've worked extremely well as local simple partnerships where people have come over from the high frequency countries learned simple DNA technology taken it back with them developed their own programs and at the moment we're trying to extend this type of idea by developing regional networks so in Asia for example that they can take these kind of this simple technology and help countries for example in Thailand they have enormous expertise now and they can generate that around countries like Cambodia where these diseases are so frequent and if you look at the next slide in the Mediterranean island populations this is Cyprus where they decided because the high frequency of this disease if they treated all their patients with blood they would by within 15 years 40% of the island would be blood donors and they would be spending twice the island's total health budget on this one disease and they decided on a preventive program of prenatal detection and counseling and you can see what's happened with this type of joint training program to the frequency of the disease over that period and as the Mediterranean islands developed these simple technology if we look at the next slide it gradually spread in exactly the same pattern north simple collaboration between laboratories training go back, set up programs in their own countries I won't go into the kind of reasons for this variability because there are enormous kind of differences in the distribution in these countries of populations for example in Thailand about 80% of the population are rural and there have been all sorts of important ethical and organizational issues but this list is now very much longer so can this kind of simple university or other institution north-south partnership be applied to the broader, some of the broader diseases of the developing world just to introduce simple DNA technology we see the next slide if we look at genomics and infectious disease obviously we've got several genomes pathogen, vectors and the human genome and we've already got some hints today about the possibilities here but there's still only possibilities so let's just go to simple DNA diagnostics and the human, what we know from as Adrian was telling us this morning about variability and susceptibility other things here that are already a value for the developing countries if we look at the next slide the of course most of you know that DNA diagnostics in communicable disease have taken off in quite a big way and we don't need to go through these in detail at all either for detection or for analysis of resistant treatment regimens there's a beautiful paper in Lancet which may not have got to over here from last week from the Oxford group but we'll see on the use of the ability to identify genes specific to mycobacteria tuberculosis rather than bovis and the development of a very beautiful simple fast technique which seems to be much more accurate than simple skin testing for identifying people with latent TB now question is are they cost effective are they too expensive for the developing countries and exactly the same technique method has been used the north south simple collaborative method between universities in this field as in the globing field if we see the next slide and this is Eva Harris's program for the Sustainable Science Institute and it's been exactly the same type of program you take groups of scientists you develop training programs you develop workshops and what you try to do is to develop simple cost effective DNA diagnostics many of these DNA diagnostics are ridiculously expensive and honestly they're not much better than standard steam microbiology but where you've got organisms that are difficult to type difficult to grow and the elegant outcome of this program has been the extraordinary value for diagnostics for specific organisms and this is mostly work in South America for the early identification of dengue types leishmaniasis and leptospirosis which has been a notoriously difficult organism so I think that's a beautiful example of when DNA technology is ready is it cost effective in the setting of a developing country yes it is and so I think one should not be negative about taking these technologies to the developing world if we could see the next slide the Adrian talked to us this morning about resistance and susceptibility to infection there are early hints now that this type of information may be useful in clinical practice some very nice studies from West Africa the MDR polymorphisms this is a gene which is involved with the identification of people like a protein probably polymorphic become poly polymorphic due to gut infections in Africa and this seems to play an important part in some of the susceptibility to AIDS therapy particularly with the protease inhibitors the very nice data from Marley suggesting that the polymorphisms in the malarial parasite which this is the one that denades chloroquine resistance drug resistance may be again very valuable in early identification of resistance in communities and then we talked a little bit this morning Adrian about the polymorphisms of the malaria resistance which have become so of such interest in recent years and the next slide just recapitulates I think Adrian's list I don't think you can see this Paul might but if you can bad cerebral malaria and what Adrian pointed out this morning was that so much of our recent work looking at these polymorphisms has taken WHO criteria this is the worst thing that can happen to you with malaria or profound anemia and if we look at the next slide this is the list that I think Adrian showed this morning the increasing list of human polymorphisms in relationship to resistance or susceptibility now as Adrian said lot of these are mild they need confirmation and so on but if sickle does offer 80% resistance to getting in the state of that child and the band 3 mutation that's so common in parts of Melanesia seems to cause complete resistance to cerebral malaria if we just look at the next slide this is a case control study in this region of Papua New Guinea where alpha thalassemia is compared with normals in a case control study what is the likelihood of you being admitted to hospital with these severe complications and if you have got homozygous for the mild forms of thalassemia the likelihood is to 0.4 and in heterozygo it's about 0.6 and the fascinating thing about these data and I think about emerging data on sickle are the fact that these children seem to be protected not only against malaria but against other severe community infections whether that's because the protection against malaria makes them less likely to pick up other community infections is not clear but these are very big effects and if one was then moving into these populations to test a vaccine, an attenuating vaccine one really has to know about these issues like sickle the polymorphisms with really big effects well of course the big science approach just to finish the next slide please over the last year the complete sequence of the malarial parasite P. falciparum has been announced the sequence of anopolis gambia which carries the wretched beast around quite remarkably actually a lot of sequence information on this form of plasmodium which is the mouse plasmodium and already a lot of information about the stages of the life cycle in terms of proteomics and patterns of protein again a lot of information appearing already about metabolic pathways which are obviously making people very very excited about the possibility of new targets for therapy and vaccines but as we heard from Peter earlier this afternoon this is all going to take a while I do get lucky breaks and my last example is next slide please was such a break which happened just a few couple of years back searching through the falciparum genome finding a metabolic pathway which is used by the parasite discovering that a useless antibiotic had been designed to target this pathway and it was no longer in use finding very quickly and remember this all relates to the genome sequence that it was effective in murine malaria and within two years the first human trials and I gather from Thailand this is looking quite promising so you will get lucky breaks along the way so I just tried to give some examples of DNA technology that is already a value in the developing countries and if we just summarize see the next slide I think the way we have to go in the future it's clear for us as well as just decent human beings really that the fear out there wherever I went doing this exercise was you're going to have new more high technology medicine in the richer countries which is just going to make the guide worse and we have to do something about that in reducing this awful gap where 90% of our research at the moment is directed at 10% of our diseases now I don't want to talk about action of governments and non-government organizations tonight they're really self evident and we've heard something very interesting information about patents at least today I just want to leave this message actually for the younger scientists in the audience and for those who are involved in education I think there's an enormous opportunity for developing these partnerships and what it requires really is a much greater understanding of the global aspects of disease in our medical schools departments among our young people it's going to take a big change in emphasis but you can do it we started doing it in Oxford about 10, 20 years ago and now we have groups all over the world who come back each year about 200 young people and we have this combination of units in the developing countries together with these types of partnerships I've tried to describe this afternoon and what we should be doing is asking the question what is cost effective DNA technology for the developing world because once you've introduced that you've got a basis and as further developments from genomics come these countries can develop their own kind of technology basis to also be done obviously at the industry level and so on I don't want to prolong that tonight I think to do that we will have to change our outlook on education and try to excite young people into more work in this field that will require revitalizing clinical research if we're going to make the best of translational research and above all it's going to be a big education problem in trying to integrate a public health world with genomics but I think we start in this small way this is the way forward now it didn't seem right for an old man like myself to have the last word at this meeting can we see the last slide please there are two messages I had tonight really one was the vital importance of phenomics as much as genomics and the we've heard about it during the day the vital importance of not ignoring clinical research if we don't accurately define phenotypes and if we don't look for the rare experiment of nature we're going to miss out William Harvey realized this in one of his last letters to a friend and the other key issue is because of the extraordinary complexity of human disease probably a sick human being is the most complex biological organism imaginable and I think Francis Crick very much realized that but I'm not going to give Francis Crick the last word about two years ago Jim Watson came to Oxford on sabbatical and he's great value for the youngsters and on the very last day was the on the last week I said to him look Jim would you give a lecture in the medical school and we'll get the entire medical school every young person and the place was packed and they're all sitting on the edge of their seats and he gave this lecture and at the end he said take some questions and everybody was terrified and then one young man put his hand up and said excuse me Dr. Watson but you made the greatest discovery in biology in the last century perhaps ever could you tell us what's going to be a discovery of equal importance in the next century and there was a long silence and the eyes rolled and you could hear all these bottoms moving along to the edge of their seat in expectation and then he said there won't be one and I think he may be right in the medical world it was 300 years after William Harvey before the circulation of the blood had any effect on cardiology it was 70 years I think it was 1880 when William Koch announced the discovery of tuberculosis 70 years until Waxman and Penicillin Streptomycin and another 70 years and we're still in trouble with tuberculosis medical advances follow quite a while after laboratory basic laboratory science advances and we shouldn't be expecting the whole of medicine to change overnight and I think this is a very important message that we have to get it's not an active message to our grantors or to the news press but we've oversold but there are things that we can do now simple things and we can do them at individual scientist individual institution lesson to start to move into the developing countries it's not too early to do that and it will form a basis for the tremendous excitement which I'm sure will come from this field in the future thank you well thank you Dr. Widerall this was an inspiring lecture but all good things have an end and I'm here to close the symposium there's no question over the past two days you've heard a dazzling array of insights into the past and the present and the future of genomics and scientific research I'm sorry that I couldn't attend today's sessions but these sessions were terrific I really think that we owe a great gratitude to the National Human Genome Research Institute and also the foundation for NIH without those two partners I can assure you that you wouldn't have seen the symposium program all the associated programs and the great event last night there's no doubt that without the support of the many government partners and private partners we couldn't have made this happen now Dr. Widerall has helped emphasize something that is dear to me and that is that in fact we need to think now of the planet as one and we need to invest across the board when we invest in science to make sure that the 90% which is not researched with the resources that we have does get researched and for someone who comes from the developing world I think this is a very important message I'd like to really give you some personal thoughts about what happened between yesterday and today and our release at noon yesterday of the human genome fundamentally I think this is going to define science in the 21st century and you've heard that many times but why is it I personally think it's going to be the challenge of the century when you look at the burden of disease in our country here and over the world when you look at the costs to social to national budgets and the social consequences of not tackling the growing burden of disease you realize that we're engaged in a race but then when you think about what humankind has accomplished through science and why we need to accomplish more you realize that in fact it is the disequilibrium between environmental conditions and humankind that we as an intelligent species are in fact responsible for that generates what I would consider an evolutionary accelerator the changes between our genes and environment and lifestyles the speed at which they're occurring is pretty unique in evolutionary history and when you if you thought about an event that occurred in the environment and you thought about the number of generations it would take evolution to adapt us to mutation and selection you were talking about 5,000 to 10,000 years of evolution for any particular change in the environment well this is exactly what we're facing we're facing rapid changes in our environment that have occurred over the past 100 years would it be food supply with the emergence of obesity would it be globalization with the emergence of general diseases and exposure to agents that we're not exposed to so at the end of the day you realize that there is a need for an acceleration of adaptation and science in fact plays that role in fact understanding the genome and having the ability to modify our own gene environment interaction scientifically is going to be a requirement for survival of the species in some ways but at the end of the day unless we do this we're engaged in a race I think that could not be one without the human genome sequencing being done first so I think there's no question that today and yesterday will be in the scientific calendar of great days so I'd like to make an announcement that we have decided to change actually the scientific calendar as you know we are on the Gregorian calendar and stars January 1 so I'd like to announce to you that today at the end of the symposium we've just finished day 1 AG this is day 1 after genome and yesterday we were basically last day BG and with that I'd like to really thank you all for your participation thank the organizers and thank Dr. Weatherall for his magnificent lecture and all the other speakers please enjoy and let's go on AG day 2


Does the narcissist miss you? Do they feel regret or sadness at no longer being able to enjoy your presence? Do they notice your absence? This has more to do with them and their feelings than it does to do with you.  They do not miss your characteristic traits or qualities. They miss how you made them feel. During the love-bombing phase, they displayed a false character to you. You gave them your attention and your admiration. This made them feel desirable or attractive. It made them feel as though they were worth something. As though their false self actually existed. You validated their false self and the illusion that they portrayed. This made them feel good about themselves. It had nothing to do with you as a person. It had nothing to do with how they felt about you. It was all about them and how they felt about themselves. They were just using you to regulate their emotions. To regulate their self-worth, self-esteem and self-importance. You were nothing more than an object which they used to serve their own agenda, their own needs. They didn't see you as anything more than that. During the devaluation phase, they abused you emotionally, mentally, psychologically and sometimes even physically or sexually. They targeted your self-esteem. They made you feel as though you could never be good enough for them or anyone else. They made you feel as though you couldn't do anything right. They projected their insecurities onto you while they were abusing you and denying that they were doing anything wrong or shifting the blame onto you. Gaslighting you. Making you question your own memory, perception and sanity. They had control and influence over you. Their behaviour had a strong effect on your thoughts and feelings. This made them feel as though their false self existed. It made them feel as though they were something significant to you. It made them feel powerful. It was all about how you made them feel. They used you like an object and pushed your buttons to make them feel however they wanted to feel. They didn't appreciate or respect your personality or who you were as a person. They didn't appreciate or respect your characteristic traits or qualities. So how could they ever miss anything about you? It was about their feelings. They cannot mention or refer to your feelings. They don't even care about how you feel. It was all about them. It was all about how they felt. They miss how you made them feel. They miss what you did for them. They miss what you gave to them. When they needed you, you were always there. You genuinely cared about them. And wanted to help them. This is a very potent source of supply for the narcissist. If they needed something done. If they needed someone to take care of them. You were always there. You provided them with amusement or enjoyment. You gave them your time and energy. You paid for meals. You bought them gifts. You gave them money. You were affectionate with them. This is what they remember. This is what they miss. They feel regret or sadness. At no longer being able to have these privileges. These special rights or advantages. That they no longer have.   The impression that you presented to the public. How you improve their image. They have to display this false deceptive appearance. Of being impressive or imposing in appearance or style. It makes people notice them and admire them. It makes people look at them as something impressive or attractive. It regulates their emotions and boosts their self-worth, self-esteem and self-importance. But it had nothing to do with them appreciating or respecting you as a person. You were nothing more than an object. Which they used to fulfill their need for narcissistic supply. They don't miss you. They don't miss your personality.  They don't miss your characteristic traits or qualities. They miss how you made them feel. They miss what you did for them. They miss what you gave to them.  Thank you for watching. I hope this video resonated with you. Please like, comment, share and subscribe. Click the bell icon to receive notifications of my future videos. If you would like to donate, my PayPal link is in the video description. Coach the inquiries you can email me at natsofacochin.com Thank you for watching and I'll talk to you soon.