>> good afternoon, everyone. welcome to all of you here in masur and all those watching over the web. today is 12/12/12. all of you numerologists must be having a special day. somebody did a little analysis here, maybe it was jackie, to
figure out just how often will that happen, where we have a date like that and it's also a wednesday afternoon lecture? well, of course we aren't going to have any more dates like that for the rest of this century, because once you get past 2012, well, you're into those dates
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that don't have months that go that high, so this is the last of the nnn date, but actually we won't have another wednesday afternoon lecture that's like this until april 4th, 2204, because the others that happen before that don't happen to be wednesdays except for one that's
veterans' day and we probably won't have a lecture that day. so live it up, people! this is a special time. and i guess for all of us, have a little tinge of the idiot savant, this is a good time to think of those things. well, that was a silly comment.
a more serious comment, this is a special day and a special lecture, because today at the wednesday afternoon lecture, we have the annual margaret pittman lecture, which has been, as you can read in your program, something that's been in place for quite a few years with a
number of very distinguished presenters, including today. and established in 1994, to honor dr. margaret pittman, who was nih's first female lab chief, and who made significant contributions to bacteriology and vaccine -- something which now happily we have a vaccine
for. and a wide variety of other contributions that she made at rockefeller and then here in the area of vaccine development for such things as pertussis and tetanus and a long career here. so we honor margaret pittman today by remembering her in this
lecture, and we always seek to identify a lecturer who represents that tradition of excellence and who's also been particularly importantly involved in mentoring, mentoring especially women scientists who have contributed to our field. and jennifer grandis, our
speaker today, very much represents that tradition and we're delighted to have her with us. she did her undergraduate work at swarthmore college. i notice a joint major in biology and art history, so this is a renaissance person.
got her m.d. at the university ouniversityof pittsburgh schoolof medicine, and remained at the university of pittsburgh to this day in a remarkable career carrying her through to training in surgery and otolaryngology. from there, to assistant professor, associate professor
and by 2004, full professor and now distinguished professor in the department of otolaryngology as well as assistant vice chancellor for research, program integration and health sciences. she's received a number of distinguished awards. i have to mention the provost
award for excellence in mentoring, and she's a member of the institute of medicine. she has to her credit, and we should express our gratitude, been very gracious in extending service to nih. she has been on lots of study sections.
i think some three pages of her c.v. goes through this, and we do really appreciate that kind of hard work, including being a member at the moment on the board of scientific counselors for nidcr. and the recipient of numerous nih grants.
her work has been consistently focused especially on cancer of the head and neck, and any of you who are ib vofle involved inclinical care will know those are some of the most difficult and frustrating illnesses to wrestle with, because of the fact that these in general have lacked an
effective treatment, that they affect a part of the body often involving swallowing and speech that makes it particularly challenging for patient and physician to figure out the appropriate management. but she has contributed to this in very substantial ways, to
carry the understanding of these diseases into the molecular era, and she will be telling us today, i'm sure talking about egfr and a variety of other pathways. the title is targeting ongoncogenic pathways in head and neck cancer.
she is going to speak, there will be a q and a, there will be a reception in the library with refreshments, but i think i should get out of the way and ask all of you to help me welcome dr. jennifer grandis, the margaret pittman lecturer for today.
please welcome dr. grandis. >> well, thank you. it is so wonderful to be here. i'm honored to have been invited to deliver this lecture, and i'd like to start by really thanking the nih for being so supportive of me and my career. it's a really atypical woman who
chooses a career in surgery and then chooses a focus on science and most people feel that's a bit of an oxymoron, and i have to say that support from the intramural and extramural program through clacollaborations and indications to participate in the review process and to
help design programs has been invaluable to my career development, and i'm most grateful. thank you. i'd like to take you on a little bit of a journey today and really emphasize the buy directional dynamics of
transizational cancer research. as a person trained primarily as a clinician it's difficult to do anything but translational research although now it's a popular buzz word. for those who aren't intimately familiar with head neck cancer, i'd like to briefly describe my
chosen focus and then emphasize all of the principles that we'll discuss in more detail are really applicable to virtually every malignancy but potentially lots of other disease processes. until recently, we really believed that most of the cancers in head and neck were
associated with exposure to tobacco and alcohol, increasingly there's an epidemic of human papilloma virus associated head and neck cancer, primarily in north america but i'll tell you that's because we're testing for it here so i've recently been to india and
china in the last couple of years. they deny having any hpv head and neck cancer but if you ask them if they've looked for it the answer is no so it's hard to know what to make of that assessment. still today, the treatment is we
cut it out and deliver adjuvant and therapy like radiation or radiation plus chemotherapy or, when cutting it out is just too morbid to imagine in terms of loss of function, we deliver combined chemo radiotherapy, chemotherapy by itself is still not particularly active in head
neck cancer. even when we cure a patient of their initial cancer, there's a very high rate of recurrence and second primary tumor formation, so the statistic that really illustrates the morbidity is that if a patient survives their first head neck cancer, they
will usually succumb to a second cancer of the air or digestive tract. despite the tremendous work in the field, the only effective chemo prevention strategy thus far is to stop smoking, we'll introduce much more effective agents for head and neck cancer.
these are the anatomic sites, the sagittal mri. i'm primarily not going to focus on nasopharynx, but focus on the oral cavities pharynx and larynx. now if you lived in europe and you wanted to buy a carton of cigarettes, this is what they
would sell you. and in our good government's wisdom, this is not allowed because it infringes on the freedom of the tobacco companies, but this was thought to be a potential deterrent to smoking in europe. however, there's a cottage
industry, i understand, of very nice looking holders, so you can buy a package of cigarettes that looks like this, and you can put it in something very pretty so you don't have to remind yourself that this is what will happen to you if you continue to smoke.
so from my perspective, the gaps in knowledge that have really driven our program over the years is we still have absolutely no idea what to measure in a patient's tumor to tell us how best to treat the patient. so there's no predicted
biomarkers. we don't really understand treatment resistance, it's not very well-defined, therefore, we can't really elucidate the resistance mechanism, even though we understand that hpv is a very different cancer, and i'll show you some data about
that. we still don't have an hpv selective therapy, i suspect that one day if we would vaccinate all of our children, we might not have hpv associated head and neck cancer, but that is clearly decades from now. i'll tell you a little story
about how our genomics is revealing new targets, new pathways and new ideas about how we can really design innovative and more effective trials, but i think the real challenge is to elucidate these groups among the tremendous genetic heterogeneity with the understanding that many
of our subgroups are going to be small but quite meaningful. so i think before we undertook genomics, this was just a sample trial with a sample of some of the agents that are under clinical development, and you can see it's most of the usual suspects.
there are receptor kinases, non-receptor kinases, signaling pathways and many agents that have been developed to block different components of this pathway, but i think it's a little playing with the dark because essentially we developed hypotheses, interrogated cell
lines and human tissues but only in the context of really validating our selective hypotheses. so dr. collins is right, i'll start with the egfr receptor, what i started working on many years ago, and as most of you in the room know, it's a growth
factor receptor, it's overexpressed in many cancers, certainly in head and neck cancers. it's really not mutated in head and neck cancer. i'll tell you a little story of ovarian 3, and it's the only validated molecular target and
what i mean by that is fda approved -- for head and neck cancer patients in 2006, so now it's in our clinical arm but we have no idea who is best treated. there are no predictive this was a new england journal paper, it's been disappointing
and it's been disappointing because we really don't know precisely what it's doing to the tumor, we don't know who should get it, we don't have positive data with the kinase inhibitors, and disappointingly last year there was a report of the definitive trial of chemo
radiation plus -- versus radiation alone and the addition was not substantial in terms of improving survival. so we simply have lacked models to be able to test for -- resistance, so to that effect, really smart graduate students took a book from the herceptin
play book and we realized that virtually every cell line that we grew in animals and that made xenographs was sensitive so clearly did not mimic the diversity of head and neck so we grew cells over time, we selected out for two models that developed resistance.
so this is the model of acquired -- resistance, and you can see down here that these are the tumors that grew over time. we demonstrated we could take them out of the animal, we could propagate them and put them back in we found there was a fragment called c11cts that has been
reported in the context of herceptin resistant breast cancer, and this fragment appeared to be increased in the setting of resistant to se tucks mab. we treated them with dual egfr kinase inhibitor, irreversible small molecule, either alone or
in combination with cetuximab. the other altered form we noted was the variant 3. this was discovered in the context of glioblastoma by darrell bigner and others and clearly it lacks most of the binding domain of egfr receptor, so we reasoned that cells that
express variant 3 would be less likely to respond to cetuximab. so to that effect, we developed a model of head and neck cancer, we have several of these and i'm happy to share them, where we made tumors that express the dirty little se little secret,it will not grow as a tissue culture.
we're hoping to overcome that with heterotopic xenograph. one can appreciate when they treat these tumors with cetuximab, they're relatively resistant but this was an experimental -- the buy directional nature when a group from germany noted that in a
phase 2 trial, that expression of variant 3 and egfr -- were independently associated with resistance to this regiment, lending some sort of credence to the idea that if we could prospectively identify patients who have variant 3 in their tumors, these would be
individuals that would potentially not be responsive to cetuximab and could benefit from her 2 inhibitor. so how do you block variant 3? it's a little challenging. the pe38 linked to -- that blocks to variant 3 specifically, there's an
antibody that was developed by lloyd subsequently at the ludwig and now through abbott 806 and it blocks both wild type and variant 3 and this is in clinical development and for reasons that aren't very well understood, in lung cancer models it's shown these
irreversible egfr inhibitors tend to be effective against verity yant 3, so that's another potential place where the biomarker variant 3 can indicate likelihood of response to these agents. so as you noticed on the first slide of signaling pathways,
stat3 is a very common downstream pathway. and i'd like to tell the story of how we got stat3, rick clows ter when he was head of nci came to visit pittsburgh and we presented our data to him, we were talking about audokrin growth and subsequent activation
of stat3, he said wouldn't you just want to block stat3, go downstream? we're like, yeah, but that's kind of challenging, the transcription factor. what really persuaded us is when we put stat3 into head and neck cancers, they became resistant
to egfr targeting, so we reasoned this was an approach worth investigating. and then work by bernie viceman and others have found that -- in primarily tongue cancers were poor prognostic indicators. but let me tell you, this is an undruggable target, thinking,
and this is only to put up to emphasize how incredibly challenging it is to block a so i'll tell you a little bit of a story. we elected to follow the play book of victor zao and try nucleotides and -- so frankly, what victor had done in
cardiovascular disease was he had developed an e2f decoy using it in the clinic at the time we got into this to prevent -- hyperplasia, so cardiovascular by pass graphs, bathed in the solution, put back into the patient, the phase 2 results were really promising, and i
will tell you, cut to the chase, the phase 3 trial was negative, but i will tell you how we've done it with stat3. in addition, though, to trying this decoy approach and lots of natural products, which all kind of work a little bit but i think we can all agree that these
natural products have many other targets and they're not really selective for any particular molecule, including stat3. so in a collaboration with the nci through the next program, we've had a really exciting run for the last 18 months or so. we developed a high content
imaging assay in collaboration with paul johnston in the drug discough reinstitute in pittsburgh and the fundamental issue is that stat3 and stat 1 have a lot of hemology but stat 1 has more of a tumor suppressor function and we don't want to block stat 1, stat3 has
much more of an oncogenic function and virtually all of the drugs that are stat3 inhibitors including the jack inhibitors block stat 1 and stat3, so in an attempt to find a stat3 selective molecule, paul designed an imaging a assay shwe screened 100,000 compounds and
initially we have a four lead, we've gotten down to probably two of these compounds and all of these compounds potently inhibit stat3, they do not for the most part inhibit stat 1, and they inhibit head and neck cancer growth in vitro, four different cell lines.
so we've got some really exciting preliminary evidence, it's probably a little bit too early to present, about the mechanism of action of a couple of these compounds. this one and this one in particular, that might lead us to select them, but we're
working with teams of chemists and teams here at the nci to really try to develop a small molecule that is not a kinase inhibitor, these are not working by inhibiting jax to humans, so give us 50 about a year. this is our decoy. this double stranded piece of
dna was dose-dependent, incorporated into the cells without -- it works in the cytoplasm, also works in the nucleus. so potentially what we could do first in animals is easy, and that is we can inject the decoy into the tumor, and i think this
is an experiment that you did, used in my lab maybe 10 years ago, did these experiments and published this paper. when they injected them with the stat3 decoy, they were growth inhibited, differs by a single base pair, doesn't bind stat3, had virtually no effect, and it
was very reassuring when john at anderson took the same decoy in his mouse model with skin cancer and could show the skin cancer was prevented largely by injection of the lesions that developed with this decoy. so we thought there was some hope for it, and again, the only
perk of being a surgeon and a scientist is you can go right to the clinic. so this is what we did around this time, fda developed the concept of a phase zero trial. they thought this would be a suitable scenario, this was the first in human stat3 inhibitor
study, so we took patients who were having resection of their head and neck cancer and we took them to the operating room, we biopsied them. then we injected the decoy, and we did the operation and then we took out the tumor, and we harvested a specimen in the
region of injection after the surgery. this was about four hours, and you can see that most of the patients demonstrated down regulation of stat3 targeting expression, in the post treatment specimen compared to the pre-treatment specimen.
so we were pretty excited about this. then a very wise grant reviewer said what about hypoxia, what about surgery, how on earth do you know that this is specific to the decoy? so we then -- we needed a control group in a phase zero
trial, and we treated half the patients with saline and half the patients with the decoy and found that in general, the decoy-treated group had greater down regulation of targeting expression compared to the saline group, and this was about 15 patients in each group and
this was great except we had to inject this into the tumor. and we knew from working with richard at vanderbilt that the half-life of this decoy was only about an hour. it was totally impractical for systemic administration. so we engaged a very talented
chemist at carnegie mellon university down the block, and with this chemist, we experimented with lots of modifications and the goal was to stabilize the molecule without losing biological potency, so we found that if we made it cyclic, and this is just
two carbon spaces on each end retaining the same sequence in the middle, we could retain the ability through fpr, we would show this modified decoy was still able to bind very acidly to stat3, so it could retain its biological potency, but we had a dramatic increase in half-life
so we're now up to 12 hours. now it becomes more representative of a drug, and it also has a much higher melting temperature of 80 degrees, so it's really unlikely to fall apart when injected into the bloodstream. and then we did the key
experiment, which is we put tumors into mice and treated them with intravenous injection of either the cyclic stat3 decoy or the cyclic mutant control, and the decoy-treated tumors failed to grow, the controlled treated tumors grew and there was significant down regulation
of target genes in the cyclic treated tumors, again, this was iv treatment so no direct injection. we published a paper just a little while ago, a couple months ago, this is what the decoy looks like, and where we're taking this is we're
finishing pharm tox studies in animal models. looks like the only thing the did to the mice was make them a little hyperexcitable, but that was temporary, and in addition, we're collaborating with a cardiologist, we've put the decoy into a micro bubble and
the idea is that we'll be able to deliver this micro bubble encapsulated decoy to the head and neck region, th viaultrasound application. so far it's working in the animal model, and lastly, we're collaborating with an engineer, who has engineered a sustained
released micro particle. our idea is that in the surgical setting, post resection, that we irrigate the wound with the decoy in these micro particles, which can be engineered so that they have sustained -- kinetics over the period of a year or two, and that might be a
reasonable way to prevent recurrence, so we're exploring different ideas. but we still have absolutely no idea how stat3 is activated in human cancers. we still remain really challenging because it's undruggable and we don't really
know which patients would benefit from a stat3 inhibitor. so just when we thought we kind of understood head neck cancer biology, we were able to engage several investigators, the team was led by eric lander, to sequence head neck tumors so at the end of the day, we sequenced
74 head neck tumors for whole -- analysis and we published this, and here is the finding that this was a typical head neck cohort that is mostly men, mean age was 58, 75% men, 80% recurrent or former smokers, and about 13% had hpv positive tumors.
we looked at hpv by several methods and i'm happy to describe that in more detail. the challenge in all surgical cohorts, and you require surgical cohorts because you need enough material for sequencing is that most hpv tumors are in the oropharynx and
the treatment of most oropharynx cancers is non-operative therapy, so even with the tcga, we have a relative underrepresentation of hpv positive head and neck cancer but it's a different disease. these are not the same tumors. in general, when we looked at
the entire cohort, the thing that jumped out at everybody and was the title of the companion paper by the hopkins and anderson and baylor group was there appeared to be notch alterations, and this was unexpected in squamous cell carcinoma of the head and neck.
18 months later, i still can't tell you what the function of these alterations are, so i'm not sure that they're druggable. but what i can tell you is that the most commonly mutated on cogene was pic3ca and otherwise it was a complex story of a lot of tumor suppressor jea genesand
here was the cure yait raited list at the time. we were interested in trying to see if there was a genetic signature that linked stat3 hyperacactivation to any kind of genetic alteration. so back to basic biology. we sequenced a lot of tumors
over the years and there are no activno -- the general thoughthas been that it's a compilation of activation of upstream receptors such as the egf receptor, pgdf receptor, but we were wondering if there were really meaningful negative regulatory proteins that by virtue of mutation were
inactivated. so we knew about this family of protein receptors about five years ago where he reported that there was an unexpectedly high frequency of mutations of these receptors in colon and in lung as people further investigated, pptrt -- stat3 was shown to be a
substrate for these two receptor cairo seen phosphatases. so specifically these phosphatases activate stat3. the role of the other ptprs has been largely unknown, there's a trickle of papers over time and almost every paper at least in the context of cancer
dem sphraits thademonstratesthese are tumor suppressor genes and there's occasional indication this they mediate stat3 -- when we look back at our cohort, i don't intend for you to look at the details here, but in our 74 patients, we found ptpr -- now with 374 tumors to look at that,
is our cohort plus -- it's a little over 40% of human head and neck cancers that appear to have loss of function mutations in the ptpr family, so this may represent an unexpected and common pathway that leads to stat3 hyperactivation. so this is just a list of the
mutations and the two most commonly -- this is where they're located and i don't mean to spend more time on it except to say that we engaged a structural biologist at the university of pittsburgh and it's been really exciting to work with them.
the crystal structure of stat3 has not been reported. we just have stat3 beta. but based on what we know, what joseph was able to do is look at all of -- this is the region that we expect binds to stat3. and this is where the mutations are, and i think you can
appreciate that the fos foe tyrosine residue of stat3 is in very close proximity to most of these mutations, so it seems to be structurally plausible that an inactivating mutation in the region that -- would lead to failure to dephosphor late stat3 and hence hyperactivation.
so this has been our central hypothesis, that stat3 hyperactivation at least in part results from loss of function mutations in this family, and we can prospectively identify patients who have those mutations and prioritize them for treatment with stat3
inhibitors as they are developed. so we made the mutations and we put them into head and neck cancer cells. i want to emphasize that in conjunction with this, what we did is we created essentially an il3 dependent analog in head and
so the model has been terrific to screen for oncogenic mutations, you take away the factor il3 and if you put in a mutation and it's an on cogene, the cells survive. but there was no such thing for head neck cancer. so we took an hp positive and
negative cell line and made it serum dependent. so i think you can appreciate when we put these mutations in in the absence of serum, we get tremendous increases in survival, so this is a dose-dependent increase in survival, when we express this
mutant form of ptprt in a head and neck cancer cell. there's hyperphosphorylation of stat3 with this -- and here is a preclinical jax stat inhibitor and there appears to be enhanced responses to at least this molecule. this molecule is off target
effects and it's not perfect. then in an effort to find more relevant models, we were able over the course of several years to learn from people and other cancers, and we're taking tumors from patients and we're growing them out at heterotopic tumor grafts in mice, so these are
tumors from patients whose tumors have mutations in these ptprs, they have hyperactivation of stat3, and you can see that they respond to treatment in this case by azd1480, a jax stat inhibitor that's in clinical development, so we are encouraged that this
might represent a plausible model for testing drugs to translate to humans. so this is our idea about a clinical trial in a window setting. we would screen patients for mutations, we would enroll them, we would treat them with this
jacks stat inhibitor, we would -- before surgery, this is a few weeks, they would perform operation. again like the decoy trials, we have the biomarkers, the mutation status at a base like, so we'd know whether or not it was a predictive biomarker.
but i also want to remind you in addition to stat3, we have this usual suspects. so what does this mean in head neck cancer? i think it's really important because what we found is when we looked back, and this is about 165 tumors we've done in
collaboration with gordon mills and n.d. anderson, so we looked at mutation and gene amply faition and we looked at -- for expression of proteins that we might hypothesize would be correlated with -- amplification. and what we found is that pic --
pi3 kinase alpha subunit and -- forms of akt were highly correlated, the levels were highly coordinated within the tumors that had mutation and the emerging story is that the frequency of this mutation with hpv negative head and neck cancers is about 15% mutated,
another 5% amplified, if it's hpv positive, it's about 30% mutated, and another 15% amplified. so it looks like right now, again, there's only about 50 hpv positive tumors in the tcga pittsburgh cohort, university of chicago has also looked at hpv
positive tumors and found this very high frequency picc3h alteration in head neck cancer, so this could be the predictive biomarker for hpv disease because quite frankly, in the world of clinical medicine, all we're doing today is we're dialing down the intensity of
treatment for hpv-positive disease, we're giving them less chemotherapy or less radiation, but we're not giving them anything that would specifically harness the pathways that are turned on in their tumor, and if one could really cure hpv-positive cancer with a
pi3 kinase inhibitor or -- or something like that, that would be really helpful for this population. so our overall approach has been to create this model that i've showned you with respect to the ptprt. we have the genomic screening
platform. we're now making all of these mutations and putting them into this platform, and then we're looking at drug screening efforts. so here's what we've done with the pi. c3ca.
this happens to be an hpv positive model. you see either amplycation or mutation is driving growth and it's driving signaling and this is also true in hpv-negative disease. and when we treat with either compound, now bez235 is an m --
pathway inhibitor that was developed by novartis. it's not being further developed because of toxicity. px866 is a pan pi3 kinase inhibitor developed at our institution, now being developed in head and neck and lung and we're doing a phase 2 trial --
and we have very similar and compelling data with other pi3 kinase pathway inhibitors, and what i want to emphasize is these are now endogenous mutations. so these cell lines have wild type and this has mutant. wild type and mutant.
so growth inhibition is dramatically enhanced in cell lines that have naturally occurring mutations of pic3ca. so here's the bottom line numbers, the numbers of amplification, positive versus negative, and then another 10%, 15% has amplification.
so this is where all the mutations are, this is interesting if you look into the tcga cohort. this looks like breast cancer. it's the only other cancer that has mutations throughout the gene. we're not sure what all these
mean, so we've made all of these and we're systematically testing them. these are previously reported hot spots, they account for about half of the mutations in head and neck cancer. in addition, though, to pic3ca, i want to emphasize that there
are mutations in other genes in the pi3 kinase pathway, a handful of the other pi3 kinases as well as m-tor. so these are the agents, a couple of the agents that we're looking at. all of them are either approved or in clinical development and
we're trying to develop will targeting different nodes in the pathway is more or less effective in conjunction with a specific mutation. perhaps most exciting for us this is now our heterotopic tumor m model. this is a patient whose tumor
had a pik3ca mutation and they're hpv positive. when we treated mice with this tumor, with the bez compound, they went away. the tumors disappeared. and this tumor was pik3ca mutant and hpv-positive. in contrast, a tumor that had
low -- akt this, is the patient's tumor, pik3ca wild type didn't have very much of a response to the pi3 kinase pathway inhibitor. this patient's tumor was hpv-negative but had the high phosphorylated -- and a mutation and it also had a dramatic
response. so what we think -- what we believe is if we can assay patients either for the mutation or even you can see just look at phosphorylated akt, it's a very nice surrogate marker for activation of the pathway, this would simply be used to enrich
clinical trial populations so that we're giving patients that have tumors like this drugs that are affected and we don't force patients that have tumors like this to suffer the toxicity and delay effective treatment because they're probably not going to respond.
so in collaboration with the university of chicago, we're doing a phase 2 clinical trial. in this case, we're using a novartis compound, this is recurrent metastatic setting, and the key thing is biopsy. so baseline biopsy, biopsy after single agent, biopsy after the
addition of ctuximab. the reason, it's real world clinical medicine and this is f. da-approved in this setting and it would be really difficult to get this through ir bs without the opportunity to retreat with cetuximab. we have modest evidence this is
far more effective than pathway targeting alone. but we at least hope in the context of sequencing and fish on all of these specimens that we can begin to test these hypotheses to really broadly apply more commonly. so in summary, ur r i think i
want to emphasize that understanding both the signaling mechanisms of any model disease, whether it be head neck cancer or otherwise, but also look at the basic biology. it's daunting, it's overwhelming, it's confusing. most of these mutations are
passengers, they're not drivers, but if we begin to put our understanding of biology and the enormous data resources that are being delivered by the tcga, we may be able to quickly identify mechanisms of resistance as well as new targets, patient specimens and relevant
preclinical models are really critical in this effort. the theme so far is -- receptors and -- downstream signaling pathways may be helpful in the setting of cetuximab resistance. there's many therapies in the early stages of development, we can't possibly look at them all
in a systematic way, we'll run out of time, so i think the challenge is really to begin to highypothesize what are the features in the patient's tumor that would predict which of these therapies they should receive. i'll stop by saying i don't get
to do anything except come here and have a wonderful time. there's a group in pittsburgh, clearly the tcga, and my colleagues at other institutions as well with my collaborators at the broad and lots of resources from the nci and the nih. [applause]
>> thank you, dr. grandis, for a wonderful tour through a lot of interesting pathways and potential actions. so we have time for questions. >> how are you? >> good to see you. >> you're not playing rock music.
>> francis didn't ask me. >> there you go. next time. i have heard it. >> but i will at any time. so in our business, we've debated back and forth the relative merits of blocking at high points in the pathway with
jax or downstream and with a stat, and there's reasonable arguments for both. >> yes. >> this is sort after two hadtwo-part question. in patients who don't have the pi kc3 mutation do you see activation of akt, suggesting
that there's auto krin production of cytokines that could be activating -- >> absolutely. >> and then even though maybe it doesn't make any sense to target both jax and stat, have you ever dumped both of those things into an assay to see do you get
synergy in any way? >> that's a really good you know, john, all the jax inhibitors block stats, right? >> but they also block -- >> lots of other things. so if we block stat downstream with jax plus another mechanism, is there any benefit to that?
the answer is we haven't tried, the challenge is using molecular strategy which is not particularly effective -- it's great as a tool but we haven't tried the decoy in conjunction with the jax inhibitor and that probably makes sense to do. >> the hpv positive patients
have a much better prognosis, right? they are much easier to treat, almost 80%, don't you think the big -- don't you think -- >> it's really interesting, i've now heard this in many settings, most recently in a summary statement.
why bother studying hpv positive head and neck cancer? it's all cured. i can tell you as a clinician, and i think the clinicians in the room can tell you, there's not a week that goes by in tumor board that we don't see an hpv positive recurrent tumor.
so in general, these patients have a better prognosis than hpv negative disease, but there are still patients with hpv positive disease that recur, and the question is, are these the patients -- is this the 30 to 40% with pik3ca mutations and the answer is we don't know yet
because they haven't been studied. -- will have impact in both of space of hpv positive head and neck cancer and hpv negative i was meeting with pat this week to really try to understand, i'm not a virologist, what is it about human papilloma virus
infection that would essentially predispose the selection of alterations in this gene, whether it be amplification or mutation, and the disappointment, of course, is it's not only an hpv positive cancer, it's a negative cancer too, so i think it's going to be
a complicated story, but worth considering in both spaces. >> so do the hpv positive patients have -- 53 mutations? >> never. >> virtually never. at least in the tcga, we haven't found in 370 some cases, we haven't found a single case of
p53 mutant and hpv positive. now again, that's 30 some cases there, then we have another 12 -- it's a relatively small number, but i think to date, there's probably maybe 108 -- positive tumors that have been sequenced and none of them to my knowledge have a p53 mutation.
a follow up on john's question. in several examples now of molecular targeting, you do well for a while and then you escape. >> and so why not already go to a strategy in which you actually look at the network connectivity here and see where the likely bypass pathways are and do --
treatment right up front rather than going down, letting everybody escape and try and catch up with it. >> i think there's two -- number one is to have models that are relevant to human beings with cancer to understand the escape mechanism.
i think our cell lines are in imperfect and we have to -- getting them from both primaries and recurrences ideally the same patients and growing -- we can understand the resistance mechanisms for targeting. the second challenge which we have been able to overcome but
it's not trivial is that sometimes your ideal cocktail is manufactured by different drug companies. and we all recognize this and we all try to deal with it but it's sometimes proved really challenging to get everybody in the same room, particularly at
the end of the day when we don't necessarily have an economic argument for why they should do this if it's a very small population of a relatively uncommon cancer, it doesn't get their attention. i recognize that as a challenge but it does mean our tool kits
for our plea pree clinical models sometimes have to be modified when we go to the clinic because engaging the people who have the drugs we can give to people is so difficult on levels that are not scientific. >> francis is going to solve
that, right? >> well, it is certainly not just unique to this situation but in so many other circumstances, so probably cancer particularly, where you'd like to do combination trials because you know from everything we've learned in how we've
succeeded in hearing things like leukemia, lymphoma, a single agent isn't going to do it. why would we think that it would be true in some of these very difficult to treat cancers, yet there are all these barriers, some of which relate to commercial situations, some of
which are regulatory. it is a major topic of discussion in the national center for advancing translational sciences but i would not tell you we have the answer quite yet. >> so jennifer, i was wondering whether you could give me a feel
for what percentage of the tumors have both activated stat and activated pi3 kinase atp pathway? >> it depends on how you measure it. i think that the best way of figuring that out right now is through the rtpa data of pcga,
and i don't believe that all that data has been uploaded and publicly available. we have a couple of heat maps that are coming out of the paper right now, it's being written, and the answer is going to be not everybody and not necessarily the same tumors.
it does look at least preliminarily that the activated akt and the activated p stat3 are not the same subgroup, but that's not always true. so i will -- when that data is locked in and finalized, i will let you know. >> somewhat more general
question, in your last slide where you talked about the designing of your clinical trial, you referred to serial biopsy, and it sort of reminds me of serial imaging. how important is that tool in general going to be to -- as a strategy to kind of dealing with
these diseases? >> that's a great question. there was a really lovely editorial i think within clinical cancer research about -- somebody did a study that was really illuminating about the number of studies that were reported at the acr or asco
that reported to have -- biomarkers, then when you looked at the publication, own 10% of them ever reported -- biomarkers which meant that people were collecting material and either doing nothing with it or more likely all the data were negative so they weren't putting
it into the publication. so i think that it reminds me that you have to have a question that you're asking in order to interrogate the biospecimen. so i think from my perspective, the most meaningful thing is what happened in the context of treatment resistance.
so if you biopsy a patient at baseline, then you give them a drug, if nothing happens, nothing happens, then that tumor grows, it's really important to understand what's happening in that tumor, and that's been really elegantly shown by jeff engelman and others at mass
general, really ee lewis naiding novel mechanisms of treatment resistance. so i think that if you have the context, it's really important to do this. and the second thing is a high quality tissue is really challenging to get, particularly
if you're talking about a fine needle aspiration or an interoffice setting, and it requires a team and a commitment, and frankly, i think it also really requires that we educate the patient and engage them as our partners, because it's not clear to them that it's
going to benefit them. and it's usually inconvenient and sometimes it's uncomfortable, and depending on the context of the study, it may or may not be compensated, especially if we're talking about going back to the operating room, so i think we've
paid an enormous amount of lip service to serial biopsies, and i think that they're critically important, but you have to be asking an important question that when you answer it with that biopsy, it will change what you do next. and i don't think we always
think that through. >> these have been wonderful questions and answers, and we will have a reception now in the library with some refreshments, if you have further discussion you'd like to have with our speaker, please come, or please come anyway.
and let us one more time thank our pittman lecturer, dr. grandis.
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- [announcer] this program is presented by university of california television. like what you learn? visit our website, or follow us on facebook and twitter to keep up with the latest uctv programs. (upbeat techno music) - i'm going to tell you, tonight, a story. and this story dates back about 30 years.
this story has a little bitof something for everybody. it has a little bit of biochemistry, a little bit of clinical research, a little bit of public health, a little bit of politics, alittle bit of racial innuendo. the only thing it's missing is sex. (audience laughs) but, well, we can see whatwe can do about that, too. by the end of the story i hope i will
have debunked the last 30 years of nutrition information in america. and i would very much appreciate it if at the end of thetalk, you would tell me whether or not i was successful or not. okay? so, in order to get you in the mood, as it were, let's startwith a little quiz. what do the atkins diet
and the japanese diet have in common? anybody? hm? oh, you have the answersright, never mind. that's right, you havethe answer right there. so the atkins diet, ofcourse, is all fat no carb. the japanese diet's all carb, not fat. they both work, right? so what do they share in common?
they both eliminate the sugar, fructose. so, with that, think aboutwhat it means to be on a diet, and what macro-nutrients you're eating and which ones your not. and then we'll go from there, and i'll try to explain how this all works. so, you've all heard aboutthe obesity epidemic. here are the numbers. these are the nhanesdatabase body mass index.
everybody knows what that is now. histograms marching everrightward as time has gone on. this was what wasprojected for 2008 in blue. we had so far exceeded and surpassed, this is not even funny. this was from 2003. the reason i show this is not just to show that the obese are getting obeser, of course, that's true, but in fact
the entire curve has shifted. we all weigh 25 pounds more today than we did 25 years ago, all of us. now, it is often said that obesity is the ultimate interaction between genetics and environment. and doctor christian vaisse, who's sitting in the back of the room, will be talking to you next week aboutthe genetic component,
which i am also very interested in. but, having said that, our genetic pool did not change in the last 30 years, but, boy oh boy, has ourenvironment sure changed. so, tonight, we're gonna talk about the environment rather than genes. now, in order to talkabout the environment, we need to talk about what is obesity. and, of course, you're all familiar with
the basic concept with thefirst law of thermodynamics, which states that the total energy inside a closed system remains constant. now, in human terms, thestandard interpretation of this law is the following. if you eat it, you better burnit, or you're gonna store it. now, who here believes that? oh, come on, you all do. i used to believe that.
i don't anymore. i think that's a mistake. i think that is the biggest mistake. and that is the phenomenoni'm going to try to debunk over the course over the next hour. because i think there'sanother way to state the law which is much more relevant,and much more to the point. before i get there, ofcourse, if you believe that, these are the two problems,calories in, calories out.
two behaviors, gluttony and sloth. after all, you see anybody on the street, "oh, he's a gluttonous sloth,that's all there is to it." tommy thompson said it on the tv show. "we just eat too damn much." well, you know, if that were the case, how did the japanese do this? why are they doing bariatric surgery on children at tokyochildren's hospital today?
why are the chinese, why are the koreans, why are the australians? i mean, all these countrieswho've adopted our diet all suffer now from the same problem. and we're gonna get evenfurther in a minute. there's another way tostate this first law. and that is, if you're gonna store it, that is biochemical forcesthat drive energy storage, and we'll talk about whatthey are in a few minutes,
and you expect to burn it, that is normal energy expenditure fornormal quality of life. because energy expenditureand quality of life are the same thing. things that make yourenergy expenditure go up, make you feel good. like ephedrine, it's off the market, coffee for two yours, thenyou need another hit, like me. things that make yourenergy expenditure go down,
like starvation, hypothyroidism,make you feel lousy. and how many calories you burn and how good you feel are synonymous. so, if you're gonna store it, that is an obligate weight gain set up by a biochemical process, energy expenditure fornormal quality of life, then you're gonna have to eat it. and now, all of the sudden,these two behaviors,
the gluttony and the sloth,are actually secondary to a biochemical process,which is primary. and it's a different wayto think about the process. and it also alleviates the obese person from being the perpetrator,but rather the victim. which is how obese people really feel. 'cause no one chooses to be obese. certainly, no child chooses to be obese. oh, you say, "oh, yeah, sure,
"i know some adults who don't care." you know, rossini, the famous composer, you know la gazza ladra,figaro, and all that. he retired at age 37 to a lifetime of gastronomic debauchery. maybe he chose to be obese. but the kids i take careof in obesity clinic do not choose to be obese. in fact, this is the exceptionthat proves the rule.
we have an epidemic ofobese six month olds. now, if you wanna say that it's all about diet and exercise, then youhave to explain this to me. so, any hypothesis that you wanna proffer that explains the obesity epidemic, you've got to explain this one too. and this is not just in america, these six month old obese kids, but these are around the world now.
so, open your minds?, and let's go and figure out what the real story is. let's talk about calorie intake, because that's what today is about. we're gonna talk about the energy intake side of the equation. sure enough, we are all eating more now than we did 20 year ago. teen boys are eating 275 calories more.
american adult males are eating187 calories more per day. american adult females areeating 335 calories more per day. no question, we're all eating more. question is why, how come? 'cause it's all there? you know what, it was there before. we're all eating more, there's a system in our body, which you've heard about over the last coupleof weeks called leptin.
everybody heard of leptin? it's this hormone thatcomes from your fat cell, tells your brain, "youknow what, i've had enough. "i don't need to eat anymore. "i'm done, and i canburn energy properly." well, you know what? if you're eating 187 or335 calories more today than you were 20 years ago,your leptin ain't working. 'cause if it were, youwouldn't be doing it.
whether the food was there or not. so, there's something wrong with our biochemical negative feedback system that normally controls energy balance. and we have to figure out what caused it, and how to reverse it. and that's what tonight is about. but, nonetheless, there are 275 calories we have to account for.
so where are they? are they in the fat? no, they're not in the fat. five grams, 45 caloriesout of the 275, nothing. in fact, it's all in the carbohydrates. 57 grams 228 calories. we're all eating more carbohydrate. now, you all know, back int 1982, the american heart association,
the american medical association, and the us department of agriculture admonished us to reduce our total fat consumption from 40% to 30%. everybody remember that? that how entenmann's fatfree cakes came into being. remember that? so what happened? we did it, we've done it.
40% down to 30%, and look what's happened to the obesity, metabolic syndrome, non-alcoholic fatty liverdisease, cardiovascular disease, stroke prevalence, all jacked way up, as our total fat consumptionas a percent has gone down. it ain't the fat,people, it ain't the fat. so what is it? well, it's the carbohydrate. specifically, which carbohydrate?
well, beverage intake, right? 41% increase in soft drinks,35% increase in fruit drinks, fruitades, whatever you wanna call them. just remember, down here, one can of soda a day, is 150 calories. multiply that by 365 days a year, and then divide that by the magic number of 3500 calories per pound, if you eat or drink 3500 calories
more than you burn, youwill gain one pound of fat. that's the first law ofthermodynamics, no argument there. that's worth 15 1/2pounds of fat per year. one soda a day is 15 1/2 pounds per year. now, you've all heard that before. that's not news to you. the question is how come we don't respond? how come leptin doesn't work? how come we can't stay energy stable.
that's what we're gonna get to. so, i call this slide, very specifically, the coca cola conspiracy. anybody here work for coke, pepsi? okay, good. all right, so, this over here, 1915, the first standardized bottleof coca cola out of atlanta. anybody remember this bottle? sure, a lot of you do.
i remember this bottle,because my grandfather in brooklyn, took me on saturday afternoon down to the local soda shopon avenue m and ocean avenue, and every saturday afternooni had one of these. i remember it very well. now, if you drank one of those every day, assuming of course thatthe recipe hasn't changed, 'cause after all, onlytwo people in the word know the recipe, and they're not allowed
to fly on the plane at the same time. you know that, okay. assuming the recipe hasn't changed, if you drank one of thoseevery day for a year, 6 1/2 ounces, that would be worth eight pounds of fat per year. now, in 1955, after world war ii, when sugar became plentiful again, and wasn't being rationed,
we have the appearanceof the 10 ounce bottle, the first one that wasfound in vending machines. you probably remember that one, as well. then in 1960, the ever ubiquitous, 12 ounce can, worth 16pounds of fat per year. and, of course, today, this, over here is the single unit of measure, 20 ounces. anybody know how manyservings are in that bottle? - [audience member] 2.5.
- 2.5 eight ounce servings, that's right. anybody know, anybody gets 2.5 eight ounce servings out of that bottle? that's a single serving, right? so that would be worth26 pounds of fat per year if you did that every day. and then, of course, over here, we have the 7/11 big k, thirst buster, big gulp, whatever you wanna call it,
44 ounces, worth 57pounds of fat per year. and if that wasn't badenough, my colleague, dr. dan hale, at the universityof texas san antonio, tells me that down there theygot a texas size big gulp. 60 ounces of coca cola, a snickers bar, and a bag of doritos, all for 99 cents. - [audience] oh. - so if you did that every day for a year that would be worth 112pounds of fat per year.
so why do i call it thecoca cola conspiracy? well, what's in coke? caffeine, good, good, so what's caffeine? it's a mild stimulant, right? it's also a diuretic, right? it makes you pee free water. what else is in coke? we'll get to the sugarin a minute, what else? salt, salt.
55 milligrams of sodium per can. it's like drinking a pizza. so what happens if you take on sodium and lose free water, you get... - [audience] thirsty. - thirstier, right. so, why's there so much sugar in coke? to hide the salt. when was the last time youwent to a chinese restaurant,
had sweet and sour pork? that's half soy sauce,you wouldn't eat that. except the sugar playsa trick on your tongue, you can't even tell it's there. everybody remember new coke, 1985? more salt, more caffeine. they knew what they were doing. that's the smoking gun. they know, they know.
all right, so, that's whyit's the coca cola conspiracy. so, are soft drinks the cause of obesity? well, depends on who you ask. if you ask the scientists for the national soft drink association, they'll tell you there's absolutely no association between sugarconsumption and obesity. if you ask my colleague,doctor david ludwig, remember, i'm lustig he's ludwig,
he does what i do atboston children's hospital. some day we're gonna open up a law firm. each additional sugarsweetened drink increase over a 19 month follow up period in kids increased their bmi by this much in their odds risk ratiofor obesity by 60%. that's a prospective studyon soft drinks and obesity. the real deal. if you look at meta-analysis,
everybody know what a meta-analysis is? it's a conglomeration of numerous studies subjected to rigorousstatistical analysis. 88 cross sectional andlongitudinal studies regressing soft drink consumption against energy intake, body weight,milk and calcium intake, adequate nutrition, all showingsignificant associations. and some of these being longitudinal, this came from kellybrownell's group at yale.
i should comment, adisclaimer, those studies that were funded by the beverage industry showed consistently smaller effects than those that were independent. wonder why. now, how 'bout the converse? what if you take the soft drinks away? so this was the fizzy drink study from christ church england james et al,
british medical journal, where they went into schools and they tookthe soda machines out. just like we did here in california. we haven't seen the data yet, but they went and did it for a year. so the prevalence of obesity in the intervention schools stayed absolutely constant, no change. whereas the prevalence of obesity
in the control schoolswhere nothing changed continued to rise over the year. so that's pretty good. so, how 'bout type two diabetes? are soft drinks the causeof type two diabetes? well, this study from jama in 2004 looked at the relative risk ratio of all soft drinks, cola, fruit punch, and found a very statistically significant
trend of sugared soft drinks, fruitades, et cetera, causing type two diabetes. and you know we've gotjust as big a problem with type two diabetes as we do with obesity for the same reasons. and this was a sugaredsweetened beverage against risk for type two diabetesin african american women. looking here at sugarsweetened soft drinks, just the downward arrow shows that
there was a significant rise as the number of drinks went up. you can see that here. whereas orange and grapefruitjuice, interestingly, did not. so, two different studies,two different increases in type two diabetes, relativeto soft drink consumption. so, what's in soft drinks? well, in america, it's this stuff, right? high fructose corn syrup.
everybody's heard of it, right? it's been demonized something awful. so much so that the corn refiners industry has launched a mega-campaign to try to absolve high fructosecorn syrup of any problems, which we'll talk about in a moment. but the bottom line is, this is something we were never exposed to before 1975. and currently we are consuming
63 pounds per person peryear, every one of us, 63 pounds of high fructose corn syrup. - [audience member] that's america? - that's america, yes. now, what is high fructose corn syrup? well, you'll see in a minute. it's one glucose, one fructose, we'll talk about those at great length. one of the reasons we usehigh fructose corn syrup
is because it's sweeter. so here's sucrose, thisis cane or beet sugar, standard table sugar, youknow, the white stuff, and we give that an indexin sweetness of 100. so here's high fructose corn syrup, it's actually sweeter, it's about 120. so, you should be able to use less, right? wrong, we use just asmuch, in fact, we use more. so, here's lab fructose overhere, crystalline fructose.
and they're starting toput crystalline fructose into some of the soft drinks. they're actually advertisingit as a good thing. phew. and that's got a sweetness of 173, so you should be able tocut that way back, right? they're not. lactose, down here, milksugar, it's not sweet at all. and glucose, i shouldpoint out over here, 74.
it's not particularlysweet, and we're gonna get to that at the end, andwhat goes on with glucose. but anyway, there's whywe use it, it's sweeter, it's also cheaper as i'll show you. so, here's high fructose corn syrup. one glucose, one fructose. notice the glucose is a six membered ring, the fructose is a five membered ring. they are not the same.
believe me, they're not the same. that's what this whole talk is about is how their not the same. and here's sucrose, and they're just bound together by this ether linkage. we have this enzyme inour gut called sucrose, it kills that bond in two seconds flat, and you absorb it and, basically,high fructose corn syrup, sucrose, it's a non issue, it's a wash.
they're the same. and they know that they're the same, the soft drink companiesand the corn refiners. because here are their missives. this comes from the cornrefiners association. obesity research showshigh fructose corn syrup metabolizes and impactssatiety similar to sugar. indeed it does, i agree. decent meetings, academicmeetings around the country.
hunger and satiety profiles energy intakes following ingestion of soft drinks, bottom line, research supported by the american beverage institute and the corn refiner's association. they are correct, there is absolutely no difference between highfructose corn syrup and sucrose. so much so that the cornrefiner's association, in attempt to capture market share,
came out with this entire ad campaign. you probably saw it on the back page of the new york times, itwas on tv, it's everywhere. "my hairdresser saysthat sugar's healthier "than high fructose corn syrup. "wow, you get your hair done by a doctor?" i didn't know i could cut hair. if you all wanna see all of them, there are a whole bunch of them.
you can go to www.sweetsurprise.com and see how you're being hoodwinked. but indeed, this is true. high fructose corn syrup andsucrose are exactly the same. they're both equally bad. they're both dangerous,they're both poison. okay, i said it, poison. my charge before the end of tonight is to demonstrate fructose is a poison,
and i will do it, and you will tell me if i was successful. none the less, here'scenter for the science and public interest and thecorn refiners association. everybody remember lastyear, when gavin newsom floated his soda tax, last february? governor patterson of newyork has since floated one. and other people arestarting to talk about it. so, why are they saying this?
well, they're saying obesity's a problem, kids are drinking soda, let's tax it. so they're talking about sodalike it's empty calories. i'm here to tell you that itgoes way beyond empty calories. the reason why this isa problem is because fructose is a poison, it'snot about the calories. it has nothing to do with the calories. it's a poison by itself,and i'm gonna show you that. nonetheless, i just wanna read you
this paragraph here in yellow. "we respectfully urge that the proposal "be revised as soon as possible to reflect "the scientific evidence that demonstrates "no material differencesin the health effects "of high fructose corn syrup and sugar." i agree. here's the important sentence. "the real issue is thatexcessive consumption
"of any sugars may leadto health problems." i agree, that's exactly right. not may, does, does. so, here's the secular trend in fructose consumptionover the past 100 years. before we had food processing, we used to get our fructose fromfruits and vegetables, and if we did that today, we would consume about 15 grams per day of fructose.
not sugar, fructose. so sugar would be 30grams, it'd be double. we're just talking about fructose, today. prior to world war ii,before it got rationed again, we were up to about 16to 24, about 20 grams. so, a small increase from the beginning of the century to world war ii. then, in 1977, just ashigh fructose corn syrup was hitting the market,we had increased that,
we had, basically, doubledup to 37 grams per day, or 8% of total caloric intake. by 1994 we were up to 55grams of the stuff per day. remember, if you wanna dosugar, then double the number. so, that's 10.2, so youcan see that more and more of our caloric intake, a higher percentage is being accounted for bysugar every single year. so, it's not just that we're eating more. we're eating more sugar.
and for adolescents today,up to almost 75 grams, 12% of total caloric intake. 25% of the adolescents today consume at least 15% of theircalories from fructose alone. this is a disaster, anabsolute unmitigated disaster. the fat's going down,the sugar's going up, and we're all getting sick. now let me show you why. how'd this happen?
why'd it happen? so, this is where the politics comes in. this is the perfect storm, and it was created fromthree political winds that swirled around all at the same time to create this perfect storm. so, the first political wind, everything bad that ever happened in this country started with one man.
and it's still being felt today. so, richard nixon, in hisparanoia back in 1972, food prices were going upand down, and up and down. i'm gonna show you that on the next slide. and he was worried that this was actually gonna cost him the election. so, he admonished hissecretary of agriculture, earl rusty butz, i love that name, to basically take foodoff the political table,
to make food a non-issuein presidential elections. well, the only way to dothat was to make food cheap. so, he was out to find all methods to be able to decrease the price of food. remember nixon's war on poverty? we're suffering from it today. that's what this is. second political wind, the advent of high fructose corn syrup.
so, this was invented in1966 at saga medical school in japan, by a guy namedtakasaki, who's still alive. as far as i'm concerned, this stuff is japan's revenge for world war ii, except, of course, that they're suffering from it now, themselves. like everything, it alwayscomes back to haunt you. and it was introduced tothe american market in 1975. so, what do you think happened
to the price of sugar whenthis thing hit the market? here's what happened. so, here's the us producerprice index of sugar going up and down, and up and down. this is not good. stability is at 100%, ifit stays nice and stable at 100%, that's what youwant if you're a politician. up and down, here's where corn sweeteners entered the market, 1975, 1980.
and you can see that since then the price of sugar has remained remarkably constant. and it did so, not just in the us, but also on the international stage. here's the london pricedoing the same thing. and when you look atthe difference in price between sugar and highfructose corn syrup, you can see that highfructose corn syrup's about half the price.
so, in other words, it's cheap. so, high fructose corn syrup is evil. but it's not evil becauseit's metabolically evil. it's evil because it's economically evil. because it's so cheap that it's found it's way into everything. it's found it's way into hamburger buns, pretzels, barbecue sauce, andketchup, almost everything. somebody emailed me the other day
and told me they went intotheir local grocery store and went through everysingle loaf of bread on the shelf, and out of 32 types of bread on the shelf, only one of them did not have high fructose corn syrup in it. so, we are being poisoned by this stuff, and it's been added surreptitiously to all of our food, every processed food. the question is why?
well, you'll see why in a minute. so, the corn refiners like to point out, "well, you know, it'sjust been a substitution. "as the high fructosecorn syrup's gone up, :the sugar's gone down. "you know, we're justreplacing, like gram for gram." well, not exactly, because here's 73 pounds of sugar per year. this is from the economic research service
of the us department of agriculture. so disappearance data. 73 pounds, up to 95 pounds by 2000. and there's somethingmissing from this slide. anybody wanna tell me what it is? what's missing? juice, juice is missing. 'cause juice is sucrose, right, sugar. and juice causes obesity.
so this is a study done by myles faith, a prospective study ininner city harlem toddlers. and the number of juice servings per day predicts the change in bmi score per month in these inner city harlem toddlers. now, where do these inner city harlem toddlers get their juice? from what, from where, from whom? from wic.
anybody heard of wic? you know what wic is? women infants children, right? a government entitlementprogram set up under who? nixon, to prevent failure to thrive. they did. this is the equal and opposite reaction. so, let's add juice in, here it is. so, most fructose itemswhen you put it together,
now we're up to 113 pounds on this graph, and i just heard from brian williams, of nbc news, after themost recent study came out, that was in the journalof clinical investigation, that we are actually up to141 pounds of sugar per year. each of us. that's what we're up to. 141 pounds of sugar per year. now, do you think that this might
have some detrimental effects on you? hasn't stopped you, has it? that's the point, it hasn't stopped you. that's why we need to talk about this. so, juice consumption increases the risk for type 2 diabetes. so this is the relative risk ratio as juice intake goes up, andthis is in the nurse's study. showing again, juice consumption,
sucrose, obesity, diabetes. okay, the third politicalstorm, that's swirling around to create this disaster,this mega-typhoon, that thing that happened in 1982, the usda, the american hearth association, the american medical association, all telling us we had toreduce our consumption of fat. now, why did they tell us that? to stop what?
to stop hear disease. did we? no, we didn't, did we? in fact, it's worked the exact opposite. we've only created more. so, now how did this come to be? why did they tell us to stop eating fat? well, in the early 1970s we discovered something in our blood called ldl,
low-density lipoproteins. you've heard of that, right? is it good or bad? - [audience member] bad. - not so bad, we'll talk about it. in the mid 1970s we learned that dietary fat raised your ldl. so, if dietary fat is a, and ldl is b, we learned that a lead to b.
dietary fat definitely increases your ldl, no argument, it's true. and then, finally, inthe late 1970s we learned that ldl correlated withcardiovascular disease. so let's call cardiovascular disease c. so we learned that b lead to c. so, the thought process by some very smart nutritionists, et cetera, the usda et cetera, said,
"well if a leads to b, and b leads to c "then a must lead to c,therefore, no a, no c." this was the logic. now, any logicians in the room? anybody see any problems with that logic? go ahead. (speaking away from microphone) - that's right, the premise is incorrect. and i'll tell you whythe premise is incorrect.
because this suggests thatthis is all transitive. but, in fact, only thecontrapositive is transitive. so, it's not no a, no c, it's no c, no a. so, the logic isn't even right. there's faulty logic here. so, this doesn't work on any level. so, i'm gonna show youwhy this doesn't work. but, before i how you why it doesn't work, i'm gonna show you that this was
a battle royal back in the 1970s. this was not a simple thing. there were people lined upon both sides of this story. so, this, over here, isa book, 1972 it came out, and it was called pure white and deadly. it's all about sugar. written by a british physiologist, nutritionist, endocrinologist, by the name of john yudkin.
now, i never knew johnyudkin he's passed away. but, i read this book about a year ago. and without even knowingit, i was a yudkin acolyte. i was a yudkin disciple. every single thing that this man said in 1972 is the god's honest truth. and if you wanna read a trueprophecy, you find this book. it's not easy to find,but you go find this book. and i'm telling you, every single thing
this guy said has come to pass. it's astounding, i am in awe of this guy. but on the other side wehad this guy over here. his name was ancel keys. anybody heard of him? so, ancel keys was aminnesota epidemiologist, very interested in the causeof cardiovascular disease. and he performed the first multivariate regression analysis without computers.
now, anybody know what that means? multivariate regression analysis? so, this is where youtake a whole lot of data, and normally you would justrun a few computer programs, but basically, the object is to try to figure out what causes what, and to try to factor out other things and determine what the contribution of various things all at once are
to an outcome that you're looking for. so, he was interested incardiovascular disease. so, what he did was he did this study, along with other people around the world, called the seven countries study. very famous, front pageof time magazine in 1980. so, here's the data onthe seven country study. so, we have the us, canada, australia, england and wales, italy, japan.
and here's percent caloriesfrom fat on the x axis, and here we have coronarydisease death rate on the y axis. and so you'd say, "oh, look at that." i mean, it's very obvious, isn't it. sure, percent calories from fat correlates very nicely withcoronary disease, right? except for one little problem. anybody see it? japan and italy?
so, how much sugar do they eat? didn't i tell you the japanesediet eliminates fructose? they never even had it 'til we brought it to them after world war ii. italy, aside from gelato,i mean what else they got? they got a lot of pasta, there's a lot of glucose, but no fructose. there's no sugar in the italian diet other than the occasionalsweet, which they moderate.
they're very careful aboutmoderating, and they cost a lot. but, here we got england,wales, canada, australia, us, you know, we are sugarholics, aren't we? we're also fataholics. so, in fact, the fatmigrated with the sugar. so, here's, this is from keys's own work. page 262, if you wanna pickup the 500 page volume. and i'm just gonna read you the one paragraph that talks about this.
the fact that the incidence rate of coronary heart diseasewas significantly correlated with the average percentage of calories from sucrose in the diet, is explained by the intercorrelation ofsucrose with saturated fat. in other words, donuts. where ever there was thefat, there was sucrose too. because these guys here eat donuts. partial correlation analysis show
that with saturated fat constant, there was no significant correlation between dietary sucrose and the incidence of coronary heart disease. okay, when you do a multivariatelinear regression analysis, you have to do it both ways. you have to do holding fat constant showing the sucrose doesn't work, and then you have to hold sucrose constant
and who that fat still works. you see that anywhere? he didn't do it, he didn't do it. he didn't do the thing that you need to do to do a multivariatelinear regression analysis. now, this was done before computers. we can't check the work. he's dead, he died in 2004. so, we're left with a conundrum.
do we believe this? do we believe this study, because we based 30 years of nutritioneducation, and information, and policy in this country on this study. and, as far as i'mconcerned, it has a hole as big as the one in the uss cole, all right, you got it? everybody, am i debunking, yes, no? let's keep going.
remember, i told youldl may be not so bad? well, here's why. because there really isn'tone ldl, there are two. there are two ldls. here's one over here, it's called pattern a or large buoyant ldl. so, everybody knows that ldl correlates with cardiovasculardisease, and that's true. i'm not gonna argue that, that is true.
but, it's not this one, pattern a ldl. these guys are so light,they are buoyant, they float. so, they get carriedthrough the bloodstream, and they don't even have a chance, because they're so bigand they're so buoyant, they don't even get underneath the edge of the endothelialcells in the vasculature to start the plaque formation process. but, over here we havethis other guy, over here,
called pattern b or small dense ldl. you see the difference? these guys are dense. these guys don't float. these guys are small, they get underneath the edge of the surface of the surface of the endothelial cells, and they start the plaque formation. and it's been shown bynumerous investigators now,
the dense ldl is the bad guy. okay, now, when we measureldl in the bloodstream, when you do a lipid profile, you measure both of them together, because it's too hardto distinguish the two. so, when you get an ldl,you're getting both ldls. the neutral one and the bad one. now, how can you tell whether your ldl is the neutral one or the bad one.
what you do is you look atyour triglycerides level in association with it,'cause your triglycerides tell you which one it is. so here, here's pattern a over here, big large buoyant ldls, and you'll notice that the triglycerides arelow, and your hdl is high. that's what you want, youwant a low triglyceride, high hdl, 'cause that'sthe good cholesterol. you want high good cholesterol.
over here, you have pattern b. and here you have hightriglyceride, low hdl. that's the bad guy, that'sthe guy you don't wanna be. 'cause you're gonna die of a heart attack. no question about it. triglyceride to hdlratio actually predicts cardiovascular disease waybetter than ldl ever did. point is, when you measureldl, you measure both. so, dietary fat raises your large buoyant.
what do you think raises your small dense? carbohydrate. okay, so here's percent carbohydrate, and here's your pattern b going up. everybody got it? so what did we do? what did we do in 1982? what did we do? we went on a high carb diet, which was
supposed to be a low fat diet, right? so, here's the low fat craze. took america and the world by storm. because the content of low fat home cooked food, thatyou cook by yourself, in your house, you cancontrol the content of fat. but when you process it,low fat processed food, it tastes like cardboard. it tastes like (bleep).
so the food companies knewthat, so what'd they do? they had to make it palatable? so, how do you make something palatable that has no fat in it? you add the, sugar. so, everybody remember snackwells? two grams of fat down, 13grams of carbohydrate up, four of them being sugar,so that it was palatable. well, we've just shown you that
that's the worst thing you could do. and that's what we've done. and we're still doing it, today. so when you find amistake, what do you do? you admit the mistakeand you right the ship. we haven't admitted the mistake, and we haven't righted the ship. so, we've our food supply adulterated, contaminated, poisoned, tainted.
on purpose, and we'veallowed it, and we've let it, thought the addition of fructose for palatability, especiallybecause of the decreased fat, and also as a ostensibly browning agent, which actually has it's own issues. because why it browns so well with the sugar in it, actually is what's going on in your arteries. because that's causing what we call
protein glycation and cross linking, which is actually contributionto atherosclerosis. so it works on your steak on the grill, it works in your arteries the same way. and removal of fiber also. now, why did we removefiber from our diet? we, as human beings walkingthe earth 50,000 years ago, used to consume 100 to 300grams of fiber per day. we now consume 12.
why? what did we do? we took the fiber out. so, why'd we take the fiber out? it takes too long to cook, takes too long to eat, and shelf life. so, people ask me, "what'sthe definition of fast food." fiberless food. i dare you, other than a salad, i dare you to go to any fast food restaurant
and find anything on their menu that they actually have to cook, that has more than onegram of fiber in it. 'cause there isn't any,and that's on purpose. because they take the fiber out, 'cause that way they can freeze it, ship it around the world,and cook it up fast, and not only is is fast cooking, but it's fast eating, which also
causes it's own satiety issues. bottom line, we have atyphoon on our hands. and then, finally, the last issue was the substitution of transfats, which are clearly a disaster, but those have been going down, because we know that those are a problem. so we've actually gottenrid of most transfats, not completely, but most.
so this is it, this is what we've done over the last 30 years. now, to the biochemistry. now, how many of you herehave taken biochemistry? about 25%. i am going to show you a lot of reactions in excruciating detail. if you've studied biochemistry, you will have an anaphylactic reaction.
if you haven't studied biochemistry, you will fall asleep. so, what i'm gonna suggest that you all do is just let me do mything, to show you that, at least it works, andjust count the arrows. you can do that, right? can you count the arrows,it's not like counting sheep. okay, you can count thearrows, and just stick with me. just let me do my thing,
and let me show you whyfructose is not glucose. 'cause what the liver does to fructose is really unique, and you've gotta understand it to understandeverything i've just told you. so, number one, fructose is seven times more likely than glucose todo that browning reaction. the advanced glycation end-products. the thing that happens on your grill, happens in your arteriesfor the same reason.
you can actually see the color too, the color change too. fructose does not suppressthe hunger hormone. there's a hormone thatcomes form your stomach called ghrelin you'veheard about, already. so, if you preload akid with a can of soda, and then you let him looseat the fast food restaurant, do they eat more, or do they eat less? they eat more.
they just took on 150calories, yet they eat more. reason? 'cause fructose doesn't suppress the hunger hormoneghrelin, so they eat more. acute fructose ingestiondoes not stimulate insulin, because there's no receptor for fructose, no transport for fructose on the beta cell that makes insulin, sothe insulin doesn't go up. well, if the insulin doesn't go up,
then leptin doesn't go up, and if leptin doesn't go up, you're brain doesn't see that you ate something. therefor, you eat more. and finally, i'm gonna show you liver hepatic fructose metabolism is completely different between fructose and glucose,completely different. and i'm going to show you,before the evening is out,
that chronic fructose exposure alone, nothing else, causes this thing we call the metabolic syndrome. everybody knows what themetabolic syndrome is? so, this is the conglomerate of the following different phenomena, obesity, type 2 diabetes, lipid problems, hypertension, and cardiovascular disease. those all cluster together,called metabolic syndrome.
i'm gonna show you how fructosedoes every one of those. i wanna show you the difference between glucose and fructose in a way that will be glaringly apparent. so, let's consume 120 calories in glucose. two slices of white bread. what happens to that 120 calories? you eat the 120 calories, 96 or 80% of the total will be used byall the organs in the body.
80% off the table. why? because every cell inthe body can use glucose. every bacteria can use glucose, every living thing onthe face of the earth can use glucose, becauseglucose is the energy of life. that's what we were supposed to eat. 24 of those calories, or20% will hit the liver. so let's watch what happensto those 24 calories.
here they go. so, the glucose comes inthrough this transporter called glut2, out here, the glucose is gonna stimulate thepancreas to make insulin, the insulin's gonna bind to it's receptor, and it's gonna takethis substrate over here called irs-1, insulinreceptor substrate 1. that's not importantright now, don't worry. and it's gonna tyrosine phosphorylate it.
and it's going to be tyrosine irs-1, which is now active, that's active. and it's gonna stimulate the second messenger here called akt. now what akt does is, itstimulates this guy down here. srabp1, sterol receptorbinding protein number 1. don't worry about it. but this is the thing that, ultimately, gets fat mechanics going.
so, you 'll see in a minute. so, one of the things that srabp1 does, is it activates this enzymehere called glucokinase, which takes glucose toglucose 6 phosphate. now, glucose 6-phosphatecan't get out of the liver. the only way to get glucose 6-phosphate out of the liver is with hormones. glucagon or epinephrine, that'sthe way it can get it out. so now, the glucose is fixed in the cell,
but it's only 24 calories worth, so it's not a big bolus of it. now, the glucose 6-phosphate almost all of it, is gonna end up going over here tosomething called glycagen. now, glycagen is the storageform of glucose in the liver. because glycagen's easyto fish the glucose out with glucagon and epinephrine. so, my question to you, and granted,
this is a physiology question, is how much glycogen can your liver store before it gets sick? the answer's any amount. it's unlimited. we have carb loaders whorun marathons, right? does it hurt them at all? we have kids with adisease where they can't get the glucose out of the glycagen,
called glycagen storage disease type 1a, or von gierke disease. they got livers down totheir knees their so big. they're hypoglycemic like all get out 'cause they can't lift theglucose out of their liver. but, they don't go into liver failure. because glycagen is a non-toxic storage form of glucose in the liver. so, the whole goal of glucose
is to replete your glycagen. so, this is good, thisis not bad, this is good. now, a little of that glucoseis gonna fall down here, it's gonna get metabolized down to this stuff here, called pyruvate. and the pyruvate is gonna enter your mitochondria, over here. remember, your mitochondria are the parts of your cell thatactually burn the energy.
they're your little factories. they make the stuff that lets you live. called atp, atp, adenosine triphosphate, that's the energy of life, right there. so, the pyruvate comes in, gets converted to something called acetyl-coa, gets metabolized by this thing called the krebs cycle, tcacycle, and you throw off atp and carbon dioxidewhich you breath off.
so far, so good? have i snowed anybody yet? you're with me? i snowed one guy back there. i'm doin' my best, i swear to god, i'm doing my best. anyway, so this stuff over here, this acetyl-coa, getsburned off in the tca cycle. maybe you won't burn all of it off,
and so, some of it may exit as citrate. and the citrate thenleaves the mitochondria through a process knownas the citrate shuttle. and then that citratecan then be broken down by these three enzymes, which are all subservient into this srabp1. this is atp citrate lyase acetyl-coa carboxylase fatty acid synthase. they're not important.
the only thing to know is these three enzymes together turn sugar into fat. this is called denovo, meaning new, lipogenesis, fat making. this is denovo lipogenesis. so you take the citratewhich came form the glucose, and you end up withsomething called acetyl-coa, which then gets packagedwith this protein here, and you end up with something called vldl,
very low density lipoprotein. now, anybody heard of that before? it's bad, that's bad. vldl is bad because that's one of the things that causes heart disease. it's also a substrate for obesity. so, you don't wanna make much of this. but the point is, youstarted with 24 calories, maybe a half a caloriewill end up as vldl.
so, that little japaneseguy with the little hat, you know, working out in the field, eating rice for the next 90 years, can he die of a heart attack at age 90? sure. but that's not so bad. if you make it to 90,you're doing alright. because that vldl coming from glucose. glucose made a little bitty vldl.
and that serves as a substratefor adipose deposition into your fat cell, here triglyceride. in addition, because of the insulin went up in response to the glucose, your brain sees that signal. and it knows that that is supposed to shut off further eating. in other words, hey, i'm busymetabolizing my breakfast. i don't need lunch.
and so, you have a nicenegative feedback loop between glucose consumption, the liver, the pancreas, and the brain, to keep you in normal negative, yinyang energy balance. this is good, this is not dangerous. this is what's supposed to happen. so now, let's talk abouta different carbohydrate. let's talk about my favoritecarbohydrate, maybe yours too. (crowd murmuring)
ethanol. ethanol is a carbohydrate, isn't it? here's the structure,carbon hydrogen oxygen, it' a carbohydrate. but, we all know thatethanol is a toxin, right? a poison, right. you can wrap yourlamborghini around a tree, or you can fry your liver, your choice. depends on how much youdrink and how often.
right? okay. so, we know that ethanolis not good for you, except, of course, alittle bit is good for you. so, we can talk about thattoo, later, if you want. but, let's talk abouthow it's bad for you. so, here's acute ethanol exposure. cns depression,vasodilatation, hypothermia, tachycardia, myocardial depression, pupillary responses,respiratory depression,
diuresis, hypoglycemia,loss of fine motor control, you all went to college. here's fructose, nothing. it doesn't do any of those. because the brain doesn'tmetabolize fructose. alcohol gets metabolized in the brain, to cause all of thosethings, but fructose doesn't. so, fructose is not anacute toxin, ethanol is. we control ethanol, don't we?
we have something called the bureau of alcoholtobacco and firearms. we have all sorts ofthings, we tax ethanol. we do all sorts of things tolimit consumption of ethanol. the nordic countries, all theliquor stores are state run in attempt to try to set theprice of ethanol high enough so as to discourage consumptionfor public health reasons. we have 1500 years of alcoholcontrol policy in this world to draw on, in terms ofhow to limit consumption.
got it? because ethanol is atoxin, and we know it. so, let's consume 120 calories in ethanol. shot of makers mark. anybody taste it? yeah, good, okay. so, 24 calories right off the top. the stomach and theintestine have something called the first passeffect, so 10% off the top,
and kidney, muscle, brainwill consume the other 10%. so there goes 20% or 24calories right off the top. 96 calories of the 120are gonna hit the liver. now, how many was it for glucose? it was 24. so, four times the substrateis gonna hit the liver, and there's the rub. this is a volume issue. we're gonna show you how.
so, the ethanol comesin, passive diffusion, there's not receptorfor it, not transporter. first thing that happens is ethanol gets converted to this guy,over here, called acetaldehyde. anybody know anything about aldehydes? like formaldehyde? right? are aldehydes good for you or bad for you? they're bad, right? 'cause what do they do?
they can cause cancer, they cross link proteins is what they do. so, if you cross link enoughproteins in your liver, what do you think happens to it? you get something called... cirrhosis, right exactly. so this guy, over here, is bad. and it generates somethingcalled reactive oxygen species. reactive oxygen speciesdamage proteins in the liver.
and the more alcohol you drink, the more of this stuff you get. so, this is one of thereasons why alcohol's bad. now the acetaldehyde will come down here to something called acetate. the acetate will enter the mitochondria, just like the pyruvate did before. will get converted to acetyl-coa and participate in the tca cycle,
just like before, to generate energy. so that alcoholics don'tdie form lack of energy, they got energy, it'severything else they don't have. they're gonna have a whole lot of citrate. because they have 96 calories that have to get metabolized. how many calories made it tothe mitochondria with glucose? about half, right? because most of it went to glycogen.
so, we've got a bigcitrate, so it's in big font to show you that we'retalking about big citrate now. and so, the big citrateis gonna get metabolized all the way to vldl by the crabp1. and so you're gonna get a lot of the ldl. and this is the dyslipodemiaof alcoholism, right here. everybody see that? so, the liver's gonna try to export this vldl out so that it doesn't get sick,
because when fat builds up in the liver, that's not good for it. some of it's gonna exitas free fatty acids, and those free fatty acids,will take up residence in the muscle, and you get something called muscle insulin resistance. so insulin resistance, that's a bad thing. that makes your muscles andyour liver now work so well. and can cause all sorts ofother problems like diabetes.
some of the acetyl-coawon't even make it out, and will precipitate as a lipid droplet, so there's your alcoholic steatohepatitis. this acetyl-coa, and this ethanol, and these reactive oxygen species can start this enzyme activated. it's called c-jun n-terminal kinase 1, or jnk1, and it really is jnk1 because it is the bridge between
metabolism and inflammation. so, when you generate jnk1, youdo bad things to your liver, which i will show you whenwe talk about fructose. so let's talk about fructose. fructose is sweet, we like it a lot. we like it in everything,we like it in our bread, we like it in our pretzels,we like it everywhere we look. so, let's consume 120 calories in sucrose. a glass of orange juice.
so, two slices of whitebread, a shot of makers mark, a glass of orange juice,all the same 120 calories. but, three different substrates. let's see what happens to the fructose. so, number one, the glucose, remember, 'cause sucrose is halfglucose half fructose, so 60 of the caloriesof the 120 are glucose. 12 are gonna make it into the liver, 48 out here for the rest of the body.
the same 20/80 split wehad before with glucose. so far, so good. but all 60 calories of fructose are gonna be metabolized by the liver. because only the livercan metabolize fructose. so, what do we call it, where when you take in a compound that'sforeign to your body, and only the liver can metabolize it, and in the process,generates various problems?
what do we call that? we call that a... poison. so, let me show you how it's a poison. so, let's watch the fructose. so, the fructose comes inthrough this transporter, now. before it was glut2, now it's glut5 no insulin, remember, 'cause fructose does not stimulate insulin.
fructose, then, gets metabolizedby this guy, over here, called fructokinase, to form something called fructose 1-phosphate. in the process, atp has to give up one phosphate to adp 'cause the phosphate had to come from somewhere,so it comes from here. now, before we had 24 calories that had to be phosphorylated. now we have 72 calories thathave to be phosphorylated.
so, we have three times the substrate, it's a volume issue, for right now. so, we're gonna lose a lotof phosphate, aren't we? so there's a scavengerenzyme in your liver called amp deaminase 1 to rescue the phosphates off therest of the atp molecule, and it takes adp down toamp, adenosine monophosphate, down to imp, inositol monophosphatase, and finally, to thewaste product uric acid.
anybody every heard of uric acid? what is it? it's a waste product. goes out in your urine. 'causes what disease? gout, right. also causes another diseasecalled hypertension. let me show you how. because uric acid, turns out, blocks
the enzyme in your blood vessels called endothelial nitric oxide synthase. and that's the enzyme that makes the stuff called nitric oxide, no. and that is your endogenousblood pressure lowerer. that keeps your blood pressure low. so, when you can't make it,your blood pressure goes up. so, this just shows thatfructose consumption increases gout in adults.
so, this is a studythat came out last year showing that fructose consumption increases the risk for gout, showing that uric acid's going up. and this is a study doneby pediatric renal fellow, stephanie winn, just published in journal of pediatrics, it's not submitted anymore, it's long in press, showing that this isin the nhanes database
in the adolescents, showingthat sugar sweetened beverages, as it goes up, your uric acid goes up. and, not only does your uric acid go up, but here's your sugar sweetened beverages, and here's your systolicblood pressure going up. and here's a study done by dan fige, at the university of texas san antonio, where he took obeseadolescents with hypertension, and he gave them the drug allopurinol.
and allopurinol is the drugthat you treat gout with, to lower the uric acid. and look what happenedto the blood pressure. systolic, diastolic, went down. showing that, in fact, uric acid is an important part of hypertension. we have a hypertensionepidemic in this country. here it is. it's the sugar.
okay, so, so far we havehigh blood pressure. the fructose will get metabolized down to pyruvate, the pyruvate will enter the mitochondriajust like before, throwing off a lot of citrate. and here's a little trick that fructose does that glucose doesn't. 'cause these to can reform this stuff over here called fructose1 6 bisphosphatase,
which can then reform with glyceraldehyde to form this guy, over here,called xylulose-5-phosphate. and i get toxylulose-5-phosphate in a moment. but i wanna point out this asterisk. that's there to remindme to tell you something. that's there to remind me to tell you that this is why thesports drink companies put high fructose cornsyrup in the sports drinks. because if you are glycogen depleted,
in other words, if you just ran a marthon, and you have no glycogenleft in your liver because you burned it all, and you take in a sports drink with highfructose corn syrup, you can replete your glycogen faster than with glucose alone. that's true. so, for elite athletes, ahigh fructose corn syrup containing sports drinkactually makes sense.
and so, indeed, sports drinks have high fructose corn syrup. the question is whodrinking the sports drinks? any elite athletes you know? who's drinking the sports drinks? the kids, right? why are they drinking it? because it's cool, right? 'cause it's cool and it tastes good.
so, before we go on, i just wanna, now, digress for a moment. 1967, university offlorida patents gatorade. everybody remember gatorade? okay, 1970, the florida gators win the ncaa championship in football. gatorade makes a big splash. okay, big deal. anybody ever taste the original gatorade?
yeah? what'd it taste like? tasted horrible. it tasted like somethingthat you might find coming out of you insteadof going into you. it tasted awful. 1992, pepsi buys gatorade, and they say, "how are we gonna market this swill?" so, what did they do?
they added the high fructose corn syrup. so, now who drinks it? fat kids, right? not even skinny kids, fat kids drink it. okay, so there's a problem here. okay, and we're gonnashow you how that works. okay, so xylulose-5-phosphate,just to show you, if you take a rat, andyou glycogen deplete him by making him run on an exercise wheel,
and then you re-feed them with starch or with sucrose, the xylulose-5-phosphate goes way up with the sucrose. so you get more xylulose-5-phosphate through this pathwayhere, going over here. so why do we care aboutxylulose-5-phosphate? because it stimulates this guy, over here, called pp2a, which then activates this transcription factor here,
carbohydrate responseelement binding protein, which then activates what three enzymes? new fat making right,the novo lipogenesis. so here's the citrate,we got lot's of that. and here we've got acetyl-coa,which is the way into fat, which then gets packaged to the vldl, and now you've got the dyslipidemia of obesity of fructose consumption, which has, been known for many years.
so, here's normal medical students, if you can call them normal, taking in a glucose load. notice, almost none of it ends up as fat. taking in a fructose load,same number of calories, 30% of it ends up as fat. so when you consume fructose, you're not consuming acarbohydrate, you're consuming fat. so everybody talks about a high fat diet.
well, high sugar diet is a high fat diet. that's the point. that's exactly the point. this is a study where they gave acute administration of fructose, and you can see the triglycerides going up compared to the control. serum triglyceride, right there. here's normal medical students, again,
six days of high fructose feeding. triglycerides doubled, de novo lipogenesis went up five times higher,and here's free fatty acids, which then cause insulinresistance, doubled. six days. so, here's the dyslipidemiaof fructose consumption. we're not done. some of the fat won'tmake it out of the liver, just like with ethanol.
and now you've got a lipid droplet, so now you've got thisnonalcoholic steatohepatitis. so, this is work that we did in our clinic looking at sugar sweetenedbeverage consumption against the liver enzyme marker alt, alanine aminotransferase, whichtells you about fatty liver. and sure enough, here'ssugar sweetened beverages against alt, and you can see a nice linear relationship in caucasians.
african americans, it'sa different relationship, and that' a' whole 'notherstory all by itself. so, there's the lipid droplet of nonalcoholic steatohepatitis. some of it will comeout as free fatty acids and populate the muscle, will also tell the insulin to go up higher. remember that jnk1? so, here's what jnk1 does.
so, the acetyl-coa and thefructose can all activate jnk1. and what jnk1 does is, remember when we used glucose, this irsbecame tyrosine irs-1 and that was good? well, jnk1, what it does, is it's serine phosphorylated irs-1. and serine irs-1 is inactive. so now, the insulin can'teven do it's job in the liver. so, now you have liverinsulin resistance as well.
that's gonna make thepancreas work that much harder generating higher insulin levels, which raise your bloodpressure even further, cause further fatmaking, cause more energy to go into your fat cell. there's your obesity. and finally, our research has shown that the higher the insulin goes, the less well your braincan see it's leptin.
and so there you've gotcontinued consumption because your brain thinks it's starving. and it's been shown in many different ways that fructose consumption changes the way your brain recognizes energy. all in a negative fashion, so that you, basically, think you're starving. your brain gets the signalthat you're starving even though your fat cells are generating
a signal that says, "hey,i'm full like all get out." so, this just shows you how it goes. so, the high insulin generates the obesity because this is that, remember the first law of thermodynamics,the biochemical force generating the energy storage as the primary phenomenon, remember, if you're gonna store it,and you expect to burn it so, here's the store it.
normally, that would make leptin, and the leptin should feed back and turn everything off, but it doesn't, because the insulin gets in the way, and the high fat diet gets in the way. also, the hyperinsulinemiastops the leptin from acting on that nucleus accumbens, and so you get an increased reward signal. so that continues your appetite,
continues more fructose,more carbohydrate, generating more insulinresistance than you can see. you generate a viciouscycle of consumption and disease, and no stopping. so, here we are,hypertension, inflammation, hepatic insulin resistance,hyperinsulinemia, dyslipidemia, muscle insulin resistance, obesity, and continued consumption. looks like metabolic syndrome to me.
so, here are the phenomena associated with chronic ethanol exposure. hematologic disorders,electrolyte abnormalities, hypertension, cardiacdilation, cardiomyopathy, dyslipidemia, pancreatitis, malnutrition, obesity, hepatic dysfunction, that's alcoholic steatohepatitis, fetal alcohol syndrome, and addiction. here's fructose.
eight out of twelve. 'cause they do the same thing. 'cause they metabolize the same way. because they are the same. they come from the same place, right. how do you make ethanol? naturally. right, you ferment sugar. hasn't changed, 'cause ithas all the same properties.
because it's basicallytaken care of by the liver in exactly the same way,and for the same reason. because sugar and ethanol are the same, every which way you turn. so, here's our clinic intervention. this is what we do in our clinic. it's as simple as you can imagine. we write this on the back of a matchbook. it's just as simple as you can make it.
we have four things we teach the kids to do, and the parents. get rid of every sugaredliquid in the house, bar none. only water and milk, there is no such thing as a goodsugar beverage, period. eat your carbohydrate with fiber. because fiber is good. fiber is supposed to bean essential nutrient. and we can talk later, if you want,
after the cameras turn off, as to why fiber is notan essential nutrient. because the governmentdoesn't want it to be. 'cause then they couldn'tsell food abroad. wait 20 minutes for second portions, to get that satiety signal. and finally, buy your screen time minute-for-minute with physical activity. that's the hardest one to do.
so, if you play for half an hour, you can watch tv for half an hour. you wanna watch tv for anhour, play for an hour. that one's a hard one, but anyway. we follow our patients every three months. so, here's my question. does it work? what do you think? yeah, it works.
so, this is bmi z-scoretime from initial visit. it works. but, we were interestedin what made it work, and made it didn't work, so we did a multivariate linear regression analysis. the thing that made it not work, sugared beverage consumption. the more sugar beverages thepatient drank at baseline, the less well lifestyleintervention worked
for all the reasons i just showed you. so, why is exercise important in obesity. because it burns calories? come on. 20 minutes of jogging'sone chocolate chip cookie. you can't do it.(audience laughs) are you joking me? so, why is exercise important? i'll tell you why, here's why.
number one, it improvesthat skeletal muscle insulin sensitivity because you're insulin actually works better at your muscle, which then brings yourinsulin levels down. which is good for you. number two, it's yourindigenous stress reducer. it's the single thing thatactually stress reduces. and if you stress reduce, what do you think your appetite does?
goes down, because stressand obesity go hand in hand, for all sorts of reasons which are beyond the scope of this lecture today. but, we can talk about it in the question period, if you want. and then finally, rememberthat de novo lipogenesis? remember those three nasty enzymes? what if you burned the stuffoff before you made the fat? that's what exercise does, 'cause it makes
that tca cycle runfaster, so you don't get the citrate leaving the mitochondria, so it doesn't get turned into fat, so it doesn't precipitate and cause all the problems you just saw. that's what they mean bya higher metabolism, yes. but it has nothing to dowith burning of calories. that is the stupidest reason that i've every heard of for exercise.
you gotta be joking me. you can't do it. i mean one big mac and you gotta mountain bike for ten hours. are you joking? so, why is fiber important in obesity? so, this is my motto in clinic. when god made the poison, hepackaged it with the antidote. 'cause fructose is a poison.
i think i've, hopefully, shown you that. but, wherever there's fructose in nature, there's way more fiber. you ever see a piece of sugar cane? it's a stick, right? you can't even chew the damn thing, right? you gotta suck the stuff out. (sucking) like that, right?
i mean, how many calories you think you're gonna get out of a piece of sugar cane? they actually did studieson the sugar plantations back in the early 1900s. all of the workers were healthy and lived longer than the sugar executives who got the processed product. how 'bout that, wonder why. so, eat your carbohydrate with fiber,
that's why we say that. that includes sugar,that's why fruit's okay. because number one, it limits how much fructose you're gonna take in, and number two, it givesyou an essential nutrient which you needed in the first place. and you get somemicronutrients along with it so that you actually, yourliver works healthier. so, here's what fiber does.
number one, it reduces the rate of intestinal carbohydrate absorption. now, sometimes that's bad. i'll tell you when that's bad. now when that's bad? that's bad when you'reat a formal function. 'cause what happens if you reduce the rate of carbohydrateabsorption in your gut? the bacteria get to it.
so, as far as i'm concerned, in life you've got two choices. it's either fat or fart. it increases the speed of transit of the intestinal contents to the ilium, and that raises this hormone over here called pyy, which goes to your brain and tells you the meal's over. that's your satiety signal.
so when you add fiber to your diet, you actually get yoursatiety signal sooner, because the food moves through faster. and then, finally, it also inhibits the absorption of some free fatty acids all the way to the colon, and then those get chopped up into littleitty bitty fragments called short chain fatty acids, and those actually suppress insulin,
as apposed to long chain fatty acids which stimulate insulin. so there are a whole bunchof reasons why fiber is good. anybody ever heard ofthe paleolithic diet? go home and read up on it on the internet. the paleolithic diet. basically, if you east everything as it came out of the groundraw, with no cooking, you would cure diabetes on a dime.
takes about a week. because you're getting that 100 to 300 grams of fiber i mentioned before. that's why, 'cause fiber is good for you. and the more, the better. - [audience member] type 2. type 2, right, type 2, not type 1. i stand corrected, type 2. now, for some fun.
that's the end of the biochemistry. phew, how'd i do? (audience applauds) i told you i'd get you through it. so, now comes the fun part. the racial innuendos, andall the political stuff. the fructosification of america, and, of course, the world. ready?
another quiz. can you name the seven foodstuffs at mcdonald's that don't have high fructose corn syrup or sucrose? - [audience member] mustard? - (laughs) no, mustard has it. (audience chatter) oh, come on, come one, the big one. french fries, but theyhave salt, starch, and fat.
so, they're not so good either. okay, what else? we'll get to coffee. hash browns, for the same reason, salt starch and fat. what else, chickenmcnuggets, i was shocked. i was shocked. no sucrose or high fructosecorn syrup in chicken mcnuggets. but, as the circuitcourt judge in new york
called them, they are stilla mcfrankenstein creation. but, nonetheless, no sucrose,i was really shocked. sausage. oh, they're terrible,they're just disastrous. but, i mean, there'snothing good in them at all, but there's not fructose. sausage, diet coke, coffee,if you don't add the sugar, and ice tea, if you don't add the sugar. by the way, the chicken mcnuggets,
we have a disclaimer, because no one eats the chicken mcnuggetswithout a dipping sauce. and there's a whole bunchof high fructose corn syrup in the dipping sauce, right? okay, good, all right. so, who's really drinking this? we talked about this before. gatorade am. so, this is an attempt by pepsi
to capture market shareon the juice market. do you think there are any elite athletes who actually drink this stuff? you gotta be kidding me. okay, this is for kids, right? so, this really blew my socks off. this was my daughter, when she was in second grade, two years ago, miriam lustig, brought these two
cartons of milk home for me, and said, "dad, you're not gonna believe this." second grade. so, here's the calories in berkeley farms 1% low fat milk, 130 calories,15 of them are sugars, 'cause it's lactose, which is okay. and here's berkeleyfarms 1% chocolate milk, 190 calories, 29 grams of sugar, all high fructose corn syrup.
it's like a glass of milk plus a half a glass of orange juice. and that's what we're giving to our kids. and do you know what the nutrition department at the sfusd says? "well, we have to get ourkids to drink milk some how." is that brilliant, or what? i don't know. now, what about wic.
so, we talked about the 112 pounds of orange juice that the kiddown in salinas was drinking. what bout wic? remember what we started with? remember? so, could this be the reason? so, here's a can of formula. 43.2% corn syrup solids, 10.3% sugar. it's a baby milkshake.
soda, coca cola, is 10.5% sucrose. formula is 10.3% sucrose. any difference? and there's a huge literature that's now coming of age that shows that the earlier you expose kids to sweet, the more they're gonna crave it later. plus, there's a new literature that shows the more sugar the pregnantwoman drinks or eats
during the pregnancy, the more that gets across the placenta, and actually causes what we call developmental programming, changing the kids adiposityeven before the kid is born, and driving this wholeepidemic even further. so, we'll close in a few minutes. but, i just wanna pointout what's the difference. here, we got a can of coke. here we got a can of beer.
and i'm not picking onschlitz, or anything. it's any beer you want, okay. so, 150 calories each, no difference in terms of total calories. percent carbohydrate, so10.5% from sucrose here, except it's high fructosecorn syrup, but who cares. 3.6% alcohol, here's the breakdown. 75 fructose, 75 glucose for the coke. 90 alcohol 60 maltose for the beer.
remember, the first pass gi metabolism takes 10% of the alcohol off the table. so, when you actually compute the number of calories hitting the liver, which remember was the big difference between glucose and fructose, remember? 72 versus 24 and startedthe whole thing into motion as term of what happens that's bad. bottom line, no difference.
so, we have something called beer belly. well, welcome to soda belly. 'cause that's whatamerica's suffering from. no ifs ands or buts. that's what it is. now, you wouldn't think twice about not giving your kid a budweiser. but, you don't think twice about giving your kid a can of coke.
but, they're the same, in the same dosing, for the same reason, through the same mechanism. fructose is ethanol without the buzz. fructose is a carbohydrate. yes, it is. but fructose is metabolized like a fat. and i've just shown you that 30% of any ingested fructoseload ends up as fat.
so when people talk about highfat diets doing bad things, no, what they're really talking about is high fructose diets, and that's what ancel keys was looking at. so, the corollary to thatis, in america at least, and around the world too, a low fat diet isn't really a low fat diet. because the fructose orsucrose doubles as fat, it's really a high fat diet.
that's why our diets don't work. and fructose, just like ethanol, for the same reason,through the same mechanism, and in the same dosing, is also as toxin. now, last, what can we do about it? can we do anything about it? how 'bout the fda? you think they can do something about it. after all, aren't theysupposed to regulate our food?
aren't they supposed to regulate what they can put in food? weren't they supposed to regulate tobacco? now they are, actually. so, you know, weird things. so, i wanna just show you what the tobacco company thinks of all this. this is actually from the ucsf legacy tobacco documents library that
stan glantz runs right across the street. stan's a good guy, like stan a lot. and he showed me this. "under the regulationsgoverning food additives," so this came from an altriaor phillip morris executive, "it is required that additives be safe, "defined as a reasonable certainty "by competent scientists that no harm "will result form theintended use of the additive."
now, does fructose meet that standard? well, the fda says that fructose, high fructose corn syrup,has what's knows as gras, g r a s status, generallyregarded as safe. now, where'd that come from? no where. it came from no where. it came from the notionthat, "well, fructose "is natural, it's infruit, it must be okay."
well, tobacco's natural too. but it's not. ethanol's natural, but it's not. a whole bunch of, you know, jamaican ackee fruit'snatural, but it's not either. it kills you. keeping on going. "a food shall be deemed to be adulterated "if it bears or contains any poisonous
"or deleterious substance which may "render it injurious to health." fructose fits that description, right? uh-uh, but now with the prevention of chronic diseases, even though it's own regulations explicitly postulate the connection between such products and such diseases. in other words, the fda will only regulate
acute toxins, not a chronic toxin. fructose is a chronic toxin. acute fructose exposuredid nothing, remember. 'cause the brain doesn'tmetabolize fructose. the liver does. and the liver doesn't getsick after one fructose meal. it get's sick after 1000 fructose meals. but, that's how many we eat. so, the fda isn't touching this.
the usda isn't touching this. because if the usda touchedthis, what would that mean? that would mean an admission to the world that our food is a problem. so, what to you think that would do? there are three things in this country that we can still sell overseas. weapons, entertainment, and food. cars? (laughs) computers?
i don't thinks so. can anybody think of anything else that another country wants of ours? what? tobacco, right, tobacco. (laughs) all right, you get the picture. so, the usda doesn'twanna know about this. 'cause this is bad news. and so, who runs the food pyramid?
the usda. it's the fox in charge of the hen house. because their job is to sell food. and who's eating it? we are. so, in summary, fructose, and i don't care what the vehicle is, it's irrelevant, sucrose or high fructose corn syrup, i don't care, fructoseconsumption's increased
in the past 30 years, coincidingwith the obesity epidemic. a calorie is not a calorie. and the dietitians in the country are actually perpetrating this on us. because the more you thinka calorie's a calorie, the more you think, well than if you ate less and exercise more, it would work. it doesn't. all of the studies show it doesn't work.
here's why it doesn't work, because a calorie is not a calorie. fructose is not glucose. we know a calorie is not a calorie. 'cause there are good fats and bad fats. there's good protein and bad protein. okay, there's good carbohydrateand bad carbohydrate. and glucose is good carbohydrate. glucose is the energy of life.
fructose is poison. you are not what you eat. you are what you do with what you eat. and what you do with fructose is particularly egregious and dangerous. hepatic fructose metabolism leads to all the manifestations ofthe metabolic syndrome. hypertension throughthat uric acid pathway, de novo lipogenesis, dyslipidemia,
hepatic steatosisthrough that dnl pathway, those three enzymes, thenew fat making pathway, inflammation through jnk1,hepatic insulin resistance because of the serine phosphorylation of irs-1, obesity becauseof the vldl transport to the adiposite, and leptin resistance promoting continuous consumption, basically starving your brain, making you think you need more.
fructose ingestion interfereswith obesity intervention, as we showed in our clinic. the more soft drinks, the less well diet and exercise actually worked. fructose is a chronic hepatotoxin for the same reason that alcohol is. the only difference is alcohol is metabolized by the brain,so you get alcohol effects. fructose is not metabolized by the brain
so you don't get those effects. but everything else it does is the same. but the fda can't and won't regulate it. it's up to us. i'm standing here today to recruit you. that's a famous saying herein san francisco, right? "i'm harvey milk, andi'm here to recruit you." i'm robert lustig, andi'm here to recruit you in the war against bad food.
and this is what's bad. with that, i wanna thank my colleagues at the ucsf department of pediatrics in our weight assessment forteen and child health clinic, ucsf department ofepidemiology and biostatistics, and also department ofnutritional sciences at uc berkeley, in particulardoctor jean-marc schwarz, who is a card carryingfructose biochemist, phd biochemist, who vetted all of these
pathways that i've shown you today, and looked at this and said,"oh my god, it is a toxin." he worked in the stuff for 15 years, and he didn't even realize itwas a toxin until he saw this. so, with that, i'll close. thanks you.
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