"Bacterial Pathogens and Cancer: the Salmonella Typhi Paradigm" and "Environmental Exposures and Thyroid Cancer in Connecticut Women"

March 31, 2021

Yale Cancer Center Grand Rounds | March 30, 2021

Jorge Galan, PhD, DVM and Nicole Deziel, PhD

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00:00Rounds we have two speakers
00:02today from male to wonderful
00:04speakers first or Hegel on my own,
00:07introduced and then the cold diesel,
00:10who Linda Irwin will introduce.
00:12I've known Jorge since
00:14before he arrived at Yale.
00:16He's now the Lucille P Marquis,
00:18professor, microbial pathogenesis
00:19and chair of the Department.
00:22In his lab studies bacterial infections,
00:24he's probably best known for his
00:26discovery and characterization of
00:27the Type 3 secretion apparatus,
00:29which is this microscopic needle
00:31that injects proteins into cells.
00:33A fantastic story,
00:34and in recognition of this work,
00:36he's received numerous awards and been
00:38elected to the National Academy of Sciences,
00:40but more recently he's got interested in
00:43the Association between cancer and bacteria,
00:45and mechanistically, how does that work,
00:47and he's shown, for example,
00:49that some bacterial toxins can
00:51induce DNA damage.
00:52And therefore are potential carcinogens.
00:54And so today we'll hear about
00:55this very exciting work.
00:57So Jorge, the floor is yours.
00:59Thanks Dan,
01:00thank you very much for the introduction.
01:03And yeah as then.
01:05Imply microbes and cancer are a lot
01:09more intertwined that many would think.
01:13If we start with the obvious that.
01:1820% of cancers are caused
01:21by microbial infections.
01:22The you know of all these examples of
01:26gastric cancer and helicobacter anogenital,
01:29cancer and HPV,
01:30and so on and so forth.
01:33So these are the known causes
01:36of microbial causes of cancer.
01:38That amount to that 20%.
01:41But by all accounts this is probably
01:44rose underestimate in terms of
01:47the influence in the etiology
01:49of cancer of microbes.
01:51But Microsoft,
01:52either toying with cancer in many other ways.
01:56For example,
01:57the study of microbial pathogens really
01:59have provided fundamental knowledge
02:01for the understanding of cancer.
02:04You, of course,
02:05are aware that Uncle genes really
02:08were discovered through the
02:10study of a chicken ritualize.
02:12And today the study of host pathogen
02:15interactions have provided insight into
02:17cancer that are extremely important
02:20for the fundamental knowledge.
02:22Of of these disease.
02:24Of course,
02:25infectious diseases as an entity
02:27are really a significant challenge
02:30in the context of cancer patients.
02:32Many of the drugs that we administer
02:35to treat cancer or course have
02:37immunosuppressive power an and
02:39that increases the susceptibility
02:41of patients to infectious diseases
02:43and imposes it challenge in many.
02:47In many therapeutic set settings.
02:49And of course, the the elephant in the room.
02:53The resident microbiome,
02:54which in the last you know five years or so,
02:58is quickly emerging as a major factor,
03:01both in terms of cancer etiology
03:03and cancer treatment.
03:05So what what I'm trying to tell
03:07you here is something that it
03:09should be obvious and that this is
03:12an extremely important aspect of
03:15cancer biology and quite frankly,
03:18is one of the most exciting times to
03:21be involved in this research space.
03:24So the that's perhaps the reason
03:26why maybe some of us were a bit
03:30disappointed when the cancer
03:31microbiology piece of the Cancer
03:34Center was interrupted.
03:35In fact,
03:36when I was invited to give this talk,
03:39I was invited as a member of
03:42the Cancer Microbiology Group,
03:44which now doesn't exist.
03:46And although I completely understand
03:48why the leadership of the Cancer
03:50Center to please this step,
03:52they had to tend to an impending.
03:55Cancer Center grant that.
04:00That obviously didn't take
04:01many of these things,
04:03and it is clear that you know cancer,
04:06microbiology or microbes really are
04:08not the this the so called cancer
04:11establishment from which reviewers will
04:13be drawn to review the Cancer Center grant.
04:17I'm not really friendly to the
04:19concept of Micros, Ann and cancer.
04:22For for whatever reason,
04:24and even other considerations,
04:25other currencies that are used in
04:28the evaluation of these grants,
04:30such As for example in CI grants.
04:34You know,
04:34people work with my girls that that
04:37don't score high on that because it
04:40will be a fundraising malpractice.
04:42If you can send your grant when
04:45I need to send it to NCI,
04:47which is much less generous and
04:50certainly less friendly to these courses.
04:52So I I although I totally understand these,
04:55I think is is an opportunity
04:57loss for leadership,
04:59particularly with the really the the history
05:01of deal with the tremendous leadership.
05:04People like Dundee Moniot or Charles Miller.
05:09In the space of Uncle Virus, for example,
05:11there is a lot of history here on this space.
05:14But life is life and the cancer
05:16establishment is the cancer establishment.
05:18This is the same establishment
05:20that 10 years ago or 20 years ago,
05:22worse naughty related to cancer immunology.
05:25It with people like blow it all the late,
05:28allowing all that was advocating for it.
05:30And he was really honestly looked down.
05:32I was a close collaborator,
05:34the law and he always complained.
05:36Of course he was shielded by
05:38the Ludwig Cancer Center.
05:40He didn't have to worry about,
05:42but anyway,
05:42I think he said more of a loss opportunity.
05:46But I totally understand why
05:48this this decision was made,
05:50so enough venting enough Priscilla Teising.
05:52Let's get back to business here and in
05:55order to put in context a little bit,
05:58what I will tell you briefly is is
06:01to consider the general mechanisms by
06:03which microbes induce cancer and and
06:06there are two types of mechanisms.
06:09If you will.
06:10The direct Uncle Genesis and that is
06:12obvious when a virus is introduces an
06:15Uncle gene itself. This is of course.
06:18The mechanisms behind HPB or a BB,
06:22for example.
06:23Or when it when they integration
06:26event itself access and origin,
06:28because obviously the viruses integrate
06:31upstream of some gene that can drive
06:34sort of proliferation and growth.
06:36That's that's direct on Go Genesis,
06:39but arguably more common is
06:42the indirect organ Genesis,
06:44and this takes several forms.
06:46For example the form in which
06:49viruses in a cost,
06:51immunosuppression and immunosuppression
06:52activates for example.
06:54Other two more viruses.
06:55In the case of Kaposi sarcoma,
06:58is an HIV HIV infection.
07:00It comes to mind or when viruses
07:02viral infection, for example,
07:04triggers chromosome instability or
07:06translocation that eventually die.
07:07Of course, leads to cancer and other
07:10aspects of the Director Genesis
07:12more related to what I'm being,
07:14I'm going to be telling you today is,
07:18for example, chronic inflammation,
07:19which is very well established to
07:22be linked to to Uncle Genesis.
07:25The production of proinflammatory
07:26cytokines that have growth promoting
07:28abilities combined with oxygen radicals.
07:30They have a mutation or mutagenesis ability
07:33leads to setting the stage for Franco,
07:36Genesis is the case,
07:38for example with Helicobacter
07:39pylori and gastric cancer,
07:41and in addition something that has been
07:44emerging over the last few years and
07:47that we sort of Pioneer in this area
07:50is the fact that certain organisms
07:52really produce direct Gina toxins
07:55that will drive the oncogenic event.
07:58So I say alluded these last two are
08:01the ones more relevant to bacteria,
08:03which is the type of microbes
08:06that we study in the lab.
08:08So bacterial is in this context
08:11bacterial colonization leads to
08:12both inflammation and genotoxin
08:14production and exposures of tissues to
08:16genotoxin and therefore predisposing
08:18those tissues to to cancel.
08:20What I'm gonna be telling you today
08:23is the paradigm of two organisms that
08:26we study in the lab. Both of them.
08:29These organisms are salmonella
08:31and campylobacter jejuni.
08:32Both of them have been very
08:35strongly epidemiological.
08:36He associated with the development
08:38of cancer Campylobacter jejuni
08:40associated with an intestinal lymphoma,
08:42and while Salmonella Typhi,
08:43one of these family that we study in
08:47the lab is really a major cause of
08:49Gallbladder cancer and Gallbladder
08:51cancer in endemic areas is actually one
08:55of the main cancers that affect those.
08:58Individuals and it infections with
09:02Salmonella Typhi and associated
09:04with a 204 risk of hip,
09:07hip,
09:07hepatobiliary carcinoma and
09:09Gallbladder cancer,
09:10so these are important causes of cancer
09:14which incidentally are not in that
09:1720% statistic that I told you about.
09:22Now,
09:22in the case of Campylobacter,
09:24what we discovered that was sort
09:27of central to understand how these
09:29organisms linked to oncogenesis is a
09:31is the characterization of a toxin
09:33that we did almost two decades ago
09:36actually scary more than two decades ago?
09:40That he said toxin that caught our
09:43attention because of what you see here in in.
09:46In these images,
09:47these are cells that are intoxicated.
09:49You see them very much expanded with a
09:52large nuclei in comparison to control
09:54cell at the same excuse me Jorge,
09:56your your slide
09:58is not. It did not advance.
10:00Papa you mean?
10:01I mean what they have you on the 1st slide?
10:06Oh gosh, that's that's not good.
10:09That can you see them this way now?
10:12Yeah, that I can see those OK when
10:14I when I do it that way because OK,
10:18yeah unfortunately because
10:19whatever it would have been easier.
10:21But thank you for letting me know.
10:23OK so anyway, so here it is the.
10:29OK, so this image is showing
10:31you the the cells that have been
10:35intoxicated with this toxin,
10:37showing this unusual morphology.
10:39In comparison we control cell
10:42and the reason these cells have
10:45that morphology is becaused.
10:47The cells are stuck on the G2M phase
10:51of the cell cycle and we found
10:54that the reason for that is that
10:57this toxin that we had discovered.
11:00It has a genotoxicity DNA damage in capacity,
11:03those this is a toxin typical
11:06toxin of we call AB.
11:08Toxins have two two types of parts.
11:11If you will the be part,
11:13which is what targets the payload to a
11:16particular cell and the payload part.
11:19The nucleus is is an endonuclease is
11:22actually an unusual in the nucleus
11:25in the sense that primary amino
11:27acid sequence would not overtly
11:29tell you that this is a new case.
11:32But when you look at the atomic structure,
11:37you can make out the catalytic side.
11:41So so this is a typical case of
11:45genotoxin that is responsible for for
11:49driving driving the day on today.
11:55Cancer development and in fact just recently,
11:58this has been formally demonstrated
12:00in an animal model that that this
12:04toxin is responsible for Campylobacter
12:07jejuni's ability to promote cancer so.
12:11It's kind of awkward to have to advise
12:13it like this, but I will go ahead.
12:16So the second example is Salmonella
12:18Typhi and I need to tell you that
12:21the the basic about something that I
12:24think people things in context again
12:26and that is that someone had typhus
12:28and exclusive pathogen of humans.
12:30It causes typhoid fever.
12:32One of those historical diseases if you will,
12:34but important for Genesis is the fact
12:37that those that survived the disease,
12:39many of them go on to persistently
12:42harbored the Organism.
12:43Within the Gallbladder and that is where
12:46the rubber meets the road and that
12:49is the reason why those individuals
12:51that are harboring salmonella typing
12:53in the in the in the areas are
12:56prone to develop Gallbladder cancer.
12:58And in the case of Salmonella the
13:01paradigm is slightly different than
13:03the paradigm in Campylobacter jejuni.
13:05But it shares it remarkably,
13:07is shares more than what would expect.
13:10You need to think in terms of evolution
13:14that Campylobacter and Salmonella are they.
13:16Couldn't be more far apart.
13:18One is an epsilon bacteria,
13:20the other is a gammaproteobacteria.
13:22It's like absolutely no evolutionary
13:25connection and yet what is remarkable is
13:28that we discover a toxin in Salmonella
13:31typhi that we call typhoid toxin.
13:34That also has the ability to
13:36induce DNA damage,
13:37as shown here in this image,
13:39and when we characterize this toxin,
13:42we were surprised to see that
13:44the active subunit of this toxin
13:46was virtually identical,
13:48that the active subunit of the
13:50completely unrelated toxin Curry
13:52by camping of active June.
13:53So this is really a remarkable
13:56piece of evolution.
13:57This is one of those head turning
13:59toxins that actually evolution put it
14:02together by fusing two toxins, one.
14:04That some of you may be familiar,
14:07it called pertussis toxin,
14:08is what makes you a what is central for
14:11the pathogenesis of whooping cough.
14:13And then these other talks in that
14:15I described earlier.
14:16They cite a little distending toxin,
14:18so this lower part of the talks
14:20in comes from pertussis toxin,
14:22and this upper Paradox income from
14:24side a little extended talks,
14:26so evolution hook them together
14:27to make this head turning toxin
14:29that Salmonella typhi encodes,
14:31and that it is responsible for the
14:33genotoxicity of these organisms.
14:35And easy sent unusual toxin in
14:37many different ways that I don't
14:39have time to go into,
14:40but one of the remarkable ways in
14:43which this toxin is unique is that it
14:45is other patient to the human host.
14:47And what do I mean by that?
14:49Well, the receptor for these talks,
14:51you know the receptors.
14:52I should say we discovered two proteins,
14:55part of policing,
14:56one in epithelial cells and CD 45 in.
14:59In immune cells,
15:00but what is important here is
15:02what does the toxin see on this
15:05block of proteins and
15:06is the glycan power and we through like
15:09Andres and other types of studies for
15:11to address these kinds of questions
15:13we discovered that what what Typhoid
15:16toxin likes if you will is glycans
15:18terminated in the sitting room.
15:20We know that many Kacian hooked to
15:22galactose and and to glucose or setting
15:25glucosamine in this particular fashion.
15:27And why is this relevant?
15:29Well, this is important because you
15:31may not know these or many of you
15:34May is that we humans are actually
15:37rather unusual mammals in many ways,
15:40and one of the ways in which terribly
15:42unusual is in our glycosylation pattern.
15:45All our sciullo glycans are
15:47terminated in a city neuraminic acid,
15:50but all other mammals in fact,
15:52like answer, terminated in Blakely,
15:54neuraminic acid,
15:55and the reason is that the
15:57enzyme that is responsible for.
16:00Can you see this slide and?
16:02Maybe.
16:02Well, whatever I continuously the inside
16:05that is responsible for putting these acts.
16:07Oxygen here is mutated in humans.
16:09We have a pseudogene there and therefore
16:11we are unique in that fashion and typhoid
16:15toxin combined likens exclusively
16:16terminated in a city in America.
16:18And in fact,
16:19if you just change one oxidant in
16:22any of these glycans that Typhoid
16:24toxin likes and you already meaning
16:26in in an array make like an array,
16:29typhoid toxin does not bind.
16:31It also has the ability to distinguish.
16:33Just one Atom of oxygen.
16:36Remarkable piece of evolution that
16:38makes it able to target human cells
16:41and have that oncogenic effect.
16:43But in addition to having a
16:46genotoxin somewhere,
16:47typhi is actually has the 241.
16:49In other words,
16:51is also the chronic inflammation
16:53part that plays a role in the
16:56Uncle Genesis of Salmonella Typhi.
16:59And so it's something that I think
17:02causes chronic inflammation of the
17:04Gallbladder and that chronic inflammation,
17:07as is well known,
17:08leads to the development of cancer
17:11or contributes to development of
17:14cancer and the paradigm here is
17:17is well known where as I said,
17:19the production of growth.
17:21Promoting cytokines combined with
17:23or radical oxygens that Armenta
17:25Genic eventually leads to the
17:27development of cancer angiogenesis.
17:30Growth stimulation and so on and so forth.
17:33So the issue is how does salmonella
17:36trigger inflammation now on this on?
17:39On the surface,
17:40this could be a rather simple story
17:43and you may know that we are in now
17:46with innate immune receptors famously
17:49put into the scientific space by the
17:52late Charlie Janeway here at Yale and
17:55this innate immune receptors have the
17:58capacity to recognize bacterial products.
18:00Uh,
18:01like polysaccharide peptidoglycan flagella.
18:03You name it,
18:04many bacterial products can be detected
18:07by this innate immune receptors.
18:10Them essentially coordinate an
18:12inflammatory response and that
18:15inflammatory response eventually
18:16leads to pathogen rejection and
18:19they acquired immune response.
18:21So this is central to the way we hosts,
18:25not just humans.
18:27But all mammals defend against microbial.
18:30Pathogens now it turns out that then
18:32from these framework it will be very
18:35simple to think that someone other
18:36triggers inflammation simply
18:38because he has plenty of LPS.
18:40He has plenty of these product
18:42and is the detection of the
18:44host that drives inflammation.
18:45In other words,
18:46this will be like a host centric view,
18:49but work that we have done in our
18:51lab for the last 15 years or so has
18:54completely turn around this paradigm
18:55and discovered that that's actually
18:57incorrect in the case of Salmonella,
19:00that salmonella really has
19:01a specific adaptations.
19:02Evolve by similar to trigger inflammation.
19:05So this is a pathogen driven process,
19:08not a host driven process,
19:10and the reason is very simple
19:12or not so simple.
19:14Salmonella, like many other microbes,
19:16when they encounter a mucosal site,
19:19being an intestinal being
19:20the Gallbladder mucosa,
19:21they need to compete with resident
19:24microbiota who has a foothold on that
19:27issue and really put up a good fight.
19:30This is actually over.
19:32One of our main barriers
19:34against bacterial pathogens,
19:36particularly in this time,
19:37is the resident microbiota.
19:39The inflammatory response crosses
19:41it causes profound dysbiosis,
19:42which is essential for someone else
19:44to be able to colonize and replicate.
19:48Not only that,
19:49inflammation makes nutrients available,
19:50electron acceptors camper sourcers
19:52that otherwise would not be
19:54available in the an inflamed tissue,
19:57and that drives the replication
19:59of the aluminum.
20:00Population of salmon are so,
20:02so is the inflammatory response that
20:04causes even though someone else
20:06and intracellular pathogen the bulk
20:09of the bacterial replication comes
20:11from this lumenal population that is
20:13fed from the inflammatory response
20:15triggered by this in this bacteria.
20:17Here. So a nice division of Labor.
20:20Now how does someone even managed
20:22to trigger an inflammatory response?
20:24Mucosal sites which are actually
20:26is pretty difficult because mucosal
20:28sites are subject to various stringent
20:30negative regulation of his native.
20:32Respected receptors precisely to
20:34prevent this microbiota that in
20:37theory can also stimulate in Amy
20:39receptors to trigger an inflammatory
20:41response and for all of us to be
20:44working with IBD or Crohn's disease.
20:46To avoid that they're very precise
20:48mechanisms to keep those innate
20:50immune receptors in check,
20:52and somebody had to trigger inflammation
20:55in that environment has does he do it?
20:58Well,
20:58it does sit through this amazing
21:00machine that Dan alluded earlier that
21:03we discovered more than two decades ago.
21:06It's an amazing sort of bacterial
21:09injection device if you will.
21:12That injects bacterially encoded
21:15proteins that.
21:17Have the capacity to modulate many
21:20signal transduction pathways.
21:22And it's the ability to stimulate
21:25those signal transduction pathways
21:26and modulate cellular process for
21:28the benefit of the pathogen
21:30specifically relevant to inflammation
21:32are three of these effective proteins
21:35that activate Rho Family GT P aces
21:37by either being exchange factors of
21:40the Pro Family GPs is or forcefully
21:43nocetti phosphatase.
21:44In the case of this particular
21:46effector that wouldn't activate
21:48endogenous change factors and activate that,
21:51and that leads to the activation of CDC.
21:5442 and then the activation of CDC 42
21:56leads to transcriptional responses
21:58that really are proinflammatory
22:00and really looked like
22:02in 18 responses.
22:03This was a bit puzzling for a
22:05number of years because CDC 42 had
22:08never been linked to innate immune
22:10responses until very recently,
22:12where we sort of cracked this little
22:15puzzle and we discovered that the
22:17activation of CDC 42 by Salmonella leads
22:20to the formation of a noncanonical
22:22signaling complex made by pack one.
22:25A target of CDC 42 and
22:27these other components.
22:28Trap 6 Tab Tak,
22:29One Tab 1 Tab 2 that leads to the
22:32inflammatory response and what is
22:34what explains the whole thing is
22:37that these signaling complexes
22:39identical to the signaling complex
22:41that is tripped by narimi receptors.
22:43So what someone in essence is doing
22:45is going down the signaling pathway
22:47so that so as to avoid the negative
22:50regulatory system and trigger
22:52essentially an innate immune response.
22:55But by non Canonical methods,
22:57so he uses other type of mechanism
22:59similar to this going downstream
23:01of Canonical signaling pathways.
23:04But since my time is up I just gonna
23:07put up a sort of a summary of these
23:10and sort of to give you a flavor or
23:14how these effector proteins can go down.
23:17Different signaling pathways
23:18intersect with signaling pathway.
23:20For example this effector can
23:22activate the rig I and MD I5.
23:25A nucleotide sensing pathway,
23:27but without the need of nuclear dice.
23:29It just simply activates regay by
23:32interfacing with dream 56 and trim 65.
23:35Two regulators of this pathway you.
23:37We could make them activates them and
23:40trips this signaling pathway without the
23:43need of The Agonist of those receptors,
23:46and the same applies to another
23:48effector here that it actually
23:50inhibits an anti-inflammatory pathway.
23:52So, but since I don't have time.
23:55I had to skip it,
23:57so I hope that you got a sense of
23:59the sophistication by which bacterial
24:01pathogens manipulate cells in in ways
24:04that benefit them but doesn't benefit us.
24:07And through the production of
24:08Gina toxins or inflammation,
24:10it leads to the predisposition to cancer
24:12and then finally last but not least,
24:15people that were involved in this work
24:17obviously and talked to work that was
24:20done a number of years ago as well,
24:22but for the inflammation pathway, who we?
24:25Indiana were involved and one
24:27whose did all this work and Mary,
24:31of course,
24:32had made the pioneering discoveries
24:34of the Genotoxin in Campillo Bacter
24:37Jejuni and set in motion all this work.
24:40And thank you very much.
24:42And with that I'm gonna stop
24:45sharing if I can.
24:47And.
24:51OK, well thank you very much.
24:52Jorge is very interesting.
24:53Very exciting work.
24:54I don't know how to swim.
24:56I should know how to stop sharing
24:58but you help me on that one.
25:00Yeah, OK.
25:02If people have questions,
25:03you can type them into the chat,
25:06or Renee's, or way
25:07to unmute them.
25:12We can, if you'd like, sure.
25:15I'm ask a quick question.
25:17I was very struck by that by
25:19what appears to be the convergent
25:21evolution of these two nucleases.
25:23Yeah, it's really very striking.
25:25Is there? What is the advantage of the
25:27bacteria to induce cell cycle arrest?
25:31What cell cycle arrest actually
25:32is also growing flammatory?
25:34So probably one of the main drivers
25:36is the Pro inflammatory response and
25:38also in the case of some type is using
25:41this activity to target immune cells.
25:43So obviously if you're a virus and
25:45you know you you know a thing or two
25:48about them and you integrate your
25:50genome in in the host, you're free.
25:53You know you.
25:54That's the way you can persist
25:56as long as you want.
25:58If you're somebody that I feel you have.
26:004761 those are the number
26:02of open reading frames,
26:04potential antigens you need to hide.
26:06You can't do that right?
26:08So the way somebody that he does it
26:11is by creating a sort of immunological
26:14suppression around the site,
26:16wherein colonizes and these
26:17toxin is central for that.
26:19For the persistent infection,
26:21by targeting immune cells.
26:22So so, and in the case of Campylobacter,
26:25of course,
26:26inflammation is central for the bug and and
26:29this proinflammatory aspect of DNA damage.
26:32Is probably what evolutionary
26:33selected for these,
26:34you know,
26:35toxins and the in the process.
26:37We you know we got clipped.
26:40Thank you are there
26:42are there other questions for Jorge?
26:51Alright, well thank you very much.
27:00I think I think Dan froze.
27:03You were frozen Dan.
27:05Oh, I'm sorry, frozen.
27:09I guess introduce you,
27:11Melinda Kay. Great don't we love
27:14the advances in technology.
27:16Thank you Doctor Glenn that was fabulous Ann.
27:20I am now delighted to introduce
27:22Doctor Nicole Diesel to present
27:24her research on environmental
27:26carcinogens and thyroid cancer.
27:28Doctor Diesel is an associate
27:31professor of environmental health in
27:34the Yale School Public Health and
27:36she received her pH D in her Masters
27:39in industrial hygiene from the Johns
27:42Hopkins School of Public Health.
27:44Her environmental exposure assessment
27:46strategies aimed to reduce exposure
27:48misclassification for epidemiological.
27:49Studies and in advance understanding
27:51of the relationship between exposure
27:54to environmental environmental
27:55chemicals in the risk of cancer
27:57in other adverse health outcomes,
28:00she serves as the Pi of a study funded
28:02by the American Cancer Society and
28:06investigating exposure to flame retardants,
28:08pesticides,
28:09and other persistent pollutants in
28:11thyroid cancer risk and of note,
28:13she is the winner of the Yale Cancer
28:17Center 2020 Research Prize in population.
28:20Science for her research on this topic,
28:22so we're delighted for your presentation.
28:24Doctor diesel.
28:25Take it away.
28:28OK, thank you so much Melinda
28:30for the generous introduction.
28:32Very pleased to be here to share
28:35some of my recent work with you.
28:38I really enjoyed Doctor Galanes presentation
28:40looking at exposure to microbial
28:42pathogens and the associated toxins,
28:45and I'll be switching gears a little
28:48bit to look at work looking at the
28:52Epidemiology of exposures to chemical
28:54toxins and thyroid cancer risk.
28:57OK, so I've advanced my slide and someone
29:00can let me know if there's any issue there.
29:04I first wanted to take a moment just
29:07to tell you about the motivation of
29:10my research and the research I'll
29:13be presenting today and talk about
29:16environmental risk factors for cancer.
29:18We know that third of cancers are
29:21attributable to modifiable factors.
29:23We often think of things related to diet,
29:26alcohol, tobacco,
29:27these so-called lifestyle factors.
29:29But this also includes infections which
29:32we just heard about as well as pollution.
29:36So how much of cancer cases can
29:39we attribute to this pollution?
29:42While a doll and Peto in their landmark
29:46study estimated about 7% of cancer deaths
29:50could be attributable to occupation,
29:52pollution and industrial products,
29:54in many experts agree that this
29:57percentage is likely grossly.
30:00Under arrest Maded due to the extremely
30:03limited data on the commercial chemicals
30:05that we encounter in our day-to-day lives.
30:09So in the United States there
30:12are 80,000 chemicals that are
30:14licensed for commercial use,
30:16and of those only 200.
30:19So not even a percentage of them have been
30:22screened adequately for carcinogenicity.
30:25And every time I share this statistic,
30:28I find it really striking.
30:32Another reason why this is so important
30:35is that you know many of these exposures
30:39are outside individual control.
30:41These are things in air pollution
30:43or water supply,
30:45the food supply,
30:46our workplaces,
30:47so we really rely on the government
30:49to protect us from exposure to these
30:52potentially harmful chemicals and
30:54our regulatory system really is quite
30:57inadequate to serve this purpose.
31:00The way it's structured.
31:02Chemicals have to be proven harmful
31:05rather than proven safe at the outset,
31:08so it normally requires researchers
31:11like myself and others in my fields who
31:15study chemicals you know for decades
31:17before we acquire enough evidence to
31:21demonstrate harm for particular chemical.
31:24And also importantly,
31:25we know these exposures are not
31:28distributed equitably across
31:30populations and that populations.
31:32Experiencing other social disadvantages
31:34are often disproportionately
31:36exposed to certain pollutants,
31:38and some of these points are
31:41highlighted in a forthcoming book
31:44chapter that I worked on with Doctor
31:48Orwin edited by Charlie Fuchs.
31:51So turning to the specific research
31:54I want to talk about today,
31:56which is related to thyroid cancer,
31:59thyroid cancer is the one of the
32:02fastest growing malignancy's.
32:03It has nearly tripled over the
32:06past few decades.
32:07As you can see in these graphs
32:10of SEER cancer incidence data.
32:13You can also know by looking at the
32:17Y axis that females have three times
32:21the incidence compared to males.
32:25Can thyroid cancer, you know,
32:28has a very good prognosis.
32:31It's more than 90% survival after 20 years.
32:35However, survivors face many. Physical,
32:39psychological and financial challenges.
32:42With the prolonged treatments,
32:45increased surveillance risk of second primary
32:50cancer and other quality of life issues.
32:56So this increase is likely certainly
32:59due at least in part to improvements
33:04and changes to diagnostic techniques,
33:07imaging techniques and
33:09an fine needle biopsy's.
33:12So there's some debate about what
33:15proportion can be attributed to
33:18this increased diagnostic scrutiny,
33:21but many analysis suggests that
33:24about half of this.
33:27Trend can be linked to
33:31these diagnostic changes,
33:34leaving half for environmental
33:37or lifestyle factors.
33:45I'm so we've hypothesized that increasing
33:48exposure to thyroid hormone disrupting
33:50environmental chemicals such as these
33:53polybrominated diphenyl ether flame
33:56retardants or PVD ES may be partially
33:59driving this increasing trend.
34:00So I'll just talk a little
34:03bit more about these people.
34:06These are actually a lot of thyroid
34:10hormone disrupting environmental
34:12chemicals in use an in the environment.
34:15These flame retardants were widely added.
34:18Too many different products.
34:20The polyurethane foam in mattress is
34:24an couch, cushions and vehicle seats,
34:26including baby car seats.
34:28They were also added to electronics
34:31like phones, cell phones, televisions,
34:34computers and the reason they were
34:37added was to meet a flammability
34:40standards such that if these products
34:43you know caught fire they would burn.
34:46More slowly,
34:47which is a good thing from a
34:50public health perspective.
34:52However,
34:53these chemicals once added to these products,
34:56did not stay bound in the matrices as
35:00indicated by their manufacturers and
35:03instead have migrated out into our homes.
35:08At home environments, cars,
35:10workplaces, etc.
35:11So due to this widespread use
35:13as well as disposal and improper
35:16disposal of these chemicals,
35:18they aren't ubiquitous and more than
35:2190% of the population here in the US and
35:26globally are exposed to these chemicals.
35:30And this also they are extremely persistent
35:34once they get into their homes or our bodies,
35:39they do not degrade very easily,
35:43so they stick around for years and decades.
35:47So due to concerns about this
35:50persistence and potential toxicities,
35:53these particular group of chemicals,
35:55the PDE's were phase outs
35:59were initiated over the last.
36:02Past decade, however,
36:03exposures do continue for
36:05the reasons I described.
36:07Their persistence,
36:08you know,
36:09their presence in products made before then.
36:14As well as their presence in
36:16the food supply and elsewhere.
36:19One other group of chemicals that
36:21will be talking about today are the
36:24polychlorinated biphenyls or PCB's.
36:26These were also used widely
36:28in electrical equipment,
36:30hydraulic machinery construction materials.
36:31These were banned in 1979,
36:33so again, you might say why?
36:36Why are we even studying these now?
36:39Well,
36:39there's still around and they're
36:41still around in our our bodies.
36:44Our bloodstreams in the environment,
36:46and in fact here in Connecticut
36:49there's been some renewed concern
36:51about these legacy chemicals.
36:53They were commonly used in buildings,
36:56including schools constructed
36:57in the 1950s to 1970s,
37:00and many of these schools now are
37:02in need of repairs and renovations,
37:06and there have been some notable
37:08schools in Connecticut that I've had
37:11PCB levels exceeding safe levels.
37:13Closures of schools you know,
37:16insufficient funds to do a proper
37:18and safe remodeling or renovations,
37:21and again, often these are in.
37:24Kind of environmental justice communities.
37:28So another reason to study these legacy
37:31chemicals is as they get phased out,
37:34new chemicals come to take their place,
37:38and many of those are also also have
37:41similar properties and so understanding.
37:44These may help us inform greener
37:47chemistry or future regulations
37:49of other other chemicals.
37:54So we hypothesize that these PV
37:57East could be contributing to that
37:59increasing trend in thyroid cancer.
38:01Here is a graph showing increasing exposure
38:05over a similar time period where we saw
38:08thyroid cancer cases start to go up.
38:11So these are measurements taken from blood
38:14samples from a blood bank. In the US.
38:17You can see about a doubling every five
38:20years of these particular chemicals.
38:25So looking at more recent data,
38:28I, as I mentioned,
38:29these have been somewhat phased out.
38:32You can see that well levels
38:35have come down since those
38:37some of those earlier years,
38:40but then they really have somewhat plateaued.
38:43Or are, you know some some
38:46particular congeners of these?
38:47In this family of chemicals are still
38:51increasing slightly an we see similar.
38:54Trends with the PCB's that levels
38:56have come down since they were banned,
38:59but then they reached this plateau
39:01in the population because of their
39:04persistence and then as new chemicals
39:06come on we may be introduced to
39:08those on top of these exposures.
39:12Hey and so why?
39:14Why do we think these may
39:16be linked to thyroid cancer?
39:19These chemicals are established
39:21thyroid hormone disruptors.
39:22Their endocrine disruptors and
39:24over here I have an image of our
39:27thyroid hormone thyroxine and then
39:30the PCB's and the PVD ES and their
39:33general chemical structure so you
39:35can see immediately how structurally
39:37similar these chemicals are.
39:39Shut thyrax, and we've got the two.
39:42Aromatic rings and then
39:44while thyroxine has iodine,
39:46these chemicals have other halogens.
39:49They have either chlorine or bromine's.
39:52Just to further illustrate when for
39:54example this particular PDE gets metabolised,
39:57it gets this hydroxyl group added.
40:01And now even more closely resembles
40:04Thyrax in so the in vitro studies
40:08have shown that these chemicals can
40:12competitively binds with thyroid
40:15transport proteins and results in
40:18reduced circulation of thyroid hormones,
40:21which could then result in dysregulation
40:25of the transport and signaling pathways,
40:29potentially leading to.
40:31Overproduction,
40:32of of hormones to compensate
40:35proliferation in the thyroid
40:37and potentially neoplasia.
40:42So as you know the the hypothalamus,
40:45pituitary, thyroid axis is this
40:48very well choreographed system.
40:50So these perturbations or
40:52dysregulation of these systems
40:54can perhaps trigger some of these.
40:56Some proliferation of the thyroid and
40:59potentially lead to thyroid cancer.
41:02I'm just I'm showing this slide
41:04to also illustrate that some
41:06chemicals have some additional
41:09hypothesized mechanisms, such as.
41:11Some have been shown to be
41:14capable to directly bind to DNA,
41:18leading to mutations and could potentially
41:21lead to carcinogenesis that way.
41:26So before we launched our study,
41:29there had only been two other
41:32studies examining this hypothesis.
41:33This idea that these PPDS could
41:36be linked to thyroid cancer.
41:38So the first two rows of this table or
41:42the two prior epidemiologic studies in
41:45the third row was the study that I lead.
41:50A couple things to point out here is
41:53that the case is the studies that came
41:57before us had moderate study populations,
42:00and ours was larger.
42:02We also looked at more
42:04chemicals and importantly,
42:06we looked at single and
42:08multi pollutant models so.
42:12So what I mean by that is that in
42:15the real world you know we're not
42:18exposed to one chemical at a time,
42:20where typically exposed to groups of
42:22chemicals or mixtures of chemicals
42:24and traditional environmental.
42:25Epidemiologic studies have looked
42:27at chemicals just one at a time,
42:29and in my work we're looking at
42:32these so-called mixtures using
42:33different modeling techniques
42:34to look at the joint effect of
42:37exposures to multiple chemicals.
42:42Similarly for the PCB's,
42:44the other chemicals there were also only
42:46two previous studies before we did ours.
42:49Also the other studies were a bit smaller
42:52and we also looked at mixture modeling.
42:55One other one shortcoming,
42:57I wanted to point out actually in reference
43:01to at least one of the other studies is
43:04that our study was a case control study.
43:07So we did collect serum samples to do our.
43:11Environmental chemical
43:12measurements after diagnosis.
43:14Whereas one other study
43:16collected pre diagnosis samples,
43:18we think you know.
43:20So we're using this post diagnosis sample
43:23to try to capture exposures in the past.
43:27While it's not optimal,
43:29we think this is actually a pretty
43:32strong and reasonable assumption,
43:34because we know that these chemicals
43:38have half lives of years and decades.
43:42Ends may may well reflect past
43:45past you some past exposure.
43:51OK, so just a few more details
43:53about the study we conducted.
43:55I LED a study within a study and
43:58that larger study was the Connecticut
44:01thyroid cancer case control study,
44:03which was led by Yahweh Chung,
44:06who was our former colleague
44:08here at the Yale Cancer Center.
44:10We focused on women because they
44:12have that three times higher risk.
44:15I showed earlier about 90% of
44:17our cases were white, so we.
44:20Focused on the white population
44:22because our numbers were really small
44:26for looking at other demographics.
44:28I do think now this is something
44:32I would like to follow up on
44:36more in another population,
44:38we focused on papillary thyroid cancers.
44:41That's about 85% of the
44:44new cases or papillary.
44:46We also collected very detailed
44:49information about demographics,
44:50lifestyle, diet.
44:51Many other risk factors that we
44:54can control for other factors.
44:57We collected the blood sample at
44:59the time of the interview and then
45:02measured the participants blood samples
45:05for 11 different peyizan 32 PCBS,
45:08which this analysis also gave us.
45:11Some pesticides like DDT,
45:13which are also structurally similar to these.
45:16These classes of chemicals.
45:19And again we looked at both pollutants,
45:22one at a time, like like most studies
45:26do and then multi pollutant models.
45:29OK, so here's some results from
45:32our study population.
45:33These are factors that differed
45:35between cases and controls,
45:37so our cases had a lower educational
45:40attainment compared to controls.
45:42They did have a history
45:44of benign thyroid disease.
45:46That's a strong risk
45:48factor for thyroid cancer.
45:50Alcohol consumption was actually.
45:55Higher, lower,
45:56lower in cases.
45:57This is one of the few cancers where
46:00alcohol actually has been consistently
46:03shown to have a protective effect.
46:06An cases also had a history of
46:09thyroid cancer and higher BMI,
46:12which has been shown now in several
46:15studies indicating another possible
46:17risk risk factor that can also
46:19be interrelated to like endocrine
46:22disrupting chemicals and also.
46:26OK, so here are some results from
46:29our single pollutant models where we
46:32looked at one chemical at a time.
46:35So these are increasing categories
46:37of exposure within each of
46:39these different pollutants.
46:41You know, odds Ratio 1 means no effects,
46:45and anything above one would indicate
46:48an Association with thyroid cancer.
46:51So you can see here that there's
46:54really not much going on with
46:56these individual models.
46:58If anything, the odds of thyroid
47:00cancer seem to be lower than those
47:03who are exposed compared to the
47:06reference group of low exposure.
47:08So the medium and high groups are
47:11not at an elevated odds of thyroid
47:14cancer except for this one chemical.
47:17This PB 153.
47:22So when we move to our
47:25multi pollutant models,
47:26the results are also somewhat null.
47:29We have two multi pollutant models
47:32here using Bayesian modeling,
47:33which I won't get into here.
47:36But here you can see that it's the
47:40picture is still pretty null except for.
47:43In this case we have this other,
47:46a different chemical PDE 100.
47:49Was associated with elevated odds of
47:52thyroid cancer using both those models.
47:58And then finally we did this one more
48:01mixture type approach of principle,
48:03components analysis and in this work
48:07we found that people who had had this.
48:11Combination of exposures which was higher.
48:15PBDE 153. An lower PDE 209 had an
48:19elevated odds of thyroid cancer.
48:26So then moving on to the PCB use in this
48:30for this one because we had so many,
48:33we had 32 different chemicals.
48:35I'm just going to present some some
48:38groups of structurally similar PCB's,
48:40which was another approach we used
48:42to look at groups of chemicals.
48:44So in this in this model this kind of
48:48we're just looking at one group at a time.
48:52Odds ratios are hovering around 1:00,
48:55so again pretty null findings. Not.
48:58We're not seeing a link between
49:01exposure and thyroid cancer.
49:04However, it said the most intriguing part of
49:08this study was when we took a closer look at.
49:12The the groups of people,
49:14people who are exposed.
49:17During who were younger
49:20during peak production,
49:21who were born during peak
49:24production of PCB's.
49:26So presumably would have their
49:28highest exposure in very early life.
49:32They consistently had higher
49:34odds of thyroid cancer,
49:36including this group of PCB's that
49:39were particularly structurally
49:41similar to thyroid hormones,
49:43so this was quite intriguing to me,
49:47suggesting maybe the timing.
49:49Of exposure could be important.
49:54OK. So just to summarize,
49:58some of the key takeaways from both.
50:00Of these studies.
50:03Strengths were that we looked at this
50:06larger population and incorporated
50:07these different models to account for
50:10Co exposure to multiple pollutants.
50:12The results were generally null.
50:14You know, we did see a few chemicals
50:17here and their associated with
50:19elevated odds of thyroid cancer.
50:22Particularly,
50:22this was more consistent when we
50:24looked at the group of women who were
50:28born during peak production of PCBS.
50:30However, this we only have 3 studies now.
50:33For these,
50:34each of these groups of chemicals so.
50:37There's really insufficient
50:38evidence to rule them out,
50:40and I think there can be some
50:42improvements to the study design to
50:45try to look at this more carefully.
50:47I think looking at early
50:49life would be important,
50:50and using a prospective design where
50:53we could have samples collected
50:54pre diagnosis could help you know.
50:57Really,
50:57try to nail nail down if
51:00anything is going on here.
51:02And then finally I just want to talk
51:05about how where I'm taking this work.
51:09I have now expanded this work in
51:11adults to looking at children.
51:14So with my collaborator Xiaomei MA,
51:16also very active in the Cancer Center.
51:19We are looking at environmental
51:21exposures and pediatric thyroid cancer,
51:23so here's some incidents.
51:25Data on pediatric thyroid cancer.
51:27It has also been increasing over time.
51:30An children are less likely.
51:32To be.
51:35Targeted for increased screening
51:37and diagnosis and imaging,
51:39so these trends are are concerning,
51:41so we have some projects underway to
51:44try to look at environmental exposures
51:47in this more vulnerable population.
51:49And with that I would like to
51:52acknowledge all my wonderful
51:53collaborators and my funding from
51:56American Cancer Society as well as
51:59the Yale Cancer Center for getting
52:01me started in this line of research.
52:04Thank you.
52:07Thank you Doctor Diesel,
52:08that was fantastic.
52:09A little alarming.
52:10I would say when we start to
52:13think about how many you know,
52:15carcinogens exist in our environment
52:17in the fact that I'm intrigued by
52:19the policy statement that we have to
52:21show harm before anything can be done
52:24and have these substances banned.
52:25Do you think there's any potential
52:28to being able to reverse
52:29that or change that policy?
52:31Or will it take years and more data to do so?
52:35Yeah, so a lot of the chemicals were kind
52:38of grandfathered in when we established the
52:41Environmental Protection Agency in 1970.
52:44There is a new act that is supposed
52:47to reverse this burden of proof,
52:49but I don't think it's going to be
52:52retroactive, so I am encouraged to with
52:55the current administration that we may
52:58start to move towards a different model.
53:00Also, in Europe they have stronger
53:03precautionary policies where if there's
53:05a safer alternative you have to use it.
53:08And you know not to wait until we
53:11prove something with certainty to
53:14take some sort of action.
53:16Great, right? So there's a couple of chat
53:19questions I'll just quickly read them.
53:22Heard a Chow asked about any data on
53:26Agent Orange and thyroid cancer.
53:28Yeah, so Dioxin's is one of the
53:31constituents of Agent Orange.
53:33Well, Agent Orange.
53:34Had you know these defoliant chemicals?
53:37So various herbicides?
53:38And then? Dioxin's
53:42that's a great question,
53:44'cause they're also very structurally
53:46similar to the other chemicals
53:47I presented, but I'd have to,
53:49and some of the chemicals we looked at.
53:52Some of the groups were dioxin, like.
53:56I'm not, I'm not sure of any
53:59specific studies coming to mind,
54:00but it it seems likely that
54:02it may follow a similar.
54:04Well, they're structurally similar
54:06to the other other chemicals. OK,
54:09great and then Jeffrey Townsend
54:11has a question where you do see
54:14elevated odds of thyroid cancer?
54:16Do you have any evidence discriminating
54:19between the two hypotheses of
54:21effects that occur due to hormone
54:24disruption compared to effects
54:25that might be arising due to
54:28induction of carcinogenic mutation?
54:29Do you see ways
54:31to do this? Yeah,
54:33that's a great question.
54:35I don't really do this
54:37type of mechanistic work.
54:39I know the the thyroid hormone
54:41disruption hypothesis.
54:42There's been a lot more
54:44mechanistic work in that area,
54:46but I'd be open to suggestions for
54:48how this could hopefully maybe
54:50inform some some mechanistic studies.
54:53I think it would be,
54:55you know, I really think that.
54:57The study could inform mechanistic
55:00work and vice versa.
55:01Yeah,
55:02that's a great great point.
55:04And then Ashida had mentioned in regards
55:06to the policy of showing harm that
55:09Europe does the reverse of the US.
55:12Do they see as a different trend?
55:18Actually, thyroid cancer cases
55:19are going up globally and the
55:21trends in exposure are consistent.
55:23Actually, they were first observed
55:26in Sweden where they have breast
55:28milk banks an they saw these flame
55:31retardants going up in human milk
55:33samples which caused a lot of alarm.
55:36At that time we didn't know if
55:38they were carcinogenic or not,
55:40but given that you know babies were
55:43going to be exposed to these chemicals,
55:46that sort of.
55:47Triggered this whole area of
55:49research on these flame retardants
55:51and other chemicals.
55:53Great
55:53and then I just have one final question.
55:56The email that we all received last
55:58week about benzene being in some
56:00of the hand sanitizers for for our
56:02COVID-19 protection? Do you have any
56:05thoughts or comments on that? Yeah,
56:07I read that I read some of the materials.
56:11I think benzene you know is
56:13a known human carcinogen.
56:14However, it is present in many sources,
56:17so I would really want to to
56:19understand how risky this is.
56:21I think we need to know how much.
56:24Benzene and how does that compare to?
56:26Like putting gasoline in your car,
56:28you know or being walking near the roadway
56:31so I didn't raise too many alarms yet,
56:33but I would need.
56:35I feel like I need more data to
56:37be able to reach that conclusion.
56:39And I mean, the so yell health,
56:42environmental, safety and health
56:43said like let's be precautionary.
56:44Let's just get rid of these sanitizers,
56:47you know, let's let's take an action
56:49before we have all the answers,
56:51so I think that's, uh,
56:52you know, very sensible.
56:54Approach OK great.
56:55Well
56:56thank you so much Dan.
56:57Do you have any other closing
57:00comments? I'll just thank both
57:01our speakers today. Two terrific talks.
57:03I learned alot. Thank you. Yes thank
57:06you. Have a great day. Thanks.