Most everyone in this room has been affected in one way or another by it, but what is it?

Transcription

1 Most everyone in this room has been affected in one way or another by it, but what is it? All information is up to date and referenced to Sam Rhine s Genetic Update Conference, University of Nebraska & SIUC cancer research conferences

2 Oncogenes Oncogenes are the genes that cause cancer. Onco = Cancer Oncology = the study of cancer and its cures There are 164 individual cancer causing genes and 544 total suppressing genes that cause cancer Total 708 possible genetic causes of cancer

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4 Is cancer hereditary? Cancer itself is NOT hereditary, if it was we would see it every generation. The tendency for cancer is hereditary. This means that you can have genes that increase your cells chances for mistakes This increase chance is what makes cancer seem hereditary However, it CAN NOT be hereditary, because it occurs in somatic cells You can inherit the predisposition for cancer. You can inherit the tendency to get cancer, but only in rare occasions is the disease inherited (TSG breast cancer).

5 Cancer in the USA Females: Breast-31% Lung -12% Colon-11% Uterine-6% DEATHS Lung-26% Breast 15% Colon-10% Pancreas -6% Ovary-6% Males: Prostate- 33% Lung- 13% Colon- 10% Deaths Lung -31% Colon -10% Prostate- 9% Pancreas- 6%

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7 Tumor Paint (Derived from Scorpion Venom)

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9 If not cigarettes Pot?? Smoking a joint is equivalent to 20 cigarettes in terms of lung cancer risk, scientists in New Zealand have found, as they warned of an "epidemic" of lung cancers linked to cannabis. CARCINOGENS- there are 55 different carcinogens found in a single cigarette

10 All cancer is genetic! All cancer is genetic (meaning it has to do with genes). It is all an abnormal phenotype (Not having cancer is normal) But, most cancer is not inherited!! Inherited means it is passed from parent to child through their germ line. (Heredity) All the non germ line cells are Somatic cells

11 All in the family Sporadic cancer is cancer that just appears within a family % of cancer is sporadic Most cancer comes from perfectly normal genes given to you by your parents Most cancer occurs when a somatic cell mutates somewhere in the body. This is called transformation This will NOT be passed on, it is in your SOMATIC cells!

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13 Point mutations Those 40,000 transcripting (protein producing) genes make up about 1.5% of the total DNA in your cells. Those genes are all made of bases (A,T,G,C) which act like the letters in the book of life We have about 2,851,330,913 bases in our DNA One single change in any of those 2,851,330,913 are a point mutation

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15 Genes don t cause cancer! Genes do NOT cause cancer. Genes do not do anything but sit in the nucleus doing nothing. Genes direct the creation of protein. (Transcription and translation) Proteins do all the work. Essentially, proteins cause cancer

16 Those darn amino acids Proteins (created from the genes found in your DNA) have multiple functions within a cell Generally enzymes act as the motor proteins that turn things off and on Indicator proteins are released into the blood stream to notify receiver proteins of important changes in the body Essentially, every system in your body is reliant on proteins

17 This Protein may be released into the blood at the end of S1 phase These 2 new proteins may be required to start M phase

18 What about the other 98.5% of our DNA If 1.5% of our DNA makes ALL of the proteins in our bodies, what does the other 98.5% do? The other 98.5% is called junk DNA because it is non-coding. IT IS NOT GARBAGE! GARBAGE YOU THROW OUT! Junk you store away in the attic somewhere. This junk called Mysterious dark matter

19 Lysogenic Virus

20 The new genome project Jan 22, 2008 we started a new genome project in which we will look for their SNPS (Single Nucleotide Polymorphisms) SNPS are located in your non-transcripts We will sequence 1,000 individual peoples genomes. This will help us understand predispositions better (for cancer, heart disease, asthma, and other common ailments). Expected to take 2 years. (Is it done yet?**) We expected thousands we currently have found 1,419,190

21 What s it worth to you? Sequencing your own human genome would sequence YOUR OWN SNPS. Knowing your SNPS is knowing your predispositions Right now, human genome sequence = about 5,000 bucks 5 years ago it was about 100,000 bucks In 5 years = about 1,000 bucks In 10 years = about 100 bucks Think what that means to your children

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23 The present of SNPs Currently, geneticists are racing to map and compare the genomes of large groups of individuals who are suffering from genetic disorders Then these disorder groups are compared to the genomes of healthy individuals This is called a Genome Wide Association Study (GWA) or (GWAS) The more GWAS we conduct the more pinpointed the SNP cause becomes

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25 Individualized Medicine Because the strength of your liver, pain tolerance differences, and even your medical allergies are all genetically controlled, someday your prescriptions and medical treatment will be tailored specifically for you. To do this we need to understand all of the SNPs

26 Your Chip In the very NEAR future, each of us will carry a chip about the size of a credit card that will contain ALL OF our SNPs This can be sequenced at any hospital to tell a doctor EXACTLY how to treat you.

27 Know your OMES: Genome we said Sum total of all your DNA Total of all your transcripts Transcriptome Total of all your proteins Proteome How all your proteins interact with everything in your body - Interactome The reason we mapped the human genome was because we wanted the human interactome

28 Human interactome Fix an interactome, cancer goes to 0 we have done this for CML leukemia 10 years ago, CML leukemia s only fix was a bone marrow transplant with a 50% failure rate, and at best, would give you 2 years NOW the fix is a daily pill that s it, one pill a day with no known human side affects CML leukemia went from a 95% fatality rate to a 95% remission rate in America in one year

29 chronic myelogenous leukemia

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31 Introns and Exons

32 Exons and Introns The gene that causes muscular dystrophy contains 189 introns and 190 exons Use exons 1 and 2 you have a gene Use exon 1 skip exon 2 move to exon 3 and you have a different gene Gene numbers don t actually matter we can make a billion different proteins from our 20,000 genes by reorganizing exons. Introns help in this organization

33 The light switch If you stop the production of a protein, you turn a gene off Turning a gene off or on is the basis of genetics If we can do this, we can cure cancer, fix diseases like muscular dystrophy, and Parkinson's disease Point mutations can turn a gene on or off Epigenetics imprinting (can do it)

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35 Epigenetics Add methyl groups (CH3) to DNA You can do this with Methylase which adds CH3 turning the gene off Demethylase can remove the CH3 and turn it on

36 Epigenetics (Methylation of DNA)

37 Repression Through Compression

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39 The next step In the non-coding DNA genes we have (within the last 2 years) found a mechanism to turn the genes off and on These genes can not code for protein but they can make RNA They will be transcribed and not translated. We have currently found 1,000+ (we are finding them at about the rate of 150 per semester)

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42 sncrnas sncrnas =Small non-coding RNA (Also called micrornas Also called mirna Also called mirs) These are tiny, only ~22 nucleotides long They are negative regulators = turn DNA off We have found that they control 20-30% of our coding genes

43 Small non-coding RNA They are endogenous (meaning they are made normally in your body everyday) They work post transcriptionally. They affect the transcript (the RNA) by homologous interaction (base pairing) with UTR (nontrascripting DNA at the ends of the transcript) By doing this, they stop translation, it is never made into a protein, it is succesffuly turned off The gene is silenced (called gene silencing)

44 Current Genome State of the Genome - September 2013: 1.5% Coding DNA - Exons = EXOME 98.5% Non-Coding DNA 28.5% - Introns = INTROME 51.5% sncrna genes + 13,000 lncrna genes plus..2,890,000 Docking Sites 20.0 % - Yet to be determined 30% - Exons and Introns of the 21,000 Coding DNA Genes

45 RNAi This RNA molecule control is called RNAi. Which means Inhibitor or interference RNA Fire and Mello, the doctors who figured this out published in 1998 won the nobel prize in years. One year faster than Watson and Crick.

46 RNAi & sncrna dsrna = Double Stranded RNA dsrna Induces a protein called DICER. DICER cuts the double stranded RNA into a 22 nucleotide long RNA strand, throws one of the strands away, and the other Becomes sncrna (mirna), the inhibitor molecule

47 Non-coding Hairpins All of the non coding mrna s can form hairpin molecules. Which makes dsrna (double stranded RNA) When this happens, it induces a special enzyme called DICER! Dicer will chop the promoter, making a 22 nucleotide mirna.

48 Where are they? This is where we have gotten our 1,000+ non-coding mirna. Where do we find them? Most are intergenic (found in-between the coding DNA genes) Some are intragenic (found within the coding DNA gene) Have we ever heard of non-coding DNA within coding DNA??? Of course, introns!

49 The Switch for Every Gene??? The current scientific thought is that every gene has a UTR regulator This regulator can suppress an abnormal protein from being synthesized from an abnormal gene. If the sncrna sequence is found for the gene, essentially we could control if the protein is produced (silencing the gene)

50 sncrna and Cancer In fact every stage of tumor development has various mirna s turned off We can use mirna to not only lead us to preventing the cancer but also, by evaluating the mirna present will tell us the stage the cancer is in.

51 Cancer Vocab Neoplasia New growth, a rapidly growing abnormal growth. Gives rise to a tumor Tumor : an abnormal mass of cells growing more rapidly than normal cells Transformation: Normal somatic cell mutates to become a cell with Malignant potential Transforms into a cancer cell Founder cell: The one single mutated cell that will develop over time into a tumor Primary tumor: the original tumor that forms at the site of transformation Metastasis: Migration of cells from the primary tumor ino remote tissue generally seed secondary tumors

52 Human Cancer Avg. human tumor will take years with multiple mutations. Once cancer hits telomerase, it gains cellular immortality and can grow forever. Cellular immortality! CARCINOGENS- there are 55 different carcinogens found in a single cigarette Most carcinogens are mutagens cause mutations in your DNA

53 Cancer Tumor = too much mitosis Mitosis = cell birth Cancer generally starts during interphase Cyclin proteins control the cell cycle. Cells go through mitosis when the cyclin proteins are present Cancer happens when the cyclin proteins occur at the wrong time.

54 Cancer and cyclin Cancer is a mutated gene in a somatic cell that makes a mutated protein that turns on the cyclin What turns on cyclin normally? (How does a cell know to go through mitosis normally) Mitosis cell signal relay Peptide growth factor is the signal in the relay. It signals the cell nucleus (likely passed from a different cell) which turns on the cyclin, which starts mitosis. (This has 43 steps within the relay)

55 Cell signal relay The gene mutation causes the relay to interpret the translated protein as cyclin, starts the relay mitosis starts when it shouldn t = cancer This relay can be started at any of the 43 relay points within the relay. These are interacting proteins. They are interactomes.

56 ATP and cancer Scientists recently found within the relay of many cancer cells, ATP, supplying the energy for the relay within the cancer cells. Can we find a molecule to inhibit the ATP??? We did, it is called, Imatinib Mesylate (Gleevec) It is what is in that little pill that stops the leukemia. It is actually used in two cancer remissions (CML leukemia & GastroIntestinal Stromal Tumor)

57 Is all cancer too much mitosis? 2001 a man (Robert Horvitz) studying C. elegans (same worm as before, different research) He understood all 959 cells within the body of that worm. They found that every developing fertilized egg for the worm has 1090 cells 131 die before adulthood These deaths are programmed cell death and called apoptosis This is exactly what happens to a tadpole s tail same thing that happened to all of our webbed fingers and toes (literally takes about a week)

58 Homeostasis When the body falls out of balance (homeostasis) cancer occurs Too much mitosis out of balance Cancer Not enough apoptosis out of balance to many cells left over cancer CANCER IS BOTH! Figured out, because if those 131 cells in C. elegans don t apoptose, they become cancerous.

59 Cancer s future The fact is, both of these versions of cancer are directly controlled by both your operator and the UTR at the other end As we learn more about these nontranscripting DNA strands we learn ways to manipulate them Such as dicer and sncrna To turn these on and off is to control the fate of cancer cells

60 The Guardian Angel For years it was believed that chemo. and rad. Treatment killed the actual tumor cell. And to some extent it does kill some cells Remarkably it was found that most of the destruction of the cancer cells was actually done after the chemo by a protein called p53. This protein locates damaged DNA (caused by chemo) and either prevents the cell from replicating or destroys the cell This is how chemo and rad. treatment can cause cancer to go into remission

61 Tumor Removal The obvious fix to any cancer issue is to remove all of an infected area This is very common with the treatment of breast cancer (Mastectomy) And, yes guys, the same is true for the treatment of penis cancer However, this can become much more difficult when concerning organs required for survival Currently, partial removal or tissue removal is the safest option, but this does not guarantee complete cancer removal

62 Have another Remarkable new science breakthroughs have occurred in the field of organ replacement therapy We have successfully cloned a wide variety of organisms (from sheep to albatross) Could I be cloned so that if I needed an organ transplant I could take it from a clone? (Movie: The Island) Is it an option to clone just the organ I need?

63 Cell Replacement Therapy With the discovery of dedifferentiation it has now become possible to revert a normal body cell back into a stem cell Called an Induced Pluripotent Stem Cell (ips) Remarkably takes only 4 signals Using ips cells we have the potential to make any of the bodies 220 cell types Currently we are making the necessary scaffolding to attach this tissue so that it can eventually replace defective tissue

64 Endless Options We have already successfully made a functioning kidney, heart, and liver in the laboratory (as 2012 we have made 4 parts of the brain) While there is still a ways to go to perfect this science, the strides we have made are amazing This could allow us to not only replace a failing organ, but to remove ALL of a cancerous tissue and replace it with healthy cells, tissue, and even organs!