{"version":"1.0.0","segments":[{"speaker":null,"startTime":1.47,"endTime":3.36,"body":"Kevin: Welcome to Innovate and React."},{"speaker":null,"startTime":3.78,"endTime":8.49,"body":"I'm Kevin Haas, and in today's episodeI will take you to the beginnings"},{"speaker":null,"startTime":8.49,"endTime":10.83,"body":"of natural product research."},{"speaker":null,"startTime":11.19,"endTime":17.7,"body":"How compounds that are coming from naturecan help to cure cancer and how chemists"},{"speaker":null,"startTime":17.7,"endTime":20.79,"body":"can help to bring them to the market."},{"speaker":null,"startTime":21.998,"endTime":27.068,"body":"Plants have probably been usedas medicine since human existed."},{"speaker":null,"startTime":27.594,"endTime":32.759,"body":"however, there were not reallystudied for their active compounds"},{"speaker":null,"startTime":32.779,"endTime":33.919,"body":"for a very, very long time."},{"speaker":null,"startTime":34.453,"endTime":35.827,"body":"in the 1950s."},{"speaker":null,"startTime":36.187,"endTime":40.477,"body":"Public pressure for doing somethingabout cancer was rising, which"},{"speaker":null,"startTime":40.477,"endTime":45.667,"body":"kicked off the foundation of theNational Cancer Institute in the US."},{"speaker":null,"startTime":46.727,"endTime":52.517,"body":"Funding increased from 0.5million to 14 million in"},{"speaker":null,"startTime":55.308,"endTime":59.798,"body":"so cancer research has beenwell funded at that point."},{"speaker":null,"startTime":60.105,"endTime":63.105,"body":"However, it was not wellorganized in the beginning."},{"speaker":null,"startTime":63.441,"endTime":65.871,"body":"And that slowly changed over time."},{"speaker":null,"startTime":66.741,"endTime":72.669,"body":"For example, most of the samplesthat were tested in the early fifties"},{"speaker":null,"startTime":73.098,"endTime":81.168,"body":"to evaluate compounds for potentialcancer agents and biological activity were"},{"speaker":null,"startTime":81.168,"endTime":83.928,"body":"done at the Solon Kettering Institute."},{"speaker":null,"startTime":84.797,"endTime":88.967,"body":"Not enough for the risingdemand for research requests."},{"speaker":null,"startTime":89.957,"endTime":93.679,"body":"To fight this shortage ofprocessing capabilities."},{"speaker":null,"startTime":93.679,"endTime":101.724,"body":"The Cancer Chemotherapy National Servicewas established in 1955 and about 10"},{"speaker":null,"startTime":101.724,"endTime":103.944,"body":"folded the screening capabilities."},{"speaker":null,"startTime":103.944,"endTime":109.074,"body":"So now they could processover 30,000 samples per year."},{"speaker":null,"startTime":110.619,"endTime":115.299,"body":"Starting with known syntheticsand fermentation products, they"},{"speaker":null,"startTime":115.299,"endTime":120.999,"body":"began to screen extracts ofnatural products in the 1960s."},{"speaker":null,"startTime":121.719,"endTime":128.829,"body":"Those were complex mixtures of unknowncompounds and structures, so it was really"},{"speaker":null,"startTime":128.829,"endTime":135.129,"body":"not easy to figure out what was in there,what was really the active compound."},{"speaker":null,"startTime":135.476,"endTime":143.426,"body":"At that time, the organizer of theNCI, the National Cancer Institute, um,"},{"speaker":null,"startTime":143.486,"endTime":146.246,"body":"plant program was Jonathan Hartwell."},{"speaker":null,"startTime":146.616,"endTime":151.716,"body":"Who was uh, the perfect choice to headthis plant screening project because"},{"speaker":null,"startTime":151.716,"endTime":157.416,"body":"he had wide experience in naturalproducts chemistry and he believed"},{"speaker":null,"startTime":157.416,"endTime":160.806,"body":"that plants had chemotherapy potential."},{"speaker":null,"startTime":161.916,"endTime":167.376,"body":"Hartwell compiled a comprehensivework on the traditional use of"},{"speaker":null,"startTime":167.376,"endTime":174.966,"body":"plants to treat cancer, complete withreferences to the literature of Asian,"},{"speaker":null,"startTime":174.966,"endTime":182.196,"body":"Chinese, Egyptian, Greek, and Romans,which all have been using plants"},{"speaker":null,"startTime":182.196,"endTime":185.106,"body":"to cure all kinds of diseases and."},{"speaker":null,"startTime":185.386,"endTime":190.246,"body":"Also cancer, although it might have beennot known that it was cancer at the time."},{"speaker":null,"startTime":191.184,"endTime":196.884,"body":"Hartwell laid his focus onwhat we call cancer plants, the"},{"speaker":null,"startTime":196.884,"endTime":202.194,"body":"plants that have shown biologicalactivities in a study in the 1950s."},{"speaker":null,"startTime":203.172,"endTime":210.205,"body":"Juniperus Sabina showed some anti-canceractivity, but did not make it further"},{"speaker":null,"startTime":210.205,"endTime":212.365,"body":"as the results were not strong enough."},{"speaker":null,"startTime":213.205,"endTime":217.645,"body":"But this was the start for hissearch in the Conifer family."},{"speaker":null,"startTime":218.202,"endTime":223.036,"body":"So he started to look deeperin this kind of trees."},{"speaker":null,"startTime":223.779,"endTime":229.004,"body":"Crude extracts have been shown potentialAnd became candidates for fractionation"},{"speaker":null,"startTime":229.454,"endTime":234.879,"body":"where the unknown crude extracts wereisolated in their individual compounds."},{"speaker":null,"startTime":235.959,"endTime":243.476,"body":"Hartwell convinced the chemist Monroe Wallto send him more samples for screening who"},{"speaker":null,"startTime":243.476,"endTime":251.01,"body":"was working on agriculture alternativesfor products like rubber, which were"},{"speaker":null,"startTime":251.01,"endTime":253.5,"body":"crucial for the war efforts at the time."},{"speaker":null,"startTime":254.82,"endTime":255.27,"body":"Indeed."},{"speaker":null,"startTime":255.27,"endTime":260.642,"body":"About one year after they metone plant named a accumulator"},{"speaker":null,"startTime":261.222,"endTime":263.137,"body":"showed potential activity."},{"speaker":null,"startTime":263.679,"endTime":263.979,"body":"So."},{"speaker":null,"startTime":264.412,"endTime":269.212,"body":"Working together with differentinstitutes had already shown potential."},{"speaker":null,"startTime":270.204,"endTime":275.186,"body":"Monroe wall wrote in his workat the Eastern Regional Research"},{"speaker":null,"startTime":275.186,"endTime":280.106,"body":"Laboratory, the joint effort ofchemists and botanists proof to be"},{"speaker":null,"startTime":280.106,"endTime":283.461,"body":"a good model for future programs."},{"speaker":null,"startTime":284.761,"endTime":286.021,"body":"Indeed, it firmly."},{"speaker":null,"startTime":286.373,"endTime":289.823,"body":"Established the fact that thosecorporations between chemists"},{"speaker":null,"startTime":289.823,"endTime":295.223,"body":"and botanists were required forsuccessful natural products program,"},{"speaker":null,"startTime":296.273,"endTime":297.953,"body":"so they had to work together."},{"speaker":null,"startTime":297.953,"endTime":304.283,"body":"The chemists, the botanists, those whoknow the plants and those who might know"},{"speaker":null,"startTime":304.283,"endTime":307.133,"body":"how to extract the active compounds."},{"speaker":null,"startTime":308.471,"endTime":315.071,"body":"They were able to obtain 20kilograms of the wood and bark of the"},{"speaker":null,"startTime":316.047,"endTime":323.021,"body":"Camptotheca acuminata, and startedfractioning the crude extract."},{"speaker":null,"startTime":323.951,"endTime":329.619,"body":"Each fraction was tested for biologicalactivity, which is why the process was"},{"speaker":null,"startTime":329.619,"endTime":332.455,"body":"named Bioactive Direct fractionation."},{"speaker":null,"startTime":332.777,"endTime":337.517,"body":"this means that from each step,the fraction which had the most"},{"speaker":null,"startTime":337.577,"endTime":343.187,"body":"biological activity was worked onnext, so they could streamline to"},{"speaker":null,"startTime":343.187,"endTime":346.427,"body":"focus on the most active extracts."},{"speaker":null,"startTime":347.297,"endTime":349.787,"body":"Narrow down where theactive compounds are."},{"speaker":null,"startTime":350.573,"endTime":357.168,"body":"In the 1960s, this was a difficultand slow process, which required great"},{"speaker":null,"startTime":357.168,"endTime":363.378,"body":"skill and intuition on the part ofthe researchers using equipments that"},{"speaker":null,"startTime":363.378,"endTime":367.068,"body":"can now be found in only museums."},{"speaker":null,"startTime":367.418,"endTime":373.333,"body":"this is due to chemists not really workingwith biological compounds that much back"},{"speaker":null,"startTime":373.333,"endTime":377.503,"body":"in the days, and they had to come upwith a lot of new techniques that are"},{"speaker":null,"startTime":377.64,"endTime":378.57,"body":"almost forgotten now."},{"speaker":null,"startTime":378.57,"endTime":378.6,"body":"Okay."},{"speaker":null,"startTime":379.558,"endTime":388.228,"body":"After years of work, they managed toisolate camtothecin, which showed activity"},{"speaker":null,"startTime":388.228,"endTime":389.878,"body":"against different types of leukemia."},{"speaker":null,"startTime":390.748,"endTime":396.54,"body":"The research on the isolationand structure of camtothecin was"},{"speaker":null,"startTime":396.54,"endTime":401.63,"body":"published in 1966 in the Journalof American Chemical Society."},{"speaker":null,"startTime":402.71,"endTime":403.065,"body":"The first."},{"speaker":null,"startTime":403.666,"endTime":409.816,"body":"Paper Wani and his colleagues publishedon a natural product with anti-cancer"},{"speaker":null,"startTime":409.816,"endTime":418.187,"body":"potential Wani describes the isolationof camtothecin as the most exciting"},{"speaker":null,"startTime":418.457,"endTime":420.017,"body":"scientific event in his life."},{"speaker":null,"startTime":420.516,"endTime":427.986,"body":"Because camtothecin showed suchpromising anti-tumor activity, the NCI"},{"speaker":null,"startTime":428.286,"endTime":431.196,"body":"decided to proceed with clinical trials"},{"speaker":null,"startTime":432.178,"endTime":440.216,"body":"in the mid 1990s, so almost 40 yearsafter the whole plant program started."},{"speaker":null,"startTime":441.116,"endTime":447.113,"body":"Two camtothecin analogons,Topo Tecan, and."},{"speaker":null,"startTime":447.347,"endTime":452.777,"body":"Irinotecan received FDA approvalfor use against ovarian,"},{"speaker":null,"startTime":453.017,"endTime":455.177,"body":"lung, breast and colon cancer."},{"speaker":null,"startTime":455.591,"endTime":461.663,"body":"So this really showed that naturalproducts can have benefits and"},{"speaker":null,"startTime":461.663,"endTime":468.353,"body":"this really shows that we can findreally potent drugs also in nature."},{"speaker":null,"startTime":468.737,"endTime":476.226,"body":"In trees, for example, or other kinds ofextracts, we can use those after many,"},{"speaker":null,"startTime":476.226,"endTime":480.846,"body":"many tests because when something isfrom nature, it doesn't always mean that"},{"speaker":null,"startTime":480.846,"endTime":484.806,"body":"it's better than something synthetic."},{"speaker":null,"startTime":485.079,"endTime":490.029,"body":"Uh, if you think about all kinds of,uh, toxins that come from nature,"},{"speaker":null,"startTime":490.35,"endTime":494.22,"body":"we know that there are, uh, alsocomponents that are bad for us, but"},{"speaker":null,"startTime":494.28,"endTime":496.74,"body":"there are also some that can help us."},{"speaker":null,"startTime":497.46,"endTime":503.064,"body":"So it's not a clear line betweennatural and synthetic, which is better."},{"speaker":null,"startTime":504.304,"endTime":509.451,"body":"However, the combination of bothmight also be great, which is part"},{"speaker":null,"startTime":509.451,"endTime":511.401,"body":"of the next story I want to tell."},{"speaker":null,"startTime":511.763,"endTime":514.223,"body":"Before I continue a quickbreak for two things."},{"speaker":null,"startTime":514.679,"endTime":516.989,"body":"First of all, thank you fortuning in and listening."},{"speaker":null,"startTime":517.499,"endTime":521.879,"body":"Secondly, if you like the show,please follow, innovate, and react"},{"speaker":null,"startTime":521.909,"endTime":523.559,"body":"on your favorite podcast app."},{"speaker":null,"startTime":523.889,"endTime":529.679,"body":"This really helps me to grow and get newguests on the show To continue, also, let"},{"speaker":null,"startTime":529.679,"endTime":534.898,"body":"me know if you have topics that you wouldlike to learn about Or if you want to talk"},{"speaker":null,"startTime":534.898,"endTime":539.818,"body":"about your research in the podcast, youcan find the contact info into show notes."},{"speaker":null,"startTime":540.418,"endTime":542.398,"body":"Thank you for your timeand back to the episode."},{"speaker":null,"startTime":542.802,"endTime":548.502,"body":"Another interesting confire wasdiscovered by chance as botanist author."},{"speaker":null,"startTime":548.566,"endTime":555.948,"body":"Barclay brought samples from the PacificYew Tree, Texes brevi folia to his lab."},{"speaker":null,"startTime":556.308,"endTime":561.018,"body":"Both of his samples were sentto the Wisconsin Alumni Research"},{"speaker":null,"startTime":561.018,"endTime":562.578,"body":"Foundation for extraction."},{"speaker":null,"startTime":563.838,"endTime":566.448,"body":"STEM and fruit, as well as stem and bark."},{"speaker":null,"startTime":567.138,"endTime":568.818,"body":"The bark showed activity."},{"speaker":null,"startTime":568.848,"endTime":575.997,"body":"So Hartwell ordered his contacts fromthe USDA to collect larger quantities."},{"speaker":null,"startTime":577.077,"endTime":583.317,"body":"On September 8th in 1964, Barkleyreturned to the spot where he had"},{"speaker":null,"startTime":583.317,"endTime":585.927,"body":"originally collected his sample."},{"speaker":null,"startTime":585.98,"endTime":591.87,"body":"and bagged 30 pounds of thebark from T. Brevifolia,"},{"speaker":null,"startTime":594.89,"endTime":598.473,"body":"which was shipped to MonroeWall at the research."},{"speaker":null,"startTime":599.343,"endTime":603.933,"body":"Triangle Institute after otherlaboratories turned it down."},{"speaker":null,"startTime":605.073,"endTime":612.895,"body":"These laboratories were reluctant becauseplants that exhibit high toxicity turned"},{"speaker":null,"startTime":612.895,"endTime":618.923,"body":"out to be poor drug candidates sincetheir toxic to everything, killing the"},{"speaker":null,"startTime":618.953,"endTime":622.253,"body":"tumor cells as well as healthy ones."},{"speaker":null,"startTime":623.033,"endTime":623.603,"body":"So."},{"speaker":null,"startTime":624.533,"endTime":628.973,"body":"It was not selective enoughand toxic in general,"},{"speaker":null,"startTime":629.621,"endTime":636.177,"body":"but Wal was interested because ofhis experience with Kemp to Aku,"},{"speaker":null,"startTime":637.802,"endTime":644.582,"body":"which was highly cytotoxic, butfrom which his group had isolated a"},{"speaker":null,"startTime":644.612,"endTime":646.472,"body":"compound that showed great promise."},{"speaker":null,"startTime":646.761,"endTime":647.931,"body":"In the previous story,"},{"speaker":null,"startTime":648.668,"endTime":655.657,"body":"so they again began the bioassaydirected fractionation, and after two"},{"speaker":null,"startTime":655.657,"endTime":660.217,"body":"years, they finally managed to isolatea crystalline compounds, one named the"},{"speaker":null,"startTime":660.217,"endTime":668.302,"body":"Taxol  after the Latin name of the treeit came from Taxes Brevifolia and ending"},{"speaker":null,"startTime":668.332,"endTime":673.932,"body":"all As they knew it contained hydroxygroup, which are alcohols, and they"},{"speaker":null,"startTime":673.932,"endTime":676.142,"body":"are usually named with the ending ol."},{"speaker":null,"startTime":676.496,"endTime":681.266,"body":"However, for this compound to be usedas a treatment, the newly discovered"},{"speaker":null,"startTime":681.266,"endTime":686.036,"body":"compound needed to be characterizedand confirmed in clinical trials."},{"speaker":null,"startTime":686.886,"endTime":692.552,"body":"So the need for more and more bark wasthere, and this was even compounded"},{"speaker":null,"startTime":692.552,"endTime":697.952,"body":"by the effect that the yield of Taxolfrom collected Bark was very low."},{"speaker":null,"startTime":698.672,"endTime":703.082,"body":"This showed the process todetermine the molecule structure."},{"speaker":null,"startTime":703.272,"endTime":707.562,"body":"This slowed the process to determinethe molecule structure because you need"},{"speaker":null,"startTime":707.562,"endTime":710.802,"body":"some quantities to prepare samples."},{"speaker":null,"startTime":711.372,"endTime":716.971,"body":"Some are samples that aredestroyed while characterizing,"},{"speaker":null,"startTime":717.481,"endTime":720.373,"body":"so you need some quantity of it."},{"speaker":null,"startTime":720.68,"endTime":725.36,"body":"To definitely learn the structureof Taxol  Wall and Wani used"},{"speaker":null,"startTime":725.45,"endTime":731.465,"body":"mass spectrometry, x-ray,crystallography, and NMR spectroscopy."},{"speaker":null,"startTime":731.906,"endTime":736.311,"body":"At the time this technique wasin its infancy and needed larger"},{"speaker":null,"startTime":736.311,"endTime":738.531,"body":"quantities than we are used to today."},{"speaker":null,"startTime":739.308,"endTime":745.128,"body":"These various tools produced amolecular structure with a formula of."},{"speaker":null,"startTime":746.465,"endTime":758.325,"body":"C47H51NO14 Wall and Wani also discoveredTaxol  was two molecules in one."},{"speaker":null,"startTime":759.255,"endTime":766.275,"body":"Basically a connection betweena large molecule and the small"},{"speaker":null,"startTime":766.322,"endTime":769.202,"body":"tail, which was a side chain."},{"speaker":null,"startTime":769.881,"endTime":776.439,"body":"Using all these informations in1971 Wall, Wani and coworkers could"},{"speaker":null,"startTime":776.439,"endTime":778.899,"body":"finally publish their results."},{"speaker":null,"startTime":779.064,"endTime":784.824,"body":"On Taxol  in the Journal of AmericanChemical Society as a communication to"},{"speaker":null,"startTime":784.824,"endTime":790.524,"body":"the editor in which they stressed theanti leukemic and antitumor activity"},{"speaker":null,"startTime":790.524,"endTime":792.904,"body":"in the newly isolated molecule."},{"speaker":null,"startTime":793.266,"endTime":798.216,"body":"However, NCI was not convinced tocontinue with animal trials because"},{"speaker":null,"startTime":798.456,"endTime":805.236,"body":"the isolation and extraction ofTaxol  from T. Brevifolia was."},{"speaker":null,"startTime":805.336,"endTime":812.316,"body":"Difficult and the tree was notreally that prevalent, producing only"},{"speaker":null,"startTime":812.316,"endTime":814.836,"body":"very small amounts of the compound."},{"speaker":null,"startTime":816.096,"endTime":823.207,"body":"Each tree yielded only about two kilogramsof bark, and in the early days of testing"},{"speaker":null,"startTime":823.411,"endTime":829.621,"body":"It needed about 12 kilograms of driedbark to obtain half a gram of Taxol."},{"speaker":null,"startTime":830.101,"endTime":832.441,"body":"So the yield was very low."},{"speaker":null,"startTime":833.131,"endTime":839.341,"body":"And the biggest problem of this is thatthe bark is kind of a finite resource."},{"speaker":null,"startTime":839.461,"endTime":843.631,"body":"It is crucial to the tree's survival."},{"speaker":null,"startTime":843.631,"endTime":848.456,"body":"So if the tree is stripped ofits bark, it dies, and then."},{"speaker":null,"startTime":848.941,"endTime":852.241,"body":"It takes a very longtime for it to grow back."},{"speaker":null,"startTime":852.931,"endTime":857.971,"body":"So Taxol  was forgotten on theshelf literally for a while"},{"speaker":null,"startTime":858.181,"endTime":862.081,"body":"until it was revisited in 1978"},{"speaker":null,"startTime":862.449,"endTime":868.767,"body":"when new tests were developed, thenew B 16 melanoma tests, which."},{"speaker":null,"startTime":868.964,"endTime":876.854,"body":"Taxol  was surprisingly active against, soin November of that year, they showed the"},{"speaker":null,"startTime":876.908,"endTime":882.568,"body":"ability to cause considerable regressionin the mammary tumor xenografts."},{"speaker":null,"startTime":883.265,"endTime":888.545,"body":"it's basically putting tissue from onespecies, putting it into another species."},{"speaker":null,"startTime":889.745,"endTime":899.98,"body":"And what they did is they managed tobreed a type of mouse that basically had"},{"speaker":null,"startTime":899.98,"endTime":902.62,"body":"no immune system, and then they would."},{"speaker":null,"startTime":903.385,"endTime":911.088,"body":"Take a human tumor and transplant itinto these mice, and then treat them"},{"speaker":null,"startTime":911.267,"endTime":917.488,"body":"with Taxol  or other compounds andsee how these tumors would respond."},{"speaker":null,"startTime":917.823,"endTime":926.379,"body":"Which increased interest in Taxol  again,so they could show that Taxol  was"},{"speaker":null,"startTime":926.856,"endTime":930.491,"body":"acting against humantumors inside a mouse."},{"speaker":null,"startTime":932.481,"endTime":940.96,"body":"And finally the interest in Taxolincreased again in the year after when"},{"speaker":null,"startTime":941.53,"endTime":946.57,"body":"Susan Horwitz demonstrated that Taxol smechanism was completely different and"},{"speaker":null,"startTime":946.57,"endTime":949.6,"body":"unique and new to scientists at the time."},{"speaker":null,"startTime":950.582,"endTime":956.745,"body":"Previous compounds kill cancercells by inhibiting their division."},{"speaker":null,"startTime":956.99,"endTime":964.08,"body":"So cancer cells uncontrollably divide,and that is what makes them cancerous."},{"speaker":null,"startTime":964.71,"endTime":972.296,"body":"So these compounds before toxol, were alljust trying to inhibit this cell division."},{"speaker":null,"startTime":973.053,"endTime":978.794,"body":"They did this by preventing the productionof the ultra fine filaments called"},{"speaker":null,"startTime":979.284,"endTime":986.446,"body":"microtubules that enable cells to dividecells, manufacture millions of these micro"},{"speaker":null,"startTime":986.446,"endTime":994.589,"body":"tules, and use them as a building blockfor the new cell when a new cell breaks"},{"speaker":null,"startTime":994.589,"endTime":1002.3,"body":"off these tules basically become fragmentsof the protein Tubulin Before Taxol."},{"speaker":null,"startTime":1003,"endTime":1008.449,"body":"Anticancer agents would work byinhibiting the polymerization of"},{"speaker":null,"startTime":1008.449,"endTime":1011.599,"body":"Tubulin to form these microtubules."},{"speaker":null,"startTime":1012.409,"endTime":1014.449,"body":"Hence, the cell could not divide."},{"speaker":null,"startTime":1014.794,"endTime":1018.034,"body":"Horwitz discovered thatTaxol  worked differently."},{"speaker":null,"startTime":1018.874,"endTime":1022.954,"body":"Instead of preventing theformation of microtubules, it"},{"speaker":null,"startTime":1022.954,"endTime":1025.054,"body":"stimulated the development."},{"speaker":null,"startTime":1025.59,"endTime":1027.3,"body":"Cells treated with Taxol."},{"speaker":null,"startTime":1027.681,"endTime":1034.205,"body":"Began putting out so many of thesemicrotubules that they were unable to"},{"speaker":null,"startTime":1034.235,"endTime":1039.245,"body":"coordinate the cell division, so they werebasically crowded with all these micros."},{"speaker":null,"startTime":1041.27,"endTime":1047.647,"body":"As a result, the cell dies because itcontinuously tries to replicate but can't."},{"speaker":null,"startTime":1047.954,"endTime":1054.814,"body":"As a result, the cell dies because itcontinuously tries to replicate their DNA"},{"speaker":null,"startTime":1055.684,"endTime":1058.024,"body":"but it cannot divide."},{"speaker":null,"startTime":1059.434,"endTime":1065.771,"body":"So Taxol  was kind of a miracle drugthen because it was completely new."},{"speaker":null,"startTime":1066.279,"endTime":1067.856,"body":"the demand was high."},{"speaker":null,"startTime":1068.356,"endTime":1073.595,"body":"They wanted to put it on the marketas fast as possible, however."},{"speaker":null,"startTime":1074.3,"endTime":1079.34,"body":"As mentioned before, the supplywas very limited because of the"},{"speaker":null,"startTime":1079.34,"endTime":1084.29,"body":"origin of the compound, the barkof a tree, which slowly grows and"},{"speaker":null,"startTime":1084.83,"endTime":1087.397,"body":"will die when the bark is harvested."},{"speaker":null,"startTime":1087.91,"endTime":1092.89,"body":"If Taxol  were made availableto all the victims of ovarian"},{"speaker":null,"startTime":1092.89,"endTime":1098.055,"body":"cancer, the institute would haveto produce 240 pounds of the drug."},{"speaker":null,"startTime":1099.56,"endTime":1109.744,"body":"That would mean killing 360,000 Pacifictwo trees, and already in 1977, harvesting"},{"speaker":null,"startTime":1109.744,"endTime":1117.764,"body":"1,500 trees for the initial testing ledto big concerns from environmentalists."},{"speaker":null,"startTime":1118.664,"endTime":1121.244,"body":"This giant number of trees willprobably eradicate the whole"},{"speaker":null,"startTime":1121.244,"endTime":1125.33,"body":"Pacific Yew tree population, sothey had to be an alternative."},{"speaker":null,"startTime":1125.9,"endTime":1130.13,"body":"Which encouraged many chemiststo synthesize the molecule in"},{"speaker":null,"startTime":1130.13,"endTime":1131.54,"body":"the lab all over the world."},{"speaker":null,"startTime":1131.96,"endTime":1137.91,"body":"Different groups started in tryingout new methods, new synthesis routes."},{"speaker":null,"startTime":1138.386,"endTime":1140.7,"body":"But the molecule is really complicated."},{"speaker":null,"startTime":1141.15,"endTime":1146.83,"body":"As I said before, when they firstelucidated, uh, structure it contains"},{"speaker":null,"startTime":1146.98,"endTime":1149.787,"body":"one big compound and the side chain."},{"speaker":null,"startTime":1151.542,"endTime":1157.283,"body":"So synthesizing them with all of these,um, chiral centers and putting them"},{"speaker":null,"startTime":1157.283,"endTime":1160.523,"body":"all into place, which really difficult."},{"speaker":null,"startTime":1161.223,"endTime":1163.023,"body":"I will link a picture to the compound."},{"speaker":null,"startTime":1163.568,"endTime":1164.738,"body":"In the show notes,"},{"speaker":null,"startTime":1164.925,"endTime":1169.335,"body":"the first success story camefrom France, where Pierre Potier"},{"speaker":null,"startTime":1170.647,"endTime":1172.537,"body":"look at the semi synthesis."},{"speaker":null,"startTime":1173.137,"endTime":1178.327,"body":"Semi synthesis, meaningtrying to use already."},{"speaker":null,"startTime":1178.657,"endTime":1181.177,"body":"Some compounds which come from nature."},{"speaker":null,"startTime":1181.177,"endTime":1190.132,"body":"In that case, specifically the needles ofthe ubiquitous Taxus baccata or English"},{"speaker":null,"startTime":1191.982,"endTime":1194.691,"body":"Yew extracted 10-deacetylbaccatin III"},{"speaker":null,"startTime":1196.993,"endTime":1199.073,"body":", commonly known as 10-DBA."},{"speaker":null,"startTime":1199.277,"endTime":1203.851,"body":"The English Yew is loadedwith this compound, which made"},{"speaker":null,"startTime":1204.426,"endTime":1206.166,"body":"the extraction much easier"},{"speaker":null,"startTime":1206.933,"endTime":1208.518,"body":"and this compound."},{"speaker":null,"startTime":1209.012,"endTime":1216.609,"body":"Is the complex core of Taxol minusthe relatively simple side chain, much"},{"speaker":null,"startTime":1216.789,"endTime":1218.769,"body":"easier to synthesize than the core."},{"speaker":null,"startTime":1219.111,"endTime":1223.611,"body":"Most importantly, 10-DBAcomes from the needles."},{"speaker":null,"startTime":1224.091,"endTime":1229.341,"body":"A renewable resource, they can beharvested without killing the tree."},{"speaker":null,"startTime":1230.151,"endTime":1235.511,"body":"After several years of trying, Potierand his colleagues succeeded in marrying."},{"speaker":null,"startTime":1236.301,"endTime":1242.906,"body":"10-DBA to a synthetic version ofthe tail to achieve a semi synthesis"},{"speaker":null,"startTime":1242.906,"endTime":1249.74,"body":"of Taxol . This accomplishment ledto many different paths to achieve"},{"speaker":null,"startTime":1249.74,"endTime":1254.941,"body":"this semisynthetic version of Taxol. Eventually Robert Holton and colleagues"},{"speaker":null,"startTime":1254.941,"endTime":1260.037,"body":"at the Florida State University developeda commercially viable semisynthetic"},{"speaker":null,"startTime":1260.757,"endTime":1268.549,"body":"procedure, which in my opinion is alwaysa point that is very difficult if you"},{"speaker":null,"startTime":1268.549,"endTime":1271.884,"body":"are only looking at the synthesis itself."},{"speaker":null,"startTime":1272.869,"endTime":1280.757,"body":"So if you think about the synthesis anduse very complicated, um, procedures"},{"speaker":null,"startTime":1281.027,"endTime":1286.277,"body":"that cannot easily be upscaled andthe whole synthesis will be difficult"},{"speaker":null,"startTime":1286.277,"endTime":1289.397,"body":"to produce larger quantities and."},{"speaker":null,"startTime":1289.818,"endTime":1294.505,"body":"I already have talked to, other scientistsin previous episodes about this."},{"speaker":null,"startTime":1294.505,"endTime":1300.675,"body":"The scale up of a reaction it'sreally crucial to make, uh, profitable"},{"speaker":null,"startTime":1300.795,"endTime":1306.138,"body":"and working synthesis that can alsobe done in the industry set up."},{"speaker":null,"startTime":1306.451,"endTime":1310.891,"body":"Then after that, Taxol  passedall the clinical trials."},{"speaker":null,"startTime":1311.338,"endTime":1315.208,"body":"With the new developedsemisynthetic route, it could"},{"speaker":null,"startTime":1315.208,"endTime":1317.698,"body":"be viable and marketable drug."},{"speaker":null,"startTime":1318.256,"endTime":1323.056,"body":"Bristol Meyers Squibb worked out a dealwith Holton to use his semisynthetic"},{"speaker":null,"startTime":1323.836,"endTime":1325.666,"body":"synthesis and began production."},{"speaker":null,"startTime":1327.016,"endTime":1332.763,"body":"So finally in December,1992, almost 30 years after."},{"speaker":null,"startTime":1333.345,"endTime":1339.771,"body":"USDA botanist first sampled and more than20 years after Wall and Wani reported"},{"speaker":null,"startTime":1339.771,"endTime":1342.801,"body":"the isolation of the structure of Taxol."},{"speaker":null,"startTime":1343.33,"endTime":1348.481,"body":"The Food and Drug Administrationgranted approval for Taxol s used"},{"speaker":null,"startTime":1348.481,"endTime":1351.421,"body":"against refractory ovarian cancer."},{"speaker":null,"startTime":1351.813,"endTime":1356.763,"body":"This really shows how complicatedthis process is from when a"},{"speaker":null,"startTime":1356.763,"endTime":1361.353,"body":"compound is discovered all the wayto it being a drug on the market."},{"speaker":null,"startTime":1361.803,"endTime":1367.473,"body":"Not only does it have to have the effectsthat we want for the drug to have, it"},{"speaker":null,"startTime":1367.473,"endTime":1372.993,"body":"also needs to be producible in a largescale, so it can be a profitable drug."},{"speaker":null,"startTime":1373.263,"endTime":1375.873,"body":"Otherwise no companywould ever try to make it."},{"speaker":null,"startTime":1376.623,"endTime":1381.963,"body":"And this really takes a long time in alot of research efforts, which also is"},{"speaker":null,"startTime":1381.963,"endTime":1384.153,"body":"why a lot of new drugs are expensive."},{"speaker":null,"startTime":1386.502,"endTime":1390.787,"body":"Since that time, Taxol  alsohas been approved for the use in"},{"speaker":null,"startTime":1390.837,"endTime":1396.607,"body":"treatment of breast cancer andAIDS related Kaposi's sarcoma."},{"speaker":null,"startTime":1397.033,"endTime":1404.808,"body":"In the end, this really is a success storyfor natural products, and Semisynthetic"},{"speaker":null,"startTime":1404.948,"endTime":1411.449,"body":"route already has a big advantage overthe extraction of the Pacific Ju Tree."},{"speaker":null,"startTime":1411.828,"endTime":1417.462,"body":"It becomes much more availablesince the needles can grow"},{"speaker":null,"startTime":1417.462,"endTime":1419.2,"body":"back and are more sustainable."},{"speaker":null,"startTime":1419.496,"endTime":1425.049,"body":"However, it's still a laborsprocess and it would be much"},{"speaker":null,"startTime":1425.049,"endTime":1426.999,"body":"more convenient if the whole."},{"speaker":null,"startTime":1427.689,"endTime":1430.567,"body":"Molecule could be synthesized in the lab."},{"speaker":null,"startTime":1430.985,"endTime":1438.095,"body":"And in an upcoming episode, I will talk toa natural products chemist about all the"},{"speaker":null,"startTime":1438.095,"endTime":1441.005,"body":"fully synthetic ways to synthesize Taxol."},{"speaker":null,"startTime":1441.225,"endTime":1447.015,"body":"This also called total synthesis,came after the big success of the"},{"speaker":null,"startTime":1447.015,"endTime":1453.388,"body":"drug and motivated many researchersto improve the synthesis because"},{"speaker":null,"startTime":1453.388,"endTime":1461.005,"body":"with such a successful drug, a lot offunding was available for the research."},{"speaker":null,"startTime":1461.184,"endTime":1464.214,"body":"A lot of funding wasavailable for this research."},{"speaker":null,"startTime":1464.965,"endTime":1471.314,"body":"so the story of Taxo is a greatexample for natural products that come"},{"speaker":null,"startTime":1471.314,"endTime":1473.53,"body":"from nature but they're synthesis,"},{"speaker":null,"startTime":1476.23,"endTime":1480.872,"body":"improves the way of getting themAnd makes them much better available"},{"speaker":null,"startTime":1481.082,"endTime":1482.612,"body":"so it can help more people."},{"speaker":null,"startTime":1483.238,"endTime":1485.248,"body":"Thank you very much for listening."},{"speaker":null,"startTime":1485.358,"endTime":1489.528,"body":"Don't forget to follow, innovate, andreact on your favorite podcast app."},{"speaker":null,"startTime":1489.948,"endTime":1494.448,"body":"This really helps me to grow, to showand get new guests on to continue."},{"speaker":null,"startTime":1494.808,"endTime":1497.958,"body":"Also, let me know ifyou have a topic that."},{"speaker":null,"startTime":1498.753,"endTime":1503.403,"body":"You would like to learn about,or if you want to talk about"},{"speaker":null,"startTime":1503.403,"endTime":1505.053,"body":"your research in the podcast."},{"speaker":null,"startTime":1505.863,"endTime":1509.823,"body":"You can find the contactinfo in the show notes."},{"speaker":null,"startTime":1511.053,"endTime":1516.993,"body":"Also now you can support show and keepme caffeinated by buying me a coffee."},{"speaker":null,"startTime":1516.993,"endTime":1518.343,"body":"Also, the."},{"speaker":null,"startTime":1519.033,"endTime":1521.073,"body":"Information for that in show notes."},{"speaker":null,"startTime":1521.583,"endTime":1525.768,"body":"Thank you very much, and until nexttime, keep innovating and stay curious."}]}