How Genetics Is Revolutionizing Cancer Research
Siddhartha Mukherjee is the author of The Emperor of All Maladies: A Biography of Cancer, winner of the 2011 Pulitzer Prize in general nonfiction, and The Laws of Medicine. He is the editor of Best Science Writing 2013. Mukherjee is an assistant professor of medicine at Columbia University and a cancer physician and researcher. A Rhodes scholar, he graduated from Stanford University, University of Oxford, and Harvard Medical School. He has published articles in Nature, The New England Journal of Medicine, The New Yorker, The New York Times, and Cell. He lives in New York with his wife and daughters.
Siddhartha Mukherjee: Tell us a little bit about what the Cancer Genome tells us about the genetics of cancer and what we have learned from the Human Genome Project followed by the Cancer Genome Project. Do you want to start and then we’ll go around?
Dr. Lewis Cantley: Sure, well, as I said earlier the first thing the Cancer Genome is beginning to tell us is that there are many, many more subdivisions of cancers than we previously could predict based on pathology alone, and I think that is going to be extremely informative. The goal now with target therapies—first of all, it’s telling us what genes are likely driving the cancer, so if you find that in lung cancer 30% of the people get a particular mutation in a gene called RAS, 90% of pancreatic cancers have exactly that same gene, and you see that those are exactly the subgroups that don’t respond to any of our existing therapies. Then you realize that we need to have drugs that target RAS in some way. All the approaches we’ve made thus far have failed for that particular target, so people are trying to figure out ways to do that; it turns out to be a difficult gene to target. So the first thing that is going to come out and has already come out is the identification of what we call drugable oncogenes, things that are mutated in the cancer EGF receptor in lung cancer for example. So those opportunities hopefully we already know a lot about those and drugs are being developed and we’re hoping to get a lot of success out of that. In some ways I think on the other hand it has been somewhat disappointing in that most of the things we’re finding from the cancer genome sequencing are things that we already knew. In some ways retroviruses that cause cancers in mice and chickens, things that Harold actually worked on as a post doc and helped develop the field; they’ve essentially done the experiments in other animals and identified the oncogenes for us, so we’re finding relatively few oncogenes that we didn’t already know about from these mutational events, but I think it’s still going to be extremely valuable.
Dr. Siddhartha Mukherjee: Do you share the disappointment about the Cancer Genome Project Harold?
Dr. Harold Varmus: No, but I would point out a few things building on what Lou just said. First we knew about the RAS genes of course well before the Cancer Genome Projects, but we knew about RAS genes and the mutations that arise in them very frequently in pancreatic, lung and colon cancer even before there was a Human Genome Project because we knew about that in the early 80s, so I think it’s useful to remind people of that because here is a tremendously attractive target for developing drugs, even for thinking about ways to diagnose cancers early and we really have had a hard time capitalizing that over the last 30 years and that is a good reminder of how difficult this all is.
The second point I’d make is that, yes, I agree that we have of course rediscovered in the Cancer Genome Atlas Project and other efforts of genomics of cancers that the oncogenes we knew about because they’re relatives of the retroviral cancer genes, sure, they’re involved quite frequently as our well know so called tumor suppressor genes. But we’re getting a much better picture of what the real complexity of cancer might be. Secondly, there are new methods that extend our ability to analyze a genome well beyond just looking for small mutations. There are some very important rearrangements. We were talking earlier about prostate cancer and one of the things that I think is a pretty good indicator of the danger of a prostate cancer can be seen by finding a rejoining of chromosomes that generates a new gene that seems to be a driver of prostate cancers and that's the kind of thing that would have been very difficult to discover without this concerted effort that is going on.
Third, there are actually changes in the genome that are not mutational. They affect the way DNA is modified by chemical processes and the way in which DNA is expressed because of changes in the proteins that coat DNA and allow genes to be expressed. Very recently there have been a surprising set of mutations that govern what we call the methylations, a kind of chemical addition to DNA that governs gene expression that is regulated by a series of enzymes and coated by genes we would not historically have thought of as oncogenes and it’s clear from some recent work about an adult leukemia called acute myeloid leukemia that these genes are playing a very important role in that disease and represent another kind of target for therapy and a way to think about diagnosis, so I think there are a lot of rather surprising things that are coming out of this and the picture, the full picture of genomic change is really very dramatic and quite wonderful.
Dr. Lewis Cantley: So if I could just add one additional thing. I don’t want to leave the impression I'm disappointed or we shouldn’t have done that, and of course the mutations that Harold was talking about I think are very exciting. It really has opened up the field, but it’s still a relatively minor subset of cancers that are involved in gliomas and AMLs.
Dr. Harold Varmus: Well I think we don’t know yet.
Dr. Lewis Cantley: Well there is- Yeah, anyway, that is definitely helping us out, but I think the other thing that we’re going to get from this is biomarkers that will allow us to do much smarter clinical trials, so that we do a clinical trial and 15% of the patients respond. If you don’t have thousands and thousands of patients it’s hard to prove that that 15% is actually relevant and the drug may fail to be approved even spite of a huge investment in the trial and many, many years and there is examples of that that we know of where it was very clear to the clinicians the drug was working, but it still didn’t get approved, so if we can design trials where we tease out early on who is going to respond and who isn’t then that 15% becomes the 100% because you only do the trial on them. They’re defined by their mutational status, the so called biomarkers that- these are biomarker-driven trials, so I think that is going to be a tremendous advantage coming out of this.
Dr. Harold Varmus: If I can make one comment about the clinical trials because this is of great interest to the public. One reason we were so successful with pediatric cancers, developing chemotherapies that cure a large fraction of pediatric cancers is because virtually every kid came to a cancer center, was entered in a clinical trial and over the course of many years a lot of disappointments, heartache, and a lot of loss of life because these cancers are very, very difficult to treat, we finally emerged with a set of principles and operating procedures for treating these kids effectively. We’ve been much less successful with adult therapy and one of the reasons I think is because the heterogeneity of the tumors as Lou is describing. The Cancer Institute is currently reorganizing its clinical trial system in a way that is designed to take advantage of the point that Lou is making. For example, in treatment of lung cancer we know that a small fraction are susceptible to inhibitors of mutant kinases and one of the drugs erlotinib just barely squeaked through its first clinical trial because they were enough patients with that mutation in their tumors. Another very similar drug didn’t squeak through because it had too many people who didn’t have that mutation and now that the Cancer Genome analysis is giving us the tools to so called stratify these patients I think all of us believe there can be much smarter trials set up, faster trials, trials that give us much more effective information about how to treat.
The Cancer Genome Atlas project, already several years underway, is transforming the way scientists think about and treat cancer.
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The world's 10 most affected countries are spending up to 59% of their GDP on the effects of violence.
- Conflict and violence cost the world more than $14 trillion a year.
- That's the equivalent of $5 a day for every person on the planet.
- Research shows that peace brings prosperity, lower inflation and more jobs.
- Just a 2% reduction in conflict would free up as much money as the global aid budget.
- Report urges governments to improve peacefulness, especially amid COVID-19.
The lush biodiversity of South America's rainforests is rooted in one of the most cataclysmic events that ever struck Earth.
- One especially mysterious thing about the asteroid impact, which killed the dinosaurs, is how it transformed Earth's tropical rainforests.
- A recent study analyzed ancient fossils collected in modern-day Colombia to determine how tropical rainforests changed after the bolide impact.
- The results highlight how nature is able to recover from cataclysmic events, though it may take millions of years.
Evolution doesn't clean up after itself very well.
- An evolutionary biologist got people swapping ideas about our lingering vestigia.
- Basically, this is the stuff that served some evolutionary purpose at some point, but now is kind of, well, extra.
- Here are the six traits that inaugurated the fun.
The plica semilunaris<img class="rm-lazyloadable-image rm-shortcode" type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTA5NjgwMS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY3NDg5NTg1NX0.kdBYMvaEzvCiJjcLEPgnjII_KVtT9RMEwJFuXB68D8Q/img.png?width=980" id="59914" width="429" height="350" data-rm-shortcode-id="b11e4be64c5e1f58bf4417d8548bedc7" data-rm-shortcode-name="rebelmouse-image" />
The human eye in alarming detail. Image source: Henry Gray / Wikimedia commons<p>At the inner corner of our eyes, closest to the nasal ridge, is that little pink thing, which is probably what most of us call it, called the caruncula. Next to it is the plica semilunairs, and it's what's left of a third eyelid that used to — ready for this? — blink horizontally. It's supposed to have offered protection for our eyes, and some birds, reptiles, and fish have such a thing.</p>
Palmaris longus<img class="rm-lazyloadable-image rm-shortcode" type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTA5NjgwNy9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYzMzQ1NjUwMn0.dVor41tO_NeLkGY9Tx46SwqhSVaA8HZQmQAp532xLxA/img.jpg?width=980" id="879be" width="1920" height="2560" data-rm-shortcode-id="4089a32ea9fbb1a0281db14332583ccd" data-rm-shortcode-name="rebelmouse-image" />
Palmaris longus muscle. Image source: Wikimedia commons<p> We don't have much need these days, at least most of us, to navigate from tree branch to tree branch. Still, about 86 percent of us still have the wrist muscle that used to help us do it. To see if you have it, place the back of you hand on a flat surface and touch your thumb to your pinkie. If you have a muscle that becomes visible in your wrist, that's the palmaris longus. If you don't, consider yourself more evolved (just joking).</p>
Darwin's tubercle<img class="rm-lazyloadable-image rm-shortcode" type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTA5NjgxMi9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY0ODUyNjA1MX0.8RuU-OSRf92wQpaPPJtvFreOVvicEwn39_jnbegiUOk/img.jpg?width=980" id="687a0" width="819" height="1072" data-rm-shortcode-id="ff5edf0a698e0681d11efde1d7872958" data-rm-shortcode-name="rebelmouse-image" />
Darwin's tubercle. Image source: Wikimedia commons<p> Yes, maybe the shell of you ear does feel like a dried apricot. Maybe not. But there's a ridge in that swirly structure that's a muscle which allowed us, at one point, to move our ears in the direction of interesting sounds. These days, we just turn our heads, but there it is.</p>
Goosebumps<img class="rm-lazyloadable-image rm-shortcode" type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTA5NzMxNC9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYyNzEyNTc2Nn0.aVMa5fsKgiabW5vkr7BOvm2pmNKbLJF_50bwvd4aRo4/img.jpg?width=980" id="d8420" width="1440" height="960" data-rm-shortcode-id="8827e55511c8c3aed8c36d21b6541dbd" data-rm-shortcode-name="rebelmouse-image" />
Goosebumps. Photo credit: Tyler Olson via Shutterstock<p>It's not entirely clear what purpose made goosebumps worth retaining evolutionarily, but there are two circumstances in which they appear: fear and cold. For fear, they may have been a way of making body hair stand up so we'd appear larger to predators, much the way a cat's tail puffs up — numerous creatures exaggerate their size when threatened. In the cold, they may have trapped additional heat for warmth.</p>
Tailbone<img class="rm-lazyloadable-image rm-shortcode" type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTA5NzMxNi9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY3MzQwMjc3N30.nBGAfc_O9sgyK_lOUo_MHzP1vK-9kJpohLlj9ax1P8s/img.jpg?width=980" id="9a2f6" width="1440" height="1440" data-rm-shortcode-id="4fe28368d2ed6a91a4c928d4254cc02a" data-rm-shortcode-name="rebelmouse-image" />
Image source: Decade3d-anatomy online via Shutterstock<p>Way back, we had tails that probably helped us balance upright, and was useful moving through trees. We still have the stump of one when we're embryos, from 4–6 weeks, and then the body mostly dissolves it during Weeks 6–8. What's left is the coccyx.</p>
The palmar grasp reflex<img class="rm-lazyloadable-image rm-shortcode" type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTA5NzMyMC9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYzNjY0MDY5NX0.OSwReKLmNZkbAS12-AvRaxgCM7zyukjQUaG4vmhxTtM/img.jpg?width=980" id="8804c" width="1440" height="960" data-rm-shortcode-id="67542ee1c5a85807b0a7e63399e44575" data-rm-shortcode-name="rebelmouse-image" />
Palmar reflex activated! Photo credit: Raul Luna on Flickr<p> You've probably seen how non-human primate babies grab onto their parents' hands to be carried around. We used to do this, too. So still, if you touch your finger to a baby's palm, or if you touch the sole of their foot, the palmar grasp reflex will cause the hand or foot to try and close around your finger.</p>
Other people's suggestions<p>Amir's followers dove right in, offering both cool and questionable additions to her list. </p>
Fangs?<blockquote class="twitter-tweet" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">Lower mouth plate behind your teeth. Some have protruding bone under the skin which is a throw back to large fangs. Almost like an upsidedown Sabre Tooth.</p>— neil crud (@neilcrud66) <a href="https://twitter.com/neilcrud66/status/1085606005000601600?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
Hiccups<blockquote class="twitter-tweet" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">Sure: <a href="https://t.co/DjMZB1XidG">https://t.co/DjMZB1XidG</a></p>— Stephen Roughley (@SteBobRoughley) <a href="https://twitter.com/SteBobRoughley/status/1085529239556968448?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
Hypnic jerk as you fall asleep<blockquote class="twitter-tweet" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">What about when you “jump” just as you’re drifting off to sleep, I heard that was a reflex to prevent falling from heights.</p>— Bann face (@thebanns) <a href="https://twitter.com/thebanns/status/1085554171879788545?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script> <p> This thing, often called the "alpha jerk" as you drop into alpha sleep, is properly called the hypnic jerk,. It may actually be a carryover from our arboreal days. The <a href="https://www.livescience.com/39225-why-people-twitch-falling-asleep.html" target="_blank" data-vivaldi-spatnav-clickable="1">hypothesis</a> is that you suddenly jerk awake to avoid falling out of your tree.</p>
Nails screeching on a blackboard response?<blockquote class="twitter-tweet" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">Everyone hate the sound of fingernails on a blackboard. It's _speculated_ that this is a vestigial wiring in our head, because the sound is similar to the shrill warning call of a chimp. <a href="https://t.co/ReyZBy6XNN">https://t.co/ReyZBy6XNN</a></p>— Pet Rock (@eclogiter) <a href="https://twitter.com/eclogiter/status/1085587006258888706?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
Ear hair<blockquote class="twitter-tweet" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">Ok what is Hair in the ears for? I think cuz as we get older it filters out the BS.</p>— Sarah21 (@mimix3) <a href="https://twitter.com/mimix3/status/1085684393593561088?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
Nervous laughter<blockquote class="twitter-tweet" data-lang="en"><p lang="en" dir="ltr">You may be onto something. Tooth-bearing with the jaw clenched is generally recognized as a signal of submission or non-threatening in primates. Involuntary smiling or laughing in tense situations might have signaled that you weren’t a threat.</p>— Jager Tusk (@JagerTusk) <a href="https://twitter.com/JagerTusk/status/1085316201104912384?ref_src=twsrc%5Etfw">January 15, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
Um, yipes.<blockquote class="twitter-tweet" data-conversation="none" data-lang="en"><p lang="en" dir="ltr">Sometimes it feels like my big toe should be on the side of my foot, was that ever a thing?</p>— B033? K@($ (@whimbrel17) <a href="https://twitter.com/whimbrel17/status/1085559016011563009?ref_src=twsrc%5Etfw">January 16, 2019</a></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>
Global inequality takes many forms, including who has lost the most children
- A first-of-its-kind study examines the number of mothers who have lost a child around the world.
- The number is related to infant mortality rates in a country but is not identical to it.
- The lack of information on the topic leaves a lot of room for future research.