A Little Crispr
It is always fascinating to discover new things, especially when they are about subjects that you sort of thought that you knew well. Take apples for instance; you bite into one and in the middle are all those seeds and one would think that if you're eating say an Ambrosia variety of apple, you could plant one of those seeds and with just a little luck you would soon have an apple tree that would give you Ambrosia apples some years later. Nay. nay, for apples are one of the most unpredictable fruits around and the odds are almost nil that a seed from that apple you're eating will produce the same type of apple (almost all commercial apples are grown from grafting onto another tree). And speaking of apples, can you think of an apple that is sweet and ripens quickly and yet millions of tons of them are thrown away each year primarily because they're too fragile to ship? If you're stumped it's with good reason for this apple produces its single seed on the outside, the bottom in fact, and its seed's covering is so toxic that even roasting it to get to the seed inside that covering produces smoke that is toxic to breathe. It is, of course, the tiny nut we call the cashew. Much of these tidbits come from the series How Does It Grow which shows quick 2-3 minute blips about the background of many of the foods that we eat, including asking such questions as "is there a canola flower?" to which the answer is "no" (watch the clip to find out about what canola oil really is and where this always-processed oil comes from).
Or here's another little discovery to me, this about sending a satellite to Pluto and taken from a book highlighting some of the Moth podcasts over the years. No big deal there except that the rockets used to send that probe have been improving through the years says story teller Cathy Olkin: To put that in perspective, when the Apollo astronauts went to the moon, it took over three days. For New Horizons the spacecraft passed the moon in just nine hours...But it will take the spacecraft nine and a half years to go from earth to Pluto. Then a signal arrives from the satellite's main computer that something is wrong and it is shutting down and sending everything to the backup computer. The signal takes 4.5 hours to reach earth, the same amount of time it takes for engineers to send a signal back to the computer to ask what is wrong. So it's like a really slow conversation. Imagine you say "hi" to someone, then you go watch three football games, and you come back and they say "hi" back. That's the kind of data rates we were getting. One small problem, the satellite was only 10 days away from arriving at Pluto; miss that window and the satellite would sail past Pluto without blinking (due to the speed of the probe, they could only do a fly-by and could not slow down enough to orbit Pluto). But back to the launch rockets. We see them take off and well, they sort of look the same don't they? But it makes sense, for if our cars are lighter and getting more fuel efficient, why not the launch rockets? It was just something I had never considered, that launch rockets would have become that much more powerful. So it was almost odd that on that same day of finishing that book, I happened to read a question in Smithsonian that talked about our learning about 3 kinds of matter in school: solids, liquids and gases. Well guess what, there's a 4th and it's "the most common state of matter in the universe"...plasma. Says the magazine: Like gases, plasmas have no fixed shape or volume; but unlike gases, which are electrically neutral, plasmas are positively charged. That charge allows plasmas to behave in ways gases can’t. The glow of a neon sign? That’s plasma at work, as is the image on your plasma TV screen. Wait, the most common state of matter in all of the universe and we've never learned that?
But also in that issue was the discussion of a new field of metagenomics which is the studying of bacteria in ancient DNA samples to try and recreate a better picture of history (in this case, the path Hannibal took in his surprise attack on the Romans, the one you read about in history in which hoards of both horses and elephants crossed the mountains); the study of bacteria is complicated but basically the author writes about microbiologist Chris Allen: By examining sediment from two cores and a trench—mostly soil matted with decomposed plant fiber—Allen and his crew have identified genetic materials that contain high concentrations of DNA fragments from Clostridia, bacteria that typically make up only 2 or 3 percent of peat microbes, but more than 70 percent of those found in the gut of horses. The bed of excrement also contained unusual levels of bile acids and fatty compounds found in the digestive tracts of horses and ruminants. Allen is most excited about having isolated parasite eggs—associated with gut tapeworms—preserved in the site like tiny genetic time capsules. “The DNA detected in the mire was protected in bacterial endospores that can survive in soil for thousands of years,” he says. Okay two things there jumped out at me...one, the detective-like piecing together of dirt to discover preserved bile and bacteria, and two, the ability of DNA to survive thousands of years without deconstructing. Again, all of this was far beyond my understanding but interesting to me because I just sent off my saliva to have my own DNA broken down, the exome to be specific (as the Helix lab* group describes it, "the part of your genetic code that instructs how your body works...every letter of 22,000 protein-coded genes."). None of this would have evolved except that at this point late in my life, I discovered that my blood dad was actually adopted and so much of what we thought we knew about his family is well, relatively (pardon the pun) unknown. Which begs the questions, who then am I?
Silly questions all, but again interesting because of the speed with which all of this personal decoding of your DNA can now be done. Beyond one's ancestry there can now be found one's genetic propensity to disease and fitness, fertility and what your body can or cannot absorb (my doc thankfully ran my first and only blood test for vitamin D and discovered that my body seems to resist absorbing it in most any fashion, be it from sunlight or milk or vegetables, all of which I take in voluminously). What other surprises might await me? The question might be reworded to ask, what other surprises might await you? But this isn't about testing or not testing one's DNA or delving into one's ancestry. Coming soon, and at even less expense is genetic manipulation, genetic snippets that you can cut and reform and customize to your heart's pleasure, possibly in your own home...and governments and scientists are growing worried.
It's called CRISPR and more specifically CRISPR-Cas9, and for a quick explanation (and you microbiologists out there, please forgive me for this truncated version), it involves manually doing what viruses and bacteria have done for ages, that of changing our genetic code by snipping and replacing certain portions (think of an attack by a virus and how your body adapts to that with your immune system). Backing up a bit, RNA is one strand of our genetic code (those ATCG letters you always see); wrap two of those strands together and you have...DNA (keep that in mind for later). For decades, scientists have struggled to breakdown our genetic coding (partial success) but snipping out any bad coding (say a disease such as malaria) and inserting another piece of coding was almost a moral question of entering an era of eugenics. The arguments pro and con are many, for if you could eliminate a disease (already being done with mosquitoes), could you also manipulate the genetics enough to say produce a leaner, less-fatty pig for eating (already being done). But why stop there? Could you target eliminating sickle cell anemia in humans (being worked on) or maybe even cancer (being worked on); and what about creating a super-athlete or a genius (hmm, eugenics)? Wait, wouldn't any or all of this be considered genetic modification (as in a GMO product)? Turns out...no, or at least not yet, even though many of the products are already on or scheduled to arrive on our shelves. Already in the works, bananas (yes, the popular Cavandish, so common worldwide, is on the verge of extinction due to a ravaging disease so genetic manipulation is being hurried along), soy, corn, wheat (most for drought-tolerance in anticipation of a dryer, hotter climate, but some are adding vitamins and resistance to diseases), perfumes (yup, synthetic new-smelling oils are just one of the products produced by Boston-based Ginko Bioworks; said Fortune in an article this past February: Fueled by $154 million from investors, Ginko recently opened its second "foundry," an 18,000-suqare-foot factory stocked with fermentation tanks, mass spectrometers, software, robots, and traditional bench biology tools to design, build, and test DNA), even allergen-free peanuts.
To attempt to explain CRISPR and Cas-9 in such a short post would be to simplify a very detailed evolutionary trait. But quickly here's an attempt in an article from Discover: 1. Bacterial DNA has unusual repeating sequences that are separated by spacers--short, non-coding segments sometimes inappropriately called “junk DNA.” These repeating sequences have been dubbed CRISPR (or Crispr), for Clustered Regularly Interspaced Short Palindromic Repeats. Near each Crispr sequence are genes for a variety of Cas (Crispr-associated) enzymes, including Cas9. 2. When faced with an external threat such as an invading virus, Cas enzymes produce a kind of “most wanted” poster: They snip off bits of the invading viral DNA and stuff them into the spacers, where they can be used as RNA guides to recognize future invaders. Researchers use this natural defense mechanism in bacteria as the basis for the Crispr-Cas9 gene-editing system, creating synthetic guides to search out whichever specific string of DNA bases the researchers choose. You can think of the system in two parts: the guiding Crispr and the cutting Cas9 enzyme. 3. When the guide-RNA locates its target DNA, it latches on, and then Cas9 cleaves through both strands of the DNA double helix. T he cut DNA is then either left as-is, silencing it, or repaired by using the gene editor to slip in a new, functioning segment. Phew, and that was the "easy" explanation.
So, could we produce a super-human, or could a terrorist produce introduce a deadly disease into a carrier such a mosquito (scientists are working on the opposite, that of taking out the ability of mosquitoes to obtain the ability to spread diseases such as the Zika virus or malaria). Home do-it-yourself kits are now available on the internet (last peek at about $65); and the UK, Sweden and China have already approved testing on human embryos. The large chocolate companies Mars and Hershey's are working on their own products (the gene sequence for cocao was cracked in 2010), and other gene-manipulated foods from strawberries to broccoli are already on, or about to be on, the market (so far, no additional labeling is required, the reasoning being genes have only been removed and not added). Type in the word "CRISPR" or "diagram CRISPR" or any of a variety of gene-editing questions in your search browser and you'll see magazine after magazine (or book after book) trying to play catch-up on this rapidly changing technology. And there's a lot of good potential out there; one article from way back in Discover told of Joanne Weidhaas and Frank Slack (at the time, biologists working at Yale University) discovering the KRAS-variant. The what?? Says the article: This biomarker, called the KRAS-variant, is linked to more cancers than any other known inherited genetic mutation. It is present in 1 out of every 4 people with cancer, and in more than half of people who develop multiple cancers. KRAS-variant carriers tend to get highly aggressive and recurrent breast, ovarian, head and neck, lung and pancreatic cancers. The KRAS-variant mutation is also relatively common in the population at large; about 1 person in 20 carries it. By comparison, the better-known breast cancer mutations, BRCA1 and 2, are found in 1 in 400. Yet despite the dangers of the KRAS-variant mutation, few doctors, let alone patients, have heard of it. Imagine the benefits of removing that marker in your genetics pool.
Which begs the question, would you want to know? This field is still so new that hearing terms played down to "easy" and "cheap" riles some scientists. As reviewer Steve Rose wrote in The London Review of Books: The problem lies in the common misconception of genes as ‘master molecules’ directing the operation of the cells in which they reside. In fact DNA is a rather inert molecule, as it has to be if it is to serve as a code. It is the cells that do the work. Cellular enzymes read, edit, cut and paste, transcribe and translate segments of DNA--the literary metaphor, universally employed by molecular biologists, isn’t accidental; they think of DNA as the language in which the Book of Life is written--in a scheduled flow during the development of the foetus, according to whether the cells are destined to become liver or brain, blood or bone. No gene works in isolation but as part of a collaboration. Many genes may be required to produce a single phenotype --more than fifty main gene variants have been shown to affect the chances that someone will contract coronary heart disease, for example-- and a particular gene may influence many different phenotypic traits, depending on which organ’s cells it is active in. It is during this period of rapid growth that living organisms are at their most plastic, responding to environmental challenges by modifying anatomical, biochemical, physiological or behavioural phenotypic traits. This is epigenetic canalisation.
So can you manipulate a virus for ill-purposes (so far, no), and can you do all this in your kitchen sink with a kit (so far, no). Discovering and manipulating genes with CRISPR is far more complicated that you or I could imagine, and a TED presentation by Ellen Jorgensen and another by geneticist Jennifer Douda do excellent jobs of quickly explaining the pros and cons (and fears) of CRISPR (the 15 minutes of your time will be well worth it). As Ellen Jorgensen opens her talk, "So, has everybody heard of CRISPR?" And for a bit more detailed version, check out Matthew Cobb's summary in the New York Review of Books, one in which he explores many of the ethical considerations of tinkering with our future generations: The problem with a gene drive is that it is essentially a biological bomb that could have all sorts of unintended consequences. If we make the mosquito inhospitable to the malaria parasite, we might find that, just as with the overuse of antibiotics, the parasite mutates in such a way that it can evade the effects of the gene drive; this change could also mean that it is immune to our current antimalarial drugs. Meanwhile, the alternative approach of eradicating the mosquito from a particular environment, as Doudna and Sternberg point out, may lead to unexpected changes in the ecology of the region—we simply do not know enough about ecology to be able to predict what will happen.
Okay, this has turned out to be quite a bit longer than even I expected, which only goes to show what happens when one tries to simplify such a detailed subject. But it is happening; in fact the first human CRISPR baby is expected to be born within a few years. Disease-free or more (new) disease-prone? Will the world of CRISPR hackers soon surpass the world of computer hackers? Will my own genetic marker results be as useless as a dated VHS tape? Who knows, it's both exciting and overwhelming, all of these advances and the speed at which it is happening. So let me bring you back to earth, back to the ground, back to where none of this really matters or more importantly, back to where you can discover in yourself what really matters. We are all the same at some point, even with our genetic differences; but sometimes all we want to do is just go home. So take 12 minutes of your time to listen to a story from The Moth, a true story of finding home...you may discover that home is worth all the genetic changes in the world.
*Occasionally the Helix/National Geographic kit will appear at 50% off the regular pricing...which is when I took advantage of the offer.
Or here's another little discovery to me, this about sending a satellite to Pluto and taken from a book highlighting some of the Moth podcasts over the years. No big deal there except that the rockets used to send that probe have been improving through the years says story teller Cathy Olkin: To put that in perspective, when the Apollo astronauts went to the moon, it took over three days. For New Horizons the spacecraft passed the moon in just nine hours...But it will take the spacecraft nine and a half years to go from earth to Pluto. Then a signal arrives from the satellite's main computer that something is wrong and it is shutting down and sending everything to the backup computer. The signal takes 4.5 hours to reach earth, the same amount of time it takes for engineers to send a signal back to the computer to ask what is wrong. So it's like a really slow conversation. Imagine you say "hi" to someone, then you go watch three football games, and you come back and they say "hi" back. That's the kind of data rates we were getting. One small problem, the satellite was only 10 days away from arriving at Pluto; miss that window and the satellite would sail past Pluto without blinking (due to the speed of the probe, they could only do a fly-by and could not slow down enough to orbit Pluto). But back to the launch rockets. We see them take off and well, they sort of look the same don't they? But it makes sense, for if our cars are lighter and getting more fuel efficient, why not the launch rockets? It was just something I had never considered, that launch rockets would have become that much more powerful. So it was almost odd that on that same day of finishing that book, I happened to read a question in Smithsonian that talked about our learning about 3 kinds of matter in school: solids, liquids and gases. Well guess what, there's a 4th and it's "the most common state of matter in the universe"...plasma. Says the magazine: Like gases, plasmas have no fixed shape or volume; but unlike gases, which are electrically neutral, plasmas are positively charged. That charge allows plasmas to behave in ways gases can’t. The glow of a neon sign? That’s plasma at work, as is the image on your plasma TV screen. Wait, the most common state of matter in all of the universe and we've never learned that?
But also in that issue was the discussion of a new field of metagenomics which is the studying of bacteria in ancient DNA samples to try and recreate a better picture of history (in this case, the path Hannibal took in his surprise attack on the Romans, the one you read about in history in which hoards of both horses and elephants crossed the mountains); the study of bacteria is complicated but basically the author writes about microbiologist Chris Allen: By examining sediment from two cores and a trench—mostly soil matted with decomposed plant fiber—Allen and his crew have identified genetic materials that contain high concentrations of DNA fragments from Clostridia, bacteria that typically make up only 2 or 3 percent of peat microbes, but more than 70 percent of those found in the gut of horses. The bed of excrement also contained unusual levels of bile acids and fatty compounds found in the digestive tracts of horses and ruminants. Allen is most excited about having isolated parasite eggs—associated with gut tapeworms—preserved in the site like tiny genetic time capsules. “The DNA detected in the mire was protected in bacterial endospores that can survive in soil for thousands of years,” he says. Okay two things there jumped out at me...one, the detective-like piecing together of dirt to discover preserved bile and bacteria, and two, the ability of DNA to survive thousands of years without deconstructing. Again, all of this was far beyond my understanding but interesting to me because I just sent off my saliva to have my own DNA broken down, the exome to be specific (as the Helix lab* group describes it, "the part of your genetic code that instructs how your body works...every letter of 22,000 protein-coded genes."). None of this would have evolved except that at this point late in my life, I discovered that my blood dad was actually adopted and so much of what we thought we knew about his family is well, relatively (pardon the pun) unknown. Which begs the questions, who then am I?
Silly questions all, but again interesting because of the speed with which all of this personal decoding of your DNA can now be done. Beyond one's ancestry there can now be found one's genetic propensity to disease and fitness, fertility and what your body can or cannot absorb (my doc thankfully ran my first and only blood test for vitamin D and discovered that my body seems to resist absorbing it in most any fashion, be it from sunlight or milk or vegetables, all of which I take in voluminously). What other surprises might await me? The question might be reworded to ask, what other surprises might await you? But this isn't about testing or not testing one's DNA or delving into one's ancestry. Coming soon, and at even less expense is genetic manipulation, genetic snippets that you can cut and reform and customize to your heart's pleasure, possibly in your own home...and governments and scientists are growing worried.
It's called CRISPR and more specifically CRISPR-Cas9, and for a quick explanation (and you microbiologists out there, please forgive me for this truncated version), it involves manually doing what viruses and bacteria have done for ages, that of changing our genetic code by snipping and replacing certain portions (think of an attack by a virus and how your body adapts to that with your immune system). Backing up a bit, RNA is one strand of our genetic code (those ATCG letters you always see); wrap two of those strands together and you have...DNA (keep that in mind for later). For decades, scientists have struggled to breakdown our genetic coding (partial success) but snipping out any bad coding (say a disease such as malaria) and inserting another piece of coding was almost a moral question of entering an era of eugenics. The arguments pro and con are many, for if you could eliminate a disease (already being done with mosquitoes), could you also manipulate the genetics enough to say produce a leaner, less-fatty pig for eating (already being done). But why stop there? Could you target eliminating sickle cell anemia in humans (being worked on) or maybe even cancer (being worked on); and what about creating a super-athlete or a genius (hmm, eugenics)? Wait, wouldn't any or all of this be considered genetic modification (as in a GMO product)? Turns out...no, or at least not yet, even though many of the products are already on or scheduled to arrive on our shelves. Already in the works, bananas (yes, the popular Cavandish, so common worldwide, is on the verge of extinction due to a ravaging disease so genetic manipulation is being hurried along), soy, corn, wheat (most for drought-tolerance in anticipation of a dryer, hotter climate, but some are adding vitamins and resistance to diseases), perfumes (yup, synthetic new-smelling oils are just one of the products produced by Boston-based Ginko Bioworks; said Fortune in an article this past February: Fueled by $154 million from investors, Ginko recently opened its second "foundry," an 18,000-suqare-foot factory stocked with fermentation tanks, mass spectrometers, software, robots, and traditional bench biology tools to design, build, and test DNA), even allergen-free peanuts.
To attempt to explain CRISPR and Cas-9 in such a short post would be to simplify a very detailed evolutionary trait. But quickly here's an attempt in an article from Discover: 1. Bacterial DNA has unusual repeating sequences that are separated by spacers--short, non-coding segments sometimes inappropriately called “junk DNA.” These repeating sequences have been dubbed CRISPR (or Crispr), for Clustered Regularly Interspaced Short Palindromic Repeats. Near each Crispr sequence are genes for a variety of Cas (Crispr-associated) enzymes, including Cas9. 2. When faced with an external threat such as an invading virus, Cas enzymes produce a kind of “most wanted” poster: They snip off bits of the invading viral DNA and stuff them into the spacers, where they can be used as RNA guides to recognize future invaders. Researchers use this natural defense mechanism in bacteria as the basis for the Crispr-Cas9 gene-editing system, creating synthetic guides to search out whichever specific string of DNA bases the researchers choose. You can think of the system in two parts: the guiding Crispr and the cutting Cas9 enzyme. 3. When the guide-RNA locates its target DNA, it latches on, and then Cas9 cleaves through both strands of the DNA double helix. T he cut DNA is then either left as-is, silencing it, or repaired by using the gene editor to slip in a new, functioning segment. Phew, and that was the "easy" explanation.
So, could we produce a super-human, or could a terrorist produce introduce a deadly disease into a carrier such a mosquito (scientists are working on the opposite, that of taking out the ability of mosquitoes to obtain the ability to spread diseases such as the Zika virus or malaria). Home do-it-yourself kits are now available on the internet (last peek at about $65); and the UK, Sweden and China have already approved testing on human embryos. The large chocolate companies Mars and Hershey's are working on their own products (the gene sequence for cocao was cracked in 2010), and other gene-manipulated foods from strawberries to broccoli are already on, or about to be on, the market (so far, no additional labeling is required, the reasoning being genes have only been removed and not added). Type in the word "CRISPR" or "diagram CRISPR" or any of a variety of gene-editing questions in your search browser and you'll see magazine after magazine (or book after book) trying to play catch-up on this rapidly changing technology. And there's a lot of good potential out there; one article from way back in Discover told of Joanne Weidhaas and Frank Slack (at the time, biologists working at Yale University) discovering the KRAS-variant. The what?? Says the article: This biomarker, called the KRAS-variant, is linked to more cancers than any other known inherited genetic mutation. It is present in 1 out of every 4 people with cancer, and in more than half of people who develop multiple cancers. KRAS-variant carriers tend to get highly aggressive and recurrent breast, ovarian, head and neck, lung and pancreatic cancers. The KRAS-variant mutation is also relatively common in the population at large; about 1 person in 20 carries it. By comparison, the better-known breast cancer mutations, BRCA1 and 2, are found in 1 in 400. Yet despite the dangers of the KRAS-variant mutation, few doctors, let alone patients, have heard of it. Imagine the benefits of removing that marker in your genetics pool.
Which begs the question, would you want to know? This field is still so new that hearing terms played down to "easy" and "cheap" riles some scientists. As reviewer Steve Rose wrote in The London Review of Books: The problem lies in the common misconception of genes as ‘master molecules’ directing the operation of the cells in which they reside. In fact DNA is a rather inert molecule, as it has to be if it is to serve as a code. It is the cells that do the work. Cellular enzymes read, edit, cut and paste, transcribe and translate segments of DNA--the literary metaphor, universally employed by molecular biologists, isn’t accidental; they think of DNA as the language in which the Book of Life is written--in a scheduled flow during the development of the foetus, according to whether the cells are destined to become liver or brain, blood or bone. No gene works in isolation but as part of a collaboration. Many genes may be required to produce a single phenotype --more than fifty main gene variants have been shown to affect the chances that someone will contract coronary heart disease, for example-- and a particular gene may influence many different phenotypic traits, depending on which organ’s cells it is active in. It is during this period of rapid growth that living organisms are at their most plastic, responding to environmental challenges by modifying anatomical, biochemical, physiological or behavioural phenotypic traits. This is epigenetic canalisation.
So can you manipulate a virus for ill-purposes (so far, no), and can you do all this in your kitchen sink with a kit (so far, no). Discovering and manipulating genes with CRISPR is far more complicated that you or I could imagine, and a TED presentation by Ellen Jorgensen and another by geneticist Jennifer Douda do excellent jobs of quickly explaining the pros and cons (and fears) of CRISPR (the 15 minutes of your time will be well worth it). As Ellen Jorgensen opens her talk, "So, has everybody heard of CRISPR?" And for a bit more detailed version, check out Matthew Cobb's summary in the New York Review of Books, one in which he explores many of the ethical considerations of tinkering with our future generations: The problem with a gene drive is that it is essentially a biological bomb that could have all sorts of unintended consequences. If we make the mosquito inhospitable to the malaria parasite, we might find that, just as with the overuse of antibiotics, the parasite mutates in such a way that it can evade the effects of the gene drive; this change could also mean that it is immune to our current antimalarial drugs. Meanwhile, the alternative approach of eradicating the mosquito from a particular environment, as Doudna and Sternberg point out, may lead to unexpected changes in the ecology of the region—we simply do not know enough about ecology to be able to predict what will happen.
Okay, this has turned out to be quite a bit longer than even I expected, which only goes to show what happens when one tries to simplify such a detailed subject. But it is happening; in fact the first human CRISPR baby is expected to be born within a few years. Disease-free or more (new) disease-prone? Will the world of CRISPR hackers soon surpass the world of computer hackers? Will my own genetic marker results be as useless as a dated VHS tape? Who knows, it's both exciting and overwhelming, all of these advances and the speed at which it is happening. So let me bring you back to earth, back to the ground, back to where none of this really matters or more importantly, back to where you can discover in yourself what really matters. We are all the same at some point, even with our genetic differences; but sometimes all we want to do is just go home. So take 12 minutes of your time to listen to a story from The Moth, a true story of finding home...you may discover that home is worth all the genetic changes in the world.
*Occasionally the Helix/National Geographic kit will appear at 50% off the regular pricing...which is when I took advantage of the offer.
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