curiosity and the CRISPR controversy

Image Credit

Not that kind of crisper. 

CRISPR is an acronym for a gene editing technique that has been cited as one of the most important biomedical discoveries of our time. Although it is not yet being used to genetically modify human embryos (think designer babies), it is only a matter a time (an initial attempt was made in China). What the acronym stands for is a bit of a science word sandwich (a clever description of complex scientific terms I recently heard listening to TWiEVO). Essentially, CRISPR is a region of DNA in bacteria that works in conjunction with an enzyme, Cas9, that is capable of cutting double-stranded DNA (the DNA comprising your chromosomes) and editing the DNA sequence. The coverage of CRISPR in the popular media has been extensive.

The reason I planned to bring up CRISPR was because of a review article published in the journal Cell on January 14^th. Its relevance here was immediately apparent due to its goal of reviewing 30 years of discoveries that led to the widespread use of CRISPR as the most effective and efficient gene editing system to date. And, unlike most reviews published in high profile peer-reviewed scientific journals, the author included personal narratives for some of the significant players. Originally my intention was to point it out and move on. I was actually going to do it last week when I was on vacation and didn’t have a lot of time to write.

And then there was the ‘Twitter storm’. The author of the Cell paper, Eric Lander, got called out in a huge way. And these were not just a few mumblings here and there, it was by major players in the field of molecular biology. The tweets got attention and eventually led to this and this.  So I took a closer look. There are essentially two labs vying for the intellectual property rights of CRISPR and they are in an ongoing patent dispute. On one side is Jennifer Doudna (UC Berkeley) and Emanuelle Charpentier (Max Planck); on the other is Feng Zhang (Broad Institute of MIT and Harvard - of which Eric Lander is the founding director). Eric Lander is thus being accused of using his status and influence in the middle of a high stakes intellectual property dispute to record a story that will, if carved into history, bring huge benefits to his institution.

The CRISPR dispute highlights several issues in addition to curiosity including the pursuit of discovery, competition, strategy, bioethics, egos, patents, awards, money, and honesty. And, in this instance, there is also potential for issues of gender dynamics to come into play as well (full disclosure, I am a woman). While I may address some of these issues in later blog posts, today I am going to focus on CRISPR, curiosity, the pursuit of discovery, honesty, and who should get credit.

As Eric Lander correctly points out, many of the early discoveries that established the groundwork for CRISPR were not pursued with the intent of developing a groundbreaking gene editing technique. This is also true for the foundational data supporting many discoveries, and one of the things I love most about science. As more and more data accumulated describing how CRISPR worked, its potential for editing genes in organisms other than bacteria became clearer. This type of critical mass occurs often in science because as data accumulate, resolution increases, and suddenly the entire picture of possibilities comes into focus. Often by multiple scientists at the same time. One well-known example of this is the theory of evolution by natural selection. Both Charles Darwin and Alfred Russel Wallace were independently accumulating data and evidence for a theory that would explain the variation they observed as they explored various plants and animals around the world. The coincidence of their ideas is not that surprising as they were both relying on data that had accumulated up until that point in history including fossil discoveries, geological data, and the work of Thomas Malthus, a political economist.

What I find interesting in such situations is how the stories associated with discoveries get woven into our discourse. Even though Darwin and Wallace presented the theory of natural selection simultaneously in 1858, it is Darwin’s name that carries the association. And this is not uncommon, as time moves forward, and stories are told and retold, one name often sticks. For CRISPR, we are at that fork in the road; whose name is going to stick? At present, Doudna and Charpentier have each received a $3 million Breakthrough Prize while Zheng was given rights to the patent. A recent story in The New Yorker on CRISPR profiled Zhang almost exclusively. And then, of course, there is Lander’s Cell review, also featuring Zhang.

The blog, Genotopia, hit the nail on the head when the writer, Nathaniel Comfort, referred to this as “whig history”. Essentially, historical accounts are often generated from a single perspective, and are largely influenced by who recorded the story, how it was portrayed, and how loud their voice was. If the accusations against Lander are true, it is clear why he didn’t address the competition occurring between these two labs in his review (although it is still surprising to me that he could completely breeze by the patent dispute, and Cell would let him get away with it). (To be fair, Doudna and Charpentier published a review in 2014, and while they cited the work coming out of Zhang’s lab, they did not include it on their major timeline of events. And, one could argue it is reasonable that they didn’t address the competitive aspect of their discovery since the review was written by them and would of course be biased.) There is clearly a lot more going on here, and Lander knew about it. Competition occurs, it is not uncommon for two labs to be working on similar things; and if you are going to write a review, especially one with colorful personal narrative, talk about it. That is my goal on this blog. Tell the story. Not the story where we dreamed up a hypothesis, tested it, and made a huge a discovery. The real story. If there is a fight, talk about it. If you have a stake in the game, don’t hide it. If there is an intellectual property dispute and the parties involved can’t talk about it, don’t pretend it’s not happening.

I will leave you with a quote from George Church (Harvard), one of the quieter players in this story, that was published in The New Yorker story: “No single person discovers things anymore……….The whole patent battle is silly. There has been much research. And if anybody should be making a fuss about this I should be making a fuss. But I am not doing that, because I don’t think it matters. They are all nice people. They are all doing important work. It’s a tempest in a teapot.” 

I would say it is multiple egos in a teapot, where the teapot environment is burdened by limited funding dollars fueling competition and battles for credit. Can credit really go to just three people? (Three is the maximum for a Nobel Prize.) And, patents? A topic for another day.

things i am curious about: utah road trip

I have been on the road in southern Utah for the last week – here are a few of my curiosities from places packed with infinite wonder.

First up is a geological formation known as the wave in the Vermilion Cliffs National Monument. The formation is Jurassic Navajo Sandstone (think dinosaurs) that is ~190 million years old. The geologic time scale has always been tricky for me to wrap my head around because of the vast amounts of time involved. Shifting from decades to millions of years is just not something my brain does easily. I welcome the humility and challenge of shifting perspectives when surrounded by such an awe-inspiring landscape.

The Wave - Vermilion Cliffs National Monument

 

Next, a burr. I couldn’t resist a throwback to the last blog post.

Burr

The wave is one among many things to see in the area so we spent a few days hiking around. We went off trail on the first day and ran into this rock formation. I think it looks like a dinosaur. Or a spaceship.

Crazy rock

We spent one day hiking through Buckskin Gulch, an extensive slot canyon not far from the wave. It is definitely a different feeling to be in the slot canyon with views of massive amounts of rock extending many meters into the sky. The curiosities in the canyon were also much different. I enjoyed documenting the diversity of items in the holes of the rock walls. During the summer monsoon season the canyon is subject to flash floods, and items flowing with the water can get caught in the holes, even holes that are more than 6 meters off the ground. There were many times when I thought, hmmm, how did that get there? The only explanation is water, and lots of it.

Items in holes of canyon wall

 

Water, on the other hand, did not plant the evidence of predator – prey interactions we found. We speculated that one predator was an owl, based on the “owl pellet” we found next to the pile of fur. You can think of this series of images as before and after; or after, later, and even later (after I picked through the pellet to see what the owl had been eating).  

Evidence of predator - prey interactions: After

Evidence of predator - prey interactions: Later, and even later

There was also a rabbit leg, and spine. A fellow canyon adventurer said she saw a crow flying over the canyon with something in its mouth. An hour later we found the leg, and spine. We hypothesized the crow scavenged these morsels, ate what it could, and dropped them to the canyon floor as it flew over. I am not including a picture of the rabbit leg, and spine.

 

Last, the petroglyphs. Talk about wonder and curiosity - daydreaming about the people, events, and cultures surrounding their origination definitely inspires a shifting perspective. It is such a small window into a previous time. One so different from now. In my quest to find the origin of the petroglyphs I discovered that because multiple Native American tribes inhabited this region, it is difficult to determine what groups they were drawn by, and in some cases it could be more than one.

Petroglyphs

PS I also wanted to mention the crazy confluence of some admirably curious people we met in the Wire Pass trail head parking lot. There was the man from San Diego taking two months off to drive around the western United States while in between jobs. His outfit included a tent on top of his FJ Cruiser. A French family touring the Americas for two years, from Canada to Patagonia, in the most tricked out custom automobile/truck/tank I have ever seen. And Heike, a tough-ass German woman that has been biking around the world since May of 2012.

More information: The wave (advanced), The wave (beginner), Buckskin Gulch, Petroglyphs in southern Utah

velcro

    Stories about engineers, scientists, and other curious people often involve ideas occurring like lightning strikes. All of the sudden it hits and shortly thereafter we have a miraculous invention. Such narratives imply that the generation of such ideas - the successful, story-worthy ones - is a rare event. One idea equals one success. Isn’t it more realistic, however, that such curious and inventive people were ruminating on many ideas? Pursuing several possibilities at once and building off of a series of lightening bolts? I think so. And I think this is important for two reasons. The first is that understanding the process of how a curious person generates and pursues ideas encourages other like-minded people to do the same. If we put mountains of pressure on ourselves to come up with that one genius idea the task becomes insurmountable. The second reason is there is much to be gained by highlighting the importance of failure, or perceived failure, on the path to success. In other words, talking about the process of pursuing ideas and understanding the inevitable barriers creates a transparency that encourages other curious people into the folds of ingenuity. This facilitates recalibration of the seemingly mountain-sized hurdles that stoke fear, and can lead to acceptance of our curiosity, ideas, and eventually action.
 

Image credit

   Velcro® Brand hook and loop is a product many of us thirty-somethings first remember from our Roos with the Velcro® zipper pocket. Velcro® is officially the registered trademark for Velcro Industries, a company started by engineer George de Mestral in 1941. The hook and loop mechanism developed and patented by de Mestral was inspired by the burr of a burdock plant (genus Arctium Linneaus 1753 - this notation tells us the genus Arctium was described by Linneaus in 1753). The story goes that de Mestral, a native of Switzerland, was on a hunting trip with his dog and both came home covered in burrs. During the process of removing the burrs de Mestral became curious about how the burrs stick, especially without any sticky substance. He put the burr under the microscope to investigate how the mechanism worked, and Velcro® was born. Really? 

   At this point in the story I am wondering two things. Was this the first time de Mestrel experienced burrs? I grew up in the northeastern United States and experienced these same (or similar) burrs (several European species of this genus have been introduced to the Americas) many times while brushing the mane and tail of my childhood horse. Thus, it seems likely that unless this was his first hunting trip, de Mestral would have had burrs stuck to him and his dog before. If that’s the case, what had changed for de Mestral in this instance that made him curious about the burrs sticking mechanism? How do we go from experiencing something on a regular basis with little to no curiosity, to wondering how it works? 

   My second question is, did he have a microscope at home? Since burrs are pretty big, he would have needed to use a dissecting microscope rather than a compound microscope, which would have required making a mount of the burr using a slide and coverslip. A difficult process for something so large. He could have had a dissecting scope, it is a good piece of equipment to have around and I highly recommend playing around with one if you ever get the chance - just about everything looks amazingly interesting from a magnified perspective; fingernails, hangnails, jewelry, hair, pencils. Really, anything you can get on the stage. But, microscopes are expensive and not routine household items, even for engineers. If he didn’t have a microscope he would have needed to save one of the burrs he so carefully removed from him and his dog (they do not have much integrity and easily break apart during the process of removal, especially from animal fur) and brought it to a facility with a dissecting scope. Further, if he were on a hunting trip he definitely would not have had access to a microscope and would have needed to save the burr for further study.

Image Credit

   I raise these questions to highlight the difference between how we perceive inventions are made, and how they are actually made. Surely curiosity did not suddenly strike de Mestral as he stood there covered with burrs. I bet he was curious about how a lot of things worked. In fact, in addition to Velcro®, de Mestral patented a toy plane at age 12, a self anchoring hair curler, a hygrometer, and a paring knife for vegetables such as asparagus that do not have a smooth surface. It is also worth noting that it took de Mestral seven years to get Velcro® into production. Seven years is a long time! His initial ideas were not met with instant accolades of genius from his colleagues. It is likely he even received enough criticism to derail most people. But he stuck with it. First, de Mestral had to convince himself it would work, and stay convinced throughout the process. Then he had to convince other people it would work as he experimented with different types of natural and synthetic fabrics and production methods. I can only imagine how long those seven years felt to him refining his ideas while wrought with hesitation and concern about failure. But he stuck with it, and so did Velcro®.

More information: George de Mestral,  For educators

intro

 

The two most popular questions I get asked when I talk about my research are 1) “What is the application?” Which means, “is that really worth your time and effort” (and taxpayer money because I am often funded by federal grants), and 2) “How did you get interested in that?” The second question is easier to answer so let’s start with that. I have always been interested in Biology; from ages 7-18 it was marine biology. I had glass shelves around the perimeter of my room with sand and shells setup to look like a beach. There were images of fish on the walls and various marine inspired knick-knacks I accumulated from birthdays and Christmases. When I went to UC Santa Cruz for undergrad I planned to major in marine biology. During my first meeting with my academic advisor, Richard something or other, he recommended I start with a major in general biology and add a marine biology emphasis later if I was still interested. I never added it. My junior year at UCSC I went abroad to Costa Rica for a tropical ecology program. Upon arrival I was asked what my main interest was. Was it plants? Was it reptiles? Amphibians? Birds? You know, what is it that I liked to study? I didn’t want to say marine biology because the program was primarily terrestrial-based so I stole an interest from a good friend of mine and said I liked to study insects. For the rest of my time in Costa Rica my interest in insects grew and gradually narrowed to beetles. After graduation, and a stint in the biotech industry, I started a graduate program at the University of Connecticut and became a specialist on the evolution of beetle genitalia. Hence, the second question, what is the application of my research?

The objects of my affection: male (left) and female (right) genitalia of scarab beetle species (genus Phyllophaga)

In the face of the many catastrophes happening around the world, what is the significance of studying beetle genitalia? This is a good question, there have been many times when I asked myself the same thing. Why don’t I put my intelligence, experience, and enthusiasm toward something more applied? A research program that directly benefits society, such as the influence of climate change on mountain pine beetle infestations. At times I think about it so much I even consider changing my career path and research focus. What I have decided to do instead is start this blog. To answer the question of applicability by showing how seemingly superfluous research creates the foundation for discoveries - discoveries that provide sustainable options to keep up with the demands of human society. Every organism with a role in bio-inspiration was discovered, named, and described by taxonomists. The habits, distribution, natural history, and reproductive behavior of each of those species were studied intensively by a second group of scientists. And the potential of that species to provide a solution to human-based issues is often recognized by yet another set of scientists. Most times, such discoveries are based on research conducted by several different types of scientists over hundreds of years. Each discovery represents a synergy of ideas from a long history of curious people dedicated to learning more. These are their stories, with a few of my own curiosities mixed in. And the result, well, I like to think of it as an account of our GDC (Gross Domestic Curiosity).

 

“If I have seen further, it is by standing on the shoulders of giants.” Isaac Newton (1676), by way of Bernard of Chartres (1130) through John of Salisbury (1159).