Oscillator is moving to the brand new Scientific American network! I'm excited for this new opportunity and sad to be leaving my old home here. I want to give many special thanks to SEED people past and present for their help and support, in particular Nikki, Erin, Greg, Evan, and Wes. And of course I have to thank all of you who read and commented and shared and supported me here, I hope you change your RSS feeds and bookmarks and come visit me at my new spot!
I'm making my way up to SB 5.0 for what promises to be a great conference. If you're going too, come say hi and smell some cheeses during the poster session!
I got a long email from one of the authors of the skull measuring study and I want to make some clarifications to my previous post. It seems that I was not as clear and thorough as I could have been in my argument.
First, my sincere apologies to all physical anthropologists and other researchers who routinely measure skulls that I may have offended with my off-hand comments. I did not intend to cast doubt on a whole field, and I am aware that there are lots of reasons to look at skulls besides comparing cranial capacity of different races, many of them very valuable to medicine and understanding human evolutionary history.
I also do concur with other bloggers that the paper was very straightforward in its methodology and writing and I found it very easy to read despite cringing every time I read the word "objectivist." I do not doubt that the authors' work was carried out objectively, showing that the original measurements were accurate. Indeed, I think it is important that criticisms of the actually old-timey and racist skull measurements are empirically accurate, and I think it is valuable to question Stephen Jay Gould's analysis of the actual numbers. When I ask "how can anyone make objective measurements on categories that are inherently not objective?" I did not mean that one could not objectively judge previous work and already existing labels. I do not think that this objectivity translates back to Morton, however, and I think the authors could have been clearer on this point. Morton categorized people in a way that is not objective, so any measurements he made, however accurate, do not necessarily give an objective picture of what different populations are like.
So perhaps this is the deeper point. Even if Morton was correct in his measurements, these measurements don't mean anything objective about races, in the 1840's or today. I am deeply upset (as the authors should be) by how I have seen their very straightforward paper interpreted in places like blog comments, where many people seem to be making the leap between cranial capacity and intelligence. I know that blog comments aren't necessarily an accurate picture of anything, but many people will likely interpret this result as objective, scientific proof that not only are racial categories stable entities on which it is possible to make measurements, but that these measurements can be linked to things like average intelligence. I believe that the authors are not actually racists, and could have been clearer in making these points so that their paper would not be interpreted as objective support for racially biased beliefs.
While measurements can be made free of bias according to scientific methods, the social realities of different people and the subjectivity of drawing racial circles around a continuously varying population of humans makes it very difficult for these measurements to be interpreted in an objective way free from social factors that may include bias. Scientists like Gould understood this, however flawed his numbers, and I believe that there can be a common ground where we don't have to misrepresent data in order to understand this crucial point.
It's not every day that you read about measuring skulls in the contemporary scientific literature. It's kind of a quaintly old-timey, quaintly racist kind of thing to do. But here we are, with a brand new paper about skull measuring in PLoS Biology. Already quite a few blog-words have been written in support of this new paper, which disproves Stephen Jay Gould's assertion in The Mismeasure of Man that George Morton's 1839 skull measurements were fudged intentionally or unintentionally by his racist bias.
I haven't read a lot of Gould, and I'm pretty convinced by the numbers in the paper that show that Morton measured correctly, so I don't necessarily want to defend Gould or get into any specifics on how to best measure skulls, but I do want to point out how completely the authors seem to miss the point about race, "objectivity," and the social studies of science. The authors do appear to be familiar with the modern social science literature on the social construction of race, which does not mean that there are no differences at all between different people from different parts of the world, but that the way we understand and label these differences change over time and depend on the social and cultural context. The results section of the paper begins with a paragraph where they address these issues directly:
In reevaluating Morton and Gould, we do not dispute that racist views were unfortunately common in 19th-century science [6] or that bias has inappropriately influenced research in some cases [16]. Furthermore, studies have demonstrated that modern human variation is generally continuous, rather than discrete or "racial," and that most variation in modern humans is within, rather than between, populations [11],[17]. In particular, cranial capacity variation in human populations appears to be largely a function of climate, so, for example, the full range of average capacities is seen in Native American groups, as they historically occupied the full range of latitudes [18]. It is thus with substantial reluctance that we use various racial labels, but it is impossible to discuss Morton and Gould's work without using the terms they employed.
The authors are reluctant to use the racial labels because they understand that those labels are not objective categories, that the way people were defined in Morton's time is different than it is today, and that there is more variation between individuals of a given "race" than there is between different populations. So here is the point: how can anyone make objective measurements on categories that are inherently not objective? How does stating the average cranial volume of an African skull vs. a European skull show, as the authors state, "the ability of science to escape the bounds and blinders of cultural contexts," when we know, through scientific studies on the variation between and within groups, that these categories are subjective and subject to change depending on the cultural context?
Last month I wrote about my friend Devin Burrill's paper about synthetic memory in yeast cells. There were a lot of really interesting questions left in the comments, and I asked Devin if she would write a guest post to answer them. She agreed and here it is, answers to your questions straight from the author!
Hello Readers!
My name is Devin, and I am so incredibly grateful to Christina for allowing me to write an entry on her awesome blog. Christina and I are friends and work together in the lab of Pamela Silver at Harvard Medical School. I am writing in response to a number of excellent questions posted about Christina's entry on my recent paper, "Synthetic circuit identifies subpopulations with sustained memory of DNA damage" (Burrill, et al. Genes & Development, 2011).
One reader asked about the initiation of heritable damage responses: "Is damage restricted to random acts of nature, or can there be such a thing as self-damage....that will nevertheless be heritable?"
DNA damage can come from within an organism, as well as from external sources. External sources tend to be obvious and well-known by the informed public (e.g. UV or IR radiation, drugs, smoking). Less obvious is the fact that pools of a DNA damaging reagent known as reactive oxidative species (ROS for short) are created all the time by our own cells via mitochondrial respiration.
Mitochondria are organelles that likely evolved from bacteria billions of years ago. They function as the "powerhouse" of the cell, generating cellular energy in the form of adenosine triphosphate (ATP) via the respiratory chain (RC) located at the inner mitochondrial membrane. Electrons move along the RC, reducing molecular oxygen at the end. If single electrons leave the RC earlier, ROS are generated. Incompletely reduced oxygen (superoxide radicals: O2-) can be transformed to H2O2, then leading to free hydroxyl radicals. Hydroxyl radicals are one of the most damaging forms of ROS, mutating the DNA backbone and even the DNA bases themselves. This source of internal DNA damage is simply part of a cell's natural biochemistry. As people age, however, ROS production tends to worsen because the mitochondria also age and become less efficient at tracking electrons all the way along the RC. This source of internal damage is actually hypothesized to be a main contributor toward the human aging process --- as promiscuous ROS production increases, so to does DNA damage caused by ROS, resulting in dysfunctional biological processes. Thus, damaged mitochondria are inherited over time as people age, though the exact mechanisms are how this happens are not completely understood.
Another reader asked about the nature of the observed cellular memory: "Do the cells that retain this memory of an experience then pass on that memory to those they have been divided into?...And how many generations does this affect?" Yes, the idea is that a single cell experiences the damage and responds in a specific way which is somehow recorded, thus changing the cell's biological makeup. We were interested in changes that were subsequently passed on to daughter cells when the original cell divided. The fluorescent memory loop allowed us to track the damage response from the original cell that experienced it to the daughter cells. We tracked the response for 48 hours after DNA damage, which means that the original cell divided approximately 20 times, resulting in lots of fluorescent daughter cells. A sustained response that lasts 20 cell generations is remarkable, given the propensity of the yeast S. cerevisiae to re-set its biological clock when its divides. However, one could imagine studying the response for even longer periods of time. There's really no limit!
The same reader then went on to ask a very important question, which really gets at the meat of the project: "Can the effects of this experience ever be completely erased from the genome if the experience itself is replicated or repeated in a particular environment? And is this perhaps one of the ways that cells evolve to anticipate and deal strategically with a multitude of problems?" I believe the reader is asking whether experiencing and responding to the damage once can impact how the cell responds to the same experience if it happens again. This question brings forward the idea of biological hysteresis --- does a past event allow a cell or system to respond differently to future events because memory of the past event persists? It's possible that initial exposure could result in heritable epigenetic marks or stable cytoplasmic factors, for example, that will permit a "better" response to a second exposure of the same damaging agent. While some previous work has looked at cellular responses to multiple doses of damaging agents, these studies are flawed by the fact that they take place at the whole population level, thereby diluting out any long-term effects that occur within distinct subpopulations. Now that we have engineered a device that allows for the isolation of two distinctly-responsive subpopulations, we can more properly examine the role of hysteresis in DNA damage response. Will one subpopulation respond better to a second dose of damage? If the system were moved to mammalian cells, would one subpopulation be more resistant or susceptible to multiple rounds of chemotherapy? In our paper, we laid the groundwork for exploring these questions and are now pursuing these very lines of research.
I cannot say how exciting it is to get questions like the ones proposed by Christina's readers. They are very thoughtful and insightful. Thank you so very much for asking them, and thank you for letting me answer them!
It's been an exciting week for me. On Monday I successfully defended my thesis! Now that I have established my scientific credibility to you all, here is a picture of me at my defense party wearing my "Trust me I'm a Dr" Dr. Pepper t-shirt and hitting my SpongeBob SquarePants piñata.
And on Tuesday I went to two really interesting events/talks/discussions about science and scientists. First up was DebbieChachra's awesome seminar "Unpacking Gender: Men and Women in Science, Technology, and More," sponsored by the Harvard Graduate Women in Science and Engineering. She described her seminar as "Power and Privilege 101," and even though I'd say I'm at least up to junior-year seminar level gender studies, she really challenged me by having us address our own unexamined privileges head-on, having us think and talk about how we benefit from and how we contribute to ways that different groups of people are stereotyped and excluded.
We all have pre-concieved ideas about what different kinds of people are like, schemas that we use to understand and categorize the world. Debbie illustrated this point with a special group of people, used car salesmen. We know what used car salesmen are supposed to be like, and this schema can protect us from getting ripped off when we're trying to buy a car. But if we meet an honest and sincere used car salesman, we don't necessarily adjust the schema we're operating on based on the evidence in front of us. Instead we will more likely assume that this salesman is so sleazy that he's gotten very good at faking sincerity. By examining how our perceptions and confirmation bias can maintain the status quo when dealing with all sorts of schemas, we can begin to make the kinds of fixes that are needed to change the stereotypes and structures that contribute to things like skewed gender ratios in some science and engineering fields.
Later in the evening I went to a lovely and lively dinner and discussion about science blogging and journalism at the Cambridge Science Festival, featuring Carl Zimmer and Ed Yong. It was great to meet writers that I admire so much and to hear their perspectives on all the positive and exciting ways that the internet and blogging are shaping science and science journalism (you can watch the video here). Overall Carl and Ed had great and nuanced perspectives on the changing science and media landscape, but with my heightened awareness of schemas I couldn't help but frame some of the surrounding audience questions and discussion of science journalism and (vs.?) science blogging in terms of our sometimes misguided underlying assumptions.
The schemas and assumptions in this case aren't about groups that are underrepresented in science, although that is obviously a huge part of the discussion when we're talking about sharing and engaging with science, but rather the assumptions we make about science, scientists, and science writers in general. For many of the comments and arguments I heard on Tuesday night, the debate between science blogging and science journalism seemed to center around an image of scientists as asocial fact producers and journalists as translators of these jargon-laced facts to a much stupider group of people known as the "lay public." But science isn't just facts, scientists aren't just robotic fact makers, science journalists aren't just fact megaphones, and non-scientists aren't just ignorant. Science and science journalism is something that real people do, people with opinions and social lives, people with interesting perspectives on the world and sometimes even a sense of humor.
Remembering that scientists are people makes it much less surprising that scientists use twitter and write on the internet, because millions of people use twitter and write on the internet for lots of reasons and for lots of audiences. We can use the internet to find scientific information and connect with collaborators, but we can also use it to connect with old friends and make new ones, to talk and learn about all of our hobbies and all of the things we're interested in. There is room in a scientific career to engage with other people and there is room online for both tweets about your breakfast and tweets about your research, blog posts by scientists and science lovers about cool things going on in the universe, and articles by journalists that share engaging stories about both the facts and the contexts of interesting scientific findings.
The best of these stories can show us new worlds beyond simple facts. I was always a nerd and I always loved science for its own sake, but even after almost a year of working in a lab as an undergrad it was Natalie Angier's book Natural Obsessions that showed me what it feels like to be a scientist, brought me closer to how the facts that I was learning in my textbooks were discovered by real people, and even made me feel more passionate about my western blots. These days I read blogs and articles and tweets by people who are interesting and interested in lots of different things and share some of those interests and a bit of their personality in their writing, whether they are students, journalists, scientists, engineers, artists, government workers, or celebrities. I can engage with and learn about people and projects similar to myself and the work I did my PhD in and areas so far out of my expertise (journalism being one of them) that I'm one of those ignorant but very interested laypeople.
All this reading makes me a better dinner date but I hope also a better scientist and a more critical and thoughtful reader of work both inside and outside of my field. One of the audience questions during "Unpacking Gender" really brought this home, and brings us full circle. "What kind of unbiased, scientific research is out there on the innate differences between men and women?" Debbie's answer was difficult and very important: we live in a society where boys and girls are treated differently from even before they are born, so it is often impossible for scientists and for other people to separate out whether an apparent difference between men and women emerges as a result of "nature" or "nurture." If we look to science as merely a source of facts that can clear up these nasty social problems, we can see statistical differences between different groups of people, but we can sometimes lose the human and social context in which these differences emerge. With the best science blogging and science journalism, we can put together the bigger picture of where the facts come from, what they mean to us, and how the facts in context can help us break out of our assumptions.
Two videos that Patrick Boyle and I made were selected for the Bio:Fiction Film Festival! One of the prizes is an online audience award, and you can watch and rate all of the films! It's such an honor to be part of this festival and to be showing our work next to that of so many amazing artists, scientists, and filmmakers, and we would be super thrilled if you voted for us!
Here are our videos! First, the world premiere of Compound 74, a fictional documentary about a possible future of synthetic drug design through synthetic biology:
You can read more about the science behind retinal prosthetics in a great article in the Guardian by one of the project collaborators, Dr. Patrick Degenaar.
Symbiosis is everywhere. From the Greek for "living with," symbiosis is simply a close association between two different species in nature. These relationships can be mutualistic, parasitic, or somewhere in between. Bacterial symbionts live inside bodies, like the bacteria that help us and other animals digest our food, and they live inside cells, like the bacteria that live in plant roots and provide their hosts with nitrogen. They can be metabolic, hygienic, or photosynthetic; ectosymbiotic, on the host surface, or endosymbiotic, inside the host's cells. Back in the 1860's biologists considered each organism to be an individual, autonomous whole, but the Swiss botanist Simon Schwendener observed that lichen is actually an association between two different types of cells, a fungus and a photosynthetic algae. Shortly after that, other botanists began to notice that the chloroplasts, the organelles that provide photosynthetic power to plant cells, resembled free-living photosynthetic bacteria. It took several decades and the rise of molecular biology to learn that these organelles had their own DNA, and to convince scientists that they had started out as bacteria.
Photosynthetic endosymbiosis created plants and still exists in many other organisms and in many forms today. The sea slug Elysia chlorotica is one of the best known examples. It rips the chloroplast organelles out of the algae that it eats and incorporates them into its highly branched digestive system, able to live off of sunlight harvested by these symbionts for several months. Almost all of the photosynthetic endosymbiotic relationships known show up in invertebrates that don't move a lot and have a very high surface-to-volume ratio, resembling very slow-moving leaves. But all this changed a couple weeks ago with the publication of a really cool paper. Ryan Kerney and his colleagues were studying a species of salamander that is known to be associated with algae during its embryonic stage. What they found was that contrary to what had been reported before, the algae were living inside of the salamander cells!
The relationship between the salamander and the algae is especially interesting because it shows just how wide the range of situations where endosymbiosis can happen. In one extreme, the slug can't survive without the algae and actually becomes photosynthetic, while the salamander can develop just fine without any algae, does not harvest any energy from the algae, and lives most of its adult life underground, away from sunlight.
In my lab, a lot of people study photosynthetic bacteria like the ones that eventually became the plant chloroplast through endosymbiosis. Projects range from basic cell biology and understanding the internal organization of the bacteria to trying to engineer them to produce useful chemicals. A couple years ago, a very awesome and very talented master's student, Henrike Niederholtmeyer (her awesomeness is directly proportional to the number of syllables in her name), was working on engineering these cyanobacteria to produce sugar.
The bacteria typically grow in fresh water, and putting them in salt water can put a lot of pressure one their membranes. To protect themselves, the bacteria produce sucrose (table sugar), which helps to balance out the osmotic pressure. What Henrike did was engineer the bacteria with invertase, the gene that splits sucrose into glucose and fructose, and with a transporter gene that lets the sugar leave the inside of the cell. Now, when the bacteria are put in salt water, they secrete sugars out into environment. It isn't a ton of sugar, but it's enough to create a symbiotic relationship between E. coli (yellow cells, red line) and the cyanobacteria (red cells):
This got Henrike and my advisor, Pam Silver, thinking about how photosynthetic symbiosis is established and how we could re-create it in the lab. At this point, I was fascinated, and convinced Henrike to let me tag along on the experiment. How could we get the cyanobacteria inside of animal cells to establish a synthetic endosymbiosis?
We were lucky to be in a very creative and supportive lab and department and to have one of the best zebrafish labs anywhere right down the hall. Sean Megason's group studies the development of zebrafish embryos and uses powerful microscopes to track every cell as the fish grows. Zebrafish are also relatively easy to microinject (if you are a professional) and clear, letting light into their cells that the cyanobacteria would need to grow. Henrike hooked Ramil Noche, a postdoc in the Megason lab, the same way she hooked me into the project, and his zebrafish skills are unmatched. He injected fresh zebrafish eggs with millions of wild-type cyanobacteria, put them in the incubator, and we waited.
The biggest surprise was that nothing happened. The embryos developed normally into a happy, swimming fish when we injected them with cyanobacteria. Even after 1 hour we could see that something was up, since the cyanobacteria-injected embryo looked normal (panel A, a red dye is used during injections to keep track of which ones are done which is why the embryo looks red), while injecting E. coli had a quite drastic result (panel B).
While the sugar secretors were the inspiration to try this experiment, they don't produce nearly enough sugar to actually support a living animal cell, and all of these pictures show normal, un-engineered cyanobacteria inside of the fish. These fish are not photosynthetic, they just live happily with photosynthetic bacteria inside of their own cells. The zebrafish cell membranes are engineered to be green fluorescent, and the green pigments in the cyanobacteria cells fluoresce red, so they look like little red dots in the images:
Here's one of the amazing images that Ramil took with the confocal microscope, where you can look at just a single plane of the fish, looking into the cells themselves. This image is of the head of a live two-day old embryo, and you can see red dots of where the bacteria are inside its eye and brain:
This result inspired me and Henrike to try and get the cyanobacteria into other cells. Some synthetic biologists are trying to create tumor killing bacteria, that can seek out cancer cells, get inside of them and specifically kill only those cells, leaving healthy cells intact. They engineer these bacteria with a gene called invasin that, as the name implies, allows them to invade mammalian cells. A second gene called listeriolysin is needed for the bacteria to escape the membrane-bound compartment that they get stuck inside, and to get into the cytoplasm. Engineering the cyanobacteria with these two genes allowed them to invade hamster cells in culture at a low but appreciable efficiency.
Listeriolysin also lets the bacteria escape from the digestive forces of macrophages, a type of immune cell that can capture and eat up bacteria. When we had mouse macrophages swallow up the engineered cyanobacteria, we saw them escape digestion and slowly start dividing, a first step for establishing a symbiosis. In the video, taken by Tami Lieberman, you can see the macrophages with the engineered cyanobacteria in them. On the left is the dish in the dark, and the white dots are the bacteria, which slowly die overnight without any light to support them. On the right the light is on, and after a while, one of the red bacteria divides into two:
Again, these mouse cells aren't photosynthetic, but these experiments show how photosynthetic bacteria can develop special relationships with animal cells. Because they aren't pathogens and don't need to steal nutrients from their host cell, these kinds of benign symbiotic associations are possible. The wide range of symbiotic possibilities found in nature can inspire synthetic biologists like us to explore and re-create these kinds of relationships as a way to study the evolution of symbiosis or as a way to design new multi-species biological behaviors greater than the sum of their parts. Endosymbiosis drove the evolution of the eukaryotic kingdom with the mitochondria and the chloroplast, perhaps endosymbiosis will play a role in the evolution of the synthetic kingdom as well.
Notes, thoughts, and news on synthetic biology by 
