Sick Papes

SICKPAPES SPECIAL ON POLITICAL ENGAGEMENT!!!

Recently, Jerry Coyne, a prominent Evolutionary Biologist, was asked his thoughts about the "Stand Up For Science” Rally held in Boston’s Copley Square, and about the upcoming March For Science, planned for April 22, 2017. “A march for science itself is just simply a march for the mechanisms that find truth. And who is going to pay attention to that?” Coyne said. “It's going to become a partisan march.” 

My fellow scientists, Sick Papes is here to tell you that Jerry Coyne is dead wrong. I am here today, hyped up on marches, rallies, and community organizing meetings every friggin’ weekend since Trump’s election, to tell you that no matter what Jerry Coyne says (especially when he says that Milo Yiannopolous is “smart and charismatic”), you should all be as politically active as possible - now and forever. If anyone out there is truly worried that fair-minded people are gonna start doubting the results of your fruit fly crosses because you went to a march against authoritarian white supremacy...you’ve got another thing coming, pal. Need I remind you that Jacques Monod was part of the armed anti-Nazi resistance, spoke out forcefully against the Soviet suppression of science, and stood with rioting students against the police? Yet somehow no one accuses his work (co-discovery of transcriptional regulation) of being a liberal conspiracy. Hell, we gave Linus Pauling two Nobel Prizes, and he literally wrote a book called “No More War!” (exclamation point included). What I’m saying is: go to the goddam March For Science in your city - it’s gonna be great.

OK listen: I can understand why some of you might be skeptical of a political march organized by scientists. I’ll admit that before I went to the Boston Rally for Science, I was myself a bit skeptical. I clearly remember the highly politicized fight over evolution during the George W. Bush years, and how this led to the rise of such shit-headed bigots as Richard Dawkins trumpeting Islamophobia in the supposed name of “Science.” I also understand the concern that no one who works on climate science wants to be accused of bias. But you know what? Scientists did not politicize climate science. The Republicans did. And they did it on behalf of the fossil fuel industry, for profit, period. Anyone who tells you its more complicated than that is wrong, or lying. (Editor’s note: I’ll admit that the vaccine thing is a bit more baffling...)

But now that I’ve seen firsthand what these Marches for Science are like, let me tell you: these Trump-era marches are not some milquetoast bullshit about standing up for “the mechanisms that find truth.” No - these rallies have the urgency and energy of fighting for our lives. Here is a small sample of what I’ve seen in the past few weeks at the Boston Rally for Science and beyond: A trans MIT professor yelling through a megaphone that they will never give up the fight for the safety of all of their students. An indigenous PhD student addressing thousands in Copley Square, explaining how the fight for environmental justice for Native people is as much a social justice fight as it is a scientific one. A Harvard doctor standing on the steps of Dana-Farber Cancer Center, explaining why biomedical professionals must speak up now because of our profession’s long and shameful tradition of actively being on the racist side of history. An environmental scientist explaining how we on the front lines against corporate abuse of poor people. A Syrian-American MD/PhD student explaining that his grandmother can no longer visit him, or seek medical treatment at his home institution because of the Muslim Ban. And, to state the completely obvious, we are fighting for the rights of our own brothers and sisters. As Karel Svoboda recently wrote in a powerful letter, the scientific community is gloriously chock full of immigrants and Muslims, not to mention all the other intersecting identities that Trump is every day attempting to dehumanize.

Keller, R & Danilchik, M. (1988) Regional expression, pattern, and timing of convergence and extension during gastrulation of Xenopus laevis. Development 103: 193-209.

The history of biology can be understood through many different narratives. These days, the most common story we use to wormhole our way back through the centuries is the story of genetics. The idea of an alphabet-like code written within every seed can be traced back to at least the first century BC, when  Lucretius published his infamous pape, On the Nature of Things**: “…each thing is born according to the nature of its own seeds…distinct basic elements compose the many things we see, in the same way that we see distinct letters of the alphabet composing many different words.” But of course, it wasn’t until 1866 that the space alien Gregor Mendel returned from the future with a literally perfect pape, showing that heredity could be accurately modeled using discrete inheritance particles (genes) rather than as a simple fifty-fifty blend of parental traits. Over the next 160 years, an onslaught of hundreds of thousands of papes described how genes encode information, how they copy themselves, and how they evolve. The illustrious history of genetics reached its zenith in 2010, when the gene for credit card debt was finally mapped by these fucking guys.

There are, however, other historical narratives of biology that are equally illuminating (and not at all mutually exclusive). For example, one could argue that the history of biology is all about microscopes getting better and better. From the first descriptions of microscopic organisms, through the fundamental insight that all plants and animals are composed exclusively of units called “cells,” through the observations (by two different female scientists back in the day) that chromosomal behavior during meiosis correlates with inheritance - many of the most of the critical breakthroughs in biology have been driven by improved optics, and this continues to be true.  Or, thinking more sociologically, one could point out that the history of biology can’t really be separated from ideas about race (especially if one happens to be my uncle and aunt, who wrote that book). Et cetera.

But today’s Sick Pape comes from a different historical narrative, and one that  we all-too-frequently forget to venerate: the age-old quest to understand how cells move. Specifically, how do groups of cells (aka tissues), coordinate their movement in an organized way during embryonic development? If you don’t think this is a critical question, feast your weeping eyes on these videos of how life begins:

(fruit fly development from Phil Heller’s lab)

(frog development from youtube)

During development, tightly orchestrated cell movements are required for us to get our heads out of our asses. Consider a type of tissue movement known as convergent extension: a sheet of cells contracts from the left and right edges, and thereby becomes longer by extending at the top and bottom. This type of movement is essential for the development of nearly all animals, including humans, in order to elongate our anterior-posterior axis. This process is deceptively complex: each cell must know where, within the tissue, it is, and must then contribute to the generation of physical forces in tandem with its neighbors, while also resisting being ripped apart by the forces applied to it. As the old song goes: “Sounds simple...but how does it work?™”

Which brings me to today’s hero. Ray Keller is one of the most important pioneers of this field largely for one critical reason: he has the best hands in the business. And I mean this literally - Dr. Keller is the most accomplished dissector of frog embryos on the planet, and I doubt that anyone who has watched him work would disagree***. Using custom “knives” made from single eyebrow hairs (!), Keller has spent the past several decades physically manipulating frog embryos in order to ask the heavy questions about how forces are organized and executed in embryos. (editor’s note: Dr. Keller also has a dope picture of a tractor on his website’s section on biophysical forces).

Today’s Sick Pape describes a now-classic experiment known as the “Keller Sandwich,” in which two specific squares of tissue are explanted from an early frog embryo, sandwiched together, and allowed to develop in culture. First of all: I triple dog dare any of you to attempt this prep. It is insane. I watched Dr. Keller make a Keller Sandwich at the Woods Hole Embryology Course in 2007, live-projecting the dissection on the wall behind him as he casually carried on a side conversation about the soothing feeling of accelerating a Harley on the open road. After watching, I went back to my bench to give it a shot, and my hands looked like Shrek had arthritis and was blackout drunk, systematically destroying every frog embryo in the dish. This is all just to say: dude can pull of crazy difficult dissections with ease. (I’ve always found it surprising that so many experiments are still limited by how good one is at difficult dissections.)

When you make a Keller Sandwich, what you get is convergent extension in a dish. The physical forces that drive axis elongation in the frog can be recapitulated in the explants, demonstrating that the organized physical movement is intrinsic to specific regions of the embryo. Thus, what’s sick about this pape is that it not only describes the physical forces that drive axis elongation in the vertebrate embryos, but also opens up an extremely productive new set of methods to study biomechanics on the cellular level. Indeed, since the 1980s, highly conserved signaling pathways have been discovered that explain how cells assess positional information and orientation within a tissue field, including the planar cell polarity (PCP) pathway (although I suspect that the Bath Salts pathway is probably involved too...). And today, there is tons of hot research into the molecular motors within cells generate the physical force that causes tissue movement. So today, as we lazily bask in this dizzying field, let us celebrate the steady hands of Ray Keller - keep up the great work!

** Or, as I translate the title, Thing Nature, aka What’s the deal with Things?

For those of you not making deep and beautiful eye contact with Pontus Skoglund right now, let me tell you a bit about the man in question. Pontus is from Sweden. He’s very handsome. His favorite color appears to be...blue. He’s also one of the great young-bucks in the field of modern evolutionary genomics. This field - known as molecular anthropology - attempts to understand how modern humans evolved and migrated into the tapestry that is like, Our Reality. At an accelerating pace, molecular anthropology is yielding huge and trippy insights into the historical shadows that are the pre-recorded modern world. Thanks to improvements in harvesting high-quality ancient DNA, low-cost & extreme-scale DNA sequencing and an ever-expanding collection of ancient remains, this field is going to continue to pop-off insights and Pontus will assuredly be helping forge the way. We sat down with him to discuss his work, deepest insecurities and the state of the field.

Disclaimer: Not only do I love the genetic history of modern humans, but Pontus is clearly the man. I am so very thankful that he agreed to do this interview and share his thoughts with the Sick Papes readership.

[SP]: As we all know too well from the The Mummy trilogy (The Mummy (1999), The Mummy Returns (2001) and The Mummy: Tomb of the Dragon Emperor (2008), if you raid ancient burial grounds for profit there’s a good chance that The Rock or equivalent will return to this world and attempt to fuck you up. What precautions do you and your institution -  Harvard Medical School - take to ensure your safety?

[SP’s note: Pontus was advised by his extensive collection of lawyers not to answer this question]

[SP]: How did you get into the molecular anthropology? Was it through an interest in molecules? Human history? A sheer act of desperation?

PS: I was studying evolutionary genetics, but the fruit fly side wasn't as fun as I thought it would be.  My favorite part was population genetics, and when I realized that population genetics could be used to study Neandertals, mammoths, and sabre-toothed cats I was more than intrigued. Then at Uppsala University in Sweden, there was this guy that had wild hair, a manic laughter, and an office with lots of boxes of human bones and pictures of socialist world leaders covered in glitter. He worked with ancient DNA.

I not very well suited either for the wet lab or the field, but can instead work on questions that people have been asking since the age of exploration using modern data science. In addition to that, there is a multidisciplinary aspect with the humanities (mainly anthropology and archaeology), which is very rewarding.

[SP]: You’ve published an excessive and excessively interesting set of papers. To illustrate your approach and logic, can you take us through your 2015 Nature paper describing evidence for multiple migrations that were responsible for the peopling of the Americas? Why did dudes think there was only 1 migration event to begin with? What evidence do you show for multiple events? Where did you get this data? Were you testing this hypothesis to start with or did you find hints in the data through exploration that led to your insight?

[PS]: This was a rare eureka moment where I was really thinking about other stuff but found a strange pattern and thought "that's strange". Two years of agonizing over the possibility of data artefacts and biases followed, but it turns out to be real.

Basically, if all Native American groups form a single origin (or migration into the Americas) their patterns of genetic variation should be symmetrical with respect to non-Americans. That is not the case, and what doesn't fit is a unique link between indigenous people in the Amazon and  Australia/Oceania. This forces us to think about what is wrong with the established scenario of a single migration through the continental ice sheets of North America. It possibly brings some fringe theories, such as earlier migrations along the west coast, in from the cold.

[SP]: Clearly you are very diplomatic and understanding of your colleagues in the scientific process and unavoidable ensuing errors. But with this work, you must have upset a lot of old people. Do you enjoy upsetting the establishment? How important are established ideas for framing your questions?

[PS:] I feel like my background isn't from the big labs, and I think it is really important that there is a diverse flora of small labs that keep the field vibrant. Hopefully this can form a healthy establishment, that brings out the best of the idea of scientific competition. We are perhaps not there yet in our field, but the case you are referring to was a very positive experience, all groups were just committed to the getting the right information out.

The most I have ever been involved in upsetting the establishment would be during my PhD studies when we were able to show with ancient DNA that farming spread through Europe by migration of people from the Mediterranean, and not as a trade of ideas or local developments. Some in the archaeological community in Northern Europe remain skeptical of this scenario to this day, I heard the other day that the archaeology 101 textbook in Sweden still sticks to the local cultural development model. Luckily, most international archaeologists seem convinced by now.

[SP]: Understanding modern human evolution seems like it requires understanding evolutionary processes across a large range of time scales, from the millions to few thousand years. What techniques to evolutionary geneticists use to analyze these differing time scales?

[PS]: With ancient DNA we can observe evolution directly over the past 50,000 years, and it is really the only way to do that in natural populations. In that sense I think Darwin would have been pretty excited about it. That's the main time frame I work in. For longer time scales we still have to resort to extrapolating from present-day genomes. One of my dreams is to be able to use ancient proteins, which degrade more slowly than DNA, to reach back a few million years, but we are far away from that still.

[SP]: On that note, in the more experimental fields of Biology, there is often a dichotomy between Biologists that develop new experimental tools and those that use working tools to understand systems they know a lot about. How does this work in modern evolutionary genetics? How vital are new statistical and computational tools? Is it good enough to use the old tools on new DNA samples or does the accumulation of new and different data necessitate tool development?

[PS]: What is often most intellectually rewarding is the rare occasions when those two happen at once so a new tool gives a major empirical insight. I have worked quite a lot to develop new population genetic and bioinformatic tools, but am not really a qualified software developer. Right now ancient population genetics has stabilized a bit in the statistical paradigm being used, owing a lot to the work of my advisors David Reich and Nick Patterson, but new and more refined questions will require ways to find answers.

[SP]: That said, would you consider yourself more of a bone master or master boner?

[Interviewer’s note: Pontus, surprisingly, declined to answer this question]

[SP]: I have an aerial question for you. To an outsider, it seems as though there are a handful of historical questions that receive a lot of attention. For example, interactions of hunter gatherers and farmers within Europe or migrations into the Americas or Austronesia. Do you think that there are a fixed, small number of these “great” questions or do think the number of important events and tractable questions will continue to grow as more is gleaned from the archeological record or genetic data itself? What could these as of yet unknown questions be?

[PS]: In some sense that is certainly true, and ancient human DNA will perhaps in part move into the more 'micro' realm of characterising individual archaeological sites. On the other hand there will be a constant push to go further back in time. Ancient DNA has a further perspective in that it is relevant also for studying e.g. speciation, adaptation and extinction, something that is not common right now, but could be where much interesting work will be done in 10-20 years.

I am also really excited about quantitatively integrating different types of DNA: human ancient DNA, animal ancient DNA, isotopic information about diet, and archaeological information, to ask more fundamental questions about the processes that have driven human history.

[SP]: Although a lot of good stuff has happened too, the last 300 years has been quite a colonial cluster fuck. Many indigenous people have been murdered, directly or indirectly. Recognizing the destruction to humanity, what additionally has been lost in terms of understanding the genetics of modern humans?

[PS]: Documenting the history of colonization and other atrocities is one of the useful things population genetics can contribute to. As for the past, I think writing the story of the diverse human groups that ended up not leaving much ancestry in present-day population is perhaps more fascinating, and arguably more important, than focusing on tracing the origins of present-day populations. It is a real opportunity to complete the history books that ancient DNA provides.

In the present-day, population genetic studies of indigenous communities can contribute to inclusiveness in the era of personalized genomics. This is sadly still far off, but I think a real positive effect of participation of these groups in genomic studies is the media spotlight it can provide to historically marginalized groups that have a unique genetic heritage. Examples of this includes the Khoe and San of southern Africa, Native American groups, and many other communities.

[SP]: If you had only 1 long weekend left on Earth, but could have any drug and UNESCO world heritage site for yourself and your crew to party, what would you do? For the record, I’d go amphetamines +  Angkor Wat + dance party.

[PS]: I'll go with SLEEP live at, shall we say Luxor? And Swedish snus.

[SP]: In addition to pre-historic humans, you’ve studied the genetics of dog domestication. Can you briefly describe this process? Is there any historical precedent for “dog vs. cat” people or is this a false dichotomy from day one?

Warner, R.E. 1963. Recent history and ecology of the Laysan duck. The Condor, 65: 1-23 [PDF]

From 2004 to 2008, I spent my summers working as a wildlife field technician, studying birds in Alaska. During one of those summers, my coworker Jeremy told me about the time he had spent in Hawaii, studying one of the rarest ducks in the world: the Laysan duck. Jeremy said that the entire earth’s population of these ducks lives around a lake on a single island, where the air is so thick with insects that the ducks just waddle-run through the swarms with their bills open, and get enough food to survive. Due to the abundance of bugs, these fat ducks never have to migrate, barely have to fly, and spend their lives sprinting open-mouthed through clouds of flies.

Jeremy wasn’t lying: Richard Warner’s pioneering study of these ducks essentially confirms this behavior:

I am not exaggerating when I say that the Laysan ducks taught me about the blunt force of evolution more than anything I have learned before or since. A group of ducks that never leaves a lake, just reproducing and reproducing and reproducing, until their world ends. There is no striving towards beauty or sophistication or complexity, there is only survival and reproduction. I realize that this is a straight-forward realization - but for me, it wasn’t until I learned about these Laysan duck that I felt evolution viscerally.

We live in a golden age of evolution research. Did you know that Peter and Rosemary Grant, the “Beak of the Finch” couple who spent years documenting shifting bird populations on an island in the Galapagos, were collecting blood samples from all those birds, and now they’re starting to sequence the genomes to characterize genes associated with beak size? Perhaps even more exciting, many labs are now watching microbial evolution happen in real time, and sequencing the genomes as they do to understand this process. Ancient humanity is being understood in entirely new ways. But it seems that the paper that had the biggest influence on my own understanding of evolution was a description of duck behavior published in 1963.

The Greek homoerotic poet C.P. Cavafy wrote a wonderful poem about how  certain experiences leave hidden easter eggs that only hatch decades later:

         Their illicit pleasure has been fulfilled.          They get up and dress quickly, without a word.          They come out of the house separately, furtively;          and as they move down the street a bit unsettled,          it seems they sense that something about them betrays          what kind of bed they’ve just been lying on.          But what profit for the life of the artist:          tomorrow, the day after, or years later, he’ll give voice          to the strong lines that had their beginning here.

                           -”Their Beginnings” 1921

I therefore wish to thank Richard E. Warner for spending several months in the from 1957-1961 watching Laysan ducks, for what profit they have brought my life.

Sick Papes Interview with Luke Gilbert!

We recently received the following letter:

Dear Sick Papes,

I am a third grader who lives under a rock. Furthermore, I cannot read. Thus, I do not know the difference between CRISPR, CRISPRa and CRISPRi. Can you please help?

You are in luck, reader! Sick Papes recently sat down with one of the world’s most qualified people to answer this all-too-common question.  Dr. Luke Gilbert has spent the past few years as a post-doc in Jonathan Weissman’s lab at UCSF, a notorious “scientific paradise,” during which time he has been going, quite literally, buck wild. Following a now-classic pape led by Stanley Qi, showing that catalytically-dead Cas9 can be used to block gene transcription, Luke has published a truly magnificent run of papers demonstrating a wide variety of ways that CRISPR can be used besides just cutting DNA. If I had to describe the addictive and jaw-dropping experience of reading these papers in real time as they came out from 2013-2016, I would say it’s something like listening to Serial, watching Making a Murderer, and reading The Mastermind, all at the same damn time. Please enjoy this educational interview!

(Full disclosure: Luke and his co-authors are on some patents for CRISPR-related techniques).

Figure 1. Effective and highly specific knockdown of GFP using CRISPRi (see below for details). From: Gilbert et al. 2013, Cell 154).

Sick Papes: Hi Luke! What is CRISPRa and CRISPRi? 

Dr. Luke Gilbert: You can think of Cas9 nuclease as a pair of programmable molecular scissors. Our work started when we decided to break the scissors, creating a nuclease inactive form of Cas9, which we call “dead Cas9” or dCas9, and which be used as a programmable DNA binding protein in both prokaryotes and eukaryotes. Why would anyone want a dead Cas9? Because we can use it to recruit any protein to any region of a genome in any organism to do things like control transcription, edit the epigenome, or image the genome in living cells [e.g. by bringing a fluorophore to a specific genomic location].

I have spent most of my time as a postdoc in Jonathan Weissman’s lab showing that we can turn any gene on and off at will by using dCas9 to recruit different protein domains that activate (CRISPRa) or inactivate (CRISPRi) transcription. Another way to describe this work is that we have created a set of programmable synthetic transcription factors.

Synthetic transcription factors are not new - if you want to hear me drone on and on and on (seriously I talked for 2 hours) about the history of synthetic transcription factors you can click here. Or if you want to hear Jonathan explain what we did in a way more coherent way click here. [editor’s note: these talks are great, and give a deep history on research into transcription.]

SP: One of the sweet things about CRISPR is that has opened up entirely new ways to perform genetic screens, where you interrogate the function of every gene in the genome. Can you explain how this field possibly developed so fast, and what benefits CRISPR offers over existing strategies?

LG: Genetic screens have a long, illustrious history in biology. Traditionally, people have done screens in model organisms using mutagenesis or transposons or have created knockout collections. In human cells, genetic screens really took off in the early to mid-2000s when RNAi screens were invented. So CRISPR screening platforms really owe a ton to the ~10 years of work using RNAi for genetic screens in human cells. This is reflected by how quickly people went from CRISPRing one gene to CRISPRing the whole genome - the first CRISPR systems were used in human cells in 2013, and within a year several groups had already created genome scale libraries. This was possible because biologists already knew how to construct a pooled library, do a screen (don’t forget the negative controls!), process and sequence screen samples, and analyze the data. I do not want to get into the relative merits of CRISPR, RNAi and CRISPRi as this conversation would literally go on for like two days [editor’s note: Dr. Gilbert politely declined our follow-up request to have a two-day conversation about this at a crystal-strewn clearing betwixt a waterfall and a lunar eclipse]. I think CRISPR and CRISPRi are new methods – in five years we’ll see what people like best. 

Figure 2. Using a tiling array to determine the most effective window for sgRNA placement for CRISPRi. TSS = transcription start site. From Gilbert et al 2014, Cell 159

SP: In cell culture, genetic screens can be done in two ways: “arrayed,” where you perturb each gene in it’s own well, or “pooled,” where you just have a single large flask of cells, each with a single gene perturbed, and you measure the outcome of some biological challenge via sequencing. Can you tell us more about just how “cheap” and “easy” these really are? 

LG: Arrayed screens are great, but they are expensive because they require robots and more reagents [editor’s note: for example, to study 10,000 genes in an arrayed screen would require 27 384-well plates for one replicate]. Thus, genome scale pooled screens are awesome because they are cheap and relatively easy. All the cells are grown together, and we use high throughput sequencing to measure how every gene included in a library controls response to a perturbation by measuring the relative abundance of each sgRNA in the library at the start and end of an experiment.

In our lab one person can do 4-8 screens at the same time because we use non-adherant leukemia cell lines that are relatively easy to passage. A pooled screen from start to finish takes about a month including sample prep post screen and sequencing and each sample costs roughly $5,000 including serum costs, sample prep and sequencing. Most people either do duplicate or triplicate screens to estimate your technical noise in a screen.

There are two main types of screens you can do in human cells, typically referred to as “positive selection screens” and “negative selection screens.” Positive selection screens [where you identify those mutants that survive some life-threatening insult] reveal genes that control resistance to a process, while negative selection screens [where you see which mutants disappear following a challenge] reveal genes required for a process. However, I don’ really think about screens as positive or negative because we do our screens in a way that reveals genes that confer both resistance and sensitivity to a process. To do this we choose to apply a measured or modest amount of selective pressure that enables the detection of genes that confer resistance and sensitivity to a process or drug.

SP: I’ve heard people draw a distinction between “technique building” and “biology” as if the two were somehow separable. I personally think this is a moronic comparison because new techniques come from biology, and techniques are what we use to do biology. What do you think?

LG: I do think there is a distinction between methods development and biology but agree that they are inseparable. I think as long as you are doing innovative science for the right long term reasons the rest takes care of it self. If you do methods development you often end up doing types of biology that you did not expect to when you started [editor’s note: and vice versa, e.g. CRISPR itself]. For example, I never thought I would be working on transcription or synthetic biology when I joined Jonathan’s lab. Or another example, many labs have now studied the biology of the Cas9 protein in vitro and in vivo: structure of the Cas9/sgRNA/DNA complex, mechanism of action, 2D vs 3D search mechanisms, fidelity of target DNA recognition. This could easily be described as either methods development or biology.

I feel like we have just started to use CRISPR for biology. Much of the published CRISPR work has been proof-of-concept or methods development. I think we are just now at a point where doing an experiment using CRISPR reagents is not a paper in and of itself but rather just another way to ask new questions about biology. 

SP: What are the big questions that you’re interested in right now, that you think these tiling screens are allowing you to study in new ways?

LG: Tiling screens are very cool. In our published work, we used CRISPRi/a tiling screens to define rules for how to use our artificial transcription factors to control transcription most effectively and to derive rules about CRISPRi/a specificity using mismatch sgRNA libraries (Figure 2). 

I think tiling screens using either Cas9 or dCas9 will be incredibly useful for mapping enhancer and promoter elements. A really cool example of this was published last year by Feng Zhang, Stuart Orkin and Daniel Bauer. I am also a huge fan of Chris Vakoc’s tiling screens. He showed you can functionally map the domain architecture of a protein using Cas9. I could see a two-tiered approach where you tile all coding exons of a gene to identify domains required for protein function and then use Jay Shendure’s saturation mutagenesis CRISPR approach to dive deep into the biology of a region of a protein you are interested in being very useful for many types of biology. 

SP: You have a background in cancer biology, right? How did this lead you to CRISPRa/i? 

LG: Hah – good question. I joined Jonathan’s lab to study a new type of anticancer drug that targets protein folding, but CRISPR seemed awesome and so I got side-tracked. I am a cancer biologist, though and have managed to talk my way into a faculty position at UCSF in the Helen Diller Cancer Center where I will be studying cancer in cancer cells and mouse models of cancer. [editor’s note: hell yeah congratulations!].

SP: Any particularly papes you think we should all be reading right now? 

LG: I will make a shameless plug for my partner-in-crime Max Horlbeck’s paper in eLife that just came out showing Cas9 and dCas9 access to DNA is impeded by nucleosomes in vitro and in vivo (Figure 3). This work was a collaboration with Lea Witkowsky in Robert Tjian’s lab. I love this paper because they used an amazingly diverse set of methods from machine learning to hard core biochemistry to show Cas9 has a problem with nucleosomes. Makes sense to me as SpCas9 never saw a nucleosome until just a couple of years ago [editor’s note: whoa].

Figure 3. sgRNA effectiveness is anti-correlated with nucleosome position, suggesting that dCas9 cannot bind nucleosome-bound DNA. From Horlbeck et al 2016, eLife.

But beyond this I would say that I have always benefited enormously from reading as broadly and as much as I can. It does not matter what you read just read constantly.

HZhang, Y., Yin, C., Zhang, T., Li, F., Yang, W., Kaminski, R., et al. (2015). CRISPR/gRNA-directed synergistic activation mediator (SAM) induces specific, persistent and robust reactivation of the HIV-1 latent reservoirs. Scientific Reports epress. http://doi.org/10.1038/srep16277

When it comes to HIV/AIDS treatment, we live in a combination best-of-times/worst-of-times. In many parts of the world, HIV/AIDS remains a catastrophic issue. Yet for people with access to treatment, there now exist many highly effective ways to treat HIV and live a long, healthy life. There are many classes of HIV drugs, each of which functions by blocking a specific step of viral replication or maturation. When taken continuously, these treatments can reduce one’s viral load to undetectable levels, and can effectively make a person incapable of transmitting the virus. This is a truly amazing state of affairs, and we at Sick Papes stand in awe of the activists and scientists who fought for decades to bring us this day. (We also spit on the grave of the homophobic shit-head Presidential Administration who actively made the crisis worse.) (We also salute the brave people like rapper Mykki Blanco who are fighting the enduring stigma of HIV.)  

However! There is a major issue for all existing treatment regimens: they must be taken continually for one’s entire life, and even a short lapse can cause the virus to come roaring back. This is because there are reservoirs of cells in your body that house “silent” copies of the HIV virus that do not replicate at all, and are invisible to the current replication-blocking treatments; whenever a person stops taking their drugs, these silent reservoirs flare up. The forefront of research on HIV treatment is therefore to find ways to target and destroy these silent reservoirs of HIV positive cells in the body, the source of perpetual risk.

Today’s Sick Pape presents a proof-of-principal for a technique to kill these silent pockets of HIV+ cells in an otherwise healthy person. To do so, the authors take advantage of a bangin’ new technique for activating any gene-of-interest in the genome. This technique, which was invented independently by several labs, involves the perpetually press-shy Cas9 protein…but with a naughty twist. Whereas Cas9 typically cuts DNA (at a genomic location controlled by a 20-bp “guide RNA”), Cas9 can be made unable to cut DNA by mutating specific amino acids in the catalytic core of the enzyme. This catalytically dead Cas9 (”dCas9″) can be fused to transcriptional activator domain, and guided to a gene’s promoter, thus transcriptionally activating that gene [insert DJ airhorn sound]. What’s more, dCas9 can also be fused to a repressor domain, or any other functional domain. In other words, we can now turn on or off any gene in the genome at will: it’s lit. 

Wenfei Hu’s lab, located in downtown Philadelphia, took advantage of this technique to activate the HIV genome in the reservoir cells where the virus hides. Once HIV has been activated, these cells can be killed by the immune system and/or existing drugs. This is obviously dope - but do keep in mind that all of this work is done in cell culture, where it is trivial to deliver dCas9 and guide RNAs to the cells. To make this technique work in humans will take some doing, but man I think someone’s gonna figure out that pretty soon. After all, Cas9 was only discovered like an hour and a half ago, and already a whole army of TED-talking Equity bros are frothing at the mouth to get rich off drugs.

Liu, N., & Lasko, P. (2015). Analysis of RNA Interference Lines Identifies New Functions of Maternally-Expressed Genes Involved in Embryonic Patterning in Drosophila melanogaster. G3 (Bethesda, Md.), 5(6), 1025–1034. http://doi.org/10.1534/g3.115.017517

There are certain eternal rhythms that calm and inspire us as we move through life. Think of the ocean: whether in difficult times or in joyful moments, it is soothing to hear the rhythm of the waves breaking on the shore, through day and night, a rhythm that stretches back through time, which predates, and will outlast, all of our human activities on this planet. 

Today I would like to talk about another soothing, natural rhythm that will likely outlast us all: the publishing of solid, reliable papes about Drosophila germ cells by Paul Lasko’s lab at McGill University. Just as the waters thaw and the buds emerge each spring, so too does the trustworthy data runneth from the papes of Lasko. Today’s Sick Pape is just one of the latest of the deeply calming publications to break its data waves on the shores of PubMed.

Since 1988, Lasko and his crew has studied germ cells. Germ cells, which give rise to sperm and egg, are among the most kaleidoscopically psychedelic cells in the body, because they literally connect the generations. Think of it this way: all of the cells in your body began as one cell, which once lived inside the ovary of your mother. Yet this cell, like all the cells in her body, came from a single cell in her mother. And so on, back to the beginning of life. In the words of Edmund Wilson (1900), who wrote the first textbook on Cell Biology, “Life is a continuous stream...the individual body dies, but the germ cells live on...”

During embryonic development, the immortal germ cells are specified from their mortal neighboring cells. This is analogous to a bee colony selecting a queen: all the other cells in the animal will function as worker bees, while the germ cells sit like a queen, doing nothing but giving rise to the next generation. And, like most biological phenomena, the molecular mechanisms of germ cell development were largely worked out using large genetic screens in the fruit fly in the late 1970s and early 1980s. Specifically, to identify genes involved in germ cell development, many thousands of mutant fly lines, each with a mutation in a single gene, were screened for defects in germ cell development. 

Paul Lasko’s early research focused on several of the genes that were identified in such screens (including Vasa, which we’ve mentioned before). Now, three decades on, one of his lab members, Niankun Liu, has continued this logical, time-tested approach to identify additional genes involved in germ cell development. Using a dope comprehensive database of Drosophila gene expression, these folks found a list of 51 mRNAs that are localized to the site of embryonic germ cell formation. They then used RNAi to systematically knock down each gene on the list, and test for defects in germ cell development. What’s more, they even took the highly commendable step of actually testing which of their RNAi lines works, so that they have a sense of which of their negative results are actually trustworthy. In the end, they come up with a handful of interesting new genes to follow up on, including a ubiquitin ligase of unknown function (check back in 30 years).

SICK PAPES SPECIAL ON ROTIFERS ACTUALLY HAVING SEX!!

Signorovitch, A., Hur, J., Gladyshev, E., & Meselson, M. (2015). Allele Sharing and Evidence for Sexuality in a Mitochondrial Clade of Bdelloid Rotifers. Genetics. doi:10.1534/genetics.115.176719

As all you puddle-suckers know, there are entire universes of microscopic organisms living in every drop of puddle water, moss-moisture, and sidewalk-juice. Indeed, it was within a drop of filthy gutter-scum that Antony van Leeuwenhoek (1632-1723) observed single-celled and other microscopic organisms for the first time. (He also provided the first microscopic drawings of human sperm, which lead to some great drawings of little tiny men scrunched up inside the head of a sperm [editor’s note: this man-in-sperm theory is no crazier than the truth of how humans develop]). The revolutionary nature of Leeuwenhoek’s observations are even more impressive considering how shitty the microscope that he used was: made of a single hemisphere of glass fixed to a metal plate, these scopes had a fixed focal distance of ~0.5mm but magnified up to 275x, and apparently had a resolution approaching ~one micron.

Today’s Sick Pape focuses on one of the types of animals that Leeuwenhoek saw when he magnified a drop of water: rotifers. Rotifers are microscopic animals (not bacteria, not amoebas - multicellular animals) measuring between ~100-500 microns, yet possessing a complex anatomy including a nervous system and a digestive system. And for the past two decades, rotifers in the genus Bdelloidea have been the subject of intense research for one reason: they never, ever have sex.

Sexual reproduction is thought to be essential for the long-term survival of a species. There are a handful of animals that will occasionally pop out a Virgin Birth, but this is typically done just for a ratings bump at Animal Planet during the holiday season. In general, there are no species that exclusively reproduce  asexually and manage to last more than a few million years. While there may be short-term Darwinian benefits cloning yourself, only sexual reproduction can provide the cosmic intermingling and chromosomal diversity that organisms need to survive the long evolutionary grind.

Bdelloid rotifers thus pose a major question: how has this species survived for hundreds of millions of years without ever having sex? Male bdelloid rotifers have never been observed, nor has anyone ever witnessed meiosis or mating. Instead, the females just happily clone themselves forever like a goddam metaphor I can’t think of right now. The big question has always been: how come these ladies haven’t gone extinct? What’s their secret?

Over the past few decades, Bdelloid rotifers have been whispering their secrets into the quivering ears of Matt Meselson’s lab. Meselson is one of the best scientists who has ever lived, responsible for “the most beautiful experiment in biology,” as well as helping to discover mRNA and many other Old Testament breakthroughs (as well as crusading for years against biological weapons). Which is just to say, he knows what the funk he’s talking about. And his lab has shown that Bdelloid rotifers have a variety of alien mechanisms for increasing their genetic diversity without having sex. Namely, these rotifers suck up random DNA from their surroundings and shove it into their own genomes, and they also shatter their entire genome and then rebuild it with errors.

And now, Meselson (who is currently in his 80s) and his lab have done something that is so rarely done these days: they have provided strong evidence that their entire premise was wrong, and that bdelloid rotifers actually do reproduce sexually. I want to emphasize that none of their past research was wrong; each of their past experiments still hold up, all the crazy DNA-sucking-and-shattering is still real, its just that these strategies exist in addition to sex (albeit, very infrequent sex).

Meselson and his squad begin their Sick Pape with an ominous threat that would terrify the Edward Snowdens and Chelsea Mannings among us: “Certain methods…offer definitive means for detecting infrequent or atypical sex.”  [Editor’s note: what you or I do in private is not the business of the Meselson lab or the State]. However, instead of using the CIA interrogation methods implied by this terrifying abstract, they stick to modest and routine population genetics strategies. Specifically, these folks test for patterns of genetic similarity between different rotifers that imply they are the product of sexual reproduction in the not-too-distant past, and they find it.

For those who want to come into the methodological weeds with me, the “certain methods” to detect infrequent sex is this: you sequence a few genes from each of several rotifers, and then look for a pattern where Gene X from rotifer 1 is very similar to its homolog in rotifer 2, whereas Gene Y is similar to its homolog in rotifer 3. This implies that there has been recent sex that has jumbled up different chromosomes between individuals in the population. To be sure that this wasn’t the result of direct DNA transfer between rotifers 1-3, these auteurs do the same test at several genes and show that the same pattern holds for all these genes, making it very, very unlikely to have been direct horizontal transfer of DNA.

We honor Ana Signorovitch, the pape’s first author, and her colleagues in the Meselson lab for having the courage to disprove themselves - an uncommon mark of high integrity - and for shining their beautiful light on an invisible little corner of our world. Of course, the timing and mechanisms of sex remain a complete mystery, so please keep up the hard work for many more decades to come!

Vidal-Gadea AG​, Ward K*, Beron C*, Ghorashian N, Gokce S, Russell J, Truong N**, Parikh A*, Gadea OE, Ben-Yakar A, Pierce-Shimomura JT. Magnetosensitive neurons mediate geomagnetic orientation in Caenorhabditis elegans. eLife. 10.7554/eLife.07493

The earth’s molten core does more than just power our cars, inspire our metal bands and keep the Ion television channel afloat, it generates a magnetic field which can help critters of the sky, water and - now it turns out - dirt, navigate. Andre ́s Vidal-Gadea and colleagues at U Texas Austin slow cook a data-brisket in a recent Elife (http://lens.elifesciences.org/07493/index.html), demonstrating the nematode worms sense magnetic fields and use this sensory information to burrow in a literal way that depends on their state of hunger and remarkably, their global latitude of origin (authors note: not the figurative latitude of running backs or chill ass life-partners). Naturally these dudes built a special box that can mimic, cancel or exaggerate the earth’s magnetic fields and effectively demonstrate the induced behavior is due to the magnetic field and not temperature or electrical side effects or anything. But perhaps this isn’t a biggie, since even some friggin’ ocean bacteria can swim or sink on the mellow vibes of magnetoreception and it’s been known since ~2004 that crushed up worms contain a bio-material that could be used to sense magnetic fields.

The nuts part is that unlike bacteria, the worms don’t just move in parallel to the field, they burrow at an angle. The authors noticed this first in their workhorse strain which was isolated from the sacred dirts of England. Fascinatingly and psychedelically and genetically it appears, worms taken from different areas of the globe choose different burrowing angles in response to the same magneto-field. WTF? Because these dudes are smarter than us, they realized that “up” or “down” in terms of soil direction requires picking a different magneto-based burrowing angle depending on where you at, from the equator to the poles. (To visualize the direction of magnetic fields, imagine like a fountain of blood shaped like arrows shooting out of one pole and entering the other pole; around the equator those arrows are parallel to soil but at the pole perpendicular; do not google any of this).  For example, in the same magnetic field, hungry worms from England and Australia burrow in basically opposite directions. The authors use a bunch of other strains from the all over the place to show a strong correlation between offset angle and what would be the “down” direction in soil. This striking correlation lends support to their hypothesis. How the f is this type of thing genetically encoded?

The authors don’t get the how, but they at least get started with where and a touch of the what. Using the nifty genetic tools that allow researchers to screen through which brain cells and genes are necessary for the behavior, dudes identify a single pair of sensory neurons (called AFD neurons in wormenclature) which are directly activated by magnetic fields and necessary for magneto-inspired burrowing. AFD neurons have been previously shown to react to temperature changes and affect locomotion, thus their new-found role suggests they’re pulling sensory double-duty to control crawling in one direction or the other. And less you think “yeah of course crawling control what else is there for a worm to do” in terms of motor behavior? they also have sophisticated asshole technique: http://www.ncbi.nlm.nih.gov/books/NBK20047/

But what about AFD neurons make them sensitive to magneto-fields and how do they calibrate that angle business? Sadly we’ll have to wait for one of these graduate students to figure it out. Shall we kickstarter them? In the meantime, we need to be satisfied with the genetic results showing that a particular type of ion channel – one gated by the second messenger cyclic guanosine nucleotide (cGMP) - is necessary in AFD neurons. These necessary channels are almost assuredly downstream of the angle-calibration signaling, but working upstream – first off by identifying the guanylate cyclase that catalyzes the relevant cGMP – might be a good start.

…A white American man travels to Borneo in search of rare mushrooms that grow in parts of the jungle where “headhunters” live - people known to decapitate outsiders that they don’t like. The American and a local interpreter are brought before the leader of the fearsome tribe, to ask if the American might join the tribe on a mushroom hunt. Before the leader answers, he gestures at the American’s shirt with a stern face, wanting to know what the English words mean. The American looks down at his shirt - which reads “Shiitake Happens” - and tries to explain the pun through his interpreter. The local tribal leader thinks for a moment, then replies:

“That is the funniest thing I’ve ever heard. You can definitely party with us.”

At least, that was my recollection of a strange and wonderful article that I read in a bathroom in Montana, in 2007. This story has stuck with me since, but the name of the mushroom magazine and the author were total blanks. Last week, when I was smoking weed and telling someone about this hilarious anecdote, a fear started to swell within me that perhaps I was radically mis-remembering it, embellishing the story beyond recognition.

I tried to Google the story, but quickly came to the horrifying truth that this story is un-Google-able. No combination of “shiitake happens,” “Borneo,” “headhunters” and “mushroom” came anywhere close (although I did spent >$1500 on Shiitake Happens paraphenalia). If you include “tribal leaders,” you exclusively get hits about Afghanistan and Iraq. It felt like all was lost, and that the substrate of this core memory was forever lost down the forgotten chasm.

The hour grew late, and I continued Googling with increasing frenzy until somehow - and I honestly don’t remember how or what combination of search terms got me there - I came upon the blog of an American mushroom enthuasiast and natural historian named Lawrence Millman, who had written about Borneo and who seemed like he may have the secret to all this. Within hours of emailing Mr. Millman, he very kindly responded from his iPad, telling me that he not only knew of the article, but had in fact written it! I was elated -  he put me in contact with the person who runs FUNGI magazine, who also responded with outstanding speed, sending me a PDF of the article, which I am happy to report is:

Millman, L. 2010 How I (Almost) Lost My Head…Over a Fungus. FUNGI Magazine Vol 3:3, p25-26.

The reason the article couldn’t be Googled was because the article had never been posted online anywhere. You’re probably wondering how this article could have been published in 2010, given that I read it in a bathroom in 2007. Great question, which I also put to Mr. Millman; it turns out than an earlier, less-polished version was published in Mushroom in 2006 or 2007, but which has no online archives.

Here’s the original anecdote, written by Dr. Millman:

“Now it was the chief ’s turn to ask me a question. I was wearing a “Shiitake Happens” T-shirt, and he wanted to know what the words meant. Through Bakhri, I explained their meaning. Whereupon the chief clapped his hands in delight and said he hadn’t heard anything so funny in years.”

The article includes tons of other wild stories. When Millman first arrives in the long house belonging to the Iban tribesmen, he notices a bag of skulls hanging from the rafters. These skulls, it turns out, are from Japanese soldiers, killed by locals during World War II to collect bounties from Allied officers. Millman notices an intriguing-looking fungus growing on one of these skulls - “a cinnamon-colored resupinate entity perhaps 8 cm long.“ Millman is prohibited from collecting a sample because these skulls are sacred objects, so he never did get to study this mysterious human-bone-eating-fungus in any more detail.

Is there anything cooler than mushroom hunting? The wicker baskets used to collect mushrooms (so that the spores may scatter upon your woodland path), the beautiful mushrooming knives, the fact that the New York mycological society was founded by the the avant garde composer John Cage - no, there is nothing cooler. Collecting mushrooms in Borneo? Doesn’t get any sicker. Thank you, Lawrence Millman!

Bickel, R. D., Cleveland, H. C., Barkas, J., Jeschke, C. C., Raz, A. A., Stern, D. L., & Davis, G. K. (2013). The pea aphid uses a version of the terminal system during oviparous, but not viviparous, development. EvoDevo, 4(1), 10. doi:10.1186/2041-9139-4-10

Ladies and gentlemen, I have spent the past few days struggling to find a way to write about the CRISPR genome-editing revolution. The CRISPR system is a truly profound breakthrough that uses just two molecular components to remove, add, or otherwise edit any gene in any living thing. Component One is an enzyme called Cas9, which cuts DNA, and Component Two is a fragment of RNA that can easily be made to guide Cas9 to any specific place in the genome. It’s insane. This system was co-opted from an anti-viral immune system that naturally occurs in yogurt bacteria, and in the past few years it has been shown to work in basically every organism on the planet, and to work very well. At this point, just two years after the system really came of age, it appears routine to systematically screen the entire human genome for cell growth phenotypes in a single flask of human cell culture in about a week.  

I was thinking that I’d write about this insanely hot pape, coming from the lab of the hero that discovered introns and exons, where they made a library of guide RNAs targeting every gene in the mouse genome, transfected these RNAs into a flask of cells capable of forming tumors but not of metastasizing, and injected the resulting cells into mice. A few weeks later, they found that some of these genotypically mosaic tumors had indeed metastasized, and by sequencing the mutant cells found in the spreading tumors they could identify what gene had been mutated in those tumor cells, and from a grand total of like six mice, they had a list of genes whose absence can lead to tumor metastasis. 

But as I started to write, something just didn’t feel right.  As undoubtedly dope as these CRISPR papes are, I just couldn’t shake the feeling that these huge CRISPR labs really aren’t really my crew. Maybe it was checking out these two CRISPR-based biotechnology companies whose websites literally just list their scientific advisors and how many millions of dollars they’ve raised from investors. I dunno - absolutely no disrespect to the jaw-droppingly productive authors of the CRISPR revolution, but I just can’t help but think about the staggering funding inequality amongst biology labs, and the growing pressure to focus on research that has direct applications to human medicine, and in the end I just felt like my heart wasn’t in it. Ladies and gentlemen, I had to walk away from that Sick Papes post, as difficult as it was.

Then I came home and re-read this wonderful paper about aphid development, chock full of undergraduate co-authors and off-the-wall insect evolution, and felt a wave of warmth and safety rush over me. The paper deals with aphids, which have one of the most bizarre lifestyles on earth: all year long, female aphids give birth to clonal female babies via virgin birth, no males involved. THEN, right before winter, they make one generation of males, which undergo normal meiosis and sexual reproduction with their female siblings, to produce an egg that is capable of over-wintering. This is the egg that will hatch in the spring to give rise to another female who will then start clonally reproducing female babies via virgin birth all over again.

Brainard MS, & Doupe AJ (2000). Interruption of a basal ganglia-forebrain circuit prevents plasticity of learned vocalizations. Nature, 404 (6779), 762-6 PMID: 10783889

We were devastated by the news that Dr. Allison Doupe, a much-loved neuroscientist at UCSF, passed away late last year, following a long battle with cancer, a struggle that she refused to let mitigate the exuberance and overflowing passion with which she carried out her research. A symposium in Allison’s honor is being held tomorrow as an opportunity to reflect upon her intellectual and personal life.

Allison was a scientific heroine of the highest order, and she published some maddeningly excellent papes. Her lab made fundamental contributions to our understanding of auditory processing, reinforcement learning, and the effects of social context on neural coding. She was also a vocal advocate for neuroethology and the study of non-traditional model organisms in systems neuroscience. Finally, Allison was an incredibly generous and vivid person.

Allison’s lab studied song learning in birds. Like humans, songbirds learn how to sing from older and wiser adults. During a critical period early in life, each bird memorizes the song of an adult tutor. It then goes off alone and practices, until its own song closely matches the template provided by the tutor.  Birds that are not tutored during their impressionable early days are forever stunted in their ability to produce a stable and satisfyingly melodious warble in their later years. This humbling fact illustrates the importance of the so-called critical period: the brief developmental window in which an animal acquires a skill that persists throughout adulthood. For humans, the critical period of childhood is not only a time in which we develop our motor capacities, but also a moment of heightened attentiveness, during which we learn the templates that guide our behavior as adults. A large part of Allison’s work was devoted to studying the brain circuits that underlie the fascinating processes of song template acquisition and vocal refinement.

During her post-doc with Mark Konishi, Allison was the first to record from neurons in the anterior forebrain pathway (AFP), a region of the bird brain analogous to the mammalian basal ganglia. The AFP is highly interconnected with the motor areas that control song production, and it plays an important but complex role in song learning. By the late 1990’s, several key observations had been made about the role of the AFP in song acquisition. First, lesioning the AFP of a young bird prevents song learning entirely. Second, inactivating the AFP of an adult bird does not disrupt singing of an already learned song. Third, as the bird develops and learns the template song, neurons in the AFP become more responsive to a bird’s own song or that of the tutor, and less responsive to the songs of other birds. 

These clues led Allison and her post-doc (and future husband) Michael Brainard, to hypothesize that the AFP monitors song production and fine-tunes motor output to more closely match the template song. To test this idea, Michael and Allison took advantage of the fact that deafening an adult bird leads to deterioration in song quality. They reasoned that, if the AFP is responsible for refining song production, then it might be the source of song deterioration in deaf birds. Indeed, when they lesioned the AFP in deaf birds, they found that the song no longer degraded. This remarkable result showed that the basal ganglia circuits of the AFP are critical for continual refinement of the bird’s song.

Over the last decade, Allison and her colleagues have continued to expose how the AFP contributes to the learning and maintenance of bird song.  This work has deepened our conception of learning itself, and how young critters of all sorts ascend from the moronic plains of un-coordination to the lofty heights of fine motor control.  One typifying leap in this direction was the discovery that juvenile experimentation is required for song learning, and that this is accomplished in the bird brain by the intrinsic injection of variability from the AFP into the song production pathway.  Work from the Doupe & Brainard labs have provided a fascinating window into how the AFP contributes to song variability, and, in doing so, revealed fundamental insights into how basal ganglia circuits contribute to motor skill learning.

SICK PAPES SPECIAL ON RACIAL DISPARITIES IN MORTGAGE LENDING:

Interview with Jim Campen, author of “Changing Patterns XXI: Mortgage Lending to Traditionally Underserved Borrowers & Neighborhoods in Boston, Greater Boston and Massachusetts,” a report prepared for the Massachusetts Community & Banking Council.

The United States of America was built on genocide and slavery, and severe racial inequalities are built into the structure of our government and society in countless ways. Some forms of structural racism are more obvious than others; the mass incarceration of people of color for non-violent offenses, the murder of unarmed black men by police who face no legal consequences, and the savage inequalities in our educational system are extremely visceral manifestations of our country’s deeply racist structures. There are other ways that racial inequalities are perpetuated that are less obvious, yet have equally destructive effects on social justice. Today we focus on one particular form of structural racism: access to mortgage loans.

In order to buy a house, you need a loan. Thus, there is a direct relationship between who gets loans, and the racial segregation of our neighborhoods and cities, and also on the ability of people to accumulate wealth via home-ownership. Our country has a long history of explicit racism in its housing policy, which has effectively “locked [black people] out of the greatest mass-based opportunity for wealth accumulation in American history.” Today, there continue to be extreme disparities in the availability and the quality of the loans available to black people and Latinos. Here is something I learned during this interview: if you divide up Massachusetts into census tracts, and ask how many of the predominantly (>75%) non-white areas are, on average, “middle- or upper-income” (very conservatively defined), the answer is: 4%. If you ask, how many of the >75% white census tracts are middle or upper-income, the answer is: 91%. Are you kidding me. 

For the past 21 years, Jim Campen (aka my dad) has published an annual Sick Report entitled Changing Patterns: Mortgage Lending to Traditionally Underserved Borrowers & Neighborhoods in Boston, Greater Boston and Massachusetts. The 2014 report was released last week, and we sat down with a computer connected to Dr. Campen to discuss the relationship between mortgage lending and social justice. 

Sick Papes: Can you explain some of the history of how racial discrimination in mortgage lending affects us? 

Jim Campen: For neighborhoods to prosper, residents need to be able to borrow to purchase, maintain, and improve their homes.  But ever since the government first began to promote homeownership early in the New Deal of the 1930s, the availability and cost of mortgage loans has been dramatically different in black neighborhoods than in white ones.  Two major periods stand out.  During the decades following World War II, suburbs grew as banks funneled money to white families abandoning central cities while refusing the make loans to the people – mainly people of color — who were left behind in urban neighborhoods.  Because the areas where banks refused to lend were sometimes outlined in red on bank and insurance company maps, this geographic neglect came to be known as “redlining.”  By the middle of the 1960s, even as the Civil Rights Movement focused its attention on Jim Crow laws and legal discrimination in the South, the central cities in the north were largely poor and black.  

Inner city residents fought back against redlining and eventually succeeded in getting two important laws enacted in the mid-1970s.  The Home Mortgage Disclosure Act of 1975 required lenders to begin reporting information on where they were and were not making loans.  (These data provide the basis for reports like mine.)  And the Community Reinvestment Act (CRA) of 1977 required banks to serve the credit needs of all the neighborhoods in areas where they did business  (“reinvestment” because community groups demanded that banks reinvest their deposits in their own neighborhoods rather than sending them to the suburbs.)   

The CRA didn’t have much impact during the Reagan years, but the Clinton administration took it much more seriously, and flows of mortgage credit to borrowers and neighborhoods of color greatly increased during the 1990s.  However, the resulting increases in housing wealth in these neighborhoods turned out to be short-lived as a result of the second major episode of lending discrimination – which turned the nature of lending on its head.  Instead of refusing the make mortgage loans in neighborhoods of color (redlining), lenders targeted these same neighborhoods for exploitative, predatory loans (reverse redlining).  These subprime loans ended up destroying more housing wealth than had been created between 1990 and 2005.  Many people got rich making these loans (and many others got rich selling securities based on them), but neighborhoods of color where predatory loans were concentrated were hit disproportionately hard by the tsunami of foreclosures.  .  

The story is obviously a lot more complicated than this, with lots of other factors playing a role, but there can be no doubt that discrimination in mortgage lending has played a central role in bringing about the highly segregated nature of U.S. metro areas.

SP: Just how unequally is wealth distributed in Boston and/or Massachusetts?

JC: I’m not familiar with studies of the distribution wealth distribution locally or statewide, although I don’t see any particular reason to think that it is very different from the appalling inequalities at the national level that have been thoroughly documents and widely publicized.  But I can offer two striking examples of racial disparities in this part of the world.  

First, the homeownership rate in Massachusetts is 69.0% for whites, but only 32.0% for people of color – that is, the white homeownership rate is 2.15 times greater.  This is the second highest disparity ratio in the U.S; smaller only that that of New York (66.2% vs. 28.5%, for a ratio of 2.32.).  The national figures are 72.0% for whites and 46.2% for people of color, for a disparity ratio of 1.56.  

Second, three tables in my new report show the incredibly stark income differences among neighborhoods with different percentages of minority residents.   (Table 14 is for the city of Boston, Table 15 is for Greater Boston, and Table 16 is for Massachusetts.)   These tables use standard income categories to classify census tracts (areas with typically 3,000 – 6,000 residents) as low-income, moderate-income, middle-income, or upper-income on the basis of the median family income (MFI) in the census tract as a percentage of the MFI in the relevant metropolitan are. In the city of Boston, for example, there are 44 predominantly-minority census tracts (that is, more than 75% minority residents) and 39 predominantly-white census tracts.  Of the predominantly-minority tracts, 91% are low- or moderate-income, 9 are middle-income, and none are upper-income.  Of the predominantly-white tracts, in contract, only 3% are low- or moderate-income, 25% are middle-income, and almost three-quarters (72%) are upper-income.  For the state as a whole, just 4% of the 98 predominantly-minority tracts are middle- or upper-income (none of these are upper-income) compared to 91% of the 952 predominantly-white tracts. [editor’s note: sorry for the redundancy of this fact, but I just couldn’t believe it.]

SP: You have consistently documented that black people and Latinos are much more likely to be denied a mortage. What do you think are the reasons for this increased higher denial rate? Are there racist bankers sitting behind a desk, personally denying loans based on race? I would (naively) imagine that there are computer programs that decide whether to approve loans, and I can’t imagine these programs are allowed to explicitly account for race in the decision, right?

JC: The key question that I think you are getting at is: what percentage of the disparities in denial rates are a result of discrimination by mortgage lenders?  That is a very interesting question that is impossible to answer on the basis of publicly-available information.  

My own belief is that the majority of the disparities are the result of black-white differences in the incomes, wealth, education, employment stability, and other factors that are legitimately relevant in judging a potential borrower’s credi –worthiness (that is, the likelihood of their making timely monthly payments on the mortgage loan that they are applying for) – differences that have resulted from our nation’s long and disgraceful history of oppressing, exploiting, and discriminating against black people and from the continuing institutional racism throughout American society.  

Having said that, discrimination by lenders almost certainly plays a role.  One type of evidence for this is the statistical studies that have been made in the few cases for researchers had access to enough data about applicants to reach a valid conclusion on whether or not race had independent explanatory power in accounting for higher black denial rates.  The most important such study was conducted by researchers at the Federal Reserve Bank of Boston in the early 1990s and found that, taking into account over thirty other variables, denials rates for blacks and Latinos were 60% higher than for equally credit-worthy whites.  (Munnell et al., “Mortgage Lending in Boston: Interpreting HMDA Data,” American Economic Review, 1996).  

The other type of evidence is that from “paired testing” studies.  In such studies, trained “testers” with appearances and profiles that are similar (except for the difference being tested for – e.g., black/white or male/female) are sent into the same situation and follow the same general “script.”  Testing is relatively easy to do for shoppers in jewelry store, applicants for rental housing, and seekers of a taxi, but is much harder in the case of mortgage lending – because lenders generally require lots of real information about the applicant (Social Security number, credit score, employment history, tax returns) and the property being purchased.  As a result, testing in the mortgage area can only be done for the initial stages of the process, when potential borrowers first approach lenders to make an inquiry.  Nevertheless, HUD has sponsored major mortgage testing studies more or less every decade and consistently found discrimination.  Closer to home, and on a much smaller scale, when I was on the board of the Fair Housing Center of Greater Boston, we did a local study in 2006 involving twenty pairs of potential mortgage borrowers.  The results were quite clear: “Overall, the Fair Housing Center found differences in treatment which disadvantaged the homebuyer of color in nine of the twenty matched paired tests conducted, or 45 percent. 

SP: If you control for other economic variables, is there still a large difference in the rate of loan denial to blacks and Latinos? 

JC: In this new report, I used the HDMA data to investigate whether the racial differences in denial rates could be explained as a result of black and Latino applicants having lower incomes.  The answer is: not very much of the difference.  In Greater Boston, for example, where the overall black/white denial rate disparity ratio in 2013 was 3.14 (19.3% vs. 6.1%), the disparity ratio considering only those with incomes between $91K and $120K was 2.69, and the disparity ratio for those with incomes over $120K was 2.86.

SP: For many years prior to the 2008 financial crisis, you were already reporting about the risks of “sub-prime loans” and “predatory loans,” and emphasizing that lenders were seeking out people of color for these types of loans. Did the financial crisis have worse effects on people of color than it did on whites? 

JC: Yes, much worse.  One indicator is the relative decreases in homeownership rates between 2008 and 2013.  While the white homeownership rate fell by 1.7 percentage points (from 75.0% to 73.3%), the Latino homeownership rate fell by 3.0 percentage points (49.1% to 46.1%), and the black homeownership rate dropped by 4.1 percentage points (from 47.9% to 43.8%).  [Joint Center, The State of the Nation’s Housing, 2014, Table A-2]

And a 2013 study by the Urban Institute found that whereas white families had an average wealth about four times greater than that of nonwhite families before the recession, their average wealth after the recession was six times greater than that of nonwhites.  [www.urban.org/publications/412802.html] 

SP: I’ve noticed that, in general, your graphs don’t have error bars and you don’t report statistical tests. Can you explain why? 

JC: That’s because I’m working with the entire “universe” of available data, not just a sample.  When you do a poll of 1,500 likely voters, this sample may not be an accurate representation of all voters in the state or nation – and statistical tests, confidence intervals, margins of error, and so forth are quantifications of how likely the sample data is to accurately reflect the data in the entire universe.  If you’re studying 50 fruit flies, the question is how likely your findings are to hold true for all fruit flies.  But HMDA data is it not a random sample from a larger universe of mortgage loans.  When HMDA data shows that the denial rate for blacks in Greater Boston in 2013 was 3.14 times the denial rate for whites, that is based on all 768 black applicants and all 25,741 white applicants that are reported in the HMDA data. There are various reasons why these denial rates might not be exactly correct, but sampling error is not one of them – and sampling error is what error bars and statistical tests are all about. 

SP: What prompted you to start publishing this study in the first place?

JC: The Civil Rights Movement was at its peak during my formative years – I was in eighth grade when Rosa Parks refused to go to the back of the bus in Montgomery and a senior in college when Martin Luther King Jr led the March from Selma to Montgomery – and I’ve been concerned with issues of racial injustice and racial inequalities ever since.  I first got interested in studying mortgage lending patterns in the early 1990s.  After a year of struggles between community and groups and local banks following the January 1989 leak of a draft report by the Boston Fed that found that mortgage lenders were discriminating against black neighborhoods in Boston, the Mass. Bankers Association finally agreed to a program that included increasing mortgage lending to borrowers and neighborhoods of color.  Their program also established the Massachusetts Community and Banking Council (MCBC) to maintain continuing dialogue between banks and community groups.  I was hired by MCBC to prepare a report on how mortgage lending patterns had – or had not — changed in the first three years of the program, and in 1995 I released a report called Changing Patterns.  MCBC seems to have liked it, since they’ve asked me to prepare annual reports ever since.  The new report is the twenty-first in this annual series.  

SP: What are some ways we can fight to change this? What are some of the groups working to fight this, on the legal level and on the street level? 

JC: The struggle for greater economic justice in the area of mortgage lending is part of the overall struggle for greater economic justice throughout American society.  Anything that results in higher incomes, reduced unemployment, better education, and less incarceration for people of color will enhance their ability to obtain good mortgage loans. 

In terms of mortgage lending specifically, there are many groups engaged in a variety of efforts at both the national and local level.   Nationally, the establishment of the Consumer Financial Protection Bureau (CFPB) as part of the Dodd-Frank financial reform legislation of 2010 was a major victory, and the CFPB has already done a lot to reduce unfair, deceptive, and abusive mortgage lending practices.  Thus, a top priority of national groups working in this area – such as Americans for Financial Reform, the Center for Responsible Lending, and the National Consumer Law Center — is to protect the CFPB from unrelenting attacks by Republicans in Congress who would like to end its ability to aggressively enforce consumer protection and fair lending laws.  

On the local level, there are local and statewide groups around the country working in this area both through advocacy work and grassroots organizing.  Many of these groups keep in touch with each other through the National Community Reinvestment Coalition, National People’s Action, the PICO National Network, and other umbrella organizations.  For several years in the 2000s, seven groups from around the country produced a joint annual report on some aspect of racial disparities in mortgage lending in our seven cities – Boston, Charlotte, Chicago, Cleveland, Los Angeles, New York City, and Rochester NY.  I did the Boston analysis on behalf of the Massachusetts Affordable Housing Alliance (MAHA), a wonderful local organization that combines home- buyer and home-owner education classes, grass roots organizing (through its Home Buyers Union), and advocacy work with the Boston and Massachusetts governments (full disclosure: I’m a long-time MAHA board member [editor’s full disclosure: he’s also a great dad]).  

MAHA helped persuade Massachusetts to establish and promote a new Massachusetts Homeownership Compact that encourages banks to pledge to increase their lending through two publicly-supported affordable mortgage lending programs.  Both the MassHousing Mortgage Program and the ONE Mortgage Program devote a high percentage of lending to exactly the kind of affordable prime mortgage loans to neighborhoods and borrowers of color that my report shows are much too scarce.  The ONE Mortgage Program that MAHA has championed is particularly affordable (the “mortgage comparison chart” at www.mymassmortgage.org shows that a lower-income borrower buying a $250,000 home would have a monthly payment of $1,004for a ONE mortgage, compared to $1,482 for an FHA mortgage) – and more than half of ONE mortgage loans in the state have gone to black or Latino borrowers.  

Fang, W., Wang, X., Bracht, J. R., Nowacki, M., & Landweber, L. F. (2012). Piwi-interacting RNAs protect DNA against loss during Oxytricha genome rearrangement. Cell, 151(6), 1243–1255. doi:10.1016/j.cell.2012.10.045

Most of us spent our childhood and teenage years under the impression the our genomes were dominated by "junk DNA." And if you're anything like me, you loved this fact. For me, there was nothing better than slowly waddling around on a Sunday morning with my genome full of total garbage. It's like my grandfather always used to tell me: "Keep your genome like you keep your pockets, boy: nearly 100% full of complete fucking trash from like a million years ago." 

Given the centrality of useless DNA to my conception of myself, I was deeply dismayed when the consortium-with-the-mostest, the ENCODE project, pronounced that the human genome is NOT, in fact, dominated by "junk DNA," but is, in fact, chock full of highly useful, if non-coding, sequence. Reader, I was distraught.

But, thankfully for those of us who love roly-poly, useless DNA, there is still at least one loveable little fatty out there that keeps a solid 95% of its genome full of trash. This rosy-cheeked buddy goes by the name of Oxytricha, and the genomic haunted house of this single-celled protozoan is the subject of today's Sick Pape.

Unlike you y tu mama tambien, every single Oxytricha cell has two types of nuclei: one called the "somatic nucleus" and one called the "germline nucleus." This is profoundly unusual, but it is just the beginning. Every time that these organisms have sex, the somatic nucleus degenerates, and in the subsequent generation, the germline nucleus is used as a template to create a new somatic nucleus.

But here's the crazy part: 95% of the germline nucleus is edited out during in the creation of the somatic nucleus! In other words, 95% of the germline genome is so useless that it literally gets deleted in the somatic nucleus, and the nucleus is completely fine without it. Now that's the kind of junk DNA I'm talking about: real, honest-to-goodness trash. Furthermore, the germline genome, which exists as very long strands of DNA just like any normal genome, is physically fractured into hundreds of thousands of fragments, most of which contain a single gene, such that the somatic nucleus contains ~16,000 chromosomes, representing just 5% of the DNA content of the germline nucleus.

What Laura Landweber's lab wants to know is how the genome is properly edited during the creation of the somatic nucleus. How does the DNA know which fragments to keep and which to destroy? In the present Sick Pape, The first observations these wonderful authors make is that there is a class of small RNAs (~27 nucleotides long) that becomes abundant during this process. And amazingly, if you map these small RNAs to the germline genome, they blanket the parts of the genome that are saved in the somatic nucleus! Thus, the obvious hypothesis is that these small RNAs serve as the signal to protect a part of the genome from destruction. To definitively test this, these folks injected synthetic small RNAs mapping to a part of the genome that is usually deleted, and bazinga! These experimentally-protected DNA stretches are retained in the somatic nucleus!

Rich, P., Liaw, H., & Lee, A. (2014). Large environments reveal the statistical structure governing hippocampal representations. Science, 345 (6198), 814-817 DOI: 10.1126/science.1255635

Have you ever felt lost and alone? If so, this experience probably involved your hippocampus, a seahorse-shaped structure in the middle of the brain. About 40 years ago, scientists with electrodes discovered that some neurons in the hippocampus fire each time an animal passes through a particular location in its environment. These neurons, called place cells, are thought to function as a cognitive map that enables navigation and spatial memory.

Place cells are typically studied by recording from the hippocampus of a rodent navigating through a laboratory maze. But in the real world, rats can cover a lot of ground. For example, many rats leave their filthy sewer bunkers every night to enter the cozy bedrooms of innocent sleeping children.

In a recent paper, esteemed neuroscientist Dr. Dylan Rich and colleagues investigated how place cells encode very large spaces. Specifically, they asked: how are new place cells recruited to the network as a rat explores a truly giant maze? Today, we huddle closely with Dr. Rich to whisper about his findings.

SP:  Do you remember when and how you first learned about hippocampal place cells? Did your interest in the hippocampus burgeon immediately, or ripen like a stubborn avocado?

Not exactly, only that it was during my undergraduate studies. I was on a neuroscience degree course and there was quite a lot of cellular and molecular neuroscience. I was interested in the more cognitive aspects of neuroscience, but I wanted to still be studying the brain per se rather than psychology.  The hippocampus and place cells seemed as though it had the higher-level cognitive aspects, but was still very much grounded to the physiology, to neurons and spikes. Some of the lecturers who taught were rodent hippocampal researchers, so I was exposed to a lot of the experimental and computational work on the hippocampus. It was also around that time that grid cells had just been discovered, so I think some of the excitement in the field trickled down to us undergraduates.

SP:  The experiments in this paper required you to record from the brains of rats running through huge mazes, up to 48 m long. Where and how did you set this up? 

DR: When we were planning this experiment, none of our normal lab rooms were large enough. One evening we wandered around prospective parts of the building, the back service corridors and such, asking “can we do it here?”, “where would we mount the cameras?” et cetera. Eventually we found a suitable space, the cage washing room in the animal facility. The trouble was that it was in full use during the week for cleaning animal cages; we were only able to use it on weekends. So, when we had an animal ready to go, we would have to set up the whole experiment just for the weekend. Starting Friday evening, we’d move everything down and set it all up, recording rig, cameras, cables, maze pieces, the lot. We ran the experiment all weekend then cleared the room in time for the start of work on Monday. Since we couldn’t really plan exactly how things would go, initially there were a lot of trips to the hardware store. We’d have some problem, and think “pipe clamps, we need pipe clamps!”, then go to the store to get pipe clamps, and by the time we got back there would be something else we needed! After the first few times we got the setup and teardown running smoothly, and then we were able to concentrate on running the experiment well.

SP:  By looking at place cell recruitment in these big mazes, you discovered that the formation of place fields is an independent Poisson process with its rate drawn from a gamma distribution. In describing the gamma-Poisson process, you cite a book called On Random Processes and Their Application to Sickness and Accident Statistics by O. Lundberg. What's up with that book?

DR: Ove Lundberg was a Swedish mathematician who did some important work on Poisson processes. The major motivation of his work was in its application to the insurance industry. This branch of mathematics, known as risk theory, had actually been pioneered by his father Filip Lundberg.

Prior to Ove Lundberg, in the 1920s, British mathematicians Major Greenwood and Udny Yule had developed the gamma-Poisson model trying to understand the distributions observed amongst accidents in factory workers. They concluded that preexisting differences offered the best explanation for the differences they saw in the number of accidents each individual suffered. At around the same time, the Hungarian mathematician George Polya was working on different mathematical models that gave similar distributions. In these models individuals would start from an identical baseline, and the occurrence of an accident (or more generally an event) would increase the future likelihood of an accident for that individual.  These types of model, which were framed in terms of drawing balls from an urn, became known as cumulative advantage or rich-get-richer models. Ove Lunberg was the first to show that these two mechanisms, preexisting differences or cumulative advantage, could actually give rise to the same stochastic process, even though the starting assumptions were very different.

I had been struggling with simulations of models in an attempt to distinguish between preexisting differences or a cumulative advantage mechanism in our data. When I found out that someone had solved the exact same problem, it was a crucial piece of information in interpreting our data.

The reference itself was actually a bit of a pain. Since it was a book, the journal wanted the whole title to be in the shortened reference list, which counted against our word limit.  So we were always joking about how much it really needed to be in, because we could get another 10 words or so if we got rid of it. But it was an important piece of the puzzle, so it always stayed in.

SP:  We are conducting this interview within a helicopter zooming across middle America. Do your results tell us anything about how place cells might represent extremely large spaces, such as the view from this helicopter space shuttle? Does your model predict an upper limit on spatial representation in the brain?

DR: This is an interesting implication of our data; it gives us an idea of what strategies might be employed in the hippocampus to allow the representation of very large spaces. The logarithmic-like recruitment of cells suggests that the hippocampal representation is able to encode a large range of environmental sizes. Also the variation of each cell’s propensity may be a way in which the hippocampus may represent different environmental scales; for instance cells with few fields, spaced far apart allow a coarse localization of position, whereas those with more fields give the fine spatial resolution once you know roughly where you are.

From the model, we can predict the behavior of place cells in environment much larger than we examined. For instance, we can extrapolate the recruitment of cells as a function of environmental size; we can read it off and see where it hits 95% or 99%. Would that length be the “upper limit” of the representation? Not necessarily. Even with almost all cells recruited as place cells, there are a huge number of locations that could be coded uniquely across the population using certain types of combinatorial code. One would have to specify a particular code in order to begin to think about an estimate of capacity in this case.

SP: In your experiment, the rat is entering an entirely novel environment, and so does not know how large the maze is going to be. But if he did have some prior expectation about the scale or shape of the maze, how do you think this would affect the rate of place cell recruitment?

DR: It’s definitely possible that an expectation of environment size may modulate some aspect of the place field representation; it makes sense for the hippocampus to optimize coding given the available information it has. However an interesting aspect of the model we describe is that it seems to be able to cope quite well with environments of different sizes even with fixed parameters. This may be a mechanism used to cope with the inherent uncertainty in the world; you never know exactly how large or small a place will be, so you have to account for either possibility.

SP: Sensory systems also use logarithmic compression to efficiently compress the broad range of input signals into the limited bandwidth of neurons. For example, the retina encodes luminance signals across nine orders of magnitude. Do you think that the logarithmic recruitment of place cells might arise from logarithmic compression in the sensory circuits that provide contextual signals to the hippocampus?

DR: Hippocampal coding is invariant to the specifics of the sensory input, place cells do not respond in a simple manner to sensory stimuli, but rather seem to integrate from a wide array of information in order to respond to place per se. Given this higher-level representation and the number of processing steps potentially involved, I’m not sure that something such as stimulus intensity (which is coded logarithmically), would directly relate to the size of the environment explored (which corresponds logarithmic-like cellular recruitment). Although the similarities may represent a common neural optimization principle, for instance, as you suggest the efficient use of a limited channel.           

SP: As a sci-fi connoisseur, you are probably familiar with Asimov's The Gods Themselves, in which scientists discover and interact with a universe that has very different physical laws from our own. In what ways is the hippocampus designed specifically for our 4-d universe, and how might it be modified to accommodate additional dimensions?

DR: How hippocampal function is adapted specifically for 3+1D environments is a tough question. One theory is that the hippocampus forms the basis of a cognitive map that allows navigation in space and also time. For instance as you go to pick up the dry cleaning, you remember that the traffic along your planned route will be bad at this time of day, so you think of a shortcut to get there faster. In order to perform such a navigational computation the hippocampus may have to draw on a geometric representation it has of space. We don’t really know how it actually does this however. Looking at differences between animals that navigate exclusively in 2 or 3 spatial dimensions would probably provide the best clues about how dimensionality is adapted for.

I don’t think we would be able to ever perceive higher spatial dimensions in the same way as we do for normal space and time. This is because there has been zero evolutionary selection of such abilities. I would guess that a system for the general n-dimensional condition would be more complex than a system for a special case, and so would be selected against during evolution; I think is likely that we are hard coded to our native dimensionality.

We might be able to get around such limitations by using some tricks. Anecdotally, humans can do pretty well in video games that employ different geometries (think Pacman exiting one side of the screen and coming back in on the other side, or teleportation mechanics in other games), so perhaps we are able to chuck complex unnatural environments into smaller independent sections that we are able to deal with. Another idea is that we could co-opt other systems in the brain. For instance, we are quite adept at navigating our high-dimensional social environments. Perhaps one could try and think about a high-dimensional space using social metaphor?

Another sci-fi classic, Flatland by Edwin Abbott Abbott, deals explicitly with this question, how one might comprehend spatial dimensions higher than one’s own. I won’t spoil the story, but will highly recommend it for anyone interested in these questions.

SP: Does it make you sad to think that plants have no idea where they are?

SPECIAL EDITION: SICK NEWSPAPES!

SICKPAPES INTERVIEWS MOTHERS NEWS!

Mothers News is an indescribably great newspape that comes out of Providence, RI, once a month. (There is no apostrophe in Mothers News because "the apostrophe is for possession or omission, and Mothers News neither possess nor omits," according to head honcho Jacob Khepler.) Mothers News does indeed write about science - including a regular "Invertebrate of the Month" column, written by the heroic Sophie Tintori, who made the amazing first episodes of CreatureCast - but the science is always mixed into a whirlpool of ancient history, local folklore, etymology, comics, art history, and emotional philosophizing about the progression of the calendar. Reading Mothers News basically feels like having an exciting new idea. 

It is hard to describe the way that Mothers News is written, so I'll just give you an excerpt, picked nearly at random, from the front page of the October 2012 issue, on the topic of Halloween:

"The word threshold is a compound word consisting of the words "thresh" meaning to tear apart or beat up or separate into parts and "hold" meaning to not do those things. It is commonly used to describe the area of a doorway that is not a door, or technically, the space that would be occupied by the door if the door was closed. Fiends, ghouls, demons, monsters, agents of persuasion, goblins, creeps, lurks, boglins, and so forth are all threshold people - they linger around the cusp of an area, at a zone of transition...Rather than wanting you dead (or alive), the threshold people delight in getting you to wobble inbetween, or just wake up and see that that's where you are all the time..." 

Clearly, the writing style and philosophy of Mothers News is a major inspiration to Sick Papes, and we were therefore giddy fanboys when we sat down with Jacob Khepler to discuss his newspape. 

Sick Papes:  The "O" in "Mothers News" is often depicted as a dung beetle, hard at work rolling an enormous ball of feces. I have a strong personal connection to dung beetles because I used to work in a lab that studies the evolution of beetle horns. In dung beetles, the males use their horns to fight off other males who try to enter their burrows and mate with the females below. But the crazy part is that male horn size is not genetically determined, it's solely based on how much food (dung) you were given as a larvae, and in fact the smallest males don't even grow horns whatsoever, they develop a completely separate mating strategy which is to dig side-tunnels into the tunnels of the large-horned males, thereby avoiding fights altogether but still gaining access to the females down in the burrows. What does the dung beetle mean to you?

Mothers News: Whoaaaaaaa thank you for telling me these things about the dung beetle!!!!! I love adding to the database on a key motif. We have adopted the dung beetle (we call ours "gloria") as our mascot for a few reasons: the least poetic reason is that we're persnickety and self-destructive, and a dung beetle is, to many people, far from cute. It's a markedly poor choice of mascot. The medium poetic reason is that the dung beetle, in ancient Egyptian mythology, pushes the sun across the sky, and it's traditional for newspapers to use solar imagery, I think to imply regularity and authority [editor's note: Holy Shit]. The most poetic reason, at this point in time, is mine to think about. :)

SP: In general, Mothers News seems committed to championing unusual or bizarre animals with spectacular lifestyles. I'm thinking particularly of the "Invertebrate of the Month" column. Why do you feel it's important to talk about unusual and bizarre animals? (Isn't it funny how we think some animals are "bizarre" but actually all animals on earth, even the really familiar ones, are completely insane??).

MN: One thing I try to do with the paper is make something that would be helpful to anyone that may pick it up - I find that when I'm having a struggle it's helpful to think about how many different strategies there are for being on the planet. examining animals with, as you say, spectacular lifestyles, makes this variety more evident (for people that may think of their cat as a cute little furry child). Also it allows us nearly immediate, but not too jarring (I hope), access to much much larger issues, like "how many things am I?" and "which one of us is me?" and so forth. Also, while i enjoy writing about animals and do so without hesitation when required, the invertebrate of the month club is written by a real scientist, not me. Shoutout to ace reporter Sophie Tintori!

SP: A while back, the Mothers News blog posted this amazing comic about modern art, which I love eternally. What is the story with this comic, and how'd you find it? 

MN: This comic is by Ad Reinhardt, who was an abstract painter in the 30s through the 60s. He was a major player in what would become known as abstract expressionism, and in addition to having his own righteous practice he was a crucial thinker - writing and lecturing extensively for these new styles and against critics that were unable or unwilling to process it. As part of his writing practice he made comics that ran regularly in a few magazines. The comics are totally unlike his art practice but both are wonderful because he's one of the world's great grouchy goofs - a truly funny guy that won't tolerate corny bullshit or intellectual laziness, too pigheaded to make something even a little unlike "something he would make". Anyway this one sums up his main riff pretty succinctly, that an artwork doesn't have to be (or isn't, or shouldn't try to be) descriptive of the world, it is (or can be, or should be) a thing in the world just like every other nice thing that hangs out in the world. A book just came out this year of all these comics, it's a ripper, and it's called "How to Look." I honestly feel like this should be required reading for all students of the arts (especially those interested in modern art), and recommended to all enjoyers thereof. He held a rare(?) position of saying something true and otherwise unspoken in an extremely clear and fun way. 

[editor's note: Here is another great modern art-related article from Mothers News, December 2012: "Picasso, France, WWII. Picasso, very famous, meets an American Soldier, who tells him in no uncertain terms that he (Picasso) is a bum, and why doesn't he paint a beautiful picture, in a realistic style, and certain things cannot be improved upon, etc.. Serviceman takes out of his wallet a picture of his fiancee back home and says "That's how a picture should look." Picasso, in horror, yells out "Good Lord! You mean to tell me you're really going to marry a creature that tiny?"] 

SP: When and how did Mothers News get started? Has your writing style changed since the beginning in a way you can identify?

MN: First issue was in May 2010, although i had a sort of proof-of-concept newspaper a few years before that, as part of a larger project, but that only had 1 issue. That's the when, and the how is pretty standard - I wanted to do it, then I started to do it, then I continued doing it. Well, there's a little more than that, because I made the first issue and as it was at the press I was filled with self-loathing and I was going to destroy it when it was done, but then the people who worked at the pressing place, who were friends of mine, really liked it, and then I felt like I had to put it out. I still think the first issue is totally stupid and goofy. Second issue is bad. Third issue it starts to get cool. Being filled with self-loathing in the time between sending it to the press and getting it back, this continues to this day. but now I feel better as soon as I can hold it in my hand. I like to pick it up from the press, sit at supreme donuts in Seekonk, MA, and sit with someone as they read it, and when they laugh I say, "What is it, what are you laughing at?" That makes me feel better.

As far as style drifts, I'd say it got less stupid over time, for a short period, and only to a point. content-wise, you can see a drift over time with the front page, moving from talking about the holidays that month and the mythology of the name of the month, to talking about the number of the month, to talking about shapes, to where I am now, which is... I don't know where I am. Open format for the time being. 

SP: My sources tell me that Mothers News has sponsored a few exceptional local athletes. Could you tell me about this?

MN: Ahhh, unfortunately, I cannot.... This is a still-in-the-works thing, yet to be fully realized and deployed. Sorry! I don't like to talk about my plans because I found that in some circumstances, the more I talk about something, the less likely I am to do it. It's like if I yak too much about something that's still on the to-do, my brain processes the feedback on the concept as reward for a job well done, and then I don't have the fire to do it... "Riffer's Bane" you could call it. I'm sure you and your readers understand. No wine before its time!

SP: Do you know any particularly good local folklore, and/or have any advice on how to get people to share their good lore?

MN: Hmmmm... I feel like there's always good lore, you just gotta lurk for it. Anything approaching "a saloon" is a good place to lorelurk, just post up for a couple days, find the person who's there most of the time (a wart), get into a dull conversation about a landmark or something, and then let it drift towards lore. The direct approach is not recommended. Saying "do you know any lore?" will most likely not result in anything of quality, partly because lore can't be accessed that way- it isn't stored in the brain in a drawer marked "lore", it's all over the place, in the lore section of other drawers. The other part is that tellers of the tale have their own agendas, and they will need to reel you in and mess around with you a little bit before they can really divulge.

SP: This is maybe a silly question, but do you write the newspaper because you have so many ideas, or do you find yourself using the newspaper as inspiration to go looking for exciting ideas? 

MN: That's not a silly question at all, that's a great question. I love to read and I love to have lots of books around and I love reading Wikipedia and doing research into a topic and going to the library. And it's wonderful to have a project that gives me a reason to do this, and to do it in such a free-form way. I definitely use the excuse of the paper to buy more books than I should, just to have more reference material on hand. I also tend to pick up old magazines in order to look at other methods of making a publication, but also (mainly?) because I just want them. I've always enjoyed reading from a varied selection of texts, that habit predated the paper for sure. I love reading, and a big part of why I write is so I can make all the various things I read hang out together and party.

SP: Do you LOVE coffee?

MN: I like coffee, but I'm not a demon. I don't really drink a ton of it, in fact I just cut down from 2 cups a day to 1. Also I don't care for fancy coffee or specialty drinks, just hot coffee with cream, that's what I like. I think I mention it a lot in Mothers News because that'sthe mood of the paper, it's like a coffee mood. A lot of people find the paper in coffee shops, and on top of that the newspaper format has an inherent breakfast connection. Also coffee is the communal beverage of North America, and a communal beverage is always an opportunity for light chat, news, and gossip. That's a tradition that I'm goes back to the dawn of humanity. Before that, even! I bet that's a pan-species tradition. Lately I've been drinking a lot of iced green tea with lemon and ginger. I make it at home, it costs 2 cents. Whenever I'm writing I like to have a nice beverage, a nice little cup of something. I think that's important, as a symbol. A cup.