Cultural Learnings

When I told a friend I would be interning this summer, he was surprised.

"Why are you doing an internship?" he asked.

"The idea," I responded, "is to get introduced to a new environment, so I return to grad school with a broader perspective."

"Sounds like Borat."

Like a foreign correspondent reporting to his home country, I gave an informal talk to the Stochastic Systems Group about my summer project. The resulting feedback helped me improve my results this summer. However, once the problem was described, there were a lot of similarities with problems familiar to the group. It was hardly Borat.

That said, there are practices at the Broad outside of my work that I would be surprised to see in my own research community. Perhaps the most surprising thing I have discovered is that people are willing to share their ongoing research with people at the Broad. Weekly seminars feature researchers from outside the Broad discussing their as yet unpublished work. Broadies see data that has yet to be made public. I was particularly surprised by this since there is some controversy that Watson and Crick's paper about the structure of DNA used unpublished data from Rosalind Franklin.

There is a catch. Attendees of the seminar must agree not to work on anything they pick up during the course of the presentation. This understanding and the honor system are what make people comfortable enough to discuss work they might otherwise keep private.

The presentations may also be a way to start collaborations. In a field driven by data, if someone provides the data for a figure on a paper, that person frequently becomes an author, even if the idea of the paper came from others. Thus, advertising results before they are published might allow other researchers to avoiding running the same experiments.

A consequence of this practice is that one rarely finds single authored papers and often finds papers with four or more authors. How does one delineate the contributions of each author? Author ordering may only give a coarse indication of an individual's contribution. An existing solution in some journals is to include an author contributions section. This section typically follows the acknowledgments and may read some like the following:

S.B.C. conceived and designed the experiments. B.S. conducted the experiments. S.B.C. and B.S. performed the analysis. S.B.C. and B.S. wrote the manuscript.

What happens if the work is primarily by two authors? The practice described to me for these instances is called co-first authorship. To do this, one simply places an asterisk next to each author's name with a footnote that reads: "These authors contributed equally to the work."

While some biologists I spoke to joked about some of these practices (one described how an author contributions section might read if each individual's contribution were described honestly), almost all of them were comfortable with the idea that providing data is a legitimate way to become an author on a paper. The same might not be true for my community, but I wonder if any of these practices would transfer well.

Variations on a Theme

Information theory, statistical decision theory, and game theory have developed methods to analyze what some may consider adversarial situations. Lessons in these fields have certainly influenced how I model problems involving adversaries. Perhaps it should come as no surprise then that such models were in my thoughts as I attempted to read about host-pathogen interactions. The work in question was a review paper from Hidde Ploegh's lab. Ploegh's lab studies mechanisms by which seemingly simple bacteria have been able to infiltrate our complex immune systems.

How does the lab conduct this research? Renuka Sastry, a researcher at the Whitehead Institute and one of Ploegh's graduate students, gave me a tour of the lab. Our first stop was at what appeared to be a cylindrical dark room.

"It's used for western blots," Renuka said. As she explained, a western blot is a technique to test for a specific protein in a tissue sample. The results are represented as lines on a plastic page, where a line indicates the presence of said protein.

Surprisingly, it takes some effort to extract this bit of information. Part of the process was unfolding on Renuka's workbench. A gel electrophoresis was running, but there were a couple differences from ones I had seen for DNA. First, the gel was positioned vertically instead of horizontally. Second, the gel looked significantly thinner than an agarose gel. Renuka's electrophoresis was one stage in an experiment to test for a particular protein. She was hoping the result would validate an observation she had made earlier.

Noticeably absent from the workbench was a computer. While there was a computer in that room, our next destination was filled with them. The mass spectrometry room is used to identify proteins, and computers are used to crunch numbers and consult databases for protein matches. Of course, the proteins come from living cultures, and in the final part of our tour, I saw one under a microscope.

What struck me during the visit was that these methods and techniques could also be applied to problems that did not involve hosts and pathogens. What drew Renuka to the work?

"I wanted to do biochemistry research," she responded. I left with a better appreciation for this research. Whether this appreciation might inspire new ways to model aspects of these host-pathogen interactions is an open question.

Cat's Cradle in a Hard-Boiled Wonderland and the End of the Brave New World

During the ITA workshop in January, Desmond Lun and I had the following exchange.

Me: So what are you doing these days? Are you a post doc?
Desmond: Actually, I'm at the Broad Institute.
Me: What's the Broad Institute?

By the time I started looking for internships, I knew what the Broad Institute was and sent Desmond my resume. I have been at the Broad now for two months, and Desmond and I work in the same group. It helps working with someone here who hails from the same research community, and our conversations span topics that include information theory and biology research.

I had a taste of the future of biology research during lunch when Desmond described his project with George Church's lab. The goal of the project is to study ways to use biology to produce renewable fuel sources. One fuel source is ethanol, and there is a well-known biological recipe to produce it. Add yeast to a sugar solution. Mix. Let it ferment.

The approach Desmond described was a little different. It turns out one can modify the E. coli genome and use the modified E. coli to produce ethanol. Driven by this success, there is an effort to see if alkanes or other fuels can be created by hacking the genome. Indeed, some start-ups are trying to capitalize on this idea.

The technology that enables such genome hacking falls into the field of synthetic biology. What is synthetic biology? The answer can vary depending on who answers, but to my understanding, synthetic biology is the study of how to design and fabricate living systems that do not exist in nature. In addition to adding and removing genes from a genome, Desmond said there exist techniques that allow one to increase the mutation rate of certain organisms. Once enough mutations accrue over the population, a researcher can then create conditions that select the mutations most suited to a task of interest. This may be the only truly parallel implementation of a genetic algorithm.

Of course, such technology also generates concern. The ETC Group is a public watch-dog for synthetic biology. They have been vocal in challenging Craig Venter's attempt to patent synthetic life and oppose the idea of scientists creating synthetic life without regulations. "Playing God in the Galapagos," the title of one of their publications, reflects this position.

These concerns are also in the public consciousness. Desmond mentioned a recent online poll asking about such technologies. The response choices ranged from complete opposition to regulations to complete opposition to the research. How do scientists feel? It turns out Church's lab took a similar poll. Surprisingly, the group was in favor of more regulations.

Neuroscience and Engineering

It was Friday morning at ISIT, and some people had already left. Like the previous days, the morning started with a plenary talk. Unlike the previous days, Friday's speaker was from outside the information theory community.

The speaker was Emery Brown, a professor in the Department of Brain and Cognitive Sciences at MIT and in the Department of Anesthesia and Critical Care at Harvard Medical School. He discussed his group's work to build signal processing algorithms in neuroscience, and he showed videos that showcased the performance of those algorithms. One video in particular stuck out in my mind. It featured an animated rat moving around an enclosure and an estimate of its position. The animated rat and its estimated position corresponded to an experiment his group conducted on a live rat using signals from roughly thirty neurons to track the rat's position.

The experiment was designed to test memory formation. The rat was introduced to the enclosure in question a few days before his group tracked its position. Furthermore, the neurons used were from the hippocampus, which is thought to play a role in memory. Indeed, Brown placed this work in the context of a series of experiments attempting to understand how the brain handles memory. However, there was something compelling about the experiment itself.

While those who study this experiment might not claim to understand exactly how memory works in the brain, they may still claim that what limited understanding of memory they have enables them to track a rat's position under the conditions of the experiment. This concrete way to describe the utility of the experiment appealed to my sense of research aesthetics.

Research aesthetics was just one of several topics I discussed with Ram Srinivasan, a postdoctoral researcher in Neurosurgery at Massachusetts General Hospital and student at Harvard Medical School. Ram earned his PhD in EECS from MIT, where he worked in part with researchers from Emery Brown's lab. He was also coadvised by Sanjoy Mitter, and his dissertation touched on the interplay between electrical engineering and neuroscience. It became clear from our discussions that his interest in this interplay dated back to his undergraduate days at Caltech.

The issue of aesthetics came up early in our conversation. We discussed the challenge of posing a concrete question. For instance, the context in which one asks another person if he is stressed can affect the answer. To contrast this with a concrete question, Ram mentioned a behavioral sciences paper that refuted a stereotype to show that women are no more talkative than men. How did the authors show this? The researchers had individuals carry around voice recorders over a period of days and found that both men and women spoke about the same number of words per day. In this case, word count in natural conversations gave a concrete way to measure talkativeness.

We discussed issues with applying standard ideas from control theory to the brain. For instance, one might engineer a control system such that sensing and actuation are distinct components. If one were to describe the brain as a control system, the delineation of sensing and actuation is an artificial choice of modeling. Such a choice may be informed by the specific application of the model. A separate but related issue is whether a distinction between motor and sensory regions in an organism actually exists. While standard dogma describes such a separation, an evolving perspective is that action and sensation are intertwined at multiple scales, from cell to organism.

In his own research, Ram is further exploring the brain-machine interface at the basic science and algorithmic levels. Having worked largely with data from collaborators and simulations during his PhD, his postdoctoral lab affords him the opportunity to design his own experiments to record single-neuron activity from awake humans. This work employs wet lab experiments to understand how movements are initiated. Additionally, he is beginning to reexamine the premise that the brain-machine interface is an estimation problem. He says his current position has given him a new perspective on the challenges of experimental design and the ways in which science and engineering research proposals can synergize to develop neurotechnology. Hopefully this new perspective will allow him to build on his earlier successes.

Outreach

I had been at the Broad for a little over a month, but I had yet to meet the co-worker standing next to me in the elevator. To avoid my tendency to shift between staring awkwardly at the elevator doors and the lighted floor number, I introduced myself. "I'm Megan," she responded, and we started a conversation.

Megan Rokop is Director of the Broad Institute's Educational Outreach Program. In addition to the research that goes on at the Broad, the Institute also sponsors a series of programs to engage with students, teachers, and the general public in the Boston area. A main feature of the program is the opportunity for high school classes to visit the Broad, where students get to conduct experiments using Broad facilities.

Megan wasn't always interested in biology. She started college at Brown as a foreign languages major, but a scheduling error placed her in a biology class. Unlike her previous experiences with the subject, which primarily involved memorizing a list of facts, the professor for this class presented the material in a way that inspired Megan's interest in the subject. "I wanted to be like him," she said of the professor.

Sure enough, Megan switched majors and eventually received her PhD in biology from MIT. After teaching at MIT for a few years, a fellow biology instructor told her about an opening for the Outreach position at the Broad Institute. Although she enjoyed teaching undergraduates, Megan recognized that not everyone benefits from a scheduling error, and saw the position as an opportunity to reach students while they were still exploring interests. When I told her I was interested in learning more biology, she was more than happy to oblige.

Our first lab involved identifying and mating different strains of Caenorhabditis elegans, a worm that serves as a model organism for investigators with interests ranging from genetics to neuroscience. C. elegans are only a millimeter long, so we needed a microscope to observe them. Once under the microscope, the distinguishing characteristics of mutant strains and sexes were clearly visible.

C. elegans are divided into two sexes: male and hermaphrodite. Mating two of the mutant strains requires the transfer of a male and hermaphrodite onto the same dish. The offspring can later be counted to determine whether their traits were dominant or recessive. After a few false starts, I was able to use a special hook to transfer a wild-type (WT) male onto the same dish as an uncoordinated (UNC) hermaphrodite. While we couldn't see the worms without a microscope, we could see the tracks the wild-type was making as he searched for his uncoordinated partner.

The second lab involved running a gel electrophoresis with an application to paternity testing. Not all DNA code for proteins, and in the non-coding regions, certain strings repeat. The number of times these strings repeat can be used to distinguish individuals and determine heredity.

One way to distinguish the number of repeats is via gel electrophoresis. The idea is to load the DNA into different wells on one side of a gel and run a current through the gel. Since DNA is negatively charged, this current causes the strands to move across the gel towards the positively charged end. Since longer sequences diffuse more slowly, sequences with more repeats don't travel as far away from the negative end.

Unlike the first lab, I worked on the second lab with a group of high school students. They were visiting from the National Youth Leadership Forum on Medicine, a summer program for aspiring doctors. After the lab, I had a chance to talk to some of the students, who were curious what a non-biologist was doing at the Broad. In turn, it was interesting to hear from the students, some of whom weren't completely set on a career in medicine. While I wasn't sure whether their experiences that week would increase their interest in medicine, mine certainly increased my curiosity about biology.