The Biological Network

By Michael Begun

Networks have bloomed in the last few years, from “The Social Network” to the deluge of scientific papers studying such varied things as the financial system and genetic diseases through networks. While we have seen the term “network science” emerge, it is not exactly clear what this means. Wikipedia describes network science as an interdisciplinary academic field, but I think that networks are better viewed as tools for making sense of complex systems. Networks are one way that we can describe collections of interactions between people, websites, words, animals, genes, and so on.

For examples of popular network studies in biology, check out these papers: ecology, public health, and cancer genomics.

Research on social networks has a surprisingly long history in sociology. But the discussion of networks across diverse fields has taken off in the last decade, especially in systems biology. This is in large part due to computers, which allow us to construct and analyze huge networks. In biology, a major use of networks is to investigate gene regulation, uncovering relationships and hidden structure among genes. A thriving research area involves inferring networks from data such as E-MAPs.

The most exciting thing about biological networks, in my opinion, is that they allow us to examine large-scale organization and processes that were once hidden. For instance, genes have been shown to interact in highly modular ways, a finding that should foster future drug discovery. Networks provide a powerful framework to investigate relationships between biological entities, and how these entities interact to produce emergent behavior. To understand the workings of things like the immune system, we’ll need to model and simulate network behavior.

Some of the more mature network research in biology focuses on network motifs. Motifs are small patterns that occur much more frequently than one would expect if the design of the network were random. Recent research has found motifs that are shared across genetic regulatory networks, neural networks, and the even the Internet. The surprising fact that some motifs are shared across different networks suggests that similar processes shape these networks. The structure of these networks is far from random, and scientists are trying to identify design principles that underlie the evolution of these networks. Some systems biologists are trying to understand the function of various motifs in regulatory networks, such as feed-forward and bifan motifs. Check out this paper on network motifs, which also happens to be the most cited ecology paper in the last decade [1].

My work this summer at the Tang Lab focused the design and organization cell-cycle networks. We know that a huge number of genes and proteins interact to orchestrate the cell cycle, and we know the role of some of these regulators on specific parts of the cell cycle. But we lack a coherent account of how the cell cycle as a whole emerges from these interactions. Understanding this requires uncovering the relationship between network structure and function. In this case, the network function is the cell cycle (which roughly corresponds to an activation cascade).

Working with a network model of the cell cycle, I’ve examined the relationship between the architecture of the network and its behavior. One technique I’ve used is to computationally search for all the networks that are capable of performing cell-cycle function, in hopes of observing structural regularities. This kind of work may help us understand the design principles of biological networks that have exhibit definable behavior like the cell cycle. Intriguingly, similar approaches have been harnessed to study the relationship between amino acid sequence and the three-dimensional protein structure.

What design features make some networks robust and others less so? This is a challenging and fascinating question that applies to many kinds of networks, like banking networks and the Internet. While biological systems have evolved to be robust, we only have a superficial understanding of the structural features of networks that endow these systems with robustness. Many researchers believe that we can apply network principles from biology to human-made systems, like the financial system, to protect against crises.

While networks seem to be everywhere now, it is important to remember that a network is simply a mathematical abstraction, a roadmap of relationships. But as representations of biological systems, networks are bridging the theoretical and experimental realms in biology. They should be at the forefront of biology for years to come.


If you’ve read this far you’ll probably like this video on network science and big data. The video features physicist Albert-lászló Barabási, who believes that networks will revolutionize drug discovery.


[1] Fox, Jeremy. “And the Most Cited Ecology Paper Published in the Last 10 Years Is…” Dynamic Ecology. <;.

A Melange of Nationalities

By Vivian Wan

Although summer is over, I’ve had these responses gathering dust on my hard drive for a while, and I really wanted to showcase the wonderful people I worked with over the summer. The Hansel Lab is not only diverse in that we had a wide range of positions from undergraduate to postdoc, but also in that almost everybody was from a different country — and the few Americans in the group were of different backgrounds. I, for example, am Chinese-American.

It was natural for us to be curious about each others’ cultures, reflecting upon our similarities and differences over lunch. In particular, it was always interesting to hear about non-American education systems in addition to American college experiences outside of UChicago. So to compile all these different points of views into one location, I interviewed the members of the Hansel Lab, asking them about their pathway through science.

1. Tell me about your education and scientific background, especially in contrast to that offered in the US. 
Christian, PI (Germany): For high school, I went to a monastery school where students picked four subjects to specialize in for the last three years of high school. I picked German (similar to English literature classes), Biology, History, and one other subject. My impression is that Germany offers a stronger education in high school, where students stay for five years, since more was taught. Whereas in the US, it seems that the emphasis and the brunt of education is given to universities.
The difference between Germany and the US is that students proceed directly to university — as in there is no undergrad — which is 5 years long. You can think of it as undergrad and med school combined. Your 5 years are split in half. The first part is where you take general classes, so there is a wide variety of subjects from zoology to botany, but there is little to no laboratory work although students may have summer lab jobs. The second half is where you focus on research. I personally spent my first 2.5 years at the university specializing in zoology, and I spent the second 2.5 studying human brain anatomy in Zurich, Switzerland. There, I worked in labs.
The second option after high school is to go to specialized schools. The translation from German is “specific high school.” If you wanted to become, for example an engineer, you would attend these schools. They are like technical schools but at a higher level.
Tahra, PhD candidate (US): I went to a small private, all-girls school for high school so there weren’t a lot of options for science classes. We did have some APs, but there were only two of us in AP physics which is what I took. At Cornell, it was all about engineering all the time. We had tons of mechanics, physics and design classes, but only bioengineers had to take bio at all. We had to determine our major by our second year and must have completed general bio by the end of that year as well. For BME (biomechanical engineering), we also had to take biochem and at least two other upper level bios, but that was about it. I got into neurobiology from my research experiences, not class.
Giorgio, Postdoc (Italy): My interest in science made me choose the so called “Liceo Scientifico” (scientific high school). In the Italian system, within each type of high school, classes are determined nationally, with little or no choice at all, apart from some optional classes usually in the afternoon with no tests or requirements, such as drama or competitive sport teams. This had 5 years of math, 3 years of physics, 2 of biology, 1 of chemistry, 1 of “astronomical geography.” These classes were compulsory together with humanities and physical education. This is considered “scientific” especially because, differently than the “classical” high school (“Liceo Classico”) it requires much more math and physics and does not requires ancient Greek. However the scientific method experiences with an experimental approach is generally very limited, and, in my case, including only some physics experiments and few simple biological experiences such as DNA extraction.
After high school, still looking forward to the idea of basic science to enjoy, understand and take care of the environment or the human organism, I chose a program in Cellular and Molecular Biology. The program required traditional general classes together with more specific ones focused on biochemistry and cellular/molecular biology. It included, for the 3 years BSc, courses of basic science, genetics and molecular biology, evolutionary and environmental biology, animal biology.
After my BSc I choose to complete the MSc in the same program. The course work was pretty intense but there was probably much less lab classes than in American programs, offering only some small lab classes, a quarter in a lab at the third year and a full year in a lab at the second year of the MSc. The program, as often for science in Italian universities, was not very flexible as it may be here, with just few optional courses, and also less focused, probably, on pragmatical issues rather than in acquiring a broad and sound scientific culture.
Heather, Postdoc (Canada): I went to the University of Western Ontario for my undergrad. I decided in my first year that I wanted to do science, and took a variety of general science courses. In my second year I focused in biology, and took more bio related stuff (organic chem, biochem, ecology, ect.). In my 3rd year I applied and was accepted into a medical science program and decided to take physiology among other things (pharmacology, immunology, anatomy). In my 4th year I was in the honors physiology program and took mostly advanced physiology courses.  However, the university also required us to take courses in languages and another social science or humanities. I chose to take English in my first year, and psychology throughout.

At the end of it all, I graduated with an honors in bachelor of medical sciences (H.BMSc) with a specialization in physiology and a major in psychology.

I did my graduate school at the University of Toronto. The first 18 months I was in a Master’s program, and then I defended and passed a transfer exam, and switched to a PhD program. After a year in the PhD I passed another exam (similar to the “quals” they have here but we don’t call it that). I was in the department of physiology, but I was also in the program of neuroscience so the few courses that I had to take in grad school were all neuroscience related. I defended my PhD thesis after 4 years.

2. What research opportunities were open to you?

Christian, PI (Germany): There were many opportunities to work in labs during the school year and the summer, however there were no established fellowship programs.
Tahra, PhD candidate (US): I worked in labs both during the school year and in the summers (as a tech, no fellowships). There were plenty of research ops if you actively looked for them and many times research could be counted as a class for credit.
Giorgio, Postdoc (Italy): The lab experience was pretty limited to few very basic labs of microbiology, histology, physics, botany, biochemistry and molecular biology. However, as an improvement in comparison to the system running in the previous decade, we were required to spend a quarter full time in a lab with our own small project at the third year of the B.Sc. At the end of the M.Sc., however, a full year was dedicated to work full time on an experimental project. The most common way to have a study abroad experience was to enroll in the European Exchange “Erasmus program”. However my personal choice was to find on my own a summer internship in Germany, unfortunately with little support from the university and professors, if any. Another opportunity I got during my PhD (although not specifically from my program) was an international summer school in Neuroscience in Japan, where I could work in a lab for a couple of months.
Heather, Postdoc (Canada): Most undergrads don’t start working in labs until their 3rd or 4th years. There aren’t a lot of fellowships for undergrads so most were volunteers or paid summer students. I didn’t start working in a lab until my 4th year honors thesis project. Then I became a paid summer student in the same lab that summer.
3. What kind of research have you done in the past?
Christian, PI (Germany): I started working on the cerebellum (what the Hansel Lab studies today) from the start, but studied the visual cortex for my PhD. In the cerebellum, I studied nitric oxide signaling. It was significant as it was the first gas transmitter found, a part of white matter pathway.
Tahra, PhD candidate (US): Until this lab, I worked in a physiology lab doing data analysis rather than acquisition. I wrote computer programs and reconstructed simulations of actual neurons to use in an ongoing study of ALS. I also worked in a neurobiology lab with zebrafish doing imaging experiments and helping to create a software that could track and analyze the fish’s movements throughout the night for studies on circadian rhythms.
Giorgio, Postdoc (Italy): I have started my experience in neurobiology during my internship in Germany and, soon after during my M.Sc project, during which I had my first experience about neuronal transmission and plasticity. Since my PhD I worked on the neuronal plasticity, first focusing on structural plasticity of cerebellar climbing fibres and their regenerative properties (using in vivo gene silencing and himmunohistochemistry), then moving to an experimental model for multiple sclerosis (the experimental autoimmune encephalomyelitis) in collaboration with people with a variety of expertise and looking both to cerebellum and striatum. Finally I have been recently working here at the UoC on synaptic and non-synaptic plasticity of cerebellar Purkinje cells mainly by means of patch-clamp.
Heather, Postdoc (Canada): Most of my research was focused on the cerebellum. My undergrad research was on the arm movements/mechanics involved with throwing a baseball. I was interested to see the differences with increasing skill and the deficits involved with patients with cerebellar lesions or disorders.  My graduate research was on motor learning in the cerebellum. I studied eye movements in cats, and looked at a the vestibulo-ocular reflex, which a reflex whose learning is dependent on synaptic plasticity within the cerebellum. I also studied whether mGluR1 and GABAB receptors were involved with learning in this reflex. In general I did a lot of behavioral stuff before I came to Chicago.
4. Any other observations on schooling?
Christian, PI (Germany): University in Germany are like state schools here with large student bodies. There are no dorms, and students find housing in apartments. American universities let students have more liberty in choosing subjects & study matter.
Heather, Postdoc (Canada): I think schools in Canada and the USA are pretty similar except for the following:
– There is a distinct difference between colleges and universities in Canada. Colleges are like community colleges and offer diplomas. Only universities can give degrees.
– Canadian universities don’t require the GRE or any other standardized test for admissions. We apply based on our high school marks and courses.
– There are not a lot of private universities in Canada. There are none in Ontario (where I am from), everything is public.
– Tuition is a lot lower. Ontario has the highest tuition rate in Canada, and I paid about $4,000-5,000/year during my undergrad. My last year of grad school the tuition as about $7,000/year. Right now, there are riots and protests in Quebec because students think they are paying too much for tuition. They only pay about $3,000 per/year.

Second Week Event Bulletin

The Chicago Biological Investigator is part of a group that is collaborating to promote the common interests and goals of science and health-related student organizations and students majoring in various sciences at the University of Chicago. Last year, the group (HS RSOs) held an informational panel on the various RSOs involved in winter quarter and a science game night in the spring. Part of what we’re around to do is have a way in which to let people know about what relevant events are happening, so we hope to have a weekly post with an updated list of upcoming events.

Wednesday, October 8

The Triple Helix Fall Social: 6:00 pm – 7:00 pm, Bartlett Trophy Lounge

Friday, October 12

Fall Career Fair [UCIHP]: 12:00 noon – 4:00 pm, Ida Noyes Hall

Tuesday, October 16

Duke University School of Medicine [UCIHP]: 12:00 noon – 1:30 pm, UCIHP Suite

Wednesday, October 17th

12:00 noon – 1:15pm, UChicago Medical Center H-103

“Emerging Controversies in Organ Transplantation”
Robert Veatch, PhD
Georgetown University

Trivia night for 1st and 2nd years: free pizza and prizes [UCIHP Fellows Event]: 6 pm, BSLC 115

Tuesday, October 23

The Triple Helix’s Higgs Boson Lecture: 6:00 pm – 7:00 pm, BSLC 115

Wednesday, October 31

UCIHP Trick or Treating: “What’s Tricking You?” Tell us and earn a treat!: 3:00 pm, UCIHP

Further Shenanigans in the Murine Cerebellum

By Vivian Wan

My work over the past weeks has been focused on studying the possible influence of the duplicated chromosomal region (in our autistic mouse model) on cerebellar Purkinje Cell degeneration or development issues.

Golgi stained murine cerebellum sections.

After a long wait for the results of our Golgi staining trials, we finally were able to see the fruits of our efforts under the microscope. As shown in the picture, we sectioned the Golgi stained cerebelli into thick slices and mounted them on glass slides. To analyze images of Purkinje Cells from these sections, I use a program called ImageJ. Specifically, I use ImageJ plugins NeuronJ and Scholl Analysis for tracing of dendrites and for branching analysis [1], respectively. The former, NeuronJ, detects the path of a dendrite as you trace it, making it easier for tracing as opposed to tracing freehand. From these tracings, I have been gathering data on the sum of the dendritic arbor lengths.

I am also quantifying branching of the dendritic arbor. One way to do this is with the second plugin, Sholl Analysis, which quantifies intersections of dendrites within a certain area [2]. The program analyzes the number of intersections within concentric circles of increasing diameter from a chosen point — in our case the cell body — and outputs a plot, showing the number of branches enclosed within the ring-like area as a function of the distance from the chosen point. The second way to measure branching requires more particular definitions of dendrite branches. For Purkinje Cells, there are proximal dendrites, which, in addition to other functional characteristics, have sparse numbers of spines, and distal dendrites, which exhibit a high density of spines. For this second method, I categorized branching by orders: the first order were distal dendrites branching from the proximal dendrites.
10x microscopic view of a Golgi stained Purkinje Cell.

10x microscopic view of a Golgi stained Purkinje Cell.

I also analyzed the Purkinje Cells in other criteria, such as measuring the distance from the start of the dendritic arbor to the end and measuring the sum of the length of the proximal dendrite. We are also considering looking at spine density (from highly magnified images) as a measurement.

On a different note, we also obtained more promising data on protein expression levels from our autistic mouse model. As exciting as it is to find a direction in which to pursue more research, as it often goes, new results only lead to more questions. Challenges may be, for instance, apparent contradictions with previous research, more controls may be necessary in light of the new results, or the new results may even challenge the original hypothesis, demanding new interpretations. How can the problems be resolved? In our case, we will continue to explore our mouse model by looking at our data with more methods. Unfortunately, as I have come to the end of my fellowship, the questions will be left open on my end. But I am thrilled to have contributed to this project and await further findings by others.


[1] Grasselli et al., PLoS One. 2011;6(6):e20791.

[2] Sholl DA, J Anat. 1953 Oct;87(4):387-406.


Mission: Crystallization Status: Success!

By Jen Hu

While my last blog post was a bit depressing, I have new and exciting news: I finally saw crystal growth. It was glorious.

Though the crystals, small and delicate, cannot be diffracted by x-ray due to their small size and shape, I am still extremely proud! I’ve grown some pretty, but currently useless, snowflake-like crystals after nearly 10 weeks of research.

As a reminder, my project involves the crystallization of a high affinity FTO protein mutant together with a single-strand DNA oligomer. While it is exciting to see crystal growth, there are two big questions that must be asked:

  1. Do the crystals truly contain a DNA-protein complex?
  2. Does our high-affinity mutant retain the same demethylation activity as FTO?

In addressing the first, there is no definitive way of ensuring that the crystals contain both DNA and protein until they can be diffracted. However, it is comforting to note that our control crystallization plate from several weeks ago, containing only protein, did not contain any crystals under the same conditions.

In addressing the second, we would like to use HPLC (high performance liquid chromatography) analysis to investigate the activity of the double mutant. The main goal of the HPLC is to analyze the DNA after the FTO-DNA reaction: is m6A still present or not? We have tried once but as this is a new technique, it may take a little while the master of the HPLC. Running an HPLC is quite similar to running a gel filtration column. A UV absorbance is used to track what flows out of the column, this time set at 266 nm for observing the presence of nucleic acids. As before, I will be watching carefully for peaks to appear, corresponding to nucleotides. We should see either four peaks or five, depending on if m6A is present or not.

In the meantime, as I refine my HPLC analysis, we’ll be optimizing the crystallization buffers for even better growth. We’ve adjusted the salt concentration, pH, and PEG size but the optimized crystals, while larger than the first set, are still needle clusters and too thin to diffract. This means more crystallization screens but with renewed hope! I think I’ve now tested over a thousand different crystallization conditions…

Life’s a Great Balancing Act

By Jen Hu

“So be sure when you step.
Step with care and great tact
and remember that Life’s
a Great Balancing Act.
Just never forget to be dexterous and deft.
And never mix up your right foot with your left.
-Dr. Seuss’ “Oh the places you’ll go!”

Over the last few weeks of purification, remembering that “…Life’s a Great Balancing Act,” may be the only thing preserving my sanity. My project this summer is to crystallize a complex of the FTO (fat mass and obesity-associated) protein with a single strand oligomer of DNA. However, even before the crystallization process starts, one must isolate the protein. This is easier said than done.

From start to finish, each minute counts in purifying your protein. However, freshness and purity often work at odds with each other. One could have a fresher protein that has undergone less purification or an older protein that is extremely pure. There are three types of purifications that I have been working with: Nickel Affinity, Mono-Q, Gel Filtration.

Quick description of each:

To use the Nickel affinity column, your protein must have a histidine tag that was incorporated onto it during its insertion into the plasmid. The supernatant from the lysed bacteria is passed through the column and any protein with a His-tag sticks to the sides. This column provides the greatest specificity and is the fastest to run. It is my favorite column for a reason.

The Mono-Q column separates based on charge. Each protein has a pI, or isoelectric point, which represents the pH at which it has a neutral charge. Therefore, by using the buffer of an appropriate pH above or below the pI, one can separate proteins based on charge. Unfortunately, our column is somewhat broken and runs very slowly. On top of that, ordering scientific equipment in China takes longer than it should. Yikes.

The Gel Filtration column separates based on size. The larger the protein, the faster it flows through the column because there are fewer routes it can take through the gel. This is the most satisfying column because you can watch the UV absorbance reading and see your protein eluting out. I literally hold my breath and watch for the peak to emerge. It’s a bit funny the things that we live for in the world of science: a band on a gel, a peak on a graph, or a p-value less than 0.05. The UV peak(s) that I live for:

The first peak is likely a dimer of the protein of interest and therefore would elute out more quickly than the monomer, represented by the second peak.

As for optimizing the purification process, the main issue I’ve been debating is whether to deal with the problematic Mono-Q column or just let it go. In the end, I decided to let it go and replace the normal protocol of Nickel, Mono-Q, Gel Filtration with Nickel, Gel Filtration, Nickel. This optimization has given me the best purity and allows me to run the quick and specific Nickel column twice.

Optimization is no easy task. When you think about it, our entire lives are based on optimizations of happiness, health, and other factors. I’ll be honest: sometimes, the protein purification process becomes a question of whether I want to stay in the lab until 10pm or explore the city of Beijing. In Chicago, I don’t think I would mind staying late since I have all year to explore the city. However, opportunities such as working in a foreign country are hard to come by. As well, it doesn’t help that even a pure and fresh protein does not guarantee a good crystal: there are hundreds of screening conditions to do afterwards. The path of science is a long and arduous one, because if you think about it: there is no end. There is always more that can be done. However, I think we should strive to keep our lives balanced and keep working towards those optimizations, not relegate ourselves to accepting a life shut indoors without sunlight or proper nutrition. Optimizing the purification has not only given me a better protein, but also a better quality of life. For me, a better quality of life includes trying all the delicious food Beijing has to offer, such as jellyfish appetizers!