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Tag: New Year’s resolution

2011 Goals

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I made a list of New Year’s resolutions last year which I am happy to say I did fairly well at achieving.

But, when I sat down again to think up what I wanted to publically commit to, I realized something. The list borrows heavily from last year, with a few slight modifications:

    • Read and blog one scientific paper a month: It’s been a staple of this blog, a lot of fun to read/write, and has succeeded in keeping me at least partially grounded in the science world that I once came from and, to some extent, still feel a part of.
    • Instead of reading Checkmate and Pawn in Frankincense from Dorothy Dunnett’s Lymond Chronicles, this year I’m aiming to read Queen’s Play – the last book in the series which my girlfriend and good friend recommend I read.
    • Continue to expand my network – I think I’ve graduated from super-shy wallflower, but I’m still not completely comfortable with the whole networking thing. The good thing about being in venture capital is that networking not only comes with the job but comes a lot easier when people know that your company has money and connections, so I will continue to work on breaking out of my introvert shell
    • Finish a rev 1 of Benchside – I failed last year, but gosh-darn-it, I will succeed this year!

But, in addition, I want to add a few other items:

    • Build out a public version of Iggregate – In addition to Benchside, I’m also working on a project I call Iggregate which I am hopeful I will be able to take the wraps off in this new year. It’ll be tough, especially with the Benchside goal, work, and my general programming incompetence, but you gotta aim high to make it anywhere big!
    • Improve my Chinese – The venture fund I work for is unique in its strong presence in US, Japan, and China. And, while my job and interests are focused on venture opportunities in the US, our recent company offsite has convinced me that I should improve my Chinese speaking and comprehension. I don’t intend (not that I ever could get) to be as fluent as a native speaker, but my goal is to be able to understand enough business Chinese that I can participate in my fund’s China team meetings without falling back on English.
    • Build out investment portfolio with more than just index funds – My traditional investment strategy has been heavily reliant on index funds due to lack of time, lack of training/practice, and fear of conflicts of interest from my consulting career. Now that I’m no longer a consultant, employed in an investment industry, and have a good friend from college who’s very interested in deploying his capital effectively and has the time to think about this non-stop (because he’s in business school), I think its about time I graduate from the low-risk, low-reward world of index funds and reallocate so my investment portfolio is 1/4 to 1/3 in specific stocks/commodities

Truth be told I’m starting to feel a little nervous about committing to all of this – but I’m also a little excited to get started. Happy New Year everybody! And good luck with those resolutions!

(Image credit)

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United States of Amoeba

Another month, another paper to read and blog about.

Most people know that viruses are notoriously tricky disease-causing pathogens to tackle. Unlike bacteria which are completely separate organisms, viruses are parasites which use a host cell’s own DNA-and-RNA-and-protein producing mechanisms to reproduce. As a result, most viruses are extremely small, as they need to find a way into a cell to hijack the cell’s  machinery, and, in fact, are oftentimes too small for light microscopes to see as beams of light have wavelengths that are too large to resolve them.

However, just because most viruses are small, doesn’t mean all viruses are. In fact, giant Mimiviruses, Mamaviruses, and Marseillesviruses have been found which are larger than many bacteria. The Mimivirus (pictured below), for instance, was so large it was actually identified incorrectly as a bacteria at first glance!

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Little concrete detail is known about these giant viruses, and there has been some debate about whether or not these viruses constitute a new “kingdom” of life (the way that bacteria and archaebacteria are), but one thing these megaviruses have in common is that they are all found within amoeba!

This month’s paper (HT: Anthony) looks into the genome of the Marseillesvirus to try to get a better understanding of the genetic origins of these giant viruses. The left-hand-side panel of picture below is an electron micrograph of an amoeba phagocytosing Marseillesvirus (amoeba, in the search for food, will engulf almost anything smaller than they are) and the right-hand-side panel shows the virus creating viral factories (“VF”, the very dark dots) within the amoeba’s cytoplasm. If you were to zoom in even further, you’d be able to see viral particles in different stages of viral assembly!

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Ok, so we can see them. But just what makes them so big? What the heck is inside? Well, because you asked so nicely:

    • ~368000-base pairs of DNA
        • This constitutes an estimated 457 genes
        • This is much larger than the ~5000 base pair genome of SV40, a popular lab virus, the ~10000 base pairs in HIV, the ~49000 in lambda phage (another scientifically famous lab virus), but is comparable to the genome sizes of some of the smaller bacterium
        • This is smaller than the ~1 million-base pair genome of the Mimivirus, the ~4.6 million of E. coli and the ~3.2 billion in humans
    • 49 proteins were identified in the viral particles, including:
        • Structural proteins
        • Transcription factors (helps regulate gene activity)
        • Protein kinases (primarily found in eukaryotic cells because they play a major role in cellular signaling networks)
        • Glutaredoxins and thioredoxins (usually only found in plant and bacterial cells to help fight off chemical stressors)
        • Ubiquitin system proteins (primarily in eukaryotic cells as they control which proteins are sent to a cell’s “garbage collector”)
        • Histone-like proteins (primarily in eukaryotic cells to pack a cell’s DNA into the nucelus)

As you can see, there are a whole lot of proteins which you would only expect to see in a “full-fledged” cell, not a virus. This begs the question, why do these giant viruses have so many extra genes and proteins that you wouldn’t have expected?

To answer this, the researchers ran a genetic analysis on the Marseillesvirus’s DNA, trying to identify not only which proteins were encoded in the DNA but also where those protein-encoding genes seem to come from (by identifying which species has the most similar gene structure). A high-level overview of the results of the analysis is shown in the circular map below:

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The outermost orange bands in the circle correspond to the proteins that were identified in the virus itself using mass spectrometry. The second row of red and blue bands represents protein-coding genes that are predicted to exist (but have yet to be detected in the virus; its possible they don’t make up the virus’s “body” and are only made while inside the amoeba, or even that they are not expressed at all). The gray ring with colored bands represents the researchers’ best guess as to what a predicted protein-coding gene codes for (based on seeing if the gene sequence is similar to other known proteins; the legend is below-right) whereas the colored bands just outside of the central pie chart represents a computer’s best determination of what species the gene seems to have come from (based on seeing if the gene sequence is similar to/the same as another specie’s; the legend is below-left).

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Of the 188 genes that a computational database identified as matching a previously characterized gene (~40% of all the predicted protein-coding genes), at least 108 come from sources outside of the giant viruses “evolutionary family”. The sources of these “misplaced” genes include bacteria, bacteria-infecting viruses called bacteriophages, amoeba, and even other eukaryotes! In other words, these giant viruses were genetic chimeras, mixed with DNA from all sorts of creatures in a way that you’d normally only expect in a genetically modified organism.

As many viruses are known to be able to “borrow” DNA from their hosts and from other viruses (a process called horizontal gene transfer), the researchers concluded that, like the immigrant’s conception of the United States of America, amoebas are giant genetic melting pots where genetic “immigrants” like bacteria and viruses comingle and share DNA (pictured below). In the case of the ancestors to the giant viruses, this resulted in viruses which kept gaining more and more genetic material from their amoeboid hosts and the abundance of bacterial and virus parasites living within.

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This finding is very interesting, as it suggests that amoeba may have played a crucial role in the early evolution of life. In the same way that a cultural “melting pot” like the US allows the combination of ideas from different cultures and walks of life, early amoeba “melting pots” may have helped kickstart evolutionary jumps by letting eukaryotes, bacteria, and viruses to co-exist and share DNA far more rapidly than “regular” natural selection could allow.

Of course, the flip side of this is that amoeba could also very well be allowing super-viruses and super-bacteria which could one day wipe out the human race to breed… but, maybe I’m just being paranoid. 🙂

Paper: Boyer, Mickael et al. “Giant Marseillevirus highlights the role of amoebae
as a melting pot in emergence of chimeric microorganisms.” PNAS 106, 21848-21853 (22 Dec 2009) – doi:10.1073/pnas.0911354106

(Image Credit – Mimivirus – Wikipedia) (Figures 1, 2, and 5 from paper)

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Collateral damage by mitochondria

Another month, another paper to read and blog about.

This month, I read a paper (HT: my ex-college roommate Eric) by a group from Beth Israel about systemic inflammatory response syndrome (SIRS) following serious injury. SIRS, which is more commonly understood/found as sepsis, happens when the entire body is on high “immune alert.” In the case of sepsis, this is usually due to an infection of some sort. While an immune response may be needed to control an internal infection, SIRS is dangerous because the immune system can cause a great deal of collateral damage, resulting in potentially organ failure and death.

Whereas an infection has a clear link to sepsis, the logic for why injury would cause a similar immune response was less clear. In fact, for years, the best hypothesis from the medical community was that injury would somehow cause the bacteria which naturally live in your gut to appear where they’re not supposed to be. But this explanation was not especially convincing, especially in light of injuries like burns which could still lead to SIRS but which didn’t seem to directly affect gut bacteria.image

Zhang et al, instead of assuming that some type of  endogenous bacteria was being released following injury, came up with an interesting hypothesis: it’s not bacteria which is triggering SIRS, but mitochondria. A first year cell biology student will be able to tell you that mitochondria are the parts of eukaryotic cells (sophisticated cells with nuclei) which are responsible for keeping the cell supplied with energy. A long-standing theory in the life science community (pictured above) is that mitochondria, billions of years ago, were originally bacteria which other, larger bacteria swallowed whole. Over countless rounds of evolution, these smaller bacteria became symbiotic with their “neighbor” and eventually adapted to servicing the larger cell’s energy needs. Despite this evolution, mitochondria have not lost all of their (theorized) bacterial ancestry, and in fact still retain bacteria-like DNA and structures. Zhang et al’s guess was that serious injuries could expose a mitochondria’s hidden bacterial nature to the immune system, and cause the body to trigger SIRS as a response.

Interesting idea, but how do you prove it? The researchers were able to show that 15 major trauma patients with no open wounds or injuries to the gut had thousands of times more mitochondrial DNA  in their bloodstream than non-trauma victims. The researchers were then able to show that this mitochondrial DNA was capable of activating polymorphonuclear neutrophils, some of the body’s key “soldier” cells responsible for causing SIRS.

imageThe figure above shows the result of an experiments illustrating this effect looking at the levels of a protein called p38 MAPK which gets chemically modified into “p-p38” when neutrophils are activated. As you can see in the p-p38 row, adding more mitochondrial DNA (mtDNA, “-” columns) to a sample of neutrophils increases levels of p-p38 (bigger, darker splotch), but adding special DNA which blocks the neutrophil’s mtDNA “detectors” (ODN, “+” columns) seems to lower it again. Comparing this with the control p38 row right underneath shows that the increase in p-p38 is likely due to neutrophil activation from the cells detecting mitochondrial DNA, and not just because the sample had more neutrophils/more p38 (as the splotches in the second row are all roughly the same).

Cool, but does this mean that mitochondrial DNA actually causes a strong immune response outside of a test tube environment? To test this, the researchers injected mitochondrial DNA into rats and ran a full set of screens on them. While the paper showed numerous charts pointing out how the injected rats had strong immune response across multiple organs, the most striking are the pictures below which show a cross-section of a rat’s lungs comparing rats injected with a buffer solution (panel a, “Sham”) and rats injected with mitochondrial DNA (panel b, MTD). The cross-sections are stained with hematoxylin and eosin which highlight the presence of cells. The darker and “thicker” color on the right shows that there are many more cells in the lungs of rats injected with mitochondrial DNA – most likely from neutrophils and other “soldier cells” which have rushed in looking for bacteria to fight.

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Amazing isn’t it? Not only did they provide part of the solution to the puzzle of injury-mediated SIRS (what they used to call “sterile SIRS”), but lent some support to the endosymbiont hypothesis!

Paper: Zhang, Qin et al. “Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury.” Nature 464, 104-108 (4 March 2010) – doi:10.1038/nature08780

(Image credit) (Figure 3 and 4 from paper)

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Slime takes a stroll

It was the end of February yesterday – which means its time to read/blog about another paper!

The paper I read for this month brought up an interesting question I’ve always had but never really dug into: how do individual cells find things they can’t “see”? After all, there are lots of microbes out there who can’t always see where their next meal is coming from. How do they go about looking?

A group of scientists at Princeton University took a stab at the problem by studying the motion of individual slime mold amoeba (from the genus Dictyostelium) and published their findings in the (open access) journal PLoS ONE.

As one would imagine, if you have no idea where something is, your path to finding it will be somewhat random. What this paper sought to discover is what kind of random motion do amoeboid-like cells use? To those of you without the pleasure of training in biophysics or stochastic processes, that may sound like utter nonsense, but suffice to say physicists and mathematicians have created mathematically precise definitions for different kinds of “random motion”.

Now, if the idea of different kinds of randomness makes zero sense to you, then the following figure (from Figure 1 in the paper) might be able to help:

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Panel A describes a “traditional” random walk, where each “step” that a random walker takes is completely random (unpredictable and independent of the motion before it). As you can see, the path doesn’t really cover a lot of ground. After all, if you were randomly moving in different directions, you’re just as likely to move to the left as you are to move to the right. The result of this chaos is that you’re likely not to move very far at all (but likely to search a small area very thoroughly). As a result, this sort of randomness is probably not very useful for an amoeba hunting for food, unless for some reason it is counting on food to magically rain down on its lazy butt.

Panel B and C describe two other kinds of randomness which are better suited to covering more ground. Although the motion described in panel B (the “Levy walk”) looks very different from the “random walk” in Panel A, it is actually very similar on a mathematical/physical level. In fact, the only difference between the “Levy walk” and the “random walk” is that, in a “normal” random walk, the size of each step is constant, whereas the size of each “step” in a “Levy walk” can be different and, sometimes, extremely long. This lets the path taken cover a whole lot more ground.

A different way of using randomness to cover a lot of ground is shown in Panel C where, instead of taking big steps, the random path actually takes on two different types of motion. In one mode, the steps are exactly like the random walk in Panel A, where the path doesn’t go very far, but “searches” a local area very thoroughly. In another mode, the path bolts in a straight line for a significant distance before settling back into a random walk. This alternation between the different modes defines the “two-state motion” and is another way for randomness to cover more ground than a random walk.

And what do amoeba use? Panel D gives a glimpse of it. Unlike the nice theoretical paths from Panels A-C rooted around random walks and different size steps or different modes of motion, the researchers found that slime mold amoeba like to zig-zag around a general direction which seems to change randomly over the course of ~10 min. Panel A of Figure 2 (shown below) gives a look at three such random paths taken over 10 hours.

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The reason for this zig-zagging, or at least the best hypothesis at the time of publication, is that, unlike theoretical particles, amoeba can’t just move in completely random directions with random “step” sizes. They move by “oozing” out pseudopods (picture below), and this physical reality of amoeba motion basically makes the type of motion the researchers discussed more likely and efficient for a cell trying to make its way through uncharted territory.

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The majority of the paper actually covers a lot of the mathematical detail involved in understanding the precise nature of the randomness of amoeboid motion, and is, frankly, an overly-intimidating way to explain what I just described above. In all fairness, that extra detail is more useful and precise in terms of understanding how amoeba move and give a better sense of the underlying biochemistry and biophysics of why they move that way. But what I found most impressive was that the paper took a very basic and straightforward experiment (tracking the motion of single cells) and applied a rigorous mathematical and physical analysis of what they saw to understand the underlying properties.

The paper was from May 2008 and, according to the PLoS One website, there have been five papers which have cited it (which I have yet to read). But, I’d like to think that the next steps for the researchers involved would be to:

  1. See how much of this type of zig-zag motion applies to other cell types (i.e., white blood cells from our immune system), and why these differences might have emerged (different cell motion mechanisms? the need to have different types of random search strategies?)
  2. Better understand what controls how quickly these cells change direction (and understand if there are drugs that can be used to modulate how our white blood cells find/identify pathogens or how pathogens find food)

(All figures from paper) (Image of Pseudopod)

Paper: Li, Liang et al. “Persistent Cell Motion in the Absence of External Signals: a Search Strategy for Eukaryotic Cells.” PLoS ONE 3 (5): e2093 (May 2008) – doi:10.1371/journal.pone.0002093

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Crazy Y Chromosomes

A few weeks ago, I set myself some 2010 goals. One of which was to make sure that I fit in reading at least one paper every month. What I didn’t say though, was that I would try to do a quick blog post on each (to help keep me honest).

I forgot exactly how I found this paper, but the subject immediately caught my eye:

Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content

What? I had always been taught that the genomic differences between chimpanzees and humans were extraordinarily small, and since I’m male, I was also drawn to the fact that it would talk about a chromosome that was very near and dear to me.

What I read was pretty amazing. Despite the fact that we are very genetically similar to chimpanzees the Y chromosomes of our two species are actually very different. The best depiction of this that I can point to is from Figure 2 of the paper (below). The two charts below are dot plots which show where the human and chimpanzee chromosomes “line up”, so to speak. The right-hand chart shows how closely related the human chromosome 21 is to the analogous chimpanzee chromosome. You can see this from the nearly perfect diagonal line, showing that the two chromosomes are pretty close to identical as you move from one end of the chromosome to the other. The left-hand chart shows a similar comparison of a human Y chromosome and a chipmanzee Y chromosome. Notice the difference?

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While it was fascinating to read what specifically was different (i.e. repeats, ectopic homologous recombination, introduction of nonsense mutations and open reading frames), what I found most interesting was the speculation as to why the Y chromosomes of two very similar species would diverge so much in such a narrow period of time. The research group’s hypothesis is that the Y chromosome holds a great deal of influence over sperm production, and because a Y chromosome will never have a “partner” chromosome the way that every other non-sex-determining chromosome does, changes in the Y chromosome are likely to have very significant changes in sperm characteristics. Because female chimpanzees oftentimes mate with multiple males, there is strong sperm competition and hence strong selective pressure for chimpanzees to have rapid evolution in the Y chromosome.

Of course, this is all just a guess. One way to test it would be to compare the human Y chromosome sequence with further primate species and see if primates where sperm competition is less intense have more similar chromosomes as humans. Another would be to see if any of the genetic changes resulted in clear sperm/testes genetic or transcriptional control differences.

But, all in all, a very cool start to what I’m hoping will be a fun 12 months!

(Figure 2 from paper)

Paper: Hughes, Jennifer F. et al. “Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content.” Nature 463, 536-539 (28 January 2010) – doi:10.1038/nature08700

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2010 Goals

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I don’t usually do the New Year’s resolutions thing. But this year, since I’m now publishing everything  to benjamintseng.com, I think the perceived public scrutiny associated with having a public list of goals for the coming year on my own personal domain name might end up being a good motivator to achieve them.

So, without further ado:

  • Finish a Rev 1 of Benchside – While I had a wild ride on Xhibitr and learned a ton, I’m hoping Benchside, the  project that I’m currently working on, will end much more successfully. Whereas Xhibitr was an online social network aimed at fashion, Benchside is a software application designed to run on your computer (not the web) which aims to help you change the way you organize the information on your hard drive. While Benchside officially started about half a year after work on Xhibitr went underway, its progress has suffered from a lack of focus on my part. Despite this, I still have strong faith in the team and the project, and I definitely want to see this through. So, by December 31, 2010, I will have a working version (even if its only barely working and cobbled together with voodoo magic and duct tape) of the core Benchside software working on my computer.
  • Read Pawn in Frankincense and Checkmate by Dorothy Dunnett – My girlfriend adores Dorothy Dunnett’s Lymond Chronicles. They were an integral part of her identity growing up, and she continues to re-read them today whenever she has extra time (and no new reading or knitting material :-)). They are also very meaty books full of well-researched 16th century European history and cultural idiosyncrasies. I’ve already read two (Game of Kings and Disorderly Knights – yes, there’s a chess theme in the titles) and despite priding myself in being well-educated, I found them very difficult to follow (I guess that’s why I read comic books?) So why read two more? In addition to my girlfriend wanting me to read them, she’s raved about the conclusion to this series (Checkmate) for years, and given her refined, educated taste in books (although apparently not in men :-)), I can’t help but want to stretch my own reading ability especially if the payoff is as grand as she has made it seem. Consequently, by December 31, 2010, I will have read both Pawn in Frankincense and Checkmate.
  • Meet at least 3 new people per conference I attend – If I have one great weakness, it is that I find it painfully difficult to talk to people I’m not familiar with. On the Myers-Briggs Type Indicator test, I rank extremely “I” (as in introvert). But, given my upcoming job in venture capital and my desire to pursue opportunities which won’t be so forgiving of my extreme shyness, I’m going to set a goal for myself to help break that habit. At every conference/industry event I attend in 2010, I will meet and have meaningful conversation with at least 3 new people.
  • Read at least 1 academic scientific paper per month – I pride myself on being a science person. In fact, with the notable exception of Xhibitr, my portfolio is full of my old scientific “adventures”.  But, as I’ve dug deeper into the technology and business world, I have unfortunately lost touch with that part of my life. Part of the reason that I still blog about science here and over at Bench Press is a desire to stay connected to those under-exercised scientific interests. This year, to help keep that connection going, and also to help me keep pace with the tech-and-science related news and innovations which give me fodder for more blog posts, in 2010, I will read at least 1 academic (as in journal) scientific paper per month.

I’m sure some of the people reading this list will think that my bar for success is set too low. And, maybe they’re right. But, hey, this is the first time I’ve done something like this, and I’m not about to set myself up for public failure :-).

Happy New Year to everyone! And best of luck with those resolutions!

(Image credit)

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