Saturday, 4 May 2013

On Boston


    I feel lost.
    These two weeks have shocked me. 
    I’ve been told the best way to get things off your mind when you can’t work is to write it down, so I 've been writing down thoughts that keep me awake at night.
    I do not know why this is affecting me so. Even one fall morning many years ago, when I walked by a TV outside my high school library, to see two tall buildings, one with smoke was billowing from it. I knew something horrible happened but I was too young to comprehend what was happening. Maybe it's because I'm older and this stuff is affecting the place that I'm living in.
    I wish I were young again. 

                                                                           I
Monday April 15, 2013. 3:00 PM 
    I’m rushing to finish my Massachusetts taxes. I said I was going to finish it the Friday before, but I got too caught up in finishing another song so now, I’m scrambling to finish. The marathon is going on; Rita Jeptoo and Felisa Lelisa have already been announced as the winners. I need to hurry if I want catch the moment when some friends will probably come running in.
    I remember my periodic CNN news check, the sinking of my stomach deep into my body, the feeling of cold water running down my temples when I see the headlines:
    “EXPLOSIONS HEARD AT BOSTON MARATHON.” 
    I remember muttering “no way,” and switching to the Boston Globe. I remember the disbelief when I see the same headline there, and worry about friends who were currently there. 
    I remember being assaulted, minute after minute of tweets and news updates. 
    Refresh.    
    Explosion at Copley square, hundreds injured. 
    Refresh.    
    Reports of a several unexploded bombs. 
    Beep.    
    Are you okay? I heard about what just….
    Refresh.    
    Sirens wailing.
    Refresh.    
    A third explosion in Copley Square. 
    Refresh.  
    Explosion reported at the JFK library. 
    Refresh.
    My friends are unharmed. None were at finish line.
    Beep.    
    You live in Back Bay. Are you okay?
    Refresh.    
    Reports of unexploded bombs found near Harvard Square. 
    Refresh.    
    Another siren, inside another injured person.
    Refresh. 
    Refresh. 
    Refresh. 
-   -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -
    Refresh.
    It is too horrible to imagine. 
    I wish it were a nightmare, that I could go to sleep and wake up back in the morning of April 15th, but then I awake and the only April 15th, 2013 that I’ll ever experience has passed. 
    I can only imagine the hurt that many are feeling.
    My heart weeps for these innocent souls, who died for wanting to watch someone cross a finish line. Lü Lingzi, graduate student at Boston University. Krystle Campbell, restaurant owner. And Martin Richard, 8 year old boy, who will never get the chance of running a marathon.
    My heart weeps for those who loved to run, whose dreams were torn when their legs were ripped off their bodies by an explosion of superheated gas and thousands of ball bearings embedding their alien metal into burning flesh. I think of the future incessant unending pain from a phantom leg that cannot be treated by simple painkillers because the leg is no longer there.
    My heart weeps for the athletes whose memories of triumph at finishing the world’s most prestigious race are now scarred with memories of despair. 
    My heart weeps for the families of the hundreds injured, whose lives won’t ever be the same as they struggle to understand what happened while praying for their survival.
    My heart weeps for the first responders, whose dreams will never forget the cries of maimed individuals, the chaotic whirr as they struggled to heal, amidst the pools of crimson on the sidewalk. 
    I am angry at whoever did these horrible acts. I do not know who they were but that does not matter. These were cowardly acts. Who bombs defenseless people? This is not like they were enemy combatants, who the ability to fight back. These were families and children, on a holiday, watching a sporting event.
    This was particularly chilling because everything was planned for maximum damage: the bombs placed at the finish line where everyone tended to congregate; ball-bearings to maim more limbs; the explosions timed to the peak moment when most runners would be arriving; one explosion slightly after another so that when people fled the first and turned to look back, a second explosion would tear them apart.    
    All week, I was obsessed with following the news. I could not turn off the radio. I could not sleep. I was haunted by the photos: of the aerial view of the blast site, with dark red blood stains still visible beside the Lenscrafters; of the girl lying in the street, while a stranger embraces her body, whispering soothing words into her ears; of terrified Carlos in his cowboy hat, preventing Jeff Bauman’s life from slipping from his macerated leg.
    As President Obama said, “every fall, you welcome students from all across America and all across the globe, and every spring you graduate them back into the world -- a Boston diaspora that excels in every field of human endeavor.” Boston harbors no prejudice and is open to teaching the whole world, yet prejudice came to this city and tried to hurt it. 
    The world weeps for you, Boston. 
    
                                                                           II
Tuesday April 16, 2013. 9:30 AM
    I visit Copley Square because I need to understand. 
    But I would get no additional understanding. 
    I see a crowd of people staring beyond the barricades at ground zero several streets away. Except for the red-blue flashes of distant cop cars, the street is empty. Half-filled water bottles and Starbucks grandes litter the ground, a slight stain memorializing where the coffee spilled, unfinished. Leftover shirts lie on the street, dropped in people’s haste to flee the two loud explosions that took the lives of 3 people.
    Aside from the perverse clicks of cameras and the many media vans behind me, no one speaks. 
    No one could speak. 
    It reminds me of a scene from I am Legend, but I am suddenly filled with a sense of guilt comparing this tragedy to a cheap summer blockbuster.
    This morning on the news, I heard people talk about returning to normal that by not doing so would be giving in to terrorists. Terrorists seek to wreck lives and we need to put our heads high and not let them terrorize us. But how can we go on as if nothing has happened? Something did happen and it would be disrespectful to the victims to ignore. We must go on, but we go on changed, stronger. 
    But right now, I don’t know how. All is silent, while the bright sun bathes this scene of desolation before us and a bird flies across the scene.
    On my way back to cross the Charles, I pass St Cecilia’s. The doors are open and a middle-aged woman is sitting at the door, reading a book.
    Is it open?
    Yes, I think we should be open.
    Thank you.
    I walk in and do something I haven’t done in a year. I begin to pray.
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    I am a scientist. I need to understand. 
    There are many things I could know if I wanted to. If I wanted to, I could learn any new hobby I desired, and provided the time was put in, I might get good at it. If I wanted to, I could ask a girl I cared for whether she liked me, and I would know. If I wanted to, I could investigate any scientific phenomena that arouses my interest, and if enough time and sweat is put in, I would come to understand.
    Yet, there are so many questions from this weekend that I will never get to understand.
    How could they do this, kill innocent people who just wanted to watch a race?
    How could bad things happen to good people, while the suspects escape unharmed?
    Why would someone curse his family, wife and children with the stigma of relatives of a terrorist for the rest of his life?
    How could there be so much evil in this world?
    Everything seems so chaotic, disorderly. All their acts at MIT point to a many rash decisions. It doesn’t make sense how refugees fleeing the Chechen wars would come to hate the country that provided them sanctuary, gave oen a wife and daughter, and offered them a chance to pursue their Olympic dreams. 
    Later events suggested that they wanted to do another bombing. Did they not see the results of their first act? The maimed limbs, innocent deaths and dreams shattered; does that not horrify them? 
    And of all potential areas, they chose to attack a sporting event, these two individuals who are reported to have been training to become professional wrestlers. How could they break the sanctity of a sporting competition?
    I like things like classical music because everything makes sense. There is a purpose to every note that is played, the harmonies that meander before settling on a tonic chord. Each instrument that comes in is not filler, but rather adds a unique coloration to the piece. Everything fits. 
    I can’t see any purpose behind these acts, done by two delusional men. Some people may cynically say that events like these remind us of our fragile existence and of our collective humanity, and are meant to teach us something. Others may say these were in some higher plan that we cannot comprehend and that it was their time to die; what twisted plan takes away someone before they have been able to live a fulfilling life? 
    But I might have to resign myself to the realization that maybe the bombings had no purpose to begin. Sometimes things don’t make sense even if it would help if they did, and that is an unsettling thought.
    I just don’t know.
    
                                                                             III
Thursday April 18, 2013. 10:57 PM
    “There is a report of an Active Shooter in the vicinity of Building 32 Stata Center. Stay clear of the area. Follow up: emergency.mit.net”
    Probably another overzealous MIT person.  Ever since the Boston bombing, the number of reported suspicious packages have increased. Earlier that day, E38 was evacuated and two days ago, E51 as well. People’s nerves were becoming too sensitized, like a child after you’ve jumped out from behind the wall to scare them. 
    But something makes me pause. The shooting is the Stata Centre, right beside the building where I work. Great. That means there will be police around, so I can’t go back to check on experiments after finishing this burrito.
    I place my phone back in my pocket, when it vibrates again. I pull it out.
    “You’re not in the Koch right? Stay there if you are. Shooting in Stata.”
    Another message from someone else. “Are you in lab?”
    Out of curiosity, I search twitter’s feed for Stata and come across a photo.
    3 cop cars surround a hectic scene. There’s blood on the ground, surrounded by hastily opened packages. 
    Oh shit. This is real.
    I rush home and turn on my computer. I turn on a police scanner and listen.
    “They have grenades.”
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   What is the nature of evil? Is it an external, insidious creature, hiding under a deceptive face, waiting for the perfect moment to strike, and when all is well, it lashes out at unsuspecting victims? Or, a more scary thought, is it ever present, coexisting in humans with good, and very easily to slip into?
    That scary, Thursday night, when we were all glued to the police scanners and following the firefight down in Watertown, we discovered who these men were. Dzhokhar Tsarnaev and Tamerlan Tsarnaev
    What scared me the most in the days after the capture of the suspects was how normal Dzhokhar seemed to his friends. He was a 19 year old kid, a sophomore in college. He had a social media page, tweeted song lyrics from tunes in Pop culture. He went to a college party two days after the bombings. His friends believe that there was no way he could be a terrorist; he was involved in the community as a Best Buddies volunteer.  He was so loved that in an interview, one of his wrestling buddies indicated he would still think “Jahar” was a good person even if it turned out that he committed these terrible acts. 
    It is tempting to rectify this anomaly by blanming an exterior entity and say he was brainwashed. Christianity has done it for a long time, saying that Satan is the source of evil. One hypothesis going around the news is that he was ensnared by his older brother, and likewise the older brother was ensnared by a “Mischa.” Some anecdotal evidence has emerged that this could have been the case; it was said that Dzokhar used to follow his brother around and that he used to say “Tamerlan this. Tamerlan that.” 
    Yet even if he was heavily brainwashed, that does not absolve him of responsibility. This was the same guy who thought through the plans, created and set off a bomb at the finish line. This was the same guy who subsequently was involved in killing an MIT Police Officer and we now know, may have been planning to do worse. He had done good deeds in the past so he knew the moral compass. He was fully aware of his actions and could have said no at any time but he didn’t. 
    It’s frighteningly relatable because many of us have done things we’re not proud of to gain recognition from someone, perhaps a crush or an older sibling. Rarely does it come remotely close to the horrors these terrorists instilled; at least I hope. And then I am reminded of history. During World War II, many normal citizens in Germany participated in terrible acts that they knew were terrible. In the famous Stanford prison experiments, students roleplaying as guards became sadistic towards their mock-prisoners and in the Milgram experiment, subjects applied stronger shocks to “test subjects,” even when they were screaming out in pain. 
    So I am resigned to admit that the capacity for evil coexists in all of us. The only solace I can get from these thoughts is that we are given a choice every breath of our waking lives, between acts of good and of the rest, and ultimately it is our choices that define us. The Tsarnaevs made terrible decisions that are now affecting tons of people in Boston, and many more around the country, whereas Officer Collier made the choice to help people and we have all been affected by him. I hope I’ve been walking down the right path.
    
                                                                            IV
Wednesday April 24, 2013. Noon. 12:35 PM.
    The last notes of Taps ring out across MIT’s Briggs Field. The off-tune notes add a sense of poignancy to this solemn occasion as thousands of people stare at the brown casket at the front, below a large American flag held up by the ladders of two fire trucks.
    Today we are here to honour Officer Sean Collier. 
    Just 4 days ago, he was sitting in his cop car, parked in between Building 32 and Building 76. It’s not uncommon to have a cop car parked around there when they need a break. I probably saw him when I went for dinner, but I didn’t notice it just like how one doesn’t notice the smile from friends until they’ve gone away. 
    Here at MIT, we have an unspoken tradition. When someone dies, we do not write them off as a number, unlike everything else here which frustratingly is referred to by digits. Course 7. Building 68. Class 7.012.  Instead, someone sets up a memorial at the site where they passed. 
    Yesterday, I saw an old couple searching for something near work. I know this because they paused in quiet realization when they saw the heap of flowers and candles that appeared overnight on the corner of Vassar and Main. They didn’t look like the usual tourists that came with their large cameras and fanny packs. They approached the site gingerly, joining the semicircle of strangers surrounding the. The woman stepped forward and stared at the faded photo, faded from the sky’s tears last night, lost in her thoughts, while MIT students hurry around them to classes to hand in their assignments. Her husband placed his hand on her shoulder, and she jolted. There was a slight hesitation. She looked around at the others before tiptoeing forward and placing the flowers among many others. Then, they left silently. 
    Today we are here to honour Officer Sean Collier. 
    I do not know him but a part of me wants to weep for this guy, my age, who was brutally murdered for some unknown reason. I do not because boys don’t cry. 
    Instead, I stare ahead as I hear the thud thud thud of four helicopters coming our way from the horizon. 
    I do not understand why he passed away. He was a good man, young and had so much ahead of him. He touched the hearts of the entire MIT community. Today, I hear from Chief DiFava about how he wanted permission to work with the homeless shelter, because he wanted to stop crimes before they occurred. Yesterday, I heard a story of how he held the hands of a student after she had been attacked by strangers. In the newspapers, I heard of a story where he asked his mother to comfort a lonely woman sitting in a diner when he was child. 
    Officer Collier’s sacrifice inspires me to do good better. Officer Collier wanted to help the homeless to prevent crimes before they occur and was a supporter of the Jimmy Fund, and so I (and perhaps others) will help finish what he started.
    I look to my right at the thousands of police officers standing, their hands up in salute while sweat drips from their brows onto their dark blue uniforms. I have never seen so many officers in my life. Behind them, I can see the rows of flags brought in from each police force that came, some coming all the way down from Canada to pay tribute to a fellow officer. 
    My thoughts turn back above me I hear the Doppler effect in action as the thud thuds build in intensity. I feel the wind from the rotating blades of the four Eurocopter AS-355N’s, spinning at 6000 rpm. I see them zoom over the brown casket at the front, one after another in an ordered maneuver, a stark contrast to the chaos that engulfed Boston a week ago. 
    It is a sight to behold. His brother said he would have liked it.
    I also raise my hand in salute to the man who saved the lives of many here at MIT. 
    Today we are here to honour Officer Sean Collier. 
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    As Boston tries to heal, one thing that haunts me to this day about that Thursday night is the motivation behind the suspects being at MIT. We now know they were not involved in the 7-11 robbery. They had the bombs and guns prepared and were planning to use them since they went to pick them up. From more recent testimony, it seems they wanted to do something here in Boston, but as a result of the carjacking, they rashly wanted to move it to New York. 
    All of us here at MIT ask the unspoken question: were they planning to do something at MIT? And if so, if Officer Sean Collier had not been shot and their plans gone awry, would I have walked into work one day not realizing a bomb was going to explode several hours later?
    It is in these times of trying that I had gone to several memorial events to commemorate the memories of the people of Boston. I have never experienced such sad music as when I went to Verdi’s Requiem, where 15 or so choirs banded together to sing in the most solemn fashion, the words of Leonard Bernstein: "This will be our reply to violence: to make music more intensely, more beautifully, more devotedly than ever before." I went to a Beethoven concert, whose choirs cried out how we would band together defiantly despite these trials, as Boston strong. And I went to visit Copley Square and Officer Collier’s memorial, where I could feel their spirit watching over the solemn events. 
    I lament the inevitable commercialization that is bound to happen of this tragedy. Already the media circus has descended upon this campus, interviewing anyone they can possibly get their hands on. There will come a day when some callous entrepreneur tries to trademark “Boston Strong,” just like how someone tried to trademark “9/11.” There will come a day when an ambitious Hollywood director decides to adapt these events, toss in an A-list celebrity and hope for the recognition that an Oscar brings.
    But until then, the city of Boston is trying to heal, to understand. Copley square has reopened. One of the suspects is now captured, the other dead. We are combing our intelligence and trying to understand why we didn’t follow up on the signs that were now clearly there. Therapy dogs have been brought in, other concerts have been planned and the MIT librarian hugged the crying student who couldn’t study for her finals. 
    I may never know why any of this happened nor forgot the emotions of those five days. But amidst this depravity, we came together as a community. We thank all the first responders who helped us and mourn those that have been lost. 
    Especially, Officer Sean Collier, who unknowingly saved us all from further tragedies. If it weren’t for him parked between two buildings, I may not be writing this today.
    Thank you.

                                                                             V
Friday April 19, 2013. 8:49 PM.
    “It looks like they have the suspect.”
    I look up from my experiment to stare at the police scanner on the iMac screen behind my bench. It had been one of the craziest days. All day, I was holed up in my apartment ever since Boston decided to shut the city down in the manhunt for “white hat,” as he had been called in online forums. I was glued from the police scanners, as if it were the 50s and the radio was the only source of news.
    Friday was like a scene from Hollywood. SWAT teams going door to door in Watertown. The rotors of helicopters buzzing above the skies of MIT. Police sirens whistling by every 20 minutes. Uncle Tsarni denouncing the horrible acts in a meme-worthy performance. The military invading UMass Dartmouth’s campus. A third suspect arrested, believed to be wearing an explosive vest. And just as I walked in to work to try and salvage my experiment that had gone several hours too long, reports of blood discovered in someone’s backyard boat. 
    I turn on XFinity and switch to CNN. At the bottom: “Boston Bombing Suspects Captured.” People were screaming and shouting on TV, some presumptuous ones yelling “U S A” as if it were that same day when another terrorist was put to justice. While we didn’t know anything now, there was one thing we did -know. It was over.
    I take my first breath in a long time. I first feel elated, and think of how lucky I was to not have been hurt both times, but then a more somber thought enters my mind as my thoughts turn to those who were not.
    By the time I am done and leave the Koch Institute, it is dark outside. I take a breath of the spring air. I see MIT Students and other people walking from one dorm to another, backpacks full again with textbooks. I see lone American flag stuck in a patch of dirt between Building 32 and 76, a faded teddy bear placed carefully at its feet, a white sign taped to its arms: “With memories from your friends in Wilmington.” I see patrons at the supermarket giving strangers knowing smiles and parents holding their child a little closer. I see the guardian Orion, watching us from the clear night sky and I am reminded of all the acts of heroism that are the stuff of legend. 
    People running to the scene to dismantle barricades immediately after the explosions. 
    Carlos Arredondo holding shut Jeff Bauman’s artery as he was rushed to an ambulance on that rickety wheelchair. 
    Hordes of marathoners racing to Massachusetts General Hospital to donate blood.
    People donating their homes and air miles to strangers so they could get away from the carnage. 
    One lone officer sitting in a police car, talking to two strangers at MIT, not knowing the chain of events about to unfold.
    Despite all the horror we had experienced, the strength of Boston found a way through these dark times. We have been changed. Our normal has shifted. But I will remember one sight that gives me a ray of hope. 
    It was the day after the bombings and silence had filled the city and the halls of MIT. I was walking back from St Cecilia’s, crossing the Massachusetts Avenue Bridge to go in to work. 
    I saw people running.

Thursday, 19 January 2012

New Research: The Evolution of Multicellularity

We are all multicellular. That is, our bodies are made up of many cells that function in a synergistic manner to create a unified whole, somewhat like how we have millions of people that function to create the ‘organism’ Canada or France. From one fertilized egg cell, we developed all the amazing coterie of cells like nerve cells, blood cells, muscle cells, etc.
Many years ago, life began as a unicellular state, like your average bacteria that lives in your gut. At some point, these unicellular organisms acquired changes that lead to a multicellular state and this was a very critical step in our evolution. With multicellularity, one can have cells that do different things like fight infection or transmit electrical signals (a necessity for cognition).

How did this transition occur? Multicellularity occurred >200 million years ago, at least 25 separate times. Scientists have found that several steps must have been needed. Firstly, the unicellular organisms must gain the ability to form simple clusters of cells. Next, the multicellular state must somehow become favored (or selected for), in comparison to the unicellular state. Finally, the cells will begin to specialize to different things within that organism.

It has long been thought that these steps will take a very long time, yet in this paper, William Ratcliffe shows that it can actually evolve in a very short time. They began with simple baker’s yeast and decided to apply pressure to evolve cell clusters. Since ten cells clustered together are heavier than one individual cell, it should settle faster in a tube due to gravity. With this premise, these scientists decided to transfer cells at the bottom of a culture to another culture, let those grow and then settle, then transfer the bottom to another culture, let them grow and settle, etc.
After 60 transfers, they found the yeast cultures were now dominated by a snowflake-like organism, with multiple cells. Moreover, these snowflake-like organisms were genetically stable; one could not detect a conversion back to a unicellular state. This argues that it had indeed evolved into a new organism. These clusters seemed to arise from an inability to separate after cell-division, rather than re-aggregation of split cells.

Even crazier, Ratcliffe found that these yeast-descendants gained classic multicellular traits. For instance, there was a juvenile phase which grew unimpeded and an adult phase which stopped growing when it reached a certain size and then released a smaller copy of themselves (see arrow on right). Since these clusters didn’t grow forever, it suggests there was some communication between the cells in this organism to arrest growth at some size, another classic multicellular trait. Even more interestingly, they found that these cells had evolved to do different things: there were cells that underwent cell suicide to release progeny.

This study is somewhat flawed however in two reasons: one they applied artificial selection pressure; it is hard to imagine alien’s spinning down yeast and then re-inoculating another culture just to evolve multicellular life on earth. Moreover, baker’s yeast evolved from a multicellular ancestor billions of years ago, so one could argue these genes for multicellularity are already present. However since yeast are not multicellular, those genes have probably been lost over the last billion years of not being used.

In conclusion, earlier in this article, I mentioned how 3 steps were needed to generate multicellularity. In this paper, Ratcliffe shows that with the appropriate selection, all three steps could occur within 60 days (or 720 generations), a remarkable discovery. This suggests that the evolution of multicellularity does not actually require a very long time. This further suggests that only a few genes may be involved. The exciting next step would be to find out exactly which genes were altered in that time period to provide clues into how multicellularity may have arisen.


Ratcliffe, WC et al. (2012) Experimental Evolution of Multicellularity. PNAS onlinePaper

Saturday, 14 January 2012

General News: Nobel Prize 2011

This blog is back up and running. For a while, I put it on hold since I was busy helping teach introductory biology, but now that it is over, I am now going to return to working on articles. Many exciting things have happened since so I thought I’d write about two major events that occurred in the last four months.

First, the Nobel Prizes! The 2011 Nobel Prize in Physiology and Medicine were awarded to Bruce Beutler and Jules Hoffmann "for their discoveries concerning the activation of innate immunity" and the late Ralph Steinman, "for his discovery of the dendritic cell and its role in adaptive immunity". This is the first immunology prize since 1996, and so the immunology community is really excited!


Our species is constantly under attack by other microorganisms, which our body defends against using the complex immune system. Mammals have two arms of the immune system, the ancient innate immune response and the more recently-developed adaptive immune response. The innate immune response is the first line of defense, a non-specific response that leads to immune cell recruitment, inflammation and attack of foreign material. The second line of defense is the adaptive immune response, in which the body mounts a more effective, specific attack against the microorganism after studying it for some time. Since this takes time to develop, the innate immune response is critical for immune function.

THE ROAD TO INNATE IMMUNITY
Insects have a relatively short lifespan, so it doesn’t seem apparent that they require a powerful immune system to fight pathogens, yet insects are highly resistant to microbial infection. Yet early inquiries into understanding how this happened lead nowhere, because it turns out insects are unlike humans in that they do not have an adaptive immune response. The first glimpse into this mystery occurred in 1981, when Hans Boman discovered that moths induced the antimicrobial peptides Cecropin and Attacin. By the 90s, several genes encoding these antimicrobial compounds were identified in the Drosophila genome. Yet no one understood what was turning on expression of these antimicrobials, a process that Beutler and Hoffmann coined “the black box.”

They explored the promoters of these antimicrobial genes and found they contained binding sites for something similar to the mammalian NF-kB (discovered by Nobel laureate David Baltimore - from MIT!), which has been linked to immune system activation. Previous work by the Nobel laureate Nusslein-Volhard had found a critical development pathway that set up the axes for dorsoventral establishment, the Toll pathway that ended in Dorsal, a NF-kB-like molecule. Through a long line meandering experiments and wrong leads, Dr Hoffmann eventually discovered a mutant, Toll which was highly susceptible to fungal and bacterial infections, for the first time proving that Toll was somewhat essential in immune responses.

In a parallel line of research, septic shock is a debilitating syndrome that causes multiple-organ failure at the end-stage of a bacterial infection. It was recognized that this was induced by a molecule common to most bacterial cells, LPS. Dr Beutler wanted to try to find the receptor that could bind LPS, so they soon discovered that mice resistant to LPS had a mutation in a gene similar to the Toll gene of the fruit fly. They demonstrated that LPS-binding to the Toll receptor activated inflammation, and when the doses were very high, the organ systems in the body would go into inflammation overload and cause septic shock.

Thus, in the grand picture of things, Bruce Beutler and Jules Hoffmann discovered a set of receptors that we now call the pattern-recognition receptors, which recognize a set of molecules that are broadly found in microorganisms but not humans. They demonstrated that it was a very ancient pathway, conserved from flies to humans. Moreover, in later work, they picked apart the pathway, allowing the development of drugs that can target the innate immune response. Indeed the fundamentalness of this pathway is indeed one reason why these two have been awarded Science's Highest Award.


THE ROAD TO DENDRITIC CELLS AND THE ADAPTIVE IMMUNE RESPONSE
One characteristic of the immune system is its incredible diversity of cells; in fact when Dr Steinmann first entered the field in 1970, it was known as God (for generation of diversity). At the time, clonal selection theory suggested that there was an infinite variety of cells in the immune system, each which recognized one antigen. Binding to a specific antigen caused one specific clone to multiply thousand-fold and promote an immune response against that antigen. This hypothesis was further enriched when Nobelist Susumu Tonegawa (also MIT ) demonstrated that the great diversity of clones was generated through genetic recombination. Yet one problem with the theory was that injection of antigens into animals did not always generate an immune response, an idea which would have critical impacts on vaccine generation.

In 1973, Steinman found that purifications of lymphocytes (mixtures of B and T cells) could not produce antibodies unless they were supplemented with “accessory cells.” Looking under the microscope, he explored the accessory cells and found the usual culprits (macrophages) but also, a weird stellate elongated cell, which he named the dendritic cells. Further studies revealed he only needed to mix 1 dendritic cell per 100 lymphocytes to induce strong clonal selection.

We now know that dendritic cells are the critical link between the innate and adaptive immune response. The innate immune response (which half this year’s Nobel is awarded for ) turns on these dendritic cells, which then go on to activate T cells for priming the adaptive immune response. Indeed, these cells have been so influential that pharmaceutical companies are now trying to develop vaccines using dendritic cells as well as treatments for allergies.

However, it is with great sadness that Dr Ralph Steinman passed away on Friday Sept 30, 3 days shy of him finding out about his Nobel Prize. Dr Steinman was a consummate scientist of the highest caliber and many colleagues value his contributions greatly. In one of his essays, he recalls Palade’s quote “For a scientist, it is a unique experience to live through a period in which his field of endeavor comes to bloom—to be witness to those rare moments when the dawn of understanding finally descends upon what appeared to be confusion only a while ago—to listen to the sound of darkness crumbling.” And indeed Dr Steinman helped clear the darkness.


REFERENCES:
Beutler's Discovery of TLRs
Hoffmann's Discovery of TLRs
Steinman's Discovery of Dendritic Cells

Thursday, 7 July 2011

New Research: No More Pain from Sunburns?

Ah, it's summer again. You're laying on your patio and fall asleep with a martini on the Ikea mini-table beside you. You doze off, dreaming about that Europe backpacking trip that you had planned with your best friend. Suddenly, you wake up and what's this? Your face hurts! Oh darn, you forgot to put on sunscreen and now your face is burning!
Many of us aren't strangers to sunburns. The characteristic red burning sensation when we've overstayed our time in the sun is a type of inflammation. Inflammation is a component of the many responses to harmful agents, including germs as well as damaged cells. Typically, the process involves the recruitment of immune cells, which destroy damaged tissue as well as germs, in an effort to promote healing. During inflammation, our pain-receptors become sensitized due to chemicals that are released from the white blood cells. Sunlight contains harmful ultraviolet B (UVB) rays, which promotes hypersensitivity to pain 24-48 hrs after exposure. In addition, UVB can cause dangerous mutations in your DNA leading to skin cancer, which is why sunscreen is very important.

John Dawes of Stephen McMahon's lab decided to study this inflammation response towards UVB. After exposing human and rat skin to UVB rays, they found both increased blood flow to the skin as well as the subject's pain thresholds dropping substantially. An analysis of genes that were turned on after UVB irradiation revealed that humans and mice share a similar response towards UVB damage. In addition, the gene that changed the most was a poorly-studied chemokine (chemicals that modulate the immune system) called CXCL5.

CXCL5 has previously been linked with certain chronic pain syndromes, so it looked like an interesting gene. They injected the CXCL5 protein directly into rat feet and saw that they were more susceptible to pain. In addition, they found that CXCL5 could attract white blood cells towards it, similar to a magnet pulling on metal. The cool thing was that blocking the action of CXCL5 raised the pain threshold after UVB treatment, so rats felt less pain in an artificial sunburn. In addition, there was less white blood cells being attracted to the site of injury.

Altogether, this study has found an interesting gene CXCL5 that is associated with the pain in sunburns. Drug companies are now considering developing a sunburn pain remedy that would contain a drug that specifically blocks CXCL5. However, one caveat is that less white blood cells will be attracted to the sunburn site, so one might get delayed healing of the damaged skin.


Dawes, J., et al. (2011) CXCL5 Mediates UVB Irradiation–Induced Pain. Science Translational Medicine 3(90):90ra60. Paper.

Wednesday, 6 July 2011

New Research: A Link between Cholesterol Metabolism and Lysosome Synthesis

In the immediately previous blog entry, we discussed how proteins are targeted to specific locations in the cell via zip-codes. One location is the lysosome, which functions as a recycling unit, containing enzymes that break apart portions of the cell marked for destruction. The lysosomal enzymes are brought to the lysosome using a specific zip-code, a chemical addition called mannose 6-phosphate (M6P).

One of the two proteins that adds M6P is made of two parts made from the same gene GNPTAB. Initially, a large premature protein is initially made, but it gets chopped into two pieces. Afterwards, the two products combine to form the functional M6P-adding enzyme. Patients with a disease called mucolipidosis II have mutations that prevents proper formation of the enzyme that adds M6P, leading to defective lysosomes and an inability to breakdown damaged portions of a cell. Ultimately, this leads to skeletal abnormalities and mental retardation, similar to Tays-Sachs disease which is also a disease of defective lysosomes.

Katrin Marschner of the Pohl lab wanted to find out what was the protein that caused the chopping of the premature protein. She found that a crucial part of the cleavage site was similar to the sites cut by the protein S1P. Further experiments revealed that S1P could also cleave the precursor to M6P-adding enzyme, creating a mature protein. Both mice with mutations in S1P and mice with mutations in M6P-adding enzyme had similar characteristics, such as defects in cartilage formation. Similar to when a pipe gets clogged, S1P-deficient cells had prominent accumulation of materials, further suggesting that S1P cleaves the M6P-adding enzyme.

S1P also known to be essential for regulating the body's cholesterol levels. At high levels of cholesterol, a molecular switch called SREBP gets anchored to the inside of the cell. However when cholesterol levels are low, S1P cuts off the anchor, freeing SREBP and allowing it to go to the nucleus where it turn on genes that make cholesterol.

As a result, drug companies have been investing money to find chemicals that can block S1P as a way to treat high blood cholesterol. Without S1P, SREBP cannot reach the nucleus and cholesterol is no longer made. However, this study suggests that such drugs would have the unwanted side effect of blocking proper lysosome function. This would lead to accumulation of garbage in the cell, something that is linked also to Alzheimer's and Parkinson's disease.


Marschner, K., et al (2011). A Key Enzyme in the Biogenesis of Lysosomes is a Protease that Regulates Cholesterol Metabolism. Science 33(6038):87-90. Paper

Monday, 4 July 2011

New Research: Nuclear Import of Membrane Proteins

All the cells in the body are made up of different components called organelles. For example, lysosomes recycle components of the cells, the mitochondria generate energy and the nucleus is not only stores the chemical blueprint of life (DNA), it also makes the executive decision of whether to turn genes on and off. Many of these organelles are separated from each other by barriers called membranes. Between all these organelles, proteins are being passed back and forth to different compartments through specific gates.

The nucleus has many gates called the nuclear pore complex (NPC) that regulate what can move across the nuclear membrane. Think of it as a filter; very small molecules can go through whereas large molecules normally cannot. However, the NPC has the ability to recognize a specific instruction on larger molecules called a zip-code. Think of zip-codes as a one-pass key; if a large molecule has a zip-code code for entry, it will be permitted to pass through the gate into the nucleus, but not back out unless it has the zip-code for exit.

We don't quite understand how proteins are moved across the nuclear membrane. Even more puzzling is this. The nuclear membrane actually has two-membranes bridged by the gates. There are proteins embedded in both the inner membrane and the outer membrane, yet it is not well understood how proteins are moved from the outer membrane into the inner membrane.

Anna Meinema from the Veenhoff lab explored this process for a specific inner membrane protein Heh2. She found that the transport of Heh2 into the nucleus depended on how well its zip-code could bind a protein called the karyopherin-α/β1 complex. karyopherin-α/β1 is somewhat like a parent that holds onto a kid as it crosses the street. In the nucleus, it holds onto proteins with nuclear zip-codes and carries it across the nuclear membrane.

She also found something remarkable. Proteins usually have a rigid structure, allowing them to interact with other molecules in specific orientations. However Heh2 transport depended on the presence of an unstructured region in the protein. Not only that, the unstructured region had to be of a sufficient length.

After further studies, she found how Heh2 was being transported across the nuclear membrane (see figure above). Before it crosses the membrane into the nucleus, the nuclear zip-code (NLS) gets bound to the karyopherin-α/β1 complex, which pulls the Heh2 across the nuclear membrane like a parental chaperone. However the NPC is a molecular sieve, with fibers (FG-Nups in the figure) that can block transport. To overcome this, Heh2 has unstructured regions which allows it to change shape for ease of passage through the fibers. After crossing the membrane, karyopherin-α/β1 releases the inner membrane protein Heh2.

Understanding nuclear import is important for several reasons. Firstly, the switches and signals that turn on genes often need to be transported into the nucleus. Secondly, viruses often hitchhike on the nuclear import machinery to be able to hijack the nucleus and produce hundreds of copies of itself. By studying this process, one day we may be able to design drugs to prevent entry of those signals or viruses during diseases.


Meinema, A., et al. (2011). Long Unfolded Linkers Facilitate Membrane Protein Import Through the Nuclear Pore Complex. Science 333(6038): 90-93. Paper.