Tuesday, November 18, 2014

Molecular Artistry: Irving Geis shed light on an unseen world

The atrium of the Parker H. Petit Institute for Bioengineering and Bioscience was swarmed by hundreds of guests on Saturday, October 18, for the BUZZ on Biotechnology, an annual outreach event geared toward teenaged students, an interactive open house to inspire future scientists, and maybe generate a little interest in attending the Georgia Institute of Technology.

The kids took part in a bunch of hands-on experiments, many of which are designed to teach something about biology at the molecular level. They went from demonstration table to demonstration table, building edible cells out of candy or extracting DNA from peas, unaware that all around them, hanging on the atrium walls, are some of the most influential images ever made of molecular biology. This is the art of Irving Geis, whose 116th birthday also happened to be October 18, a former Georgia Tech student who did more for myoglobin’s street cred than anyone before him.

Geis, who died in 1997, was a pioneer whose seminal, oft-reproduced painting of a sperm whale myoglobin molecule for Scientific American in 1961 basically launched the field of molecular illustration, an artist whose complex and colorful depictions of an unseen living world have helped inspire and enlighten generations of students and scientists.

“We all knew about Irving Geis,” says Sheldon May, a biochemistry professor who helped start the Petit Institute and led the effort to bring Geis’s work to the atrium shortly after the building opened 15 years ago. “Anyone who taught biochemistry used his illustrations. He was an amazing artist, strongly influenced by Da Vinci, and he did it all in a time before computer graphics.”

Geis, born in New York City in 1908, moved to Anderson, South Carolina, as a kid. He thought he wanted to be an architect, so he attended Georgia Tech from 1925 to 1927 with that in mind.  He didn’t graduate from Tech, but his experience in Atlanta obviously left an impression, according to his daughter.

“My father couldn’t carry a tune and almost never sang, but he taught me the song, I’m a Ramblin’ Wreck from Georgia Tech, when I was six years old,” says Sandy Geis. “It was my favorite thing to sing. Can you imagine? A six-year-old kid singing, ‘a hell of an engineer’ at the top of her lungs.”

Geis may have enjoyed his time at Tech, but he just wasn’t bound to be an architect, and went on to earn a Bachelor of Fine Arts at the University of Pennsylvania (1929) and after earning a degree in design and painting from the University of South Carolina in 1933 he moved back to New York to work as a freelance illustrator. He did a lot of work for Fortune magazine, including a drawing of the circulatory system that marked his venture into scientific illustration. “He was very proud of that. It really jumpstarted his interest in biology,” Sandy Geis says.

During World War II, Geis worked as chief of the graphics section of the Office of Strategic Services (OSS, the predecessor of the CIA) and later as art director for the Office of War Information. Following the war and for the rest of his life he worked as a freelance artist, and from 1948 on he shaped the genre of scientific illustration. That was the year he started contributing to Scientific American, where he produced some of the most iconic images of scientific illustration, the most famous in 1961.

“The myoglobin painting was a landmark in his career, and in science. It was really the first illustration of the molecular world,” says Sandy Geis, whose father typically spent a few weeks on a project – learning the subject, talking with the scientist writing the article he was dressing up, and producing an illustration. But the myoglobin watercolor painting took six months, because it takes a while to break new ground.

“There was always a back and forth dialogue with the authors, the scientists,” Sandy Geis says. “Between his photographs, and sketches, and the constant dialogue, he was able to elucidate whatever they said. It was a complicated process, and my father was such a perfectionist.”

The myoglobin illustration accompanied the article by British biochemist John Kendrew, who described the structure of myoglobin, a protein found in muscle tissue, and recruited Geis to convert his physical models of myoglobin into a painting. It became the first molecule that most people ever actually saw.

“He was the preeminent molecular illustrator,” says May. “He used art to beautifully demonstrate the structure and function of molecules.”

The myoglobin painting increased demand in Geis’s talents. From 1963 until his death he illustrated a number of major books on biochemistry and molecular biology, including three that he co-authored with Richard Dickerson, the UCLA biochemistry professor, who had worked with Kendrew on solving the first high-resolution x-ray crystal structure of myoglobin in 1958.

“It was never clear whether Irv illustrated my books, or I wrote Irv’s captions,” Dickerson wrote in the journal Protein Science in 1997, following Geis’s death. “In the end, it didn’t matter; together we could do more than either could have done alone.”

According to Dickerson, his co-author’s genius wasn’t in depicting a protein exactly how it looked, but drawing it in a such a way that showed how the molecule worked, an artistic process that Geis called, ‘selective lying.’ Geis, wrote Dickerson, “was very taken with the importance of using art to put across scientific concepts.”

Geis also illustrated several editions of the Biochemistry, a nearly ubiquitous textbook that Georgia Tech scientists like May and Loren Williams are very familiar with.

“I’d loved his work for years, but at first, I didn’t know he went to Georgia Tech, until I found a copy of his obituary,” says Williams, a biochemist who discussed with May the idea of bringing Geis’s work to the Petit Institute building, which opened in 1999.

May reached out to Sandy Geis, “called her out of the blue,” he says. Around the same time, the Howard Hughes Medical Institute was working on acquiring the Geis archives, but May called first, “and one thing led to another. She was very happy that we were doing something to perpetuate her father’s contribution to science.”

Sandy Geis happily donated the illustrations that hang on the atrium walls, three floors up. She hopes his work will continue to inspire scientists, as it has for generations.

“I’m glad that his work is displayed at Georgia Tech,” she says. “Because his passion was to teach, really, to influence as many scientists and students of science through the generations. And that’s what he did. Two Nobel Prize winners told me personally that the books by Dickerson and Geis were a big influence for them.”

Shortly after Georgia Tech acquired the artwork in 2000, the Howard Hughes Medical Institute purchased the Geis Archives, which includes art as well as correspondence and private journals. But the dozen Geis pieces in the atrium are rare treasures (even without the 1961 myoglobin piece) that helped have given the Petit building a sense of colorful equilibrium. The molecular art serves as a fitting offset to the massive Cell Wall, the nine-piece, 12 foot by 24 foot painting by artist Karen Stoutsenberger Ku (typically is one of the first things anyone notices when they enter the Petit Institute atrium).

“When we moved into the building, the Cell Wall was all there,” May says. “But we, the biochemists, were thinking, ‘what can we do from an artistic point of view?’ The engineers at the time were all cellular oriented, and we were very molecular oriented. We wondered what we could do from a visual point of view to play up the fact that this institute brings together the molecular and the cellular, the science and the engineering. And we remembered those illustrations from the Biochemistry textbook. Of course! Irving Geis!”

In his lifetime, Geis evolved to the point where, especially in his later years, he was an occasional scientific lecturer. It was easy for the casual student of the visual arts to confuse him as some kind of molecular scientist.

“My father understood the science, and he understood scientists,” Sandy Geis says. “He could speak their language – he was an interpreter of their language. But first and foremost, he was always an artist.”

Friday, September 19, 2014

Something Stupid About Being Stupid

Here in the 21st century social media culture, where everyone has their own personal sounding board (you know, like this blog), where empathy has given way to self-absorption, where conscience has given way to trendiness, where the fervent desperation for immediate and constant attention is worn on our cyber sleeves (i.e., "status updates"), leading to an overabundance of pixelated crazy (and occasionally useful and interesting -- you know, like this blog) shit floating all around us, it is nice to know that it is OK to be stupid ... as long as we are productively stupid. That's the essence of a 2008 essay by Martin Schwartz in the Journal of Cell Science.

"Productive stupidity means being ignorant by choice," writes Schwartz (a former University of Virginia professor who is now at Yale) in his essay, entitled The importance of stupidity in scientific research, which I found hanging on the office door of the eminently cool Tom Barker (and here: http://jcs.biologists.org/content/121/11/1771.full), a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech.

"In science," Barker told me, "if you know all of the answers already then you're in the wrong place." But his contention and Schwartz's welcome message apply to almost any field involving research and researchers, like writing, and especially journalism.

I've always loved research, so I've got lots of experience with stupidity, as Schwartz defines it. And since I don't embarrass easily, I've not been particularly shy about letting the countless sources I've bothered know just how stupid I am (a trait that I share with many journalists). A question I've gotten a million times from sources is, "what's your story about?" My typical stock answer: "I don't know. Haven't written it yet." Usually followed by: "I'll know more after talking with you. That's why I'm talking with you."

I might have some ideas, an angle I'd like to pursue, and specific questions that need answers. But if I'm just seeking answers to support my preconceived notions, then I'm not really doing research -- I'm looking to justify my point of view, which is limited by my preconceived notions. I'm not talking about being objective (a bullshit unattainable dream, considering we're humans). I'm talking about honest discovery. Self-gratifying justification is not the same as discovery, which is a place I can't arrive at unless I begin with stupidity (a condition which comes surprisingly easy to me).

But for some researchers with untamed egos -- scientists, journalists, whoever -- this place of ignorance is repugnant, hellish, embarrassing proof that their shit does not, in fact, smell like blueberry muffins. To them I say, get over it. You were born stupid. We all were, even Einstein. Of course, this truth can be really difficult for smart people who can't remember ever being stupid, who are accustomed to knowing a lot of stuff, and getting a lot of answers right.

"No doubt, reasonable levels of confidence and emotional resilience help," writes Schwartz, who believes that education (science education in particular, but to my mind, any education, institutional or otherwise), can do more to ease the transition from learning the obvious, or knowing the known, to making our own discoveries. "The more comfortable we become with being stupid, the deeper we will wade into the unknown and the more likely we are to make big discoveries."

Now that's something that I can wrap my stupid head around.

Wednesday, August 13, 2014

(En)lighten up: The biology of depression

The sad thing about depression (besides the fact that is is depressing), is most people (even people with clinical depression) don't give a damn about this particular disease, until someone like Robin Williams takes the fast and horrible way out. 

We will mourn the loss of an influential person, a great artist like Williams, and then tune into our next flavor of the day, and the hands of time keep spinning while the list of quiet casualties (i.e., the not famous, living their lives of quiet desperation - thank you, Mr. Thoreau) keeps rising. And by casualties, I don't necessarily mean suicides. For people who have struggled with a major bout of depression, it can be a pretty serious wound by itself, with plenty of side effects. 

Taking the "lighten the hell up" approach doesn't usually work. But this isn't about eliciting cheap and temporary sympathy for these folks (most of whom lead the most ordinary of lives, content the great majority of the time). It's about awareness, and understanding a widespread issue (and maybe supporting whatever measures and efforts there are to reduce the bad shit). 

Since the news broke about Williams' suicide, the responses have run the gamut from one extreme to another, from criticism that he took the coward's way out, to the deepest sympathy. Personally, having faced the D-demon myself, I fall into the latter category. I certainly can't empathize with a person who was as globally beloved as Robin Williams, but can definitely understand the problem of facing the dark defenseless and hopeless. 

Depression is a complex thing. It isn't a case of the blues, not just that. Nor is it exactly like addiction, as some cyber-therapists have alleged -- admit you have a problem and deal with it, damn it ... go to a 12-step program! The thing is, as with most disease, of course you have to admit a problem and deal with it, otherwise, the disease generally wins. Like with cancer or diabetes or so many other things. 

With that in mind -- the squishy nexus of biology and depression -- here's a link that might help you better understand the biology behind depression: http://well.wvu.edu/articles/the_biology_of_depression

There's also this: http://www.allaboutdepression.com/cau_02.html

This also is really interesting: http://www.yalescientific.org/2011/02/uncovering-the-biology-of-depression/


Some of what we know is, at least 15 million adults in the U.S. suffer from a major depressive disorder in a given year; people with depression are four times as likely to develop a heart attack than those without a history of the illness (and after a heart attack, they are at a significantly increased risk of death or second heart attack); there is a high prevalence of depression that co-occurs with other illnesses (cancer, AIDS, Parkinson's); major depressive disorder is the leading cause of disability in the U.S. for ages 15-44 (and the leading cause of disability worldwide among persons five and older -- FIVE!!??); depression ranks among the top three workplace issues, following only family crisis and stress (which often lead to depression ... such a vicious cycle); its annual toll on U.S. businesses amounts to about $70 billion in medical expenditures, lost productivity and other costs; oh, and there are more than 30,000 suicides in the U.S. each year, at least two thirds of them caused by major depression (Robin Williams, hello!). 

The good news is, about 80 percent of those treated for depression show an improvement in their symptoms generally within four to six weeks of beginning medication, psychotherapy, attending support groups or a combination of these; but here's the thing: Despite its high treatment success rate, nearly two out of three people suffering with depression do not actively seek nor receive proper treatment and an estimated 50% of unsuccessful treatment, or non-treatment for depression is due to medical non-compliance (including financial factors). 

Meanwhile, smart people are working on the problem. Here's something about research that Georgia Tech is involved in:  http://news.emory.edu/stories/2014/04/precise_brain_mapping_improves_response_to_dbs/


The bottom line is, most folks haven't read this far because, quite honestly, depression isn't sexy (as opposed to liver disease and ribosomes and molecular biology and the other sexy stuff you're used to reading on this blog). Most folks just don't care, and they won't, until someone like Robin Williams takes himself out (to wit, this blog entry), and even then, most folks  are typically wired to a 24-hour news cycle, in which today's celebrity suicide gives way to tomorrow's new shiny thing. 

Good luck out there, be kind to each other. The world will keep spinning either way, at least for another four billion years or so. How it spins and how nice the ride is for the humans tethered to the big blue ball depends on the lot of us.


P.S. Here's a blog post by yours truly, of a more personal (and hopefully helpful) nature: http://fourcrickets.wordpress.com/2014/08/13/this-one-got-to-me/




Monday, August 11, 2014

Holy Grail: Getting closer to an HIV cure


This is the one. This is the project that Phil Santangelo will be talking about when he’s 80 and retired and rocking on the front porch, in some distant future – a promising, healthier future for mankind because, well, this is the one.

Santangelo, associate professor in the Wallace H. Coulter Department of Biomedical Engineering at the Georgia Institute of Technology, is helping lead a research team that was recently awarded a $5.5 million grant from the NIH/NIAID (National Institute of Allergy and Infectious Diseases) for their role in a national, multipronged effort to once and for all cure HIV/AIDS.

“This is like the Holy Grail for a molecular imaging person who’s interested in infectious disease. From my point of view, this is it, this is huge,” says Santangelo, who is partnering with Emory’s Francois Villinger as principal investigators on the research, supported by the aforementioned R01 (which is the original and historically oldest grant mechanism used by the National Institutes of Health, or NIH).

The prospect of eliminating HIV from infected patients may be achievable with novel anti-retroviral therapies, but it would require new tools with greater sensitivity than what is now available. So the research aims to create and improve imaging technology to better monitor HIV reservoirs, the thought being that if you attack these elusive reservoirs, you can stop HIV. Santangelo says a finish line is in sight. Almost.

Here's the dilemma. A person who's infected with the HIV virus is treated with anti-retroviral drugs. They appear to work. Within a month, the virus is undetectable in the blood stream. It's been suppressed. But if you take the patient off the drugs, the virus comes back. It rebounds. "The drugs work but they are not sufficient to clear the virus. And really, we don't know why that is yet," Santangelo says. "Where is the virus? Where are the active reservoirs during suppression?"

The prospect of eliminating HIV from infected patients could be close at hand, but such a lofty goal will require new tools with greater sensitivity than currently available to monitor the progress of novel anti-retroviral therapies – not only in blood but also in organs that harbor such reservoirs and sites of residual viral replication in vivo.

“We’re not necessarily in this project, quote, creating the cure. But we’re creating a tool that’s going to give us a lot more information about how you might go about doing that,” Santangelo says. “Otherwise, it’s a shot in the dark, you’re just trying different approaches.  It’s trial and error. In the drug development world, trial and error is useful, but not ideal, and certainly not efficient”

This research and resulting improvements in imaging technology, he says, will eventually give drug developers more information than they’ve had before, about how drugs are affecting very specific parts of the body.

“It’s about giving them much more powerful information about what’s happening, as opposed to downstream information,” says Santangelo, whose research areas include molecular imaging, nano-biophotonics, and optical microscopy. The long-term aim is to cure HIV, he adds, “and we’re working on a tool to help facilitate that.”

And that, he adds, is the reason the research got its funding – the NIH wants this tool in its toolbox. The grant covers five years, but it’s been a seven-year journey to this point. It began with a discussion between Santangelo and Emory professor Eric Hunter, whose research is focused on the molecular biology of HIV and other retroviruses.

“We were sitting around a table and Eric basically said, ‘one thing we’d like to know is, where is the virus? Is there a way to image this?’ I said, ‘I have no idea, but let’s see if we can figure that out.’ So I went back to the drawing board and thought about ways to approach the problem,” Santangelo says. “But that’s how it started – a group of people sitting around the table, asking, ‘how do we address this?’ and me being crazy enough to say, ‘I’ll try this,’ because I don’t say no to anything.”

Hunter introduced Santangelo to researcher/pathologist Villinger. They went after and received a $30,000 boost from the Woodruff Foundation, then got $100,000 from the Georgia Research Alliance, “and these were so important in pushing the momentum forward,” Santangelo says.

Then they received $450,000 from the NIH in the form of an Exploratory/Developmental Research Grant Award (R21) and now, $5.5 million, to support the work of an all-star team of researchers, including (among others) principal investigators Santangelo and Villinger, as well as Ray Schinazi, who directs the Laboratory of Biochemical Pharmacology at Emory, who is a co-investigator.

The overall goal, according to Santangelo, is to create or improve an imaging tool that will determine how the virus is being affected by a new drug strategy, and also to help promote new drugs that Schinazi is working on – “to clear HIV, and also to make current drugs more effective,” says Santangelo, who believes that by enhancing current imaging technology, particularly CT (computed tomography, or CAT scanning) and PET (positron emission tomography), he can track the reservoirs, including active viral reservoirs.

“If you can figure out where the reservoirs are, if you can figure out how long they are being affected by the drugs, and how the drugs are actually changing the reservoirs, we might be able to clear them,” says Santangelo, who looks like a kid contemplating a super toy that hasn’t been invented yet. “And if you can clear these reservoirs, you could cure AIDS, and if you can cure AIDS, well, that would be pretty awesome.”

Monday, August 4, 2014

Seeds of Innovation

Three interdisciplinary teams with wide-ranging goals at the Parker H. Petit Institute for Bioengineering and Bioscience have gotten off to a fast start on pioneering explorations in biotechnology, thanks to a homegrown program that supports innovative early-stage research.

The winning teams of the 2014 Petit Bioengineering and Bioscience Collaborative Seed Grant are working to improve the prediction of disease (Hang Lu and Patrick McGrath), design better drug delivery strategies to fight cancer (M.G. Finn and Susan Thomas), and unveil (and better understand) the processes through which cell receptor signaling is initiated (Robert Dickson and Cheng Zhu).

Each of these fledgling collaborative teams was awarded $100,000 for two years to kick-start new research en route to long-range aspirations.

“The seed grant program is fantastic, because it supports bold ideas that don’t have preliminary data,” says Lu, a professor in the School of Chemical and Biomolecular Engineering. “Patrick and I have been wanting to work on this particular idea of evolving model systems to study multigenic diseases. We are extremely happy to have the support to pursue it now. We’re hoping to garner preliminary data to seek NIH funding in the long run.”

The program, now in its third year, gets to the heart of the Petit Institute mission, as it encourages a multidisciplinary approach to cutting-edge research, with each team bringing together an engineer and a scientist in a collaborative research endeavor, addressing complex biotech challenges by combining the distinct strengths of each lab. For example, as Lu and McGrath (assistant professor in the School of Biology) explain in their proposal, “Technologically and conceptually, what we propose here has never been done before. This pilot is truly enabled by the genomics know-how of the McGrath lab and the technological advancement of the Lu lab, which is a unique combination not found elsewhere.”

By applying a directed evolutionary approach, they expect to eventually be able to identify interacting genes that can be used as biomarkers for lifespan and age-related diseases, “and also as synergistic drug targets that can be used to ameliorate side-effects by lowering dose-levels of pharmaceuticals.”

Zhu, professor in the Wallace H. Coulter Department of Biomedical Engineering, he and Dickson, professor in the School of Chemistry and Biochemistry), are “trying to develop methods that allow in situ measurements of protein-protein interactions in live cells,” says Zhu. “The lacking of such methods hinders the development of a broad field in biology.” Currently, no method allows this kind of crucial measurement, Zhu and Dickson say in their proposal.

Meanwhile, Finn (professor and chair in the School of Chemistry and Biochemistry) and Thomas (assistant professor in the George W. Woodruff School of Mechanical Engineering) are working on a project with what they say will ultimately “impact the drug delivery field by introducing a new chemical means to temporally control drug release,” according to their proposal.

“In some ways, this approach runs counter to the prevailing drive in the field toward ever more sophisticated ways to respond to environmental cues,” the researchers say, adding, “While such technologies are undoubtedly valuable, there is also value in a cleavage mechanism that one can use like an alarm clock.” Stretching the analogy a bit further, they describe an alarm clock in which the start and end times, and intensity (and composition of the alarm) are all programmable.

“Results from this study,” Finn and Thomas say in their proposal, “will form the basis of numerous collaborative grant applications and a long-term collaboration between two labs with distinct but synergistic expertise aimed towards the design and effective drug delivery strategies for cancer therapy.”

Funding for the seed grants comes mainly from the Petit Institute’s endowment as well as contributions from the College of Sciences and the College of Engineering. Each research team receives $50,000 a year for two years, with the second year of funding contingent on submission of an external collaborative grant proposal.

Monday, July 28, 2014

Altered States: Study offers new hope for people with sickle cell disease

Ed Botchwey is not a hematologist. He’s very clear about that. Botchwey runs a tissue-engineering lab at the Parker H. Petit Institute for Bioengineering and Bioscience, with a focus on regenerative medicine.

That’s been his professional history – tissue engineering and regenerative medicine. But there’s a piece of personal history that carries a bit more influence, and that, perhaps more than anything else, is what led Botchwey and his research team to publish in the journal Blood, the most cited peer-reviewed publication in the field of hematology.

Their research and paper, with the running title, “Sphingolipid Metabolism in Sickle Cell Disease,” represents a sharp turn for Botchwey and his colleagues, who shed new light on causes for some of the disease’s pervasive and devastating symptoms, while offering new hope for patients who struggle with the disease, people like his sister.

“As it turns out, my sister has sickle cell disease, and I have a student, the first author of this paper, Anthony Awojoodu – his sister has it. So this is something we felt very passionate about,” says Botchwey, associate professor in the Wallace H. Coulter Department of Biomedical Engineering (Coulter Department), who didn’t set out to research sickle cell disease (SCD). It just sort of happened. He was just following a logical trail of research.

“We’d been looking at certain classes of signaling lipids and how they regulate inflammation. Part of our goal was, and still is, exploiting certain inflammatory responses to help in tissue regeneration,” Botchwey says. “But along the way, we recognized that some of the enzymes that are central components in the metabolism and production of these signaling lipids were responsive to stresses in cell membranes.”

Like, for example, the stresses that cause the telltale geometric distortion of red blood cell (RBC) membranes in SCD. It occurred to Botchwey that SCD would make a great model system in which to observe the relationship between membrane stresses, inflammation and the metabolism of these sphingolipids. Turns out, there’s a very close relationship.

Their findings reveal for the first time that sphingolipid metabolism is indeed dysregulated, or altered in SCD. Membrane stresses associated with SCD activate sphingomyelinase (SMase), an enzyme that contributes to progression of the disease (SMase has been implicated in vascular inflammation). SMase, in concert with other enzymes, also causes elevated production of microparticles, which contribute to what Botchwey calls, “this chronic inflammatory state that underlies so much of the pathology of sickle cell disease.”

What encourages Botchwey is the research also illuminates potential new strategies to regulate inflammation through modulating sphingolipid metabolism – results that may also be applicable to other red blood cell disorders, not just SCD. What’s more, a promising therapeutic solution is already close at hand – the antidepressant, amitriptyline.

“We wanted to know, can you pharmacologically inhibit SMase in order to reduce these pro-inflammatory microparticles. And we found that, in fact, we can, and we’re excited about it. If you can cut off one of the primary means whereby sickled red blood cells are perpetuating a chronic inflammatory state in the patient, then you may be cutting off a wide range of the disease consequences associated with SCD,” says Botchwey. “Amytriptyline happened to factor quite highly in our survey of potential inhibitors of SMase. You can find certain papers that will make an indirect association to what we’ve shown.”

Sure enough, there are 30-plus year-old research papers that explore the inhibitive effects of tricyclic antidepressants on SMase in various contexts, and Botchwey’s team connected the complicated dots. But there has been next to no research on the role of SMase and sphingolipid dysregulation in SCD (a disease that affects millions worldwide), and that surprises Botchwey.

“It’s a mystery to me.” says Botchwey. “When you think about a disease as prevalent as this one, as well understood as it is, in terms of what the underlying genetic mutation is, and you consider all the tools we have at our disposal for correcting such mutations, you would think this would be a curable disease. I’ve lamented the fact that it’s not cured, but never considered that I might be part of the research that might lead to a cure.”

Botchwey, whose work is supported by the NIH and NSF, as well as the Petit Institute and Coulter Department, led a research team that included Awojoodu, a native Nigerian who was responsible for recruiting Petit Scholar, Alicia Lane, to the team.

“They struck up a very productive working and mentoring relationship, and this paper is partly the culmination of that,” says Botchwey, whose collaborators in the study also include Phillip Keegan, Yuying Zhang, Kevin Lynch from the University of Virginia, and BME assistant professor Manu Platt.

Botchwey, not a blood guy, says this research represents a new direction for him, one he might not have taken if he didn’t make the move several years ago from the University of Virginia to the Georgia Institute of Technology, and the Petit Institute.

“Like I said, I’m not a hematology researcher, but the opportunity to take risks resonated with me. It’s a risk to go in new directions, and Georgia Tech enabled me to take that risk,” he says. “The multidisciplinary, interdisciplinary environment here is one in which I felt comfortable asking what I perceived to be a frontier question that impacted a disease I felt passionately about. I don’t know if that would have happened if I’d stayed where I was.”

Friday, July 25, 2014

Reading the Signals: Something about Your Liver



Sometimes, it’s OK to blame the messenger. I’m not referring to me, of course. I’m referring to Notch, which is a what, not a who. Notch is a cell signaling system, a protein, and it exists in all animals, including you.

Notch plays a key role in embryonic development, and in our adult selves it’s responsible for a bunch of different cell differentiation processes, employing the “psst, pass it down,” mode of message delivery. The first molecule in a signal pathway receives the note and activates another molecule, which activates another, and so on, until the last molecule is activated and the cell function is carried out. 

So, they pass along messages, these molecules that comprise Notch. We need Notch. It is important in some vital cell functions, but sometimes those chatty molecules get a little too loud and, quite frankly, need to shut the hell up, because higher level Notch signaling and abnormal activation can lead to bad things, like cancer, or multiple sclerosis. Or, as a group of Georgia Tech researchers found out, loud-mouthed Notch can make a diseased liver even worse.

They found this out using zebrafish with fibrotic livers – livers with lots of scar tissue, a symptom of chronic liver disease. Fibrosis typically result in cirrhosis, which means a loss of liver function, which usually comes with a grim choice between a liver transplant and certain death. Basically, it’s a perfect storm of terrible things that feeds on itself, because sustained fibrosis is like putting handcuffs on hepatocytes (liver cells), inhibiting their ability to regenerate and therefore make a heroic, therapeutic response. 

At it’s essence, this is a communication problem, based on the study, led by Chong Hyun Shin, a really nice scientist from South Korea who runs a lab at the Parker H. Petit Institute for Bioengineering and Biosience at Tech (See her picture? Doesn’t she look nice? She is. And she’s smart. And if you want your pickled liver to ever see the bright side of life again, you should be nice to her if you ever meet her, because her research could, maybe, lead you down that sunny path).

Anyway, Shin and her team studied (among other things) the effects that different levels of signaling have on the regeneration of these hepatocytes. Specifically, they discovered that lower level Notch signaling promotes cell regeneration (which is good), while high levels suppressed it (bad). And they discovered another signaling system, Wnt, plays a key role in managing Notch’s message. Wnt, basically, is the guy at the sound board turning down the bass to give the song some needed equilibrium. In other words, Wnt’s interaction with Notch modulates the therapeutic, regenerative capacity of liver cells: Wnt signals can suppress Notch signals, so basically, when Wnt is loud enough to suppress Notch, hepatocyte regeneration can happen. Heal thyselves, liver cells, heal thyselves!

The data, says Shin, “suggest an essential interplay between Wnt and Notch signaling during hepatocyte regeneration in the fibrotic liver, providing legitimate therapeutic strategies for chronic liver failure … ” And there’s the hopeful news for you and your abused liver.
 
Their findings were published recently in the journal Hepatology, so grab a copy from the magazine rack. I think there’s also a feature story on how the interaction of tequila with some Mexican foods makes your liver do a salsa dance, along with recipes, Q&A’s, and advice from some of the most popular and sexy celebrity scientists working in the field. Or something.

Bottom line, I guess, is that Shin’s study offers an opportunity to balance some of the fundamental drawbacks in stem cell therapy, while opening up new avenues of cellular regeneration therapy, endogenously – inside of you, in other words, which, if you think about it, takes us to a whole new frontier in the locally grown movement. But I wouldn’t start shopping for new, organic human livers at the farmer’s market any time soon.