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.”

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.

Astrobiology and Looking Way, Way Back

From now on, whenever I grab a cup of coffee at le Petit Café, I’m going to give silent thanks to Loren Williams for his persistent badgering about 20 years ago, when he was part of the committee that planned the building I work in, home of the Parker H. Petit Institute of Bioengineering and Bioscience.

 

“Every meeting I’d say, ‘I want a coffee shop.’ They were talking about designing bathrooms, labs, offices, and I kept saying that I wanted a coffee shop. I’m from Seattle,” says Williams, who kept hammering away at the committee’s leader, Bob Nerem (founding director of the Petit Institute). “Finally Bob said, ‘If you shut up, we’ll get a coffee shop.’”

 

Williams is a chemist who calls himself an ‘astrobiologist,’ which is one of those professions that hasn’t quite been fully realized yet, like ‘time traveller.’ Come to think of it, he’s kind of a time traveller, too. 

 

“An astrobiologist, generally, is somebody who studies life in the whole universe,” says Williams, who directs the NASA-funded Center for Ribosomal Origins and Evolution (Ribo Evo) at Georgia Tech. “Part of that is trying to determine if there is life beyond Earth, and part of that is trying to understand the organic chemistry within our solar system, in space.”

 

In considering the possibility of extraterrestrial life, and looking for the cosmic chemistry that may herald such life, Williams and his team are peeling away billions of years of evolution to understand prebiotic processes of Earth.

 

“Our primary focus is on understanding life on the ancient Earth, and we’re looking all the way back, four billion years,” says Williams, who thinks of it as rewinding the tape of life. Instead of cutting into an old tree to read about the climate 200 years ago, his lab uses the ribosome to study ancient biology, or pre-biology. The ribosome is the oldest macromolecular assembly of extant life, a molecular fossil imprinted with clues from the dawn of existence.

 

“Part of NASA’s mandate is to study the Earth, the history and the future of life, its part of their job,” Williams says. “If we want to know what to look for on Mars or Titan or another place, the ancient Earth serves as a good proxy.”

 

Maybe it’s fitting that a guy who looks back into prehistory for clues about life’s origins (and hints for what to look for on distant worlds) should have one of the most prehistoric-looking websites on the Georgia Tech campus. Looks can be deceiving. This is a case of ugly duck syndrome gone amok. 

 

His site, http://ww2.chemistry.gatech.edu/~williams/, is a cyber relic, a homely homemade site that Williams created in 1992, and he hasn't updated the look since, writing the html code himself. But if you go his site and click the “Molecular Interactions” link, it takes you to the most visited site on the World Wide Web (according to Google) for, well … molecular interactions.

 

Go ahead and do a Google search. You don’t need quote marks. There at the top of 9.9 million search results for molecular interactions is a tool that Williams created, and updates, and has even translated to Spanish to reach a wider audience.

 

“I originally wrote that up for my students and put it on the web, because it seemed like a safe place to have it, and they could have access. Somebody put a counter on my site and wondered why I was getting hundreds of downloads a day. It was that document,” Williams says. “Ten people are reading it at any given time, students all over the world, every day. I swear I didn’t do that on purpose. It just seemed like a good way to organize my stuff and not lose it."

 

So, Williams is a world-renowned scientist in one the world's leading institutes for training engineers, and he'll happily explain the difference between the two professions. 

 

"Engineering and science are two very different things. For example, you'd never want to drive across a bridge built by a physicist," he says. "But if the bridge fell down, and you really want to understand gravity, don't ask an engineer."

Inside the Engineer's Mind

This is from the Parker H. Petit Institute for Bioengineering and Bioscience web site. 
Here's a link: http://ibb.gatech.edu/hg_news/309011
Or, you can read it here:

You know this one: “The optimist sees the glass as half-full and the pessimist sees the glass as half-empty, but the engineer sees a glass that’s twice as big as it needs to be.” It’s an old joke that demonstrates, anecdotally, how engineers think, which is something that Joe LeDoux, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering (BME), has been very interested in.

But, rather than ruin an old joke by explaining the punch line, LeDoux took a more empirical approach to understanding the engineering mind. He designed and taught a course on the subject, then wrote about it. And last month, LeDoux and a group of Georgia Institute of Technology students presented a paper to the American Society for Engineering Education (ASEE) that asks, what is it that makes someone an engineer, and what distinguishes engineers from other professionals?

The paper, written by LeDoux, BME research scientist Alisha Waller, and a trio of undergraduates who actually took the class – Jacquelyn Borinski, Kimberly Height and Elaine McCormick – shares the co-authors’ experience in the course, called “Habits of the Engineering Mind,” taught last year by LeDoux at Oxford University as part of Georgia Tech’s study abroad program.

“Taken with a sense of adventure, I decided to teach a course on a topic that I had been thinking about for some time,” LeDoux writes in the paper, presented last month in Indianapolis at the ASEE Annual Conference and Exposition. “The idea was to explore the possibility that engineers have a characteristic way of thinking.”

But there was no textbook, no syllabus, and LeDoux had to basically develop the course from scratch, without the aid of pre-existing conceptions (except, perhaps for a few old jokes about engineers) or guidelines for how to teach it. “As a result, I was a true ‘co-learner’ with my students,” he says. “It was such a powerful and rewarding experience that three of my students and I decided to write a paper about it, to share our experiences with the broader academic engineering community.”

So he developed a set of five long-term learning objectives to help guide the way. A year or more after having taken the course, students will (1) have an understanding of the fundamental ways of engineering thinking, as evidenced by their ability to estimate unknown quantities, represent complex problems diagrammatically, engage in model-based reasoning, and employ multiple engineering habits of the mind as a set of lenses through which to view and think about real-world problems and systems; (2) be able to critically read, analyze, and discuss what philosophers of engineering have written about engineering ways of thinking, and be able to formulate and defend their own arguments about what they think are engineering ways of thinking; (3) see the value of, and be adept at, seeing opportunities for employing engineering habits of the mind as thinking tools in every day, non-engineering contexts; (4) have established a connection between the engineering habits of the mind that were identified and explored in class to their own personal interests and experiences; and (5) recognize that a person’s ways of thinking are influenced by their profession, culture, upbringing, and context, and that a much richer understanding of a problem or system is developed by employing multiple ways of thinking.

The course was dense with reading material, and writing assignments, and discussions, and much of the content was philosophical, rather than technical in nature, so this was definitely outside the norm for a traditional engineering professor and his students. Nonetheless, LeDoux reflects, “the course exceeded my expectations,” and he wonders if success in the Study Abroad program means the course could become a permanent offering on the Georgia Tech campus.

According to LeDoux, the students “learned a great deal about what it means to be an engineer by reading and reflecting on philosophical writings about engineering, and by learning and applying engineering ways of thinking to make meaning of systems that they encounter in their everyday lives. I believe these students are now more aware of their own thinking processes and those of other engineers, and are more sensitive to how these thinking processes affect the work they do and the designs they create, which will, in the end, make them more effective engineers and problem solvers.”

The Scientific Method

This was found and shared by my good and brilliant friend Alan Hall, the definitive Renaissance Man (check out his terrific reporting and writing at socionomics.net). Anyway, here's an old video of a great and still useful old lecture by Nobel Prize winning physicist Richard Feynman. It's science for the rest of us, and a worthwhile 10 minutes:

http://www.geek.com/news/richard-feynman-explains-the-scientific-method-in-1964-lecture-1488517/

I Enter the World of Not So Mad Science

I’ve always had kind of a soft spot for mad scientists. Always been a fan. Good or evil, it didn’t matter. I didn’t care if they were trying to save mankind or enslave it, to improve the world or destroy it.

From Frankenstein to Frank ‘N’ Furter, whether they were conquering death or causing it, these dudes (and they were pretty much all dudes, the glass ceiling being what it is in mad science like most other professions) captivated me, held me in a chemical spell. Maybe it was their earnest, creative spark, or their penetrating sincerity and faith in whatever scheme they were engaged in. They were always so damned sure of themselves, the mad ones.

In fact, these guys made such an impression on me at an early age that I created a cartoon character called Poindexter in high school. It became a cartoon strip in college, called ‘Poinzy.’ It’s your typical boy meets world, boy tries to destroy world story.

Standing about 5’2” and weighing in at 92 pounds, Poinzy is picked on mercilessly by the other kids at school. As a means for revenge, he tries to concoct a chemical quick fix, but is mutilated in a lab explosion that blows off both of his hands, forcing him to build new metal hands – deadly claws, really – using his teeth.

First he exacts terrible revenge at school, and then becomes a self-made (and worse, self-taught) megalomaniacal scientist, a not-so-super villain whose amazing, impossible inventions always seem to backfire, if he doesn’t destroy them himself on a whim.

In one strip, for example, he builds a planet-sized spaceship and fills it with thousands of Poindexter clones, the ultimate weapon to destroy the Earth. But at the last moment, he orders his clones to fly the ship into the sun, which they do, singing “We Are Marching to Pretoria,” as they sweat and melt faithfully in their stadium seats, while Poindexter flies off in an escape pod.

By the way, this all started in the 1970s, before Star Wars and its planet-killing Death Star(s), before Freddy Kruger and his murderous claw hands, and before the animated TV show, ‘Dexter’s Laboratory’ (the only similarities between that Dexter and mine was that they both wore lab coats and glasses – mine definitely wasn’t for kids). So, while much of Poindexter was derivative (I blame the movies and their perverse if sometimes subliminal impact on me), it didn’t steal from those things.

But it didn’t occur to me until fairly recently that Poindexter was really about biotechnology. He cloned himself, repeatedly, building and destroying army after army of contrived doppelgangers. He changed himself, gave himself wings and gills, and at one point, an array of bionic weapon limbs: eight arms that could shoot bullets or fire or missiles, or grab, stab and cut (an incarnation that my co-conspirator in much of this “work,” Mike Ricks, and I dubbed ‘Cephalopod’).

Basically, Poindexter was an evil bioengineer, which means he’s the opposite of the people I write about at Georgia Tech, in the Parker H. Petit Institute for Biotechnology and Bioscience. The smart people I work with use engineering principles to analyze and solve problems that plague mankind, while Poindexter uses his knowledge of science and engineering to cause them.

That minor difference aside, this is my roundabout way of saying that Poindexter is kind of what led me here to Georgia Tech, via the scenic route. I’ve worked as an Indian in a Wild West show, a pin chaser and short order cook in not one, but two bowling alleys. I’ve worked on factory production lines, in different warehouses, on a construction crew; I sold knives door to door, and operated a printing press; been a truck driver, a sports writer and a business journalist. But now, I’m as close to being a Boswellian Ygor as I’ll ever be, and my back is still straight. Give it time.

I have a hard time describing myself as some kind of ‘science writer,’ considering my preparation for this gig involved, among other things, creating a mad scientist cartoon character, and repeated viewings of Fantastic Voyage. There's the 25-plus years of journalism, sure ... but I haven’t taken a biology class in 30 years. Maybe I’ll catch up eventually. For now, I'm content in being a simple storyteller, a guy who writes about really cool stuff and people at a really cool university.

So, my intent is to use this blog as a place for stories from Georgia Tech’s bio-community (it used to be a bio-quad, but we’re growing). Please understand (as if it isn't clear enough already) that the human behind this is only half-mad, and not a scientist, but also remember what film director David Cronenberg said: “Everybody’s a mad scientist, and life is their lab. We’re all trying to experiment to find a way to live, to solve problems, to fend off madness and chaos.”