Synthetic enzyme, weight loss miracle

Obesity is a huge problem worldwide, costing our healthcare systems billions of dollars every year. The World Health Organization estimates that about 1.2 billion (yes, billion) people around the world are overweight, and among those between 200-300 million are clinically obese.

Figure 2: Obesity in America, courtesy of the New Yorker

Obesity is a tough health problem because it’s existence can exacerbate a whole variety of other medical disorders. From type 2 diabetes to cardiovascular problems, the list is pretty large. Curing this epidemic would not only mean a healthier world, it would remove a huge burden on our hospitals as well. Well it seems like that cure may be upon us thanks to some obesity researchers from the Helmholtz Diabetes Center in Munich, Germany!

In a recent paper published in Nature Medicine, investigators have created a pretty incredible weight loss drug that reduced weight in laboratory mice by a third while preserving their lean muscle. Their strategy was a classic tour-de-force of synthetic biology: inspired by nature, improved by man.

There are three enzymes involved in this story: GLP-1, GIP, and Glucagon. The first two enzymes are used by the body to help control appetite and blood glucose levels, while the last enzyme is used to increase glucose in the blood. While increasing blood sugar may seem like a bad idea, it actually does assist with burning fat. In obese patients, the ability to respond to these enzymes is dampened. This is also why losing weight after being overweight for a while can be quite difficult – your actual biochemistry changes to make it tough!

Strategies using these enzymes individually have had limited success, so to circumvent this biologists engineered a molecule that displays characteristics of all three. As you can see from the graph below, the results are pretty remarkable.

Figure 1: A chart showing weight loss in mice. The black line is the control while each other line represents a different form of the drug. The most dramatic loss is seen when the highest concentration of drug was used!

So there you have it, yet another way in which synthetic biology is changing our lives. While we have yet to see this drug used in human patients, I think it’s safe to say that we should be seeing more news out of this team in the near future!

I’M SORRY

Alright, so I’ve been totally dropping the ball lately regarding the content on this blog…I PROMISE I’ll write things up over the weekend and have all new things ready for you by next week!

I recently got put on a project at work that is intended to find feasible therapies for Wolman disease, a disorder in which your cells can’t metabolize cholesterol properly. I’m hoping to eventually write this up for a publication, so I’ll be somewhat sparing of the details of the project…when I can divulge more, I will!

In other Francis-you’re-kind-of-a-scientist-now news, I started my first induced pluripotent stem cell cultures yesterday, which I’ll be further differentiating into other forms of stem cells such as neural and mesenchymal stem cells. This is my first experience with handling stem cells, so I’m pretty stoked to get the ball rolling on this project. Unfortunately, it means I’ll have to be at work to take care of them every day (including weekends) indefinitely, but at least I’ll be working on a pretty sweet project. Cool stuff! Here’s a picture of the little guys: aren’t they adorable?

Figure 1: Those large clumps of cells are stem cells! The smaller bits floating around are debris/dead cells

Have a fantastic, science filled weekend!

P.S. Did you hear the Philae lander that landed on that comet determined that the water present was different from that found on earth? Full disclosure: the water (also known as heavy water) found on the comet was only different in that it had an extra neutron – the structure was the same. Heavy water is found here on earth  (contrary to many news headlines that I’ve seen lately), but it’s much rarer than regular water!

In the pursuit of a cell-fie: Part 2

2014 has been one of the craziest years for science. We even landed on comet, for God’s sake! Needless to say, this year has been pretty kind to the biological sciences as well, with some key innovations being made in the pursuit of an artificial cell. So sit back, relax, and let’s go over some key innovations that have been made this year!

You’ve got to move it move it

Researchers this year from Technische Universität München published a pretty cool paper in Science where they constructed artificial vesicles that could move on their own. Pretty amazing! To achieve this, they coated the inner surface of the vesicles with proteins called microtubules, which are the proteins that allow your cells to move (they also provide structure in what is known as the cytoskeleton. They also added motor proteins called kinesins that move microtubules, pushing the little cells forward. Of course, the energy molecule ATP was also added as fuel and BOOM! We have movement!

Figure 1: A high resolution photo of the artificial cell! Via TUM

And here’s a cool video of the cells moving:

Part 3 is just around the corner! See you all in a few days!

In the pursuit of a cell-fie, Part 1

Have you ever taken time to look up at the night sky and gaze in amazement at the web of stars in the sky? Nature has the uncanny ability of inspiring a sense of wonder and awe when you sit down and wonder, “Gee, how does it all work?” I would argue that you’d probably get that same sense of wonder if you sat down and thought about the endless list of processes and reactions that your body has to undergo everyday just to keep you alive. There are about 37.2 trillion cells in the human body, with thousands of different functions represented in the various tissues. That’s 372 times the number of stars in the Milky Way! When you consider that these cells must all interact with one another and look out for their own survival, you can see why constructing a completely artificial biological organisms would be pretty challenging!

Figure 1: The Milky Way

To make this task more feasible, scientists for many years have been trying to start with the cell, the smallest functional unit of life. Biologically speaking, a living cell must meet certain criteria that are rather difficult to fulfill artificially.  These are listed here:

1. Homeostasis: A cell must be able to regulate its own internal environment

2. Metabolism: A cell must be able to turn chemicals into energy

3. Adaptation: A cell must be able to response to stimuli from the environment and response appropriately

Stretch goals:

4. Reproduction: A cell must be able to replicate itself

5. Organize: Ideally, artificial cells would eventually organize themselves into more complex things like tissue and organs

6. Grow: Through metabolism, cells should be able to grow in size (or at least replicate to make the organism bigger)

Figure 2: The goal – are you up to the challenge?

If I gave you a laboratory and some supplies, could you do it? It certainly seems like a herculean task! Thankfully, researchers around the globe are hard at work to make such technology a reality. The journey to create an artificial cell dates back to the 60’s, where Thomas Change at McGill University created a cell with an ultrathin membrane made of nylon and other crosslinked proteins, which contained a slew of things such as hemoglobin and various enzymes.

In the 1970’s, this technology was revamped to make a completely biodegradable cell, and in 2011 researchers at Harvard University reported creating the first fully synthetic cell membranes.

The genesis of synthetic cell membranes marked an important step in crafting a fully artificial cell, but the issue of an artificial genome (collection of genetic material) still remained. Artificial DNA synthesis has been around for a while (I’ll cover this in another blog post), but it took until 2010 for researchers at the J. Craig Venter institute to create a cell with a fully artificial genome. I’ll spare you the minute details, but workflow of the experiment is as follows:

1. Design a genome on the computer.

2. Synthesize that genome artificially. In the case of the above experiment, the genome of a bacterium known as Mycoplasma mycoides was designed on the computer and crafted.

3. Insert the genome to a different cell. The researchers transplanted the M. mycoides genome into a different bacterium, M. capricolum.

4. SUCCESS!

Their M. capricolum began only producing protein products from M. mycoides, proving that their genome switcharoo was a success. The cells were even able to replicate, a triumph for the field! So as a proof of concept, humans can design fully functional artificial genomes. Done and done!

Note, however, that although the genome is artificial, we are still relying on the native bacterial machinery to translate those genes into proteins. Ideally, every part of these cells would be completely manmade, but it’s clear that our foray into the creation of artifical life is having some success! In recent years (especially in 2014), huge advancements have been made in these other areas of cell creation. To see how biologists have figured out how to make cells move and carry out their own reactions, check out part 2 of this blog series on Monday!

Nature, improved

The vast majority of you who read my blog are probably aware of my obsession (a strong word perhaps, but apt) for science: wake up, eat, science, sleep, repeat. As a result of both curiosity and my natural tendency to wander the internet, I tend to focus my energies on learning things within a specific area due to an article I read or something of that nature. I call these “kicks”, and for the next few blog posts I’m going to introduce you to a recent obsession of mine: synthetic biology.

Figure 1: Obligatory futuristic depiction of your DNA!

For centuries, humans have had to operate within the confines of nature. Want to cure your fever? Find an herb. Want to have bigger cows? A combination of careful breeding and finger crossing should do the trick! Now when we’re faced with a problem (say, why don’t we have better cancer-fighting enzymes), we are presented with a third option: make it up. We now have the power to craft our own custom DNA, create new cells, and effectively “edit” life as we know it.

Will these technologies be known to history as man’s triumph over the universe, or will they be our downfall? I’ll leave that for the ethicists to decide, but you can’t deny that these technologies are pretty interesting! So stay tuned for some background into synthetic biology and where our technologies are at in 2014. You don’t want to miss it!

Surviving Thanksgiving

Without a doubt, the most troubling (and usually hilarious) comments I hear about science happen around the Thanksgiving table. Whether it’s your crazy uncle from out of state or your neighbor’s grandma, Thanksgiving small talk tends to erupt into a storm of nonsense.

“Global warming? Yeah right – did you feel how cold it was yesterday?”

“You know, the government actually does have a cure for cancer. They just want to help fuel the pharmaceutical industry”

And so on and so forth. To help you prepare for such encounters, here are a few of my favorite videos/infographics summarizing some key scientific concepts. Happy eating and safe travels!

1: The top 10 things you need to know about Ebola, via the CDC

2. This FANTASTIC video explaining climate change from Veritasium

3. This video explaining the fundamentals of evolution

4. Top 10 things to know about stem cell therapies

5. Preparing for landing on Philae

6. And finally, and perhaps most importantly: what happens when you eat too much?

http://www.washingtonpost.com/posttv/c/embed/168a5c54-73e6-11e4-95a8-fe0b46e8751a

Linking autism and the genome

With the dawn of advanced genetic sequencing and the completion of the Human Genome Project, science is rapidly trying to dissect the genetic causes for a wide variety of human disorders. Some of the most perplexing human disorders fall on the autism spectrum, which includes things such as autism and Asperger syndrome. Disorders on the autism spectrum are characterized by deficits in social/communication skills, repetitive behaviors, and cognitive delay (in some cases).

Researchers have desperately been trying to link particular genes to autism spectrum disorders (ASD) for many years, as successes in this field may potentially lead to promising therapies. While this problem has certainly been daunting, scientists recently reported in eLife that they have made an interesting connection between a gene called SEMAPHORIN 5A (SEMA5A) and ASDs.

Before I talk about SEMA 5A and it’s role in the brain, I want to briefly emphasize the sheer complexity of your brain. The human brain is certainly one of the most fascinating structures in all of nature, with 80-100 billion neurons making 100 trillion connections to process thousands upon thousands of thoughts a day. Everything from your thoughts on the meaning of life to whether or not you want to wear a coat outside can be reduced to a collection of neurons firing together. That’s pretty wild!

Figure 1: Your body has to coordinate the formation of BILLIONS of these neurons!

As you can imagine, the way in which these neurons connect with one another (these connections are known as synapses) is very tightly controlled. Exactly how this is done is the topic of a lot of research labs around the country (including the lab I worked in as an undergraduate) and is a very fascinating area of research.

SEMAPHORIN 5A is known as an autism susceptibility gene, which are genes that are associated with high risks of developing ASDs. SEMA5A is a protein that controls the formation of dendritic spines, which are projections from dendrites, the part of the neuron that receives input from neighboring neurons.

Figure 2: A comparison of neurons when the SEMA5a gene is deleted. Focus on the two red boxes: the red box on top is when SEMA5A is present, and the red box on the bottom

The difference is pretty dramatic, and mice with SEMA5A deleted gained many of the behavioral characteristics that humans with ASDs have. The exact reason why an increase in dendritic spikes causes behavioral abnormalities is still not very clear, unfortunately.

I know what you’re thinking – so what? Why does this matter? While it may seem like the knowledge gained from this paper seems somewhat limited, keep in mind that this gene, in conjunction with many other genes, are required for a properly functioning neural circuit. If we can understand what genes go awry in different diseases, we are one step closer to fine tuning therapeutics to target those specific genes!

Rough.

If you recall, I mentioned that there was a possibility that I would receive the placebo in my clinical trial, which is just saline. Well, it looks like I actually received the vaccine…

As the day went on yesterday, my joints started to feel really achy. Hips, knees, and lower back. At one point during the night, it felt like someone had tied my legs to a truck and told it to drive off – ouch! My temperature also hit about 101.6 degrees, which is a pretty good fever. What’s worse is that my raging fever alternated with strong chills, so I had to adapt to feelings ranging from hellfire to Arendelle.  I know this is for the good of humanity and whatnot, but there were definitely points last night where I thought to myself, “Damn, was this worth it?”.

And it definitely was! As sudden as the symptoms began, they left without a trace. I woke up this morning feeling great and my fever had completely abated. I went for my regularly scheduled appointment and blood draw and my nurse said I was good to go! If my case is at all similar to the other patients in my cohort, I should be in the clear for the time being. I’ll be receiving a booster shot of the vaccine in about a month, so I’ll let you know if it’s any better the second time around! At least I’m theoretically immune to Ebola, right?

Have a stellar weekend!

My adventures as a clinical trial patient!

Today, I was dosed with an experimental vaccine for the Ebola virus known as VSV-EBOV, produced by a company called NewLink Genetics. Before I go on with my post, here are a few disclaimers.

1. This vaccine DOES NOT contain, nor did it ever contain, Ebola. I will AT NO POINT receive Ebola. Thus, there is no risk of contracting Ebola.

2. My participation in this study is completely voluntary and is in no way related to my work at the National Institutes of Health (NIH).

3. I am not contagious in any way, shape, or form with Ebola. While this vaccine does take advantage of a different virus, the only way you could catch it is by kissing me. Sorry ladies!

As I’ve blogged about before, there are currently only two vaccines in clinical trials for the Ebola virus, with several more in active development. For more information regarding the composition of the vaccine, check out my previous blog post. If you aren’t inclined to read the whole thing, here is the basic idea:

1. The vaccine contains a virus known as the vesicular stomatitis virus, or VSV. VSV infects farm animals such as cattle, horses and pigs. The virus cannot reproduce in healthy humans, although it may cause some very mild flu-like symptoms.

2. This virus has been engineered to produce a glycoprotein that belongs to Ebola. While the virus itself is not Ebola, this small component is enough for the body to produce an antibody response as if I was infected with Ebola.

3. Now that my body has been primed in this manner, I (theoretically) should be immune to future Ebola infections. Don’t worry, this won’t ever be tested!

The purpose of this phase in the study is to determine if the vaccine is safe in humans. While VSV has been used in many other clinical trials (safely, I might add), the vaccine must have unique data in order to proceed with clinical development. This study is a double-blind study, which means that neither myself nor the research team will know whether or not I’ve received the actual vaccine or the placebo (just saline). That being said, here is an overview of what happened to me today!

“A Phase 1 Randomized, Double-Blind, Placebo Controlled, Dose-Escalation Study to Evaluate the Safety and Immunogenicity of Prime-Boost VSV Ebola Vaccine in Healthy Adults”

Step 1: Arrival

Last week, I was screened at the NIH Clinical Center for things such as HIV and Hepatitus, which would have disqualified me from participating in the study. Those results came back negative (phew), which gave the team the green light for me to continue forward! I arrived at the NIH at around 7:30 this morning, and after having my car searched I entered the actual Clinical Center for my appointment.

Figure 1: The NIH Clinical Center, America’s Research Hospital

The NIH Clinical Center (or Building 10, as it’s known around here) is a very interesting place! The Center itself is not your average hospital – it doesn’t provide services such as labor and delivery or other basic services you would expect at your local hospital. Designed as research facility, the Clinical Center contains more than 1,600 laboratories that are manned by over 1200 physicians, scientists and dentists. I genuinely felt fortunate to be at the Clinical Center as a healthy volunteer. Many of the patients here have very rare or undiagnosed diseases, which really cemented how important the continuation of medical research is for me. I made my way up to the clinic to begin my appointment, passing by countless families, patients and scientists alike.

 

Step 2: The Visit

As soon as I arrived at the clinic, I was ushered into an examination room where my case manager gave me a general physical exam. After he confirmed that I was healthy, I was sent down to phlebotomy for a blood draw and urine collection. Remember that the purpose of the vaccine is to generate antibodies against Ebola, so this blood draw is intended to be a “baseline” measurement.

The nurses here are professionals – I’ve never had an easier time giving blood! I blinked and it was all over. The nurse who took my blood told me that she had been in the same spot for about fifteen years – I guess practice really does make perfect! All in all, they took 66 milliliters of blood split into about 15 different tubes.

Figure 2: That’s a lot of blood!

While I was in the phlebotomy department, the Clinical Center’s pharmacy was busy making the vaccine. There are no stockpiles of this vaccine lying around (at least, not in Maryland), so it has to be made fresh every time I receive a dose!

Step 3: Injection

I returned to the clinic and received the vaccine. Nothing too crazy here. Pokey thing goes in, stuff is injected, pokey thing comes out. Easy! I initially felt a little soreness around the site, but nothing more painful than I’ve received with other routine vaccinations. Note that out of the 13 people in my cohort, 3 will receive a placebo vaccine, which contains only saline. It’s entirely possible that I received a placebo – I won’t know until the study is over!

I stuck around for about an hour just to make sure I didn’t have any, err, dramatic responses to the vaccine. Thankfully I didn’t and was able to return to work right after my visit!

Figure 3: The diary card I’ll be using to monitor my symptoms.

For the next year, I will be monitored for any adverse reactions to the vaccine. This includes regular visits the clinic (which means regular blood draws) as well as monitoring my symptoms via a diary card and thermometer. I’ll be updating you all on how I’m feeling, as well as with more information regarding the status of the vaccine and it’s implications in the fight against Ebola!

Sensationalism in Science: Is this for real?

For some people, reading over science headlines in your local paper or favorite website can be a little scary. With articles talking about “3 parent babies” and the emergency of a new “stupidity virus” infecting half of our population, it’s easy to think that we have entered bizarre futuristic world where mad science runs unabated. Is this really what’s going on? Today, we’re going to talk a little about journalistic sensationalism and why it harms the conversation gaps that we’re trying to bridge between scientists and the general public.

I’m not saying there isn’t any truth to some of these crazy titles. 3 parent babies do technically have genetic material from three people. The so-called stupidity virus does slightly reduce some aspects of cognitive function in humans. These two stories, however, are much more complicated than their headlines may have you believe. I’ll talk more about the above two stories in more detail in a future post, but the point is that you can’t really convey the subtleties of a new technologies or discoveries in a sentence. In reality, you should be prepared to critically evaluate and engage every headline you see, science or not. There is usually much more than meets the eye!

A few days ago, I saw a post entitled the “9 Disgusting Things the FDA is Letting You Eat” pop up on my Facebook feed. What scandal! If we can’t trust the FDA to keep crazy things out of our food supply, how can we trust going to the grocery store ever again? As with most posts of this nature, the truth is really that frightening. Let’s dive into a few examples.

Figure 1: Keep out of my pantry, big scary government!

The very entry lists “sawdust” as the first FDA approved disgusting additive. It then goes on to talk about how the actual additive is known as cellulose, which is derived from wood when used in food. So why isn’t this a bad thing? Cellulose is an incredibly important polymer that makes up the cell walls of plants. What else has cellulose besides wood? Every plant on Earth. Whether your body receives cellulose derived from wood or from celery is moot, as your cells cannot tell the difference between the two. Harmful? Hardly.

Another post lists “human hair and duck feathers”, which probably just sparked horrific memories of you finding a hair in your lunch back in middle school. The post goes on to talk about how the real additive is L-cysteine, which is removed from hair and feathers. Here’s an image of what L-cysteine looks like, and what your body sees when it is added to your food:

Figure : The ever terrifying L-cysteine. Gross, right?

L-cysteine is an incredibly important and common amino acid in the human body and is present in a wide variety of things. As with the “sawdust above”, we arrive at a common theme that characterizes many food-based science articles. Regardless of where the L-cysteine came from, your body won’t be able to tell the difference. A molecule is a molecule is a molecule, any way you slice it. Harmful? Of course not!

Another axiom to keep in mind (especially important in food science) is that disgusting doesn’t mean harmful. Just because the source of a particular amino acid or vitamin may sound gross doesn’t mean it’s bad for you!

In the end, many of these articles aren’t really so scary after all. Sensationalism is used to grab a reader’s attention, but it’s usually very misleading and in the case of articles about scientific information, reckless. It’s the responsibility of both journalists and scientists to make sure that any discussion we have with a reader is frank and honest. Until we get to that point, expect plenty of misleading articles and topics to gain a lot of attention and traction in the coming years. So the next time you pick up your paper or open your favorite website, make sure you ask yourself:

Is this for real?