And so it begins…

I love science fiction. As both a Star Wars fan and a scientist, I often find myself daydreaming of what the future holds for both technology and mankind. As we continue to progress as humans, we will inevitably hit numerous ethical speed bumps (or speed mountains) along the way to becoming the most advanced species in the universe.  Want to get to Mars? Live forever? Cure all human disease? All of these things sound great, but these advancements are always tied to some pretty hard choices.


Figure 1: Sometimes the choice won’t be this easy! The answer is cake, by the way.

A few months ago, I blogged about how genetic engineering has the potential to help cure a variety of human diseases. I also mentioned how thought leaders in the genetic engineering space proposed that a moratorium be held on any attempts to use such technology to edit a human embryo. Well it seems like that those requests were ignored, as a study was recently published in Protein and Cell attempting to correct the gene that causes beta thalassemia in embryos. This disease results in misshapen hemoglobin, the component of your blood that carries oxygen. Misshapen hemoglobin leads to anemia, so you can see why someone would want to cure it! In the above paper, 86 embryos were used in an attempt to correct the mutation. They used CRISPR/Cas9, a very clever system discovered in 2012 that has the ability to hone in on specific regions of DNA, cut out the gene in question, and replace it with a different one. Only a small number correctly replaced the mutated gene with a normal copy, and the process also generated mutations in other unintended parts of the genome.

Let me be very clear here. The researchers (at least, to my knowledge) never intended to implant these embryos into an actual womb. As controversial as this study was, it actually provides us with important confirmation of what we already suspected – we simply need to learn more about how gene editing technologies like CRISPR/Cas9 work before we can hope to use them in an actual embryo. The success rate for this paper was pretty small. The success rate if we want to start using this routinely? 100%.

This technology has the potential to rid the human race of a whole host of genetic disorders, but the fact that we are still extraordinarily naive about how exactly such technologies will behave in an actual embryo cannot be understated. The majority of scientific institutions throughout the world seem to agree with me, with over 170 companies, patient groups, and research institutions stating that a moratorium is necessary. Nature and Science, two of the world’s most influential journals, rejected the paper due to its ethical dubiousness.

Just as choosing whether or not to pursue such research will always remain a difficult choice, it is inevitable that this sort of research will continue to be attempted. It doesn’t matter if 1000 research centers say that it is dangerous – it only takes on lab. The argument can certainly made that unless we try these techniques in actual humans, we’ll never truly know if they work or not. There is only so much that you can do in a laboratory before one needs to make the scientific leap. This leap has been taken many times throughout the history of science, and it’s always fraught with the unknown.

Take, for example, Edward Jenner. His name may not be familiar to you, but his invention of the vaccine has saved millions of people around the world. How did he discover this? He inoculated the 8 year old son of his gardener with pus from a person with cowpox, then challenged him with the virus. This worked beautifully, but it certainly seems a little ethically questionable, don’t you think?


Figure 2: Edward Jenner advising a farmer to vaccinate his family

Of course, we know better now. We have better informed science, and we have better models upon which to test our ideas. So when will we see the successful correction of a mutation in a human embryo? Only time will tell, but I can guarantee that it’ll happen sooner than you think!

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Transduction, s’il vous plait?

As most of you are aware, I work for the National Center for Advancing Translational Science (NCATS) here in Rockville, MD. We often talk about translational research at the office – how it works, how we can improve on it, and how we can use it to make people healthier. But what is translational research?

The vast majority of biomedical research in the United States is known as basic research. This research seeks to understand the fundamental mechanisms that govern life – how genes are regulated, what proteins influence biochemical pathways in the body, and so on and so forth. I think that this research needs relabeling, as basic seems to imply a lack of complexity (at least, that’s what it sounds like to me!). The word fundamental would probably be more apt here, as this research is absolutely critical to applied research. Applie research uses the information gathered in basic research to create new therapies for humans, such as new medical devices or new drugs. The process by which knowledge is transformed from basic to applied research is known as translation, which is the challenging topic that my institute focuses on.

This is certainly easier said than done. As you can imagine, a vast amount of basic research is performed around the world every year, yet the rate at which we develop new therapies is much lower. 200 billion USD was spent on research and development last year ($90 billion in the US) alone in the life sciences, while thousands of scientists work around the clock to figure out new ways to tackle problems in human health. Do you know how many drugs were approved by the FDA last year? 41. Forty. One. This is actually much higher than the 21 per year that the FDA averaged over the past decade.

Okay, let me be a bit transparent here. That figure is of novel drugs approved, which means that the drugs were completely brand-spankin’ new. This would be in contrast to repurposed drugs, which are drugs that have already been developed by can now be used for another disease. But even if that number of drugs were in the hundreds, it is still abysmally low relative to the amount of money that we put into research. What gives?

Have you ever volunteered for a walk to help fund medical research? Maybe you’ve donated some money here and there to foundations promising to accelerate research. If you’ve been in either of those scenarios, I’m sure you’ve felt frustrated that it seems like the amount of energy and money that we spend trying to cure diseases usually results in very limited results.

In the end, it boils down to one thing: it’s really really really really really really x 1000 difficult to move an idea found in the laboratory to the clinic. So difficult in fact, that my institute was founded on the very premise of solving this as a systematic problem. Once we can solve this problem, we will be able to utilize the vast wealth of basic research that scientists around the world have spent their entire careers on. As the Isaac Newton once said, “If I have seen further it is by standing on the shoulders of giants“.

Before I let you go, I’m going to spoil the ending a little. Despite the sort of dreary tone this blog post holds, I am infinitely optimistic that we will only continue to improve the way in which we discovery new drugs and develop new medical interventions. Costs will go down, precision will go up, and most importantly, the quality of life for sick patients around the world will soar. But before we can cross the quagmire that is translation, we’re going to need some supplies. What makes translation so difficult? Where do we need to improve on? This is what I’ll be discussing in the next few blog posts, so stay tuned for more!

Achoo! How drugs saved my life.

I’ve been over winter since about mid-January, so when March 20th rolled around I was more than happy to greet the new season. Cherry blossoms, warm weather, and warm rain showers. Best season ever, right?

WRONG. WRONG. WRONG. WRONG.

I love most of spring as much as the next guy, but when those pollen counts start ticking higher and higher my body begins a heavy revolt. I start to sneeze, my nose runs, my eyes itch, and my mind starts to become overwhelmed. It heavily affects my ability to focus and is an overall huge hindrance to my productivity – not good when you’re working in a lab! For today’s post, I’m going to focus on something that has kept me from having a meltdown over the past few weeks – antihistamines.

Figure 1. This is why I don’t like going outside. Yuck!

When you experience and allergy attack, be it hives or a runny nose, your body is mounting an immune response to a perceived threat. My immune system, for example, hates cats, grass, and trees. When it detects bits and pieces from these things in the form of dander and pollen, it ramps up the production of antibodies against these allergens. These antibodies then bind to cells called mast cells which contain large amounts of histamine. Once released, this histamine causes a variety of the symptoms you normally associate with an allergic response. For example, these antibodies can bind to mucous membranes in your nasal cavity, leading to a histamine release which causes sneezing and nasal congestion.

Antihistamines work by blocking the receptors that recognize histamine, resulting in a reduced immune response. The earliest antihistamines developed, also known as first generation antihistamines, were not very specific to the histamine receptor. This lead to some undesirable side effects, including drowsiness thanks to their ability to cross the blood-brain barrier into the central nervous system. This is why if you’ve taken one of these medications (i.e. Benadryl, ChlorTrimeton), you may have had to avoid driving! Because of this side effect, some modifications to these first generation antihistamines are used to treat insomnia (i.e. ZzzQuil).

Then came the second generation antihistamines, which were much better at targeting their intended histamine receptors and only crossed the blood-brain barrier to a small extent. These “non-drowsy” medications include Claritin, Allegra, and Zyrtec. Despite being in the same class of antihistamines, all of these different medications have varying chemical structures and potencies. Your results may vary!

Figure 2: A schematic of how antihistamines work. Note how the antihistamines block histamine from binding to their intended receptors!

Finally, one of the most popular classes of allergy medications in recent years has been the nasally administered corticosteroids, which includes Flonase and Nasacort. These nasal sprays work in a slightly different way than the above medications and aren’t technically antihistamines. These corticosteroids bind to glucocorticoid receptors in the nasal passages, which are important in downregulating immune activity (inflammation).

In my experience, Flonase has worked the best for me. Each person is different, however, and may require different regiments of allergy prevention medications to be effective. For more information, go see your doctor! In the meantime, I’m going to go back into the lab, happy and heavily medicated.

Don’t touch my embryo!

In a recent commentary in Nature, leading scientists in the field of genome editing warned against altering the genetic code of human embryos. The authors claim, and rightly so, that it is likely that we will see a great number of studies in the near future that have attempted to edit the embryo at the molecular level. With the advent of very advanced gene editing techniques, we have the power to alter the expression of genes at will, or knock them out completely. Okay, that’s probably a gross oversimplification, but you get the picture!

genome editing
via Shutterstock

The reasoning behind pursuing this technology makes sense. If a patient has a deleterious gene mutation that causes cancer, for example, just remove the gene and insert a healthy one. Easy, right? Indeed, this technique has been performed repeatedly in cells in vitro (in a test tube, glass dish, etc) and in some model organisms such as monkeys, but human beings are whole other ballgame. And as you can imagine, nothing in biology is quite that simple. Editing one gene could affect its interactions with other genes or edit the wrong genes, and these ramifications may not become apparent in entire humans until its too late.

Ethical conversations like this one are extremely important to the advancement of science. Just as our science should be used to inform the public, the public should be used to inform our scientific decisions. I am a very strong proponent of research into genetic modification, as these tools will be immensely powerful in combating the diseases of today and tomorrow. I also acknowledge, very strongly I might add, that this technology is in its very early infancy. Will changing the DNA of an embryo cause untold changes in the developed human? Yes? No? Maybe? The truth is that we just don’t know for sure, and it will likely require years of intense research to find out the answer to that question.

I think it’s very tempting for scientists to march forward with a disregard for what is ethical – we, of course, possess the technical knowledge to pursue such endeavors. To dismiss the ethical risks that are usually paired with scientific advancement, however, would also risk losing the trust that the public places in the scientific community. Thus, it is immensely important that these processes are transparent and that we are able to engage the public  in an active conversation, no matter the outcome.

I encourage you all to read the original commentary hyperlinked above. Keep an eye out for an increasing debate in the field of gene editing – it’s going to get very interesting!

Vaccine Update – plasmapheresis time!

Long time no update! A few days ago, I was informed by the study team that I had  either the highest or second highest (they wouldn’t specify) immune response to the experimental Ebola vaccine. As such, they are interested in harvesting the antibodies that my body has generated for use in a potential transfusion to a patient suffering from an Ebola attack. I’m glad my white blood cells are such active little guys! Side note: the data this decision was made on was based on an analysis of my blood conducted in December. The analysis takes a while, so rather than wait to see what my blood has looked like over the past few months the team decided to go ahead and retrieve my plasma now.

Using premade antibodies provides an Ebola patient with an extra leg up on the disease. Antibodies are used by the body to discern which things in the body aren’t supposed to be there (antigens), so having antibodies against Ebola allows an Ebola patient’s immune system to recognize the virus faster and mount a defense of its own. This is how ZMapp worked, which was a monoclonal antibody produced in a tobacco plant that was given to a few of the earliest health workers returning from Africa with Ebola.

To get this process started, I underwent what is known as a plasmapheresis. This is when the staff at the clinical center harvests my plasma, which is the “liquid” part of the blood and is the part that contains all of the antibodies that I have against Ebola. About 55% of your blood is made up plasma. This plasma is then split into different parts and frozen, ready for use should the need arise. A small portion will also be used for further research.

You may have friends who have had this procedure done before – it’s not that uncommon! In essence, my blood is removed , spun in a centrifuge, the plasma is removed and the remaining components of the blood are returned to me. The apparatus looks something like this:


Figure 1: The plasmapheresis process. Note that my red blood cells, white blood cells, and platelets are returned to me with the addition of some saline to make up for fluid loss.

And my procedure looked something like this:

plasma

Figure 2: The fairly large needle in my arm is able to both draw and return blood, no second needle necessary!

plasma!
Figure 3: The resulting plasma and the fantastic nurses at the NIH Clinical Center!

All in all, it was a very pleasant experience! The only side effects that people tend to experience is a feeling of faintness, similar to what you would feel during a typical blood donation. The machine also circulates an anticoagulant through the blood, which ensures that the blood doesn’t gunk up the system. The anticoagulant can cause tingling in the lips and fingers, but I didn’t have any of that. The bed I was in had a memory foam mattress and I was given copious snacks upon the completion of the collection. I’ll start with giving three times – the protocol itself allows for up to 20 collections. Hopefully my nurses aren’t tired of me by then!

The 40 million dollar placenta

Well, more like placentas. Last year, the National Institutes of Health announced that it was embarking on a new research program studying the placenta. Today, it also announced that $41.5 million would be earmarked for research projects within the program. The policy wonks reading this are probably thinking who the hell would pay so much taxpayer money learning about the placenta? Don’t we have better things to research? As with most things within biomedical research, the true value that research brings needs to evaluated with your critical thinking caps on!

*I was going to put a picture of a placenta here, but I refrained from doing so for the sake of my readers with sensitive stomachs!*

The placenta, according to the National Institute of Child Health and Human Development, is one of the least understood organs. You’re probably aware of its vital role for the fetus: it allows the fetus to feed, remove waste, and receive gases critical to normal growth. We normally look at the placenta indirectly via ultrasound and blood tests, and we can also examine the tissue after birth has occurred. How the placenta changes throughout pregnancy is still a bit of a mystery, so by investing research in this area the NIH hopes to glean new information of how the cells grow and adapt to support the developing fetus.

Why is this important? As I’ve stated above, the placenta is critical in maintaining the health of the child, so if anything were to go wrong in proper placental development it could lead to potentially life-threatening conditions in the womb. These conditions, including gestational diabetes and preeclampsia (high blood pressure during pregnancy) can lead to miscarriages or premature deliveries. A greater understanding of this critical organ will hopefully gives us the ability to better prevent these tragedies from occurring in the future.

The Epigenome

Today, a slew of very important research papers were published in the journal Nature describing a pretty incredible feat of science – the sequencing of the epigenome (well, mostly).

Most of you are probably more familiar with the sequencing of the human genome via the Human Genome Project. Led by the National Institutes of Health (NIH), this endeavor mapped all of the genes in the human body and concluded in the early 2000’s. The implications of this new knowledge were pretty huge! From a better understanding of the genetic basis of cancer to more personalized drug therapies, scientists gained a very important milestone in the difficult journey of learning how our bodies work.

Today, we gained another milestone through the sequencing of the epigenome, which are the modifications on the genome that affect which genes are expressed in a given cell. Think for a moment of how diverse the cells in your body can be – some can fire electrical signals to send messages throughout the nervous system (neurons) while some are engineered to produce that insulin that controls your blood glucose (beta cells in your pancreas). The genetic material in these cells, no matter where they are, is exactly the same, give or take the occasional mutation here and there. What makes the cells different from one another are what genes are turned on and off, which is partially controlled by your epigenome.

epigenome
Figure 1: The epigenome controls which genes are “unwound”, revealing their information to your cells. ADAPTED FROM ILLUSTRATION BY SIGRID KNEMEYER, PREVIOUSLY ADAPTED BY LAUREN SOLOMAN

This $300 million project, again supported by the NIH, was quite challenging to say the least! With the human genome project, scientists only had to worry about one genome. The epigenome, however, differs from cell to cell, making any attempts to sequence it pretty onerous. This makes sense, as the epigenome is essential for defining an individual cell’s identity! The efforts mentioned above sequenced about 111 different tissues, with more to come in the future.

So in the end, why does this matter ? Our knowledge of the epigenome will allow us to notice smaller differences between people at the molecular level, which can lead to a better understanding of what causes human disease. For example, scientists may reexamine patients with cancers caused by genetic mutations and ask themselves “what role does the epigenome play in this disease?”. With insight from the now-sequenced epigenome, they may discover that certain genes are inappropriately turned “on” in cancer patients, leading to therapies that target those specific genes.

Keep an eye out for more developments in this field – they’re going to be pretty monumental!