Friday, December 30, 2016

December's SciDay Friday!

It's the last Friday of December and that means one final chance to talk about some science from the month. I'm only going to highlight four papers today, mainly because I didn't prepare this month's post as much as I typically do. Damn you, cookie-induced comas. But if you want to read more about the science from all of 2016, check out this Nature News Feature highlighting ten scientists who were vital this year. Not to be outdone, Science News has a rundown of their own.

The first paper can be found in Science Translational Medicine and explains some of the coolest science being performed right now. Researchers in Boston have developed a personal cancer vaccine for patients who suffered from acute myeloid leukemia (AML). Leukemia cells were isolated from patients with AML and fused together with dendritic cells (a type of immune cell that creates antigens which help the immune system recognize the stuff that shouldn't be there, like viruses and other cancer cells). These hybrid cells, part cancer and part immune, were injected back into AML patients who were in remission after successful chemotherapy treatment. The idea is that these hybrids would teach the other immune cells in each patient how to recognize the antigens from their own cancer and help them root out any leukemia cells that survived chemotherapy...thereby preventing recurrence of their cancer. Twelve of the seventeen patients have remained relapse-free for over four and a half years! Although some patients did relapse after this therapy, the rate of success warrants a closer look at this approach as a means of combating relapse or even as an initial treatment of metastatic cancers. The technology will need to be refined but this proof of principle in actual cancer patients is an awesome development.

The next paper investigates how animals experience time and I have to say, it's about time I started talking about time considering this blog is called Ripples in Time. Researchers in Portugal used drugs and optogenetics to manipulate midbrain dopamine neurons in mice to identify changes in their perception of time. (Quick refresher: Dopamine is a neurotransmitter that is involved with reward and behavior [among other functions] and optogenetics is the manipulation of the function of cells in live animals using fiber optic cables and light.)

Researchers found that dopamine neurons in the midbrain are directly involved in judging periods of elapsed time, either when the neurons are stimulated to release dopamine or suppressed. Since neural circuits are way beyond my expertise, I'm going to quote the end of this article to get the point across. The writing in brackets are my own to help clarify:

"Situations in which DAergic [dopamine neuron] activity is elevated naturally, such as states of high approach motivation, response uncertainty, or cognitive engagement are associated with underestimation of time. Conversely, situations that decrease DAergic activity, such as when fearful or aversive stimuli are presented, are associated with overestimation of time. These observations, together with our data, suggest that flexibility in time estimation may confer an adaptive advantage on the individual." 

This is direct evidence that the neuronal activity of some of the dopamine neurons in animal brains directly affect how we experience the length of time of events. So when I went to see Star Wars Rogue One I didn't even notice the movie was over two hours long because I was so excited while watching...whereas when I vacuumed the house earlier this week it felt like it took forever because my 'cognitive engagement' was low. Our perception of time is directly related to how stimulated we feel. This is cool stuff and may suggest how different people experience the timing of the same events in different ways. The results of this study also implied that the changes in perceptions in time were altered on the scale of actual seconds. This got me thinking. Maybe it isn't the Force that gives Jedi their ultra-fast reflexives, just really efficient dopamine neurons. But I digress... 
 
The third paper is an oddball, which I've tried to incorporate into each of these posts. Scientists in Europe used satellite data to measure changes in land surface water over the entire globe between 1984 and 2015. The satellite imagery had a resolution of less than 100 feet, which is pretty incredible, and this a first of its kind survey. A few summarized points of the findings:

-Globally, land-surface water has increased almost 94,000 square kilometers (about the size of Lake Superior, according to the researchers)
-The addition of this surface water is evenly distributed among the continents and linked to locations with reservoir building, dam construction, and are perhaps even influenced by changing local climates
-Over 70% of surface water loss was concentrated in the Middle East and Central Asia and linked to drought, river diversion and other human activities

I wanted to highlight this paper for a variety of reasons. I agree with the authors that this type of open-source mapping of available water resources is essential for the sustainability of clean and available water in the future. I think it is also smart to recognize that water loss and gain is influenced by human activity, drought, and maybe even the changing global climate, and charting the areas where the greatest changes are occurring can help predict areas that will need help in the future. Imagine in thirty years if the Middle East and Central Asia lost almost all of their surface water and the problems that could pose socially and politically. 

My main problem with this paper is that the authors try to present this data and incorporate their own commentary on climate change. I think that climate change is inherently a major influencer of water availability in our world...it would be foolish not to think so. But the presentation of this data, particularly in the abstract, was written in such a way to first highlight the loss of global surface water and gloss over the fact that surface water actually had a net gain. I felt it was poorly worded and emphasized the wrong aspects of the data - the most important findings being the location and availability of surface water and where in the world changes in local climates (droughts) and human activity (dams) play a major role in this critical resource's availability and its management. It's a small, nit-picky critique, but it rubbed me the wrong way.

Oh well.

The last paper focuses on CRISPR (again!). I've talked about this technology in my last few posts and I feel it is so important that everyone understands the implications that I'm going to close my 2016 discussion about this topic. This time I'd like to feature a paper that came out in Cell and identifies natural compounds that inhibit Cas9, the essential enzyme component in the CRISPR gene editing system. Remember, the CRISPR system is a type of naturally-occurring immune system for bacteria which is applied against invading viruses that infect those bacteria. Inside the CRISPR gene system for the bacteria Neisseria meningitidis, researchers found three genes that code for proteins that inhibit the activity of Cas9 and therefor the CRISPR system. Several genes, related in function, are also found in the genomes of bacteria-infecting viruses. Together, this means that viruses have evolved a way around the CRISPR system and now those genes are being shared (and evolving on their own) between bacterium. 

The great news is researchers now have a way of inhibiting the CRISPR gene editing tool in animal cells with a natural protein found in bacteria. These proteins can be used as a drug/brake-system to limit off-target effects of CRISPR usage, protect specific tissues from being edited, and a way to prevent unforeseen downstream complications that may arise when using the CRISPR system in humans. I've long been concerned with the lack of restraints on the usage of CRISPR technology but the discovery and use of these enzymes is a step in the right direction with respect to control and safety. 

Wooo hoo! #science.

So that wraps up 2016. When I'm finished with teaching in January I'll write a few detailed posts about some controversies in science...starting with the reproducibility crisis. Until then, I wish you all a very wonderful and happy New Year and a great 2017!

Thursday, December 1, 2016

November (Sci)Day....Friday?!...Nope, Thursday!

I like to think I'm an organized person but keeping track of commitments and dates on my calendar has always proved challenging for me. So that's why November's SciDay Friday post, meant to be on the last Friday of November, is now today on a Thursday in December. I blame the copious amounts of turkey, gravy, and cranberries I stuffed into my mouth last week. My stupor lasted until Sunday and I completely forgot last Friday was November's last. At least I'm only a calendar day late.....

So without further adieu, it's time we talk a little bit about the science that was published over the last month!

I've posted extensively now on CRISPR and gene editing, including what it is and the ethics behind this new technology. The field is moving so fast that every month there are dozens of new articles refining this technology and applying it in disease research. Much of what I have previously discussed are my fears about the misuse of gene editing, but today I'm going to highlight why this technology could revolutionize healthcare.

Back in the mid-2000's, scientists were trying to find a way to get around the ethical and social dilemmas of using embryonic stem cells in their research. In 2006, researchers in Japan led by Dr. Shinya Yamanaka, published a report  highlighting the discovery that fibroblasts (cells found in our connective tissues in the body) could be 'reprogrammed' back into an embryonic-like state. With a combination of viruses and specific proteins, adult cells in the body could be reprogrammed and then induced in cell culture to grow into almost any other cell type - just like embryonic stem cells!

This discovery sent shockwaves throughout the biomedical field. The reprogrammed cells, called induced pluripotent stem cells (iPS cells), quickly became the hottest technology and Dr. Yamanaka ended up winning the Nobel Prize in 2012. The use of this new capability was obvious right away in that gene editing in mammals was now a reality. In 2007, a great paper came out highlighting the medical capabilities of iPS cells Briefly, scientists took fibroblasts from mice with sickle cell anemia, reprogrammed those cells into hematopoietic stem cells (HSCs; these cells are the stem cells that live in our bone marrow and give rise to all of our blood cells), fixed the mutation in the beta-globin gene that causes sickle cell anemia, and then transplanted the corrected HSCs into mice via a bone marrow transplant. The new stem cells seeded the bone marrow and gave rise to normal blood cells - curing these mice of their disease. This was one of the first applications of targeted gene therapy as a way to cure a genetic disease.

However, the technology has its complications. Viruses are required for the reprogramming and could be dangerous if used in humans, it's a difficult and expensive procedure, and it's not always successful. CRISPR technology can be the next generation of this approach because it's cheaper to use, more precise (in some instances), and will eventually be more broadly applicable than iPS cells. Today, gene editing is limited to diseases that have single-gene mutations that give rise only in a subset of adult tissues. That's why most gene editing protocols target blood-cell diseases, like sickle cell anemia or Beta-thalassaemia, because human HSCs can be edited and returned back to the original donor. Gene editing protocols that would fix a disease-causing gene in all the cells of the body (or within multiple tissue and organ systems) would have to be performed at the embryonic stage or soon after and that enters into the grey areas of ethics I've talked about before.

The paper I'd like to highlight today stays away from those murky waters for the time being. Researchers at Stanford isolated HSCs from human patients with sickle cell anemia and used CRISPR to perform gene editing on those cells to replace the mutated version of the beta-globin gene with a corrected version. The new cells were then grown in culture and in mice and expressed the correct version of the gene. This study highlights novel methods to purify 'corrected' stem cells from those cells that weren't successfully edited, so that in theory, a purified population of healthy HSCs could be reintroduced back into the human donor. This a first-step in patient-based, gene-editing therapy that could fix a disease in a particular tissue caused by a single gene (otherwise known as a Mendelian Disease).

There are many hurdles still to get over, but this is proof-of-principle that CRISPR is on the cusp of ushering in a new era of personalized medicine. That of course is how things are progressing in the United States. However, over in China, the wild west of scientific research these days, the first human clinical trials using CRISPR have just started. Clinicians have isolated immune cells from a single patient with lung cancer, induced a genetic mutation in those cells (using CRISPR) to make them more aggressive in fighting that cancer, and put the edited cells back into the patient. This has never been done before and is truly at the frontier of research. No one knows if this will be successful, what the long-term effects will be, or whether the patient will live. It's all unknown and clinical trials in the United States begin sometime in 2017.

Okay, enough about CRISPR and gene editing. But, we're going to keep our feet dipped in the gene pool (har har) for just a few more moments if you'll indulge me.

Many people wonder if our traits, behaviors, and diseases are caused more by genetics or our environment: the old nature vs. nurture argument. I'm a firm believer that our genetics and our environment work in harmony together to influence the way we grow and live with the world. In many cases, genetics holds almost complete sway (e.g. Huntington's Disease, BRCA1/2-related breast cancers, cystic fibrosis) and in other cases our diet, behaviors, and environment are major influencers (e.g. smoking, diet-induced heart disease and diabetes, environmental mutagens and cancer). And for almost everything in life, it's usually a delicate balance between environmental cues and genetic risk.

Last month I discussed how our ancestry influences genetic responses to bacterial infections. This month I want to highlight two studies that also support the nature AND nurture reality of our world. The first paper examined how diet and genetic risk factors contribute to the onset of coronary artery disease (CAD). The researchers found that even among people with 'high risk' for CAD, based only on genetic risk factors, those that adhered to a healthy lifestyle (i.e. non-smoking, no obesity, a healthy diet, and exercising at least once a week) had a 50% less chance of developing CAD. In fact, in every genetic risk category for CAD (low, intermediate, and high), there was a significant decrease in the likelihood of developing CAD for those who had a healthy lifestyle. If that doesn't scream nature AND nurture I don't know what does.

Another interesting paper that I'm still trying to wrap my mind around studied the effects of social status on immune function in monkeys. The researchers found that those monkeys with low social status were more apt to pro-inflammatory immune responses and significantly different total counts of immune cells. Additionally, social status influenced gene-expression patterns in response to challenges to the immune system.

This is an intriguing finding in that it supports the current observations that low socioeconomic status (SES) in human society is correlated with increased risk of disease. (Ahhh, there's that word -correlation.) This paper steps in the direction of finding the mechanisms that actually contribute to the phenomena of low SES and disease, and the primary reason I am highlighting it. We're beginning to move from correlation to direct mechanisms and causation. But we must keep in mind that this study was performed in monkeys, using manipulated social conditions, and it is still a far jump from humans in many regards. So I bring this up so that we are aware that SES most likely directly influences response to disease and this paper identifies the immune system as a major player in this observation (not surprisingly), but more, direct proof is still needed in humans.

Switching gears, two papers this month are pushing ideas from science fiction into the real world. Researchers implanted electrodes into the brains of primates that stimulated leg movement and allowed weight-bearing and walking after by-passing the spinal cord. This interface worked in both healthy primates and those with spinal-cord injuries and a paralyzed leg. The stimulation allowed the paralyzed monkeys to walk (without training) and this technique will eventually be used in humans with spinal cord injuries. The second paper uses a similar technique to establish an interface to help a patient with ALS communicate more effectively with caregivers.

This type of research is phenomenal and brings hope to many paralyzed individuals. The intersection between computers, biology, and neuroscience is going to pioneer some amazing discoveries in the future and I can't wait to see it!

Last of all, I thought I'd highlight a very cool and odd-ball paper (at least for me as a geneticist). To preface, I must say I am not a fan of Donald Trump (no surprise there). After the election I tried as hard as I could to be silent about the results but as friends on Facebook know, I've posted and commented here and there. Trump's pick to lead the Environmental Protection Agency is questionable at the very best and the nomination of Tom Price to lead the Department of Health and Human Services, which the NIH and my work falls under, also has a few causes of concern.

Trump has yet to nominate a candidate for Secretary of the Department of Energy, but if it isn't some oil or gas tycoon I'd be shocked. That's important for a few reasons, particularly for climate change and green energy research. Earlier this month Science published a report which detailed a new method to synthetically create complex organic compounds using carbon dioxide as a carbon source. This is akin to photosynthesis in plants and is a large step in the direction of synthetic photosynthesis in the laboratory - a process still only partially understood. This finding is a big breakthrough for engineering new technologies that may one day be used to grow new plants or scrub our atmosphere of green house gases. The potential is enormous for engineering, energy, healthcare, climate change, and growing our economy. (These results here need to be improved upon, expanded, and replicated...but it's a wonderful development.)

I highlight this because this study was funded by the Department of Energy and is the exact type of cutting-edge science that could be tossed out by the Trump Administration in their purge to get rid of all climate change funding. Even though this research has climate implications, the usefulness of this technology for so many other fields and our economy means that this work is both incredibly important to push forward AND protect from budge cuts. Whether or not you believe in climate change (and you really should take a hard look at the evidence, because climate change IS happening whether or not you want to believe it), this type of research can be caught in the crosshairs of an Administration that clearly isn't interested in facts and could seriously harm America's potential in technology development.

There's a war on science brewing in this country. Discussing these issues may help protect some of this important work, regardless of who is running the show. In the coming months, I plan on writing about some important topics in science in a new series of posts (in addition to my monthly research updates). I'll be posting about hot topics including vaccination (which Trump has been wishy-washy on, unfortunately), the reproducibility crisis in science, and we'll discuss how and why it is so important to be able to differentiate pseudoscience from real science.

Thanks for reading! Have a Merry Christmas and Happy New Year!