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." 

-from Soares et al., Science, 2016.

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!

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!

October SciDay Friday!

It's the last Friday in October, which means a new science post, continued attempts at walking through leaves, preparing for the coming onslaught of Christmas advertising, and the Cubs waiting for next ye......wait a minute...what's that?.....yep....WORLD SERIES AT WRIGLEY FIELD! I can't believe the Cubs are still playing baseball this late into the year AND for all the marbles. It's a strange feeling typing that particular combination of letters. 

Today I'm going to highlight some interesting papers as always, but there are a few societal issues I want to reexamine and discuss as well. So we'll go from aging and gene expression, to health disparities, sprinkle in some marijuana to get us in the spirit of inebriated debate, and then back to the social implications of CRISPR technology and gene editing that I've touched on before.

First the papers!

It's a challenge to boil down a month's worth of research into a few concise points and this week I've been struggling with what to talk about. But considering I work at the National Institute on Aging, I guess I can always dip back into the comfortable realm of the topics I am surrounded by the most to help me find something to talk about*.

*Disclaimer: Although I work for the National Institutes of Health, the opinions expressed in this post and all others before and after on my websites are my own and not the official representation of the United States government.* (Yes, I've had to include this statement in previous scientific talks and I felt it best to just put that out there right now, particularly for things I'll bring up at the end. I've also realized that many of the articles I link in my posts are often behind a pay wall. I understand if this causes frustration and if you can't access a particular article you can always email any scientist that you may know and they will be happy to oblige you with said article....in the spirit of scientific education, collaboration, and public discourse. [Cough])

It's long been known that as humans age our tissues and bodily functions begin to degenerate. Researchers in the UK and the Netherlands studied the rate at which DNA mutations accumulate in adult stem cells (ASCs) that were isolated from study participants and grown in tissue culture. ASCs are different from embryonic or pluripotent stem cells, which can divide and turn into almost any tissue in the body. Instead, ASCs belong to one type of tissue, such as the liver, or heart, or brain, and they stimulate new cell growth and generate 'younger' cells for that particular tissue. Often this is to replace the older cells that are being turned over. The study confirmed that as we age, all the stem cells in our tissues also age and accumulate random DNA mutations as they replicate their DNA and divide. These seemingly random mutations can lead to predisposition to age-related diseases, like cancer. 

The exciting finding is that although the ASCs from different tissues tend to accumulate DNA mutations at the same rate, the locations of theses mutations in the genome is very tissue-dependent and perhaps not random. This hints at the prospect that some tissues may have better ways of protecting their DNA from disease-causing mutations than others. Although the full mechanism of why this occurs in some tissues and not others has yet to be figured out, it's a promising lead on refining our understanding of age-related disease. 

The next study, conducted at the Albert Einstein College of Medicine in New York, examined whether improvements in health and technology in the last two decades have increased the maximum lifespan of human beings: currently set around 122 years of age. They reported that there appears to be a fixed, upper-limit to increasing the human lifespan and we may never push beyond 120-125 years old. It also appears this boundary is largely influenced by genetics. That's not to say some new technology or gene editing technique in the future may not push this barrier higher (we'll touch on this below), but as of right now nothing current is believed to have expanded human life span to 150-200 years. 

As someone who studies aging, I'm not surprised by this result. It is an awfully difficult thing to protect multiple systems of the body from failing as we get older. Human aging is at the intersection of genetics and the environment (such as drug intervention, diet, sheer luck) and until the genetics are fully understood, it will be difficult to get past 130 years or so, in my opinion. I will go out on a limb and say that perhaps one or two people will push 140 in our lifetimes, but I'm not convinced they would be anything but bed or chair bound (although I hope not because that sounds miserable.) 

Another paper I'd like to highlight came out in Cell late last week. Cell is a great journal, although it can be a little data-heavy and at times the basic science presented can be hard to extrapolate to public health. However, the journal has pushed hard to be innovative and now every paper has a graphical abstract - a visual diagram or picture summarizing the paper's findings in addition to the traditional written abstract. I find the graphical abstract of many papers to be the best part, particularly for scientific work I don't understand at all. I'd like to see more journals adopt this change. Anyways, back to my main point, researchers in the US and Canada discovered that genetic ancestry and natural selection plays a role in how immune cells respond to pathogens. We've long known that different ethnic populations are susceptible to certain diseases and we coming to understand that genetic background can influence how a disease can progress given an individual's ancestry. 

This study provides strong evidence for this on a genetic and molecular level. The authors found that immune cells isolated from European Americans or African Americans each have a unique subset of genes that are expressed in response to the same environmental pathogen. Another important finding is that a large portion of these genetic responses were selected for by local adaption/evolutionary events in our history as a species. This means that local environments, for any given population, naturally selected for particular immune responses to infections and this may contribute to why, today, some populations are more at risk for certain diseases. 

This has enormous implications for our own understanding of healthcare, disease response, and current human evolution. It also underscores the need to continue to push for basic and translational research in underrepresented populations in scientific studies; including women, African Americans, indigenous populations, Africans, Latin and South Americans, Asians....pretty much everyone that's not a Caucasian male, who have been the dominant demographic in a large majority of studies from the late 1800's to late 1900's in the United States. This type of work is so important to truly understand how disease affects each individual and may ultimately help clinicians and scientists better understand disease prevention and progression. It will ideally be a cornerstone of the Precision Medicine Initiative  and will certainly be useful to solve some of the huge disparities in health that affect many Americans in our country. I'll use this as an opportunity to promote my own research, which was just published this week in the journal Scientific Reports. Our laboratory found a profound difference in gene expression in immune cells when comparing African American and white women who have hypertension. Our results suggest that inflammatory diseases, like hypertension, have a racial context to them that need to be further examined to develop better drugs and preventative measures. 

I'm going to pivot gears very quickly and just point out that the crystal structure, aka the shape, size, and conformation, of the human cannabinoid receptor CB1 has been solved. CB1 is the protein target of THC, the chemical in the marijuana plant that gets you stoned....and trippy...and dude, what are we talking about it? Oh yeah, pot! Solving the protein structure of THC's receptor will have important implications for designing new drugs that can induce the same health benefits of marijuana (yes, there are some) without the need to smoke a joint and get high. Crystal structures offer insight into how molecules interact and give scientists a more precise target to develop new drugs. I'm excited to see if any new breakthroughs in medication are tied to this discovery, particularly for mental health issues. 

And now that we're ready to tackle some more 'heady' issues, here's a few social dilemmas to chew on to cure your case of the munchies. Earlier this year I wrote at length about geneticist Dr. George Church's desire to synthesize an entire human genome in the test tube. As a quick recap, we now have the technology to artificially generate most of the human genome in the laboratory, and the Genome Project-Write was put forth as the scientifically-led initiative to get this done. Dr. Church had an interview this week with the Journal of the American Medical Association (JAMA) where he detailed out his ambitious plan to synthesize the human genome for scientific study, all in the hopes of identifying new mechanisms for disease control and prevention, organ transplantation, and other noble health endeavors. This is all fine and good, but I still have some problems with this technology, particularly the fact that we still don't completely understand the ethical ramifications of synthesizing our own human genome. The lack of transparency on aspects of this project are also concerning. Dr. Church attempted to address this issue in his interview:

"JAMA: Your paper in Science stressed responsible innovation. So how does your group plan to move forward responsibly?

Dr. Church: One of the things that we have done already is that most of our new technologies are accompanied by papers on policy, ethics, social, and legal aspects. Another thing is doing it very openly, transparently. So, for example, the meeting [at Harvard in May] that received some attention on this was videotaped and that’s publicly available. The consensus view of the organizers and many of the participants is represented in [the Science paper published in June] that’s publicly available. I think that level of transparency is critical. Also, looking out for any safety and efficacy issues, making sure there’s a dialogue with the FDA on anything that’s intended for diagnostic or therapeutic components."  

Source

I find this a little laughable, only because he fails to mention that the very 'first' meeting about this project was in May 2016 and that was done behind closed doors without invitation to the public or the press. Sure, the videos are available now about the meeting, but the hand-waving and reasoning for secrecy about this meeting is about as solid as Trump's defense on not releasing his taxes. And I put first in quotes because if you read the article announcing this initiative that Dr. Church references, this topic stemmed from talks at a meeting way back last year in October 2015...with little public discussion or input then as well. You're not starting off on the right foot if the very first two meetings aren't widely publicized or available for public discourse. 

Now, I'm not saying Dr. Church or anyone involved with this project has nefarious ideas in mind. Far from it. But this interview is the perfect example of the cognitive dissonance that many scientists share (and many politicians), in that the scientific enterprise must ALWAYS be done in the public eyes, especially when using public funds, and starting off a major initiative like this with closed meetings is not even living up to the standards the project's leaders are advertising. It's very frustrating and an example of science that has lost touch with the public. 

I brought this topic up again for another, more important reason. Last week I was in Vancouver (amazing city with wonderful people) for the annual meeting of the American Society of Human Genetics. Several of the panels and platform sessions discussed the role of genetics in future healthcare. One session focused on the impact of gene editing (using CRISPR technology) in society and its role in healthcare and disease prevention in newborns. I'd estimate there was an audience of at least 400-500 people, many of them geneticists, and several of them asked questions to the speakers and moderators concerning the ethics of modifying our own genomes. 

Questions such as:

-If we use CRISPR technology to increase human lifespan, what is the impact on the climate? On our natural resources? On healthy aging?

-If we use CRISPR to 'fix' polymorphisms that confer disease risk in a newborn, does that mean all babies would need to be first created in vitro?

-How can we use this technology if we still don't understand the implications on a generational level? 

-Won't only the wealthy be able to afford this type of gene therapy? 

-How can we help adults who are already sick?

But perhaps the most important question was asked by a transgendered scientist named Emily, who asked: What is to stop people from using this technology to allow parents to change the race or sexuality identity of their unborn child? What do we do then? 

If you just thought of the movie GATTACA, you aren't alone. It's such a tough question, weighing so many different factors that I can't even begin to scratch at the surface. I'm so glad Emily asked that question and it stumped the moderators. I bring this up here and now because in the same interview between JAMA and Dr. Church, he mentions this:

"JAMA: What’s the difference between a gene editing tool like CRISPR-Cas9 and the type of genome-scale engineering that you’re proposing?

Dr. Church: With editing you might change 1 base pair in a genome—like 1 character in a book. With synthesis you might need to make a whole new edition of a book, where you’d have to make many changes to fix many genes. If you want to make 100 edits with CRISPR, it might be more cost-effective to bring in a few thousand base pairs of DNA that include those 100 edits as 1 big chunk and then essentially do 1 edit that accomplishes 100 things at once. If you wanted to change all triplet codons for all of the genes, for example, that would be very hard to do by editing in the conventional sense, where you change 1 at a time. You might have to make 10 000 to a million changes. It might be easier just to synthesize that and pop it in as 1 edit."

Source

What Dr. Church is suggesting is synthesizing an artificial human genome that now even skips the need to edit using CRISPR, instead just building and designing the thing with as many base changes as one would want, anywhere in the genome. It's an incredible idea...in the playing with fire/flying too close to the Sun kind of way. Imagine 'fixing' every cancer-predisposing polymorphism in the human body...or every polymorphism known to be associated with increased lifespan and healthy living. It's a noble idea. However, some of these known locations in the genome are only associated with a given outcome and disease. There is no proof yet they are a driver gene for a particular process. We also don't yet understand what effect all of these changes at one time would have. Remember, our human genome was refined throughout human evolution to be what it is today. Changing everything at one could have disastrous, unforeseen consequences. You can see what I am inferring to here - what does this imply for Emily's question on gender, race, and sexuality in society?

These are all very hard things to grasp and think about but these questions have to be addressed before moving forward in any substantial way. What makes me happy is that a lot of people are starting to ask these questions and at other major scientific meetings. In fact, the programing for the annual meeting for the American Association for the Advancement of Science (AAAS) next February is riddled with talks about gene editing, with some heavy hitters in the field including Emmanuelle Charpentier, George Church, and Alan Leshner. I wish I could go to see what some of them have to say. 

So there you go, a little something to think about today. That's it for October, now go enjoy what's left of your buzz and have a great weekend. GO CUBBIES!

September SciDay Friday!

It's the last Friday of the month, so as promised, it's time for another post on some interesting scientific studies.

Last month I posted about a vaccine that immunizes and protects mice from the Zika virus. Finally in the print version of Science, the same research group has published on the efficacy of three different versions of their vaccine in rhesus monkeys. The importance of these results cannot be overstated, given that rhesus monkeys are primates. This provides further evidence that humans can be vaccinated against Zika (Phase I clinical trials of a human vaccine are already underway). The vaccination program will also be supplemented by an influx of over one billion dollars that was part of Congress' stopgap budget that was passed this week to fund the government through December 9th. Huech.

Several genome sequencing studies were published this month that shed light on biodiversity on Earth, as well as further our understanding of human migration tens of thousands of years ago. The first is a comprehensive analysis of the mitochondrial DNA sequences of more than 4,500 mammalian and amphibian species from around the world. This analysis provides evidence that biodiversity is greatest in tropical regions (surprise, surprise) and associated with areas that have smaller human footprints (surprise, surprise). I'll note that this is a preliminary, genetic analysis on biodiversity and there is no direct evidence presented here that humans are the cause of the decreased biodiversity discussed in this study. But it's not a stretch of the imagination to think that we are the cause of global decreases in biodiversity. This study is merely the first stop on the road to validating this relationship using genetic approaches.
*Note: in case you haven't heard of the term Anthropocene, that's the epoch we live in now. It means  human activity has measurably and directly impacted Earth's geology and global ecosystems.

The second paper details a study that sequenced the genomes of over 80 Aboriginal Australians and closely-related Papuans. It provides strong evidence that when humans first migrated out of Africa there was only one 'Out of Africa' event that gave rise to modern-day humans. This doesn't mean earlier humans didn't venture from Africa before this, but it does imply that all of us living today are descendants from this single 'event' of migration. I think that's amazing and further exemplifies how our genomes are living history books.

A very exciting finding published in Nature concerns the development of the drug aducanumab, a potential therapy for patients with Alzheimer's Disease (AD). Many AD patients suffer from neurodegeneration associated with plaque build-ups in the brain which are caused by a misfolded protein called amyloid-Beta. Aducanumab is currently in clinical trials and the reported findings in this present study indicate successful treatment of these plaques in AD patients using this drug. This could be a major breakthrough in a devastating disease. I'm looking forward to seeing the rest of the clinical trial results and whether this drug gets fast-tracked for approval by the FDA.

The last study I'll talk about today is probably my favorite, if only because it focuses on the tardigrade. The tardigrade is a microscopic water animal that is one of the most resilient animals ever discovered. These things live everywhere, can endure the harshest of environments (even surviving in space), can go decades without food or water, and are all-around bad-asses. Sequencing of the tardigrade genome last year found that almost one-sixth of its entire genetic repertoire was acquired from other species through a process called horizontal gene transfer. Genes from bacteria, fungi, plants, and Archaea were identified in the tardigrade genome. This month, researchers from Japan published findings on a protein identified in the tardigrade genome that protects DNA from damage and may help the tardigrade survive in extreme environments. The protein, called Dsup, was introduced into human cells and protected those cells from X-ray-induced DNA damage. The most exciting part, however, is that the discovery of this protein could be important for finding new methods to prevent DNA damage in humans, such as protecting our skin from sun UV damage and preventing melanoma. Perhaps expressing this gene in our bodies could be useful to promote longer lifespan, since we accumulate DNA damage as we age. Who knows! The biomedical applications could be endless.

Well there you have it, some science for your Friday afternoon.

It's August's Friday (Sci)day!

On the last Friday of each month, I am going to highlight important discoveries that have been made in science during that month. August has been a great month for scientific research. As laboratories splurge on last minute reagents and supplies before the government fiscal year ends, there has also been an extraordinary flurry of publications outlining high-impact discoveries. Today I'm going to discuss a handful of them - studies that will take us from viruses, to cancer biology, and all the way to Proxima Centauri, the nearest star to our Solar System.

I'll mention beforehand that I'm going be highlighting only Nature research in this post. Please don't get the impression this is the only journal that has published high impact research this month. However, my personal bias had played a role in this, as I've only had time to read through Nature Publishing Group's websites this week. Part of that has been the fact that I've finally submitted revisions to my own manuscript that is currently under review at Scientific Reports, a journal that is part of NPG. But I wanted to get this post out today, so it's a trade off I'm comfortable with. I haven't posted in two months and that's been way too long.

1. The most important article, in my opinion, was published yesterday, called Vaccine Protection Against Zika Virus from Brazil. This groundbreaking paper highlights a multi-national effort to develop a new vaccine against the famous Zika virus. Researchers have developed two strategies to completely immunize mice from Zika infection (particularly against those strains associated with birth defects observed in infected, pregnant women in Brazil and the United States). Two methods achieved immunization in mice. One method was the classical inoculation using purified, inactivated virus. The second method involves a DNA plasmid that expresses several of the virus's genes that teach the immune system to recognize viral proteins and develop antibodies against the virus. These initial studies were only in mice, but the jump to humans is coming soon enough. It's a fantastic development.

*Climbs onto soapbox*

Unfortunately, I have to put this paper into the political context of our election. Vaccine development is an essential arm of the biomedical research enterprise. Trump, who very well could be President, is inexplicably in the camp of people who believe that vaccines cause autism (newsflash: they don't!), and it concerns me that a possible leader of our country could be so science-naive. Research, like the development of the Zika vaccine above, is imperative to the health and safety of everyone. If Trump is elected, I hope that vaccine funding (and science funding in general) doesn't take a major hit.

*Climbs down from podium*

Okay, let's get back to the science!

2 & 3. Two awesome papers out this month dive into the world of cancer biology. The first, Tumor-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis, is a mouthful of a title but the discoveries are very important. The authors identified proteins expressed on endothelial cells that rogue cancer cells latch onto and use to leave the blood stream, enter into a new tissue, and develop into a metastatic tumor (the process in which a cancer cell can leave the bloodstream, push through the endothelial cell layers of the blood vessels, and enter underlying tissue is called extravasation). This discovery will hopefully lead to the advancement of new targeted therapies against this mechanism in order to prevent metastatic tumor formation and death in patients with aggressive cancers. It is also another example of how cancer cells can hijack our own body's normal physiology to grow, adapt, and invade surrounding tissues.

This highjacking of normal physiological functions is akin to the next paper I want to highlight called, Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. First, props to the authors for including the name of the most famous X-Men villain as the first word of their manuscript title. I love it. Second, the authors were extremely clever and hijacked a natural type of bacteria found in the ocean, and using physiological functions and properties common to both these bacteria and solid tumors, were able to develop a new type of drug delivery system to bring drugs to tumors in mice. SUCK IT CANCER!

In the late 1980s, researchers discovered a species of bacterium in the ocean that created their very own iron chains and used these little iron-filled chains to align themselves along local magnetic fields. These bacteria used those magnetic fields to guide themselves to areas of the ocean that were oxygen-depleted (similar to hypoxic environments within solid tumors). In the current paper, scientists coupled liposomes to the outsides of these bacterium and injected them into mice with tumors. You can think of liposomes as tiny, tiny little packages that were stuffed full of anti-cancer drugs. The bacteria were guided to the center of the tumor by a magnetic field created outside of the mouse that the researchers placed near the mouse's tumor. The bacteria were able to follow the magnetic lines into the center of the tumor, which is depleted of oxygen, and deliver the drugs to the local environment. FUCKING BRILLIANT!

This paper was a proof-of-concept that bacteria with an affinity for hypoxic environments could be guided to deliver drugs. Studies on safety, efficacy, and what kinds of drugs and cancers could be treated will need to be performed. But this is some really awesome work that could open up a new avenue for targeted cancer therapy.

4. Now we're going to travel all the way out of the body, out of the solar system, and over to Proxima Centauri, our closest celestial neighbor just over four and a half light years away. Proxima Centauri is a red dwarf star, and it was just discovered that there is an Earth-sized planet orbiting Promixa that may also fall within the long-sought after 'Goldilocks Zone' - a distance far enough way from this particular star that could support liquid water on the planet's surface.

That's pretty awesome, and the fact that it is so close (galactically-speaking) is astounding. Does that mean humans could definitely live on this planet? Hell no, but that doesn't rule out an eventual trip to the planet to check it out for other life. Interestingly, earlier this year Stephen Hawking, Russian entrepreneur Yuri Milner, and Facebook's Mark Zuckerberg, proposed a new idea to send a small fleet of tiny probes (no bigger than phones) to check out our neighbor Alpha Centauri, in the neighborhood of Proxima. These little guys could sail over to this star system using solar sails and get there in about 20 years. So let's pretend it takes 10 years to develop the technology, 20 years to get the probes to Proxima and this little planet, and then 4.5 years to beam back photographs and other information (at the speed of light) back to Earth. In 35-40 years, literally in our lifetimes for those contemporaries of mine, we could be looking at actual pictures of a star and it's planet up-close. I'll take it. And couple that with a landing on Mars and now we've really experienced science fiction.

5. & 6. The last two papers I want to quickly highlight have to do with big data and genetic sequencing. The first is another effort to sequence the human exome, meaning those RNAs that code directly for protein. This massive exome sequencing project identified new protein-coding mutations and variants in over 60,000 humans and increases our knowledge of what kinds of mutations are associated with disease. It will take years to parse through all the data, but there could be some enormous findings hidden in there.

The second project brings us full circle and back to viruses, where we started at the beginning of this post. Recently, there was a large sequencing initiative to catalog and identify Earth's virome - that is to say, the collective of all viruses on Earth. You wouldn't know it, but viruses are EVERYWHERE. But don't worry, a vast majority are not harmful to humans at all, as they target bacteria and other single-cell organisms. However we really don't know the breadth and scope of what is out there and this paper is another looking-glass into a world we are still exploring. I anticipate this will also provide some important discoveries in the coming years. Remember those magnetic bacteria? They are found in the ocean. Perhaps we'll find a virus that can target and kill cancer cells, and perhaps they dwell in the ocean too. We'll never know unless we look. This is a great first step in that direction.

So there you go, a recap of research in August!

Bard College and A New Story

Well, I'm up in New York for the weekend at Bard College to have faculty training for the Citizen Science Program. I'll be a faculty member for the 2017 class of freshman next January. It's an exciting and innovative new program where all Bard freshman, regardless of major, take two weeks of science coursework between the fall and spring semesters. I'll get a chance to teach history and art students the fine 'art' of scientific experimentation and hypothesis-driven research. It should be a great opportunity to get a different perspective on science in the community and in the real world. It will also help me hone my teaching skills and give me the chance to promote science literacy. I've really been looking forward to this. There are 26 other faculty members and I've met most of them now and they are all exceptional people.

In other news, a short horror story of mine, called The Alchemist's Final Experiment, was picked up by the new magazine publisher ECM Network. The story is featured in issue 4 of their magazine, called A Darker Dawn, and can be purchased for $3 and downloaded to your e-reader in a .pdf. If you're curious about my writing and want to help get this publisher off their feet, please think about getting a copy! All proceeds to the magazine and there are other featured short stories and fiction work by upcoming horror authors. You can also browse the editorials, short poems, and original artwork.

That's all for now. Go Poland at the Euro Cup!

That Time When a Group of Geneticists Turned into Frankenstein's Successors

If you've been to my blog before, you know that I love science. I love the amazing things science can do, what it can contribute to society, and where it can take us. Because science can move so fast, there are times when I am admittedly more hesitant than others to embrace a particular technology or breakthrough, i.e. genome editing using CRISPR (you can click here for a rundown of that technology and what I think it means for science moving forward).

But today I have to admit the wind has been temporarily removed from my sails as the world finally got an idea of what went down on May 10th, 2016 at Harvard. Dr. George Church, world-renowned geneticist, held a closed-door meeting with numerous other geneticists, bioethicists, lawyers, and industrialists about the emerging field of synthetic biology - specifically whether it was worth building a human genome from scratch. The media caught word of this and a few days later several articles were published, with rampant speculation as to what was discussed. Research opinion articles started to come out from others in the field (not invited to the discussion) with some very valid talking points about feasibility, practicality, and important societal, moral, and ethical considerations. I have since learned that the entire meeting was videotaped and will be put up live online in the coming days. It was only withheld (apparently) because the corresponding peer-reviewed article calling for a new initiative to synthesize the human genome was still under consideration.

I have to admit I think Drs. Boeke, Church, Hessel, and Kelley (referenced here as BCHK, the co-first authors of the article summarizing this May 10th meeting) really handled this poorly. There should never be a closed-door discussion about the use of new technologies in molecular biology, especially without the involvement of the general public and press. All of this secrecy leaves a bad taste in my mouth. For something like this, where so many people have an opinion to contribute, doing it this way does not cast the endeavor in a good light. And in addition, there were other meetings back in October 2015 at NYU (which didn't get much press) that also contributed to the paper put out yesterday. This is cited at the end of the article, which I link to below.

OK, so what the hell is going on here?

In a nutshell, Drs. BCHK and others published a Science Perspectives article promoting the launch of the so called Human Genome Project - Write (HGP-Write). A publicly-and privately-funded initiative to synthesize a complete human genome from scratch in order to push forward several areas of biomedical research. The idea is to build a synthetic human genome (using natural DNA bases) to work within a living cell and address fundamental questions about development, immunity, disease, and other biological questions about genetics. I'm not going to get into the scientific merits of the proposal today (I will soon). But I will mention that the technology to do something like this, and on this scale, needs to be refined. This technology has been utilized to synthetically engineer the genomes of select bacterial and viral species, but this is small potatoes compared to the human genome.

I'm bringing this up here because my immediate reaction to his was very skeptical and there are some outstanding issues that aren't raised in the paper that I think need to be immediately addressed:

1. BCHK conveniently use acronyms to mush together several essential topics in this discussion. They say in the article, "HGP-Write will require public involvement and consideration of ethical, legal, and social implications (ELSI) from the start. Responsible innovation requires more than ELSI, though, and involves identifying common goals important to scientists and the wider public through timely and detailed consultation among diverse stakeholders."

This is all well and good, but when your first substantial meetings on this topic are closed-door, this kind of blows all credibility out of the water....not to mention ELSI is a convenient way to shrug off some of the vital roles these topics by clumping them all together and conveniently under one umbrella concept.

This is immediately followed with, "We will enable broad public discourse on HGP-Write; having such conversations well in advance of project implementation will guide emerging capabilities in science and contribute to societal decision-making."

Again, all well and good on its own. Except at the end of the article they also say, "The goal is to launch HGP-Write in 2016 with $100 million in committed support, from public, private, philanthropic, industry, and academic sources from around the world."

If the goal is to launch in 2016, how can any discussion be "well in advance", as suggested earlier? In science a 'well-advanced' time frame often means a year or two out, not in the coming months. This is especially true for the academic, extramural peer review program used by most institutions. This isn't enough time, especially because the debate about CRISPR is still ongoing.

2. Francis Collins, Director of the NIH, has already stated in response that the NIH, "has not considered the time to be right for funding large-scale production-oriented [projects]...whole-genome, whole-organism synthesis projects extend far beyond current scientific capabilities, and immediately raise numerous ethical and philosophical red flags."

Not quite a ringing endorsement is it? I think this is an important response that shouldn't be ignored. To be fair, Dr. Collins was the spearhead of the Human Genome Project, and may feel some personal protection over the human genome since he sequenced it (credit goes to Dr. Venter too, for spurring the government along from a sluggish start). Dr. Venter is the guy from industry who helped contribute to the sequencing of the human genome AND he's the guy that built one of the first bacterial genomes (like what I mentioned above) at his own company. I can already see this turning into Part 2 of the  'Publicly-funded vs. Venture capital-funded' battle royale that waged two decades ago during the Human Genome Project.

Yes folks, scientists are all about the drama, too. 

3. A few other very important tidbits that haven't been addressed:

-Once this thing gets built (which will certainly take a long time), who then owns it? Can the entire human genome be patented? What about huge stretches of DNA sequence surrounding a single gene? I shudder at the thought.

-Several of the authors have financial stakes and considerations with companies that perform genome synthesis or work with related technologies. While these relationships have been disclosed in the Science article, I can't help but think many of these scientists could financially benefit from a massive endeavor in this area. I'm not saying that's already happened, but it's a possibility that makes me a little curious and that certainly could happen.

-There was an appalling lack of concern, scientifically-speaking, in two key biological areas:

i. There are still parts of the human chromosomes, including sequences at the telomeres, centromeres, and within long CpG stretches, that are still a little ambiguous with respect to a streamlined, definitive sequence. This will need to be resolved to make an accurate and functional genome.

ii. More importantly, there was no mention at all about epigenetics. The human genome is heavily  chemically modified along the backbone and the nucleotides themselves. These modifications govern how the genome is 'read' by the molecular machinery and how genes are expressed. The chemical signature of the human genome, often called the epigenome, is essential to proper function of our DNA on a variety of levels, and also includes the tens of thousands of copies of proteins that help structure the chromosomes and maintain its integrity. If we are just stringing together some base pairs, without the context of the nucleus and the epigenome, what biological value can really be obtained that makes this worth doing? I'm not convinced yet and the lack of any discussion about this troubles me. The epigenome is incredibly complex, maybe even more so than our actual DNA sequence. Changes in the epigenome are heritable and contribute to a variety of processes in our body and in disease states. This has to be addressed.

So, I'll leave it at that for now. Enjoy this little quote from Mary Shelley's Frankenstein and a nice picture of Gene Wilder as Dr. Frankenstein.

"Man," I cried, "how ignorant art thou in thy pride of wisdom!"

Thoughts from Balticon 50!

Balticon 50 was the largest gathering of nerds I have ever been a part of. I saw people dressed up as Boba Fett, Daenerys Targaryen, Dr. Strange, Hodor, a Jedi Knight, Dr. Who, Arya, Princess Leia, and someone dressed up as a demon, with face and arms painted red, horns out of the forehead, and carrying a huge club that had fake metal spikes and a ridiculous tongue coming out the middle of it, like it was smiling (not sure if the demon was from a computer game or anime series or anything at all), and lots of other cool costumes. They were all awesome. Some dude was walking around as the Winter Soldier and if the guy had admitted he was really Sebastian Stan in real life I wouldn't have been surprised. Here's the one picture (below) I snapped of some cosplayers. They were really nice, from Washington state, and I later saw a picture of the same guy at the convention photo booth. He was wearing a different costume. I think he brought one for every day of the event. Again, I shamefully admit I am not sure what they are referencing:

The photo was snapped during the only major hiccup I experienced at the convention. On Friday evening the fog machine for one of the presentations sounded the fire alarm and the entire hotel had to evacuate:

This photo doesn't do the crowd justice. It was packed outside with people. Thankfully, there was no fire and we proceeded back in.

Balticon is the Baltimore Science Fiction Society's annual science fiction and fantasy convention. It was the 50th anniversary of the event and they landed the big guy, George R.R. Martin, as their guest of honor. (I saw at least three people dress up like him too, with costumes so good I had to stop and look them over for a second or two to confirm they weren't him.) There were also loads of other people there too. On Saturday morning my friend and I got into an elevator and Connie Willis walked in to ride up with us. She's the award-winning author of the novels Blackout and All Clear and is the most decorated science fiction author ever. Her books are awesome and I was just about to tell her I thought so when the bell dinged and we were getting off and going our separate ways. We were in that little box for about twenty seconds but I never said anything. I'll get a word in next time, but it exemplified to me that this would be a random and fun event.

GRRM spoke for an hour on Saturday. He was interviewed by some guy I had never heard of (he's the one on the left of the picture for those who have no idea what George looks like). Julia and I caught most of it, which didn't concern itself much with A Song of Fire and Ice. He did explain his thought process as his novel A Game of Thrones ballooned into the epic fantasy series that it has become today. He also talked about the Vietnam War, New Jersey, and comics books. He is very well spoken and entertaining. Sadly he didn't comment on the current state of The Winds of Winter. I did hear that on Sunday he read a new chapter from the Greyjoy POV.

I apologize for the terrible quality of this photograph. Clearly, I am not good at taking pictures.

The rest of the time I was sitting in seminars, watching panels, and meeting really nice people. I learned a lot about writing science fiction and fantasy. Sarah Pinkser, in particular, was phenomenal. She's a local Baltimore resident (like myself) and winner of this year's Nebula for Best Novelette, called Our Lady of the Open Road. She gave a wonderful workshop on prepping stories for publication and she gave great input and advice about the craft. Congratulations Sarah!

All in all it was a successful Balticon, in addition to my sister visiting for the weekend, which was a blast!

The 'Seed and Soil' Hypothesis: When Scientists from the 19th-Century were Ballers and Shot-Callers

Think of London in the late 1880's and you might think of Jack the Ripper, or Queen Victoria, or the establishment of the first competitive league of football. But what would probably not be on your list is Stephen Paget, surgeon at the West London Hospital and Metropolitan Hospital in London. In late 1888, while Scotland Yard was investigating the gruesome murders in White Chapel, Mr. Paget was busy putting together a research article that would be published in The Lancet, just over 127-years ago, on March 23rd, 1889. Mr. Paget's paper, The Distribution of Secondary Growths in Cancer of the Breast, is a short, two-page article exploring metastatic tumors in cancer patients. The opening reads:

"An attempt is made in this paper to consider "metastasis" in malignant disease, and to show that the distribution of the secondary growths is not a matter of chance."

Mr. Paget observed that in women diagnosed and killed by breast cancer, a high proportion of secondary tumor sites were found in the liver and in a few other organs and tissues. He wrote:

"Then as regards "metastasis." Here, too, we shall find evidence of predisposition; we shall see that one remote organ is more prone to be the seat of secondary growth than another. In cases of cancer of the breast, it is strange how often the liver is the seat of secondary cancer.....This frequency of secondary disease of the liver is of course a familiar fact; but it acquires fresh interest when we contract it with the immunity enjoyed by other organs. The spleen has, so to speak, the same chances as the liver; its artery is even larger than the hepatic artery; it cannot avoid embolism. Yet the liver was the seat of 276 cases; the spleen in 18 only. Such a great disproportion cannot be due to chance."

What Mr. Paget observed was that some organs and tissues preferentially developed secondary metastatic tumors and this was dependent upon the tissue of origin of the primary tumor, in this case the breast. Concluding his article he wrote:

"All reasoning from statistics is liable to many errors. But the analogy from other diseases seems to support what these records have suggested. The eruptions of the specific fevers and of syphilis, the inflammations after typhoid, the lesions of tuberculosis, all show the dependence of the seed upon the soil. The best work in the pathology of cancer is now done by those who, like Mr. Ballance and Mr. Shattock, are studying the nature of the seed. They are like the scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observation of the properties of the soil may also be useful."

His words are compelling and quite prophetic, as we'll explore in a moment. The 'seeds' he talks about refer of course to cancer cells, which had already been identified back in 1845. Decades earlier, German scientist Rudolf Virchow first proposed the idea that cancers and cancer cells are abnormal versions of normal cells. Virchow was one of the first scientists to observe cancers of the blood and named these blood cancers leukemia. (As a side note, I find it interesting that Virchow did not believe in Darwinian evolution, which happens to also play a fundamental role in cancer progression and is commonly known as micro-evolution - but that's a topic for another day.)

What Paget brings to light for the first time in his paper is his reference to the 'soil', or the environment in which a metastatic cancer cell finds itself in after separating from the primary tumor and riding the circulatory or lymphatic systems towards another tissue. Each of our organs needs specific nutrients, hormones, metabolites, and signaling molecules to function properly. The local tissue and cellular environment of the brain will have a different chemical make up than that of the liver, or lungs, or bladder (some factors do remain common). Paget hypothesized that these tissue- and organ-specific environments can either stimulate or inhibit metastatic cancer cells growing into secondary tumors. Paget's theory would become known as the 'seed and soil' hypothesis.

Paget had both his supporters and detractors when he published his paper, as is often the case in science. Unfortunately the nature of what cancer is, how it initiates and progresses, and how to treat it, was still completely unknown at the turn of the 20th century after his paper had been published. Like Einstein's theory of gravity waves, the knowledge didn't exist to empirically test his prediction.
But in the last 30 years, the onset of molecular biology finally began to explore and reconsider Paget's hypothesis. The 'soil' he mentions is now referred to as the tumor micro-environment, and it plays an essential role in secondary tumor growth. How and why specific tumors relocate and metastasis to specific organs is still on ongoing discussion. Last November, a team researchers from the University of Texas and elsewhere shined a spotlight on this question when they published their recent work in Nature. Their paper, Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth, finally confirms Paget's predictions definitively.

To make a long (but elegant) story short, Zhang and colleagues proved that when cancer cells from primary breast tumors metastasize to the brain, the micro-environment in the brain is fertile soil for breast cancer cells to grow into secondary tumors. Their experiments demonstrate that astrocytes, a type of cell abundant in everyone's brain, can signal to the freshly-deposited metastatic cancer cell and promote its growth, division, and subsequent tumor formation. It's definitive proof that the 'soil' influences the 'seed' in metastatic cancer and that this phenomena occurs specifically in the brain (for specific cancers originating from the breast). Simply put, astrocytes make little packages (called exosomes) that contain signaling molecules and proteins that are delivered out of the astrocyte, into the micro-environment of the brain, and picked up by the invading cancer cell. Once the cancer cell opens these packages, the content inside promotes the growth of the cell into a new tumor.

The results are challenging and thought-provoking, as most significant scientific breakthroughs tend to be, because the mechanism proven in this paper implicates normal, healthy brain cells as essential players in the development of metastatic tumors. Unfortunately, this means that not only do cancer cells arise as mutated offspring of our own normal cells, but our own normal cells can also promote the growth of metastatic tumors in specific organs. (This was already proven for primary tumors. Scientists have previously shown that tumors and tumor cells recruit the help of local cells in the surrounding micro-environment of the primary tumor to promote its own growth. So the 'seed and soil' hypothesis is also an important paradigm in this respect.)

The good news is that this work details new mechanisms of tumor growth that could serve as targets for drug therapy and personalized medicine. I won't go into detail, but this paper identifies specific molecular factors involved in this signaling process that could also be therapeutic targets. It's a well-executed research story that draws on both historical and contemporary scientific work and theory. The researchers concluded their study (and pay homage to Mr. Paget) by saying:

"Beyond a tumour cell autonomous view of metastasis, our findings highlighted an important plastic and tissue-dependent nature of metastatic tumour cells, and a bi-directional co-evolutionary view of  the 'seed and soil' hypothesis." 

Now I want to take a step back for one moment to discuss scientific theory, evidence evaluation, and prediction in a more fundamental sense. Above we have two examples of researchers who made an observation, gathered evidence, and made a prediction based upon those observations and results. Incredibly, 127 years ago was not too early to predict something like the tumor micro-environment. Paget did this without the use of molecular biology or even the knowledge of the existence of genes (Gregor Mendel's work on genetics and inheritance wouldn't be re-discovered until the early 1900's). Many scientific contemporaries of Paget's were making predictions that would end up being validated once new technology was developed to address those predictions. I wrote a previous post about the recent confirmation of gravity waves, a theory put forth by Einstein nearly a 100 years ago! The fact that the echoes of these individuals can be heard a century later is remarkable. However, what is more important is that this is evidence that the scientific method of evidence gathering and hypothesis generation is a bonafide, tried-and-true methodology. It is the backbone of nearly all scientific progress and most of technology development.

It is also why it's so frustrating to me that people choose to be selective about the science they believe in or consider accurate. It's deeply concerning that politicians and individuals can choose to believe in the latest cancer medication or weapon technology, yet are staunch climate-change deniers or don't believe in the efficacy or power of vaccines (spoiler alert: the HPV vaccine works, is safe. and is drastically reducing HPV prevalence in teenage women). For each of this issues, it is the same scientific method that tested all the science and technology we have available to us. Picking and choosing what we want to believe can be a dangerous precedent when it comes to science and more scientists need to be proactive about discussing and communicating these issues.

I will note here that there are always cracks in the system. Humans are human after all, and ego, bias, financial incentives, and even simple mistakes are influencing factors on what we believe and promote. There is actually an entire website dedicated to highlighting retracted scientific papers that are fraudulent or manipulated or even pulled because of simple errors in analysis. However, these retracted articles are a small portion of what is published each year and this website highlights the growing list of additional checks and balances within the scientific community that go beyond the initial peer-review process and will hopefully allow research to become even more transparent (open access journals are another layer to this process).

The hardest challenge for some in science today is that sometimes it takes a long time to fully validate a theory. It took 20+ years to go from identifying cancer-causing genes all the way to the development of new drugs that target said genes. For some, like Paget and Einstein, it can take a lot longer, but it is just as satisfying to see when their hypotheses are validated too.

A Little Shameless Promotion

I'm excited to announce that the Kids, Vol. 1 horror anthology, which I have a story in, is now live on Amazon for pre-order!  This collection of horror stories features numerous authors from around the world, including some of Britain's finest horror writers.

It's a pleasure to be part of something like this, and honestly new territory for me (I'm not used to promoting books for sale). However, it's sitting pretty at #1 in the UK for horror anthologies on Amazon and it is now #25 in the U.S. So if you are interested in reading about what terrible, creepy things kids can do....this anthology is perfect and I highly recommend pre-ordering! The book will also be available in paperback.

Thoughts on Gravitational Waves: Ripples in Space-Time and Quilts

If you haven't heard, Einstein was correct (again!) in predicting the existence of gravitational waves in space. This week scientists confirmed their existence with the first-ever, direct evidence of gravitational waves by measuring the disturbance in the fabric of space-time when two massive black holes collided almost a billion years ago. It proves without a doubt that the very nature of space can produce waves, just like the surface of the ocean, and that these waves can be detected. Our universe can ripple in response to some huge event. And better yet, the first person to observe the signal was a post-doc! (I'm also giddy because this now takes the name of my blog and nudges it from science fiction closer towards science.) There better be some physicist somewhere who is salivating to get an NSF grant to study the implications of these measurements on time travel. Maybe we can actually go back in time and pretend Trump was never seriously running for President?  

Anyway, it's huge news. Not only is Einstein validated yet again, but there are now new tools to study how the cosmos functions and respond to cataclysmic events - especially the destructive and awe-inspiring nature of black holes. Maybe we can finally prove where all of Schrodinger's cats go when they disappear when the boxes are opened. (What's at the center of black holes? Answer: a shit-ton of cats!). I'm also curious how this will shake out for the Nobel Prize Committee. The 1993 Nobel Prize in Physics went to Joseph Taylor and Russell Hulse for their discovery of indirect evidence of gravity waves (they measured radio waves emanating from a pair of spinning neutron stars as a proxy for gravity waves). Someone has to win for the direct evidence right? I think so. But has anyone ever won for a topic which was already given an award? I don't know. I'll have to look this up. 

In more personal news, I guess I should mention something about writing, as part of this blog's mission is to talk about writing-related topics. Recently, I've found that it's hard to stay motivated. I think most people can relate. The last month with our move, work projects, the epic Baltimore blizzard...I was finding more and more excuses to avoid both house-related projects and working on my science fiction stories. I partially blame my malaise on the fact that most of my projects right now need massive editing. So instead of the luxury of writing whatever comes to mind or imagining new stories, I've been knee-deep in cutting scenes, changing scene order, fixing dialog (a very problematic area for me) and extensive re-writes. And although my work is benefiting from these changes, it can be very hard to muster the motivation to re-re-re-work something in order to hopefully make it better. I've come to learn it's very true the story really takes shape during the editing process. 

Thankfully when it comes to getting motivated I eventually ran out of excuses. I'm now living four blocks away from the Baltimore Science Fiction Society (BSFS). I've known about this group ever since moving to Baltimore over two and a half years ago, but I've never had the chance to pay a visit. So if I couldn't manage a five minute walk I was never going to make it over there.

Thankfully I did.

Thursday night I got to participate in my first ever writer's critique circle. Every other week the BSFS hosts a circle where you can read your work out loud and others can chime-in with constructive criticism and/or mark copies of the story for review at home. It was a nerve-wracking experience. Other than reading out loud to my wife, I've never read to anyone, let alone a group of people I'd just met five minutes before. I usually share my stories with family and friends and they are kind enough to provide me excellent feedback, but I've never done this with strangers. However to my surprise, it was a great experience. Not only did I learn a lot about my own story, the creative juices flowed as I listened to others make comments and suggestions on both mine and others' work. I plan on going again and I think the additional input will help me become a better story teller. It also gave me a window to see how others craft their stories. 

I love story-telling. That's why I write - to tell stories. And to me, writing a story is like making a large quilt. The entire thing is made up of small threads and strands that weave together. Editing reminds me of fixing all the errors after the quilt has been made. Sometimes when I'm reading over my work and making edits all that is required is a little tug and a small thread is woven back into its proper place. Sometimes I feel like I am taking a big pair of scissors and ripping the pattern open. I'll pull out large strands or chunks and patch it all up again, hoping the new threads seal the hole I've created. (I realize that this is probably not quite how a quilt is made but I'm determined to stick with this analogy.) I'm really hoping that after editing the overall pattern remains the same, but I also hope every change is making the pattern better. The hardest part is making sure all the unintended wrinkles and ripples are smooth again after I make a cataclysmic change so it looks as if the entire quilt were made at one sitting. It is tiring and tedious and I hope all the hard work pays off. The input I get from friends and this writing group is invaluable to this process.

Thursday night's meeting made me realize anybody could benefit from this sort of thing. Whether you draw or make music or make movies, design houses...anything. Go out and find a group of people who do something similar and talk to them. I was struck how helpful this could be at work, too. I know at the NIH there are small groups of anonymous readers who will critique a manuscript and give editorial input. But what about how to actually craft and present the data? Almost like a journal club, if you will, where you could meet and discuss how to tell your research story so that it is as strong as it could be before publication. Even a group of close colleagues helping to give input on how a data figure looks, order of the data, or similar conversations would be enormously helpful as one is writing up a paper. Maybe there is such a thing at work? I'll need to look into it. If there is, I'll report back. 

On a totally unrelated note, if you aren't watching the English Premier League then you aren't excited about the awesome games this weekend. Tottenham have a big draw against Manchester City, with huge implications for the top of the table (that's the English word for standings - which sounds more stoic and gentlemanly I think). Leicester City also squares off against Arsenal, another Top 4 match-up. They should be a lot of fun and if you don't watch soccer (aka football) it's a solid weekend to give it a try. Football is over anyway, right?

Back again, soon-ish. Cheerio!