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."
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."
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!
