Tighten Up or the Zombie Genes Will Get You

Tighten Up or the Zombie Genes Will Get You

by Guest Blogger,
Tyler Kokjohn, Ph.D. 

Tighten brainWhat happens when we die?  This immensely interesting question has been answered in several different ways.  The scientific study of death is challenging and results acquired from near death experience (NDE) subjects have produced controversy, not consensus.  However, scientists have managed to figure out quite a few things about how our cells die and sometimes, refuse to die (1).

Our understanding of the death process is rudimentary and a recent study of dead animals yielded some unexpected results (2, 3).  These scientists were working under a general assumption that the transcription of genes into RNA (gene expression) would cease quickly after death as physiologic failures mounted.  Examining animals that were indisputably and irreversibly dead, their experiments revealed a wide range of brain and liver genes actually became more active during the post mortem period.  Some genes just kept chugging along after death.

Absolutely fascinating, but what good is this knowledge?  The investigators offered some speculations (3).  If an afterlife for certain genes is found to be a general and reproducible phenomenon it might provide another means for forensic investigators to determine times of death.  Death is a complex process in which organs and body parts perish at markedly different rates.  This situation makes it possible to remove still-viable body parts from the dead and transplant them into others where they may continue to function for years.  More work may reveal that gene expression profiles provide a better means to assess the state of preservation and health of donated organs before they are transplanted.  Cadaveric transplants clearly provide tremendous benefits, but defining procedures for how and when potential donors may be declared dead poses significant medical and ethical challenges (4).  The criteria employed influence what materials will be possible to transplant and the outcomes can sometimes be confusing; hearts harvested from donors declared deceased using cardiac death criteria have been transplanted successfully (4).

The mechanism causing some genes to become activated after death must still be determined, but the investigators have suggested a plausible model to investigate.  They hypothesize that DNA chromosomes unwind in dead cells, allowing genes to become more accessible to the enzymes that transcribe them into RNA.  At this stage it is unclear if and when the post mortem chromosome unraveling process begins or how genes activated after death might influence cell preservation.  Perhaps donor organ preparation processes in the future will include measures to prevent activation of certain genes or inhibit their effects.  However, this area is so new that transplant scientists could easily discover allowing some genes to be activated after death is beneficial.

Researchers investigating brain cancer made sense of some puzzling observations when they realized disruptions in chromosome structure ultimately activated genes promoting malignancy (5).  Additional experiments using CRISPR gene editing methods support their idea specific changes in DNA folding patterns trigger cancer-promoting gene activity and suggest how to mitigate these pathologic alterations (6).  Whether the same mechanisms underlie other cancers is under active investigation.  It will be fascinating to see if death-induced genes are related to any diseases or the ageing process and how closely their activities correlate with DNA unwinding in living cells.

Perhaps it will become as routine for physicians of the future to assess the physical condition of your chromosomes as it is to take a peek at your tonsils today.

“That last gene expression profile suggests your chromosomes are starting to unwind.  I am going to prescribe a topoisomerase activator to tighten them up. Otherwise a zombie gene might wake up and give you cancer.”                    

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(1)   L. Hayflick.  1994.  How and Why We Age.  Ballantine Books, New York.
(2)   M. Leslie.  2016.  ‘Undead’ Genes Come Alive Days after Life Ends.  Science, 22 June 2016.   http://www.sciencemag.org/news/2016/06/undead-genes-come-alive-days-after-life-ends
(3)   A. E. Pozhitkov et al.  2016.  Thanatotranscriptome: Genes Actively Expressed After Organismal Death.  bioRχ, 11 June 2016. http://www.biorxiv.org/content/early/2016/06/11/058305
(4)   R. D. Truog and F. G. Miller.  2008.  The Dead Donor Rule and Organ Transplantation. The New England Journal of Medicine, 14 August 2008 (359:674-675).  http://www.nejm.org/doi/full/10.1056/NEJMp0804474
(5)   G. Kolata.  2015.  Brain Cancers Reveal Novel Genetic Disruption in DNA.  The New York Times, 23 December 2015. http://www.nytimes.com/2015/12/24/health/brain-cancers-reveal-novel-genetic-disruption-in-dna.html
(6)   W. A. Flavahan et al.  2016.  Insulator Dysfunction and Oncogene Activation in IDH Mutant Gliomas.  Nature 529(7584):110-114. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831574/

 

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The Genomic Gutenberg Project – Writing the Living Novels of the Future

The Genomic Gutenberg Project – Writing the Living Novels of the Future

by Guest Blogger,
Tyler Kokjohn, Ph.D.

Koheleth SeqDecoding the over 3 billion DNA base pairs comprising the human genome was a monumental scientific/engineering achievement.  Learning to read genomes was only the beginning and leading scientists propose it is time to develop the capacity to literally write them (1).  Pushing far beyond today’s limits The Human Genome Project-Write will develop the ways and means to manufacture large DNA molecules and edit genomes with them.  One of the ultimate goals is to synthesize the complete genetic code of any organism, including humans.  There seems little doubt the spin-off technologies from the project will be transformative and will almost certainly foster an avalanche of new discoveries in many fields.

It is impossible to envision the full implications of this audacious proposal, but many scientists are in a total tizzy over the amazing prospects.  However, past experience with emerging technologies reminds us there is no certainty every grand vision will come to pass or each idea proposed will be achievable.  Many years ago futurists speculated every home would have mini atomic reactors to generate power and nuclear-fueled vacuum cleaners to help with the housework (2, 3).  Today’s reality – utility companies determined to strangle the rooftop solar industry.  Ideas like deleting potentially dangerous prions (1) seem solid at first glance, but no one knows what function(s) are performed by these genes.  Could eliminating selfish DNA elements (1) change the ways genes are grouped and controlled in living cells and accidentally promote cancer induction (4)?  The unknowns are numerous, but potential complications do not constitute a compelling case to halt the new research initiative.  On the contrary, investigating and understanding them will improve understanding of basic cell biology which might ultimately yield important benefits for human health and wellbeing.

Controversy has been a feature of genomic synthesis work since viral chromosome construction projects generated concerns years ago (5, 6).  Techniques have advanced enormously since the first small viral genomes were assembled, suggesting how fast Shakes writercapabilities might evolve if The Human Genome Project-Write is approved (7).  However, a public storm erupted before the proposal had been outlined (8) with thorny ethical questions and troubling scenarios cropping up immediately (8, 9).  Would someone synthesize Einstein’s genome?  How would such a thing be used?  Extrapolating further, might researchers attempt to stitch together an artificially reconstituted Albert Einstein?  In fairness, no one has proposed anything that extreme.  In addition, proposals along these lines appear ill-considered.  Human beings may not be a true tabula rasa at birth, but environment, education, culture and life experience all play critical roles in development.  It might be technically feasible to duplicate genomes, but it still may never be possible to reproduce persons.  Fiction readers may remember how the nature-nurture idea was explored by Ira Levin in The Boys from Brazil(10).

While many ethical and safety issues concerns raised over The Human Genome Project-Write are hypothetical, it is important to recognize the era of human-constructed life has begun.  Despite daunting technical obstacles, scientists have created and cultured the first artificial bacteria (11).  This synthetic life form has no living analogs, no true evolutionary kin and no known natural ecological niche, but Dr. Venter’s genomic creative writing group has proven it is possible to compose a total biologic fiction that actually works.  They built the thing, but the scientist/creators are not omniscient and do not know what functions are performed by about one third of the genes in their handiwork (11).  Having raced into unknown territory they must now wait to see if these new living fabrications adhere to their own private, unpredictable rules.  One book of life has been re-written and there is something new under the sun.  The problem is no one is quite sure what this thing will do.

The Human Genome Project-Write might be the 21st century genetic equivalent of invention of the movable type printing press by Johannes Gutenberg.  The groundbreaking accomplishments of today only hint at the forthcoming not-of-this-natural-world fictions when future scientific Shakespeares are empowered to publish their own living novels.

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(1)    J. D. Boeke et al.  2016.  The Genome Project-Write.  Science, 8 July 2016 [353(6295):126-127].http://science.sciencemag.org/content/353/6295/126.full
(2)    S. Dalquist.  2004.  Timeline – A Chronology of Public Opinion on Nuclear Power in the United States and United Kingdom.  Massachusetts Institute of Technology.  http://web.mit.edu/skd/www/dalquist-nuclear-opinion.pdf
(3)    R. Strohmeyer.  2008.  The 7 Worst Tech Predictions of All Time. PC World, 31 December 2008. http://www.pcworld.com/article/155984/worst_tech_predictions.html
(4)    G. Kolata.  2015.  Brain Cancers Reveal Novel Genetic Disruption in DNA.  The New York Times, 23 December 2015. http://www.nytimes.com/2015/12/24/health/brain-cancers-reveal-novel-genetic-disruption-in-dna.html
(5)    J. Couzin.  2002.  Active Poliovirus Baked From Scratch.  Science, 12 July 2002.  http://science.sciencemag.org/content/297/5579/174.2.full
(6)    S. M. Block and D. Kennedy.  2002.  A Not-So-Cheap Stunt.  Science, 2 August 2002 [297(5582):769-770].  http://science.sciencemag.org/content/297/5582/769b
(7)    J. Temple.  2014.  Autodesk Builds Its Own Virus as the Software Giant Develops Design Tools for Life Itself.  Recode, 5 May 2014. http://www.recode.net/2014/5/5/11626456/autodesk-builds-its-own-virus-as-the-software-giant-develops-design
(8)    A. Pollack.  2016.  Scientists Talk Privately About Creating a Synthetic Human Genome.  The New York Times, 13 May 2016.  http://www.nytimes.com/2016/05/14/science/synthetic-human-genome.html?src=me
(9)    D. Endy and L. Zoloth.  2016.  Should We Synthesize a Human Genome?  Cosmos, 12 May 2016.  https://cosmosmagazine.com/society/should-we-synthesise-a-human-genome
(10)  S. Martelli.  2011.  The Boys From Brazil by Ira Levin – A Review.  The Guardian, 6 August 2011.  https://www.theguardian.com/books/2011/aug/07/boys-from-brazil-levin-review
(11)  E. Callaway.  2016.  ‘Minimal’ Cell Raises Stakes in Race to Harness Synthetic Life.  Nature, 24 March 2016 (531:557-558).  http://www.nature.com/news/minimal-cell-raises-stakes-in-race-to-harness-synthetic-life-1.19633

Also of interest on JayVay – We Will Replicate You Wholesale  https://jayvay.wordpress.com/2016/05/19/we-will-replicate-you-wholesale/

 

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Remember Ted’s Frozen Head?

Remember Ted’s Frozen Head?

by Guest Blogger,
Tyler Kokjohn

Could people in the next century see a Tweet and news story like this?

jer-earth-thumb.jpg

Re-animated 20th century baseball legend Ted Williams discovered destitute and wandering Boston as his batteries run down JayVayCentury22. #NowhereToGo

JayVay Century 22                                                                                                 July 4, 2116
The Official Online Repository of All Things Jeremy Vaeni

Ted W CardThe legendary Ted Williams has experienced a series of mishaps and legal difficulties after his cryopreserved (frozen) head was revivified and fused with a battery-powered robotic device.  Unable to make a living after the Supreme Court ruled unanimously that autographs produced by the mechanical contrivance now performing his bodily functions were counterfeit, a second ruling that all persons officially declared dead remain ineligible to receive social security pensions in perpetuity has left him financially destitute.  The Major League Baseball Players Association has deferred reinstatement of his pension until attorneys determine whether the secret process used to reactivate Mr. Williams violates an organizational ban on the use of performance-enhancing substances. 

An anonymous group of investors alleged to include transhumanist promoter-entrepreneurs conceived and funded the effort to reanimate Ted Williams’s cryopreserved head to exhibit the latest advancements in organo-robotic amalgamation technology. The newly resurrected Mr. Williams was informed he would headline a nationwide tour of major league ballparks providing clinics on the art of hitting.  Unfortunately, it soon became obvious that the currently operational Mr. Williams could not hit baseballs like the natural-born original version.  Mr. Williams ultimately refused to make public appearances, objecting to being put on display as a freak.  Infuriated over mounting expenses involved in maintaining a total ingrate who would not perform as desired and unable to sue for breach of contract, one investor attempted to physically disconnect Ted’s main battery unit.  This confrontation revealed that although his home run days are over, the Marine could still swing a mean left.  Charges of attempted murder against the outraged attacker were later dropped due to the insurmountable legal complexities posed by Mr. Williams having been declared legally dead over a century earlier.

Ted’s fate is uncertain and if you would like to contribute…

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Ted FrozenIf scientists and technologists in the 22nd century still adhere to the norms and procedures guiding researchers today, the scenario above will probably never come to pass.  In the event the future custodians of the frozen remains of Mr. Williams did not reject a revivification scheme outright, they would (or should) seek formal approval to proceed from a committee of persons not involved in the project.  The committee provides an independent assessment of the merits and risks of the proposed work and most important, takes the authority to proceed out of the hands of those most likely to have a conflict of interest.

As amazing advances become routine, perhaps scientists of the future will be subject to fewer regulations.  In Regenesis (1), George Church and Ed Regis contend that objections to new technologies peak at the stage of first adoption, before they are perfected (page 85).  Citing in vitro fertilization procedures as an example, they go on to declare that once the problematic technical issues with a new approach are eliminated, ‘the moral high ground can invert’ to a point where withholding its use at times may actually become unacceptable.

Clearly, public acceptance of new technologies can change substantially over time.  Reactions to gene editing work conducted in human embryos suggests the scientific community also adapts quickly to emerging developments.  What turned out to be well-founded rumors of human embryo gene editing prompted ethical soul-searching and a swift call from a group of leading scientists to impose important constraints on some studies (2, 3, 4).  However, one year later as research teams were gearing up to conduct their own experiments, the second published journal report of human embryo editing produced little reaction (5).  If concerns over technical proficiency are the dominant basis for objections among the general public to new biomedical advances, maybe the code of ethics currently constraining research and development will be revamped to reflect this attitude.

Current norms for safe and ethical research practices represent an evolving consensus crafted from years of hard experience.  New technologies and situations may require the creation of entirely new rules or the modification of longstanding policies.  The relentless pace of research means this alteration process is actually continuous and often contentious.  For example, a proposal to expand informed consent requirements to include stored bio-specimen samples has caused researchers to object their work will be hampered for little gain (6).  How the scientists of the future will go about their work hinges on the outcomes of research projects today.  Will the Personal Genome Project (7) revolutionize medicine or might participants come to regret surrendering their private data?  Will the gene drive research community voluntarily conduct research openly or remain behind closed doors (8)?  Is one practice more likely to lead to mistakes?  The only certainty ahead is that the rules will change.

The talented scientists of today will lead humankind into the future.  Along the way, societies must demand these ambitious researchers envision the full implications and aftermath of their efforts.  The discoveries to come will no doubt be awe-inspiring.  However, enthusiasm runs cold whenever we remember the frozen head of Ted Williams.

  1. G. Church and E. Regis.  2012.  Regenesis. How Synthetic Biology Will Reinvent Nature and Ourselves.  Basic Books, New York.
  2. E. Lanphier et al.  2015.  Don’t Edit the Human Germline. Nature, 26 March 2015 (519:410-411). http://www.nature.com/news/don-t-edit-the-human-germ-line-1.17111
  3. D. Baltimore et al.  2015.  A Prudent Path Forward for Genomic Engineering and Germline Genetic Modification.  Science, 19 March 2015 [348(6230):36-38]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394183/
  4. D. Cyranoski and S. Reardon.  2015.  Embryo Editing Sparks Epic Debate.  Nature, 29 April 2015 (520:593-595). http://www.nature.com/news/embryo-editing-sparks-epic-debate-1.17421
  5. E. Callaway.  2016.  Gene-editing Research in Human Embryos Gains Momentum.  Nature, 19 April 2016 (523:289-290). http://www.nature.com/news/gene-editing-research-in-human-embryos-gains-momentum-1.19767
  6. S. Reardon.  2016.  Science Academies Blast U.S. Government’s Planned Research-ethics Reforms.  Nature, 29 June 2016 (535:18). http://www.nature.com/news/science-academies-blast-us-government-s-planned-research-ethics-reforms-1.20191
  7. The Personal Genome Project http://www.personalgenomes.org/
  8. A. Regalado.  2016.  Meet the Moralist Policing Gene Drives, A Technology that Messes with Evolution.  Technology Review, 7 June 2016.  https://www.technologyreview.com/s/601634/meet-the-moralist-policing-gene-drives-a-technology-that-messes-with-evolution/

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