We Will Replicate You Wholesale

We Will Replicate You Wholesale: 
Envisioning the Human Genome Project, Part 2

By Guest Blogger,

Tyler Kokjohn, Ph.D.

Frankenstein at work in his laboratory

Leading scientists, biotechnology entrepreneurs and influencers met last week to discuss a possible second phase of the Human Genome Project (1).  The first phase involved the physical mapping and determination of the DNA nucleotide base sequence of the entire human genome.  The possible second phase would involve improving the capacity to synthesize DNA.

The New York Times reported the meeting was private and attendees were requested to refrain from contacting the news media or posting on Twitter during the event.  These restrictions produced sharp criticism from scientists objecting to holding discussions with such enormous ramifications behind closed doors (2).  However, Dr. George Church suggested that the critics were inaccurately representing the aims of the conference and organizers, including Dr. Church, consider the ethical issues already addressed sufficiently.  In addition, Dr. Church explained the meeting was closed to news media and attendee communications were restricted because the organizers had submitted a paper to a scientific journal.  Many journals bar the public release of information until it has been published.

Notwithstanding the feelings among the conference organizers the ethical issues were covered, a discrete, invitation-only get-together may have reflected the fact that original title and goals for the conference were extremely provocative; the Human Genome Project 2 (HGP2) would seek to synthesize a complete human genome in a cell line.  Both the conference title and the goals were re-worked into something less audacious before the actual meeting was held.  Misunderstanding or not, the battle is joined.

Part of the intent of the conference was to outline strategies to improve DNA synthesis technology.  Creating entire synthetic genomes will require the production of large, high quality (i.e. correct sequence) DNA molecules at affordable costs.  For the moment, dreams of synthetic genomes are limited by DNA fabrication capacities.  However, the original Human Genome Project faced daunting technical obstacles which were overcome or circumvented.

If creating artificial human genomes is on the back burner, what will they do?  Maybe the work of Dr. J. Craig Venter offers a model (3).  Dr. Venter and associates created a synthetic bacterium with the possibly minimal size genome necessary to allow independent growth in culture.  Seeking to reduce life to its functional limits, Dr. Venter’s group may be on a fast track to the full synthesis of a working genome from scratch that could provide an ideal platform for genetic engineering purpose-built artificial microbes (4).  Perhaps the blueprints for human organs will be cobbled together and placed in animals modified to eliminate endogenous viruses (5).  That might create an ideal source of organs that could be safely transplanted into humans.

Should limits once again quickly become milestones, HGP2 may take us to the point where chemically synthesizing a human genome from scratch is feasible.  If Dr. Venter and the original Human Genome Project taught us anything it is that technology can advance with astonishing speed (6).  Dr. Church noted in his book with Ed Regis that objections to new technologies peak as it is poised to spread, but doesn’t yet work well. Once the technical bugs are worked out, the moral high ground can invert (7).  If and when science enables human entities to be replicated wholesale the groundswell he anticipates may turn out to be an earthquake.

_____________________

(1)    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

(2)   D. Endy and L. Zoloth.  2016.  Should We Synthesize a Human Genome?  Cosmos, 12 May 2016.  https://cosmosmagazine.com/society/should-we-synthesise-human-genome

(3)   E. Callaway.  2016.  Minimal Cell Raises Stakes in Race to Harness Synthetic Life. Nature, 24 March 2016. http://www.nature.com/news/minimal-cell-raises-stakes-in-race-to-harness-synthetic-life-1.19633

(4)   M. Eisenstein.  2016.  Living Factories of the Future.  Nature, 16 March 2016.   http://www.nature.com/nature/journal/v531/n7594/full/531401a.html

(5)   S. Reardon.  2015.  Gene Editing Record Smashed in Pigs.  Nature, 6 October 2015.  http://www.nature.com/news/gene-editing-record-smashed-in-pigs-1.18525

(6)   R. Preston.  The Genome Warrior.  The New Yorker, 12 June 2000. http://www.mindfully.org/GE/Venter-Genome-Warrior12jun00.htm

(7)   G. Church and E. Regis.  2012.  Regenesis – How Synthetic Biology Will Reinvent Nature and Ourselves.  Basic Books, New York, NY.  (p. 85)

 

Also of interest on JayVay and The Center for Bad Ideas

            https://centerforbadideas.wordpress.com/2013/02/11/making-franken-sense/

https://jayvay.wordpress.com/2015/04/08/rewriting-all-the-rules-the-arrival-of-       genomic-editing/

 

###

Gene Drives – Will Conqueror Biomolecular Bots Dictate a New Book of Life?

Gene Drives – Will Conqueror Biomolecular Bots Dictate a New Book of Life?
By Guest Blogger,
Tyler Kokjohn, Ph.D.

 A new DNA engineering technique known by the strange name CRISPR-Cas9 allows scientists to edit the genomes of living cells with unprecedented ease and precision (1).  The method has only been in wide use for a few years, so it is hard to envision all the breakthroughs it will foster.  However, it is already clear the implications will extend far beyond the laboratory and clinic.

Conqueror WormThe CRISPR-Cas9 DNA editing system is versatile, but scientists have extended its capabilities by creating powerful new forms of this technology which function as gene drives (2).  A gene drive disperses genetic alterations or DNA cargo rapidly through a population by overruling the normal patterns of inheritance.  A recipient of a gene drive receives the complete genetic information needed to synthesize the enzymes and guide molecules required to edit pre-programmed DNA targets.  This new genetic information is incorporated directly into the recipient genome and will be transmitted to all progeny during sexual reproduction.  Because they will work automatically and are self-spreading after their release, gene drives may make it possible to edit the genetics of entire populations of wild animals to suit human specifications (3).

Gene drives may provide an effective means to control invasive species as well as a wide range of zoonotic diseases like malaria, dengue, Zika fever and Lyme disease (4).  Despite the urgency, gene drives are wholly unproven control methods that must be tested to confirm their efficacy and safety.  The problem with natural ecosystems is their innate complexity; everything literally is connected to everything else.  That complexity can make it impossible to foresee adverse events and some issues only become apparent after the passage of considerable time.  Even simple changes may create a chain reaction of ramifications.  For example, the wide use of the nonsteroidal anti-inflammatory drug diclofenac in veterinary medicine was probably deemed to have few significant environmental impacts.  However, while safe for many animals, vultures feeding on carcasses of diclofenac-treated animals developed lethal kidney failure due to deposition of uric acid (5).  When vulture populations in India collapsed, feral dog populations expanded as this food source became available.  An increased number of wild dogs seems to have been an important factor in a sudden surge of human rabies (5).  That using diclofenac in veterinary medicine would result in a chain of events culminating in more human deaths from rabies would have been hard to predict before the fact.

Scientists involved with gene drive technology have undertaken proactive efforts to fully inform their colleagues and the general public about issues involved in its use (2).  One general problem with released gene drives is that their impacts, good or bad, could become permanent.  In fact, some propose creating ‘crash drives’ intentionally designed to change the species composition of ecosystems (6).  Crash drives that interfere with reproduction might provide a precise means to eliminate undesired organisms like mosquitoes.  Using and evaluating such potentially powerful technology will demand extraordinary care (2) because release of a crash drive might ultimately result in the deliberate extinction of an entire species.  Assessing the benefits and risks of gene drives will be challenging because natural environments are complex, dynamic and sometimes just plain surprising.

Gene drives are immensely promising, potentially far-reaching tools.  Their intended impacts on targeted species could range from tiny genetic tweaks to total annihilation.  Predicting the full environmental consequences of their use is essentially impossible.  Recently, concerns over whether fully autonomous weapons are a permissible military technology prompted serious discussion (7).  The future use of gene drives warrants similar deliberation.  Sovereign, self-spreading and as immortal as the species they will conquer, these invisible biomolecular bots could turn out to be more fearsome than killer robots.  Unless we are careful or perhaps just plain lucky, freed or escaped gene drives could become DNA dictators empowered to rewrite the book of life.

 

_________________________

(1)    H. Ledford.  2016.  CRISPR:  Gene Editing is Just the Beginning.  Nature, 7 March 2016. http://www.nature.com/news/crispr-gene-editing-is-just-the-beginning-1.19510

(2)   K. M. Esvelt et al. 2014.  Emerging Technology: Concerning RNA-guided gene drives for the alteration of wild populations. eLife 2014;3:e03401 https://elifesciences.org/content/3/e03401

(3)   J. Lunshof.  2015.  Regulate gene editing in wild animals. Nature 521:127 (14 May 2015) http://www.nature.com/news/regulate-gene-editing-in-wild-animals-1.17523

(4)   R. Stein.  NPR Morning Edition, 5 November 2015.  http://www.npr.org/sections/health-shots/2015/11/05/451216596/powerful-gene-drive-can-quickly-change-an-entire-species

 (5)   C. Biondolillo. 2014.  Scientists Call on Spain to Ban Vulture-killing Drug.  Science, 28 March 2014.  http://www.sciencemag.org/news/2014/03/scientists-call-spain-ban-vulture-killing-drug

 (6)   N. Wade.  2015.  Gene Drives Offer New Hope Against Diseases and Crop Pests. New York Times, 21 December 2015. http://www.nytimes.com/2015/12/22/science/gene-drives-offer-new-hope-against-diseases-and-crop-pests.html?_r=0

 (7)   Author Anonymous.  Killer Robots:  The Case for Human Control.  Human Rights Watch, 11 April 2016.  https://www.hrw.org/print/288611

 

Also of interest on JayVay  

https://jayvay.wordpress.com/2016/04/29/trust-them/           https://jayvay.wordpress.com/2016/04/19/titanic-opportunities/          https://jayvay.wordpress.com/2015/04/08/rewriting-all-the-rules-the-arrival-of-genomic-editing/

 

###

You Can’t Catch Alzheimer’s Disease, Can You?

You Can’t Catch Alzheimer’s Disease, Can You?

By Guest Blogger,
Tyler Kokjohn, PhD.

Transmissible ADAlzheimer’s disease (AD) does not spread from person to person like a cold virus, but some recent findings suggest the unsettling possibility it might be transmitted through medical procedures (1).

Deadly diseases have been transmitted through medical procedures such as blood transfusions, organ transplants and surgery.  In fact, this new concern about AD was sparked by the grim legacy of a past medical practice in which hormone preparations obtained from human cadavers were injected into children who were not growing normally.  What the physicians did not know at the time was that pathologic prions, abnormally shaped proteins producing the rapidly lethal neurodegenerative illness known as Creutzfeldt-Jakob disease (CJD), contaminated some of these hormone preparations.  Over two hundred cases of fatal CJD appeared ultimately in patients who had received cadaveric growth hormone supplements (2).

An unforeseeable sequence of events is thought to have led to the cadaveric growth hormone therapy tragedy.  CJD is a rare disease most often appearing in persons over age 60 (3).  Although clinically obvious CJD is rare, protein mis-folding occurs spontaneously during normal aging and many outwardly healthy persons die with some pathologic prions in their brains.  Perhaps these individuals would have succumbed to CJD if they had lived a little longer.  Hormone therapy necessitated pooling pituitary tissue from large numbers of deceased donors some of whom probably harbored toxic CJD prions without exhibiting any signs or symptoms of disease.  Unfortunately, over 200 hormone recipients received enough pathologic prions during their treatments to develop CJD in short order.

Examination of brain tissue samples from a small group of the growth hormone recipients who died of CJD revealed half of them had amyloid deposits reminiscent of those found in AD patients.  However, these patients were much younger than the typical AD patient and finding such amyloid deposits in them was unexpected.  After ruling out the possibility the results could be explained by genetic mutations linked producing early onset AD, the investigators recognized there was an alarming possibility some CJD prion-contaminated growth hormone injections also transmitted this key pathologic change linked to AD dementia as well.

Another medical procedure, transplantation of cadaveric dura mater, the tough outer covering of the brain, has also been recognized to have transmitted CJD.  A second study of several deceased CJD patients who had received transplants of cadaveric dura mater (the tough outer covering of the brain) revealed the presence of AD amyloid pathology in some of them.  The observations may be explained in several ways, but the results are consistent with the idea that that dura mater transplants also promoted amyloid pathology development.

These new observations have potentially staggering implications.  Scientists do not know how prions produce the massive neurodegeneration characteristic of CJD, but they have convincing evidence the process begins when a normal protein changes its shape.  These abnormal prions seed and spread this neurotoxic change throughout the brain by initiating a relentless chain reaction which forces their remaining normal relatives to adopt the pathologic shape.  The toxic seeds may appear spontaneously, but CJD has been confirmed to have been transferred through several types of medical interventions including contaminated growth hormone injections, surgical procedures and transplants.  Pathological changes associated with several neurodegenerative disorders may spread through the brain using similar prion-like mechanisms (4), prompting concern that medical procedures could also spread AD and other conditions as well.  Discovering some recipients of cadaveric growth hormones and dura mater grafts who died of CJD (5) also had amyloid deposits suggests these treatments introduced the seeds necessary to initiate both CJD and AD-like pathologic changes.

CJD is a rare disease and to see an explosion of cases due to hormone replacement therapy and transplants was shocking.  Cadaveric pituitary hormone replacement therapy was eliminated over 30 years ago when brain extracts were supplanted by synthetic preparations and dura mater grafts are no longer performed.  While the epidemic of induced CJD seems to have subsided, the question now is whether another problem has been exposed.  AD is a far more common affliction than CJD, suggesting that hormone replacement injections and transplants were much more likely to have introduced amyloid seeds than CJD prions.  The true proportion of persons injected with cadaveric hormones or receiving dura mater transplants who consequently developed amyloid deposits in their brains is unknown.  This group is still comparatively young and only a small number of them have come to autopsy and been studied to date.  Conceivably a high proportion of them are incubating prions today and could go on to ultimately develop dementia or suffer the toxic effects of amyloid deposits.

Unfortunately, because AD is widespread, if the ideas as to how this pathology extends itself are correct the number of persons being seeded with toxic amyloid through medical procedures might be enormous.  Pathologic prions are notoriously difficult to inactivate (6) and with neurosurgery where there is a high risk they might be present, stringent methods are employed to prevent their spread.  Because pathologic prions are so tough to eliminate there is a possibility that medical protocols performed with less stringent precautions such as general surgery conducted at other body sites, transplants and blood transfusions have all been inadvertently spreading the seeds of toxic amyloid.  It is important to note that what has been seen in the deceased pituitary hormone and dura mater graft recipients is not precisely AD, but an apparent transmission of amyloid pathology similar to that typical of demented patients.  In addition, to date only brain-associated materials have been identified as a possible source of putatively neurotoxic amyloid seeds.  However, even if ‘only’ an amyloid pathology was seeded and spread within these patients, such deposits are potentially toxic and therefore cause for great concern.

AD is not contagious, but is it transmissible by medical procedures?  At this point we still have only a vague understanding of the natural history of prion diseases.  Newly arising information suggests a pathological change linked to AD, amyloid deposits, could be seeded or accelerated by some invasive medical interventions, but the frequency of such events and the degree of threat posed by them is uncertain.  Work is in progress to confirm these observations and establish their potential implications for human health

_________________

(1)   A. Abbott.  2016. The red-hot debate about transmissible Alzheimer’s.  Nature 16 March 2016. http://www.nature.com/news/the-red-hot-debate-about-transmissible-alzheimer-s-1.19554

(2)   B. S. Appleby et al.  2013.  Iatrogenic Creutzfeldt-Jakob disease from commercial cadaveric human growth hormone.  Emerging Infectious Disease. 19(4): 682–684. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647424/)

(3)   Creutzfeldt-Jakob Disease Fact Sheet.  http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm

(4)   G. Miller. 2009.  Could they all be prion diseases? Science 326:1337-1339.  http://science.sciencemag.org/content/326/5958/1337.full

(5)   A. Abbott.  2016.  More evidence emerges for ‘transmissible Alzheimer’s’ theory.  Nature 26 January 2016. http://www.nature.com/news/more-evidence-emerges-for-transmissible-alzheimer-s-theory-1.19229

(6)   D. Dormont.  2002.  Prion diseases: Pathogenesis and public health concerns. FEBS Letters 529:17-21.  http://onlinelibrary.wiley.com/doi/10.1016/S0014-5793(02)032684/abstract;jsessionid=A70616D5CBA695BB66402DBAB86FBBEC.f04t02

###