CRISPR Genomic Editing – Dark Night of the Soul

Success has a thousand fathers, failure is an orphan

An announcement the first CRISPR genetically engineered human babies had been born in China produced quite a reaction (1).  Denounced widely across the world as unethical, a Chinese government investigation revealed serious faults with the research of Dr. He Jiankui along with violations of state regulations (1).  Notwithstanding the proverb about success having a thousand fathers, few probably want to be linked to an alleged scientific first described by a leading expert in the field as reckless and medically unnecessary (2).  Unfortunately, a Stanford University researcher was dragged directly into the debacle with charges he had provided critical aid and advice to Dr. He (1).         

Stanford University moved quickly to investigate whether any of its researchers were complicit in the unethical exploits of Dr. He.  The findings were unequivocal; the Stanford researchers neither participated in the editing of human embryos for implantation and birth, nor did they have any research, financial or organizational ties to that work (3, 4).  Further, the Stanford University report reveals when Dr. He did not halt his effort following expressions of ethical misgivings from his colleagues, the researchers then recommended he follow standard practices for research with human subjects, including identifying an unmet medical need for the work (3).       

Stanford researchers have been exonerated, but the situation was resolved in a narrow sense and going forward the scientific community remains in a muddle.  Stronger safeguards have been called for (2) and Stanford University reiterated its willingness to work on developing shared guidelines (3), but with scientific research now globalized and a hodgepodge of organizations involved it is not clear how that might come about. 

An Exoneration, Not a Resolution

The good news is that the objective evidence revealed the Stanford scientists did not support what Dr. He proposed to do.  It could be that the fallout from these events will make others more mindful of ethical pitfalls and help avoid them in the future.  However, how and where to report troubling confidential confessions of a colleague working at another institution in another nation is not obvious. More conflicts and dilemmas are certain to follow.  It may not require too many more demonstrations that researchers have few means to formulate, police and enforce operational standards before political forces intervene.   

Researchers are action oriented, but, although some seem confused about this, perceived scientific merit on its own never constitutes an ethical justification for an experiment.  The danger for the scientific community is that ethical dilemmas and transgressions are occurring with regularity across a broad range of fronts (5, 6).  Genomic editing of humans has had its dark night of the soul with the CRISPR babies scandal.  At some point the scientific community must recognize it can no longer afford to create more orphans. 

 

(1) Pam Belluck.   Gene-Edited Babies: What a Chinese Scientist Told an American.  The New York Times, 14 April 2019.  https://www.nytimes.com/2019/04/14/health/gene-editing-babies.html

(2) Jennifer Doudna.   He Jiankui.  Time 100 Most Influential People, 2019.  Time.com. http://time.com/collection/100-most-influential-people-2019/

(3) 2019.  Stanford Statement on Fact-Finding Review Related to Dr. Jiankui He.  Stanford News, 16 April 2019.  https://news.stanford.edu/2019/04/16/stanford-statement-fact-finding-review-related-dr-jiankui/

(4) Pam Belluck. Stanford Clears Professor of Helping With Gene-Edited Babies Experiment.  The New York Times, 16 April 2019.  https://www.nytimes.com/2019/04/16/health/stanford-gene-editing-babies.html

(5) Sara Reardon.   Pig Brains Kept Alive Outside Body for Hours After Death.    Nature, 17 April 2019.  https://www.nature.com/articles/d41586-019-01216-4

(6) Denise Grady.   Risky Stem-Cell Treatments Come Under F.D.A. Scrutiny – Again.  The New York Times, 3 April 2019.    https://www.nytimes.com/2019/04/03/health/stem-cells-fda.html

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Rewriting Ecosystem Genetics – How Has That Worked for Us So Far?

Reports published in The New York Times reveal a dangerous antibiotic resistant microbe is spreading across the world (1).  The amazing plot twist to this medical horror story is that we created the monsters that now stalk us.  A studied silence facilitated the spread of our new foes; medical care facilities were understandably reluctant to announce they had been colonized by potentially life-threatening – and invisible – invaders (1, 2).  Unfortunately, the genesis of these beasts has deeper roots than a failure to disclose its presence to prospective patients.

Survival of the Most Resistant

A yeast species, Candida auris, has been identified as the cause of an emerging infectious disease now popping up in immune-compromised human patients across the world. (1).  Because C. auris strains are typically resistant to one or more of the anti-fungal agents physicians would ordinarily use to combat this class of microbe, an infection with one of them may become an intractable complication and perhaps a direct cause of death for some critically ill patients (1). 

Microbes are ubiquitous in the environment, and although it is an oversimplification, an old microbiologist’s quip, ‘everything is everywhere, the environment selects,’ offers some insights into the current situation.  In this instance it is suspected drug resistant C. auris strains may have prospered as a direct consequence of human activities, specifically the broad employment of fungicides to protect seeds and crops from destruction by molds.  Adding powerful fungicides to the environment and agricultural products antagonizes sensitive microbes, as intended.  However, resistant species and strains survive, reproduce and sometimes disseminate.  In essence, it is likely human activities created environmental conditions favoring the emergence of resistant C. auris strains and a globalized economy helped them spread (1). 

A Familiar Story

C. auris is a new addition to the roster of our microbial pathogens, but the general story is one that should be familiar because it has been repeated many times over multiple decades (3). The antibiotic miracle which has saved so many lives is an epic tale of spectacular successes, crushing failures and vanquished enemies that resurrect or have been replaced with new foes (3). A factor common to many of these events is selection for increased microbial drug resistance by our medical and agricultural practices.  Antibiotic treatments are Darwin’s selection conjecture taken to its most brutal extreme where drug resistant microbes survive, thrive and multiply in environments laden with anti-microbial agents.  Penicillins and many other wonder drugs that once eradicated deadly bacterial infections are now useless against many of our genetically reconfigured enemies.  To enter a hospital today is to venture into a jungle of antibiotic resistant microbes of our own creation.  Our food animals, stuffed full of antibiotics for economic reasons, are living pathogen incubators.  Triclosan and food additives may be changing the composition of our essential microbiomes with unknown long term health ramifications.  In a world drenched with antimicrobial agents, resistant bugs reign supreme.

The Red Queen Rules

Humans have been conducting technology-enabled, mass scale genetic adulterations of the environment for decades, we just didn’t consider that was what we were doing in those terms.  Think of the insecticide DDT (4).  We once used it in bids to attempt chemical genocides of disease vectors and agricultural pests.  As we achieved spectacular successes against our enemies, our actions also set in motion a genetic selection process.  Eventually, along with other consequences, we ended up with ecosystems occupied by genetically transformed squatters resistant to DDT.  Our interventions did ultimately change the genetic compositions of our living, dynamic environments, just not in the way we originally intended.

Vicious cycles of action-genetic reaction unintentionally trapped us on a technology treadmill.  The solution to the rise of resistant insects has been to devise new types of toxic insecticides.  The answer to an emergence of herbicide resistant weeds, creating new generations of plant killers.  When antibiotics failed, new generations were synthesized or entirely novel mechanism classes developed.  The questions stayed mostly the same, but we never seem to get to any ultimate solutions or final answers.  These cascades of sequential product washouts may be harming us more than our microbe enemies.

 

If the rise of microbial resistance to antibiotics over the decades teaches us anything it should be a sense of great humility.  Not appreciating the remarkable scope, interconnectedness and evolutionary flexibility of prokaryotic genomes, a common and confident consensus among authorities a few decades ago was that the war against infectious diseases had been won (5).  However, to defeat antibiotics bacteria were not limited to mutating their own chromosomal genes, several types of accessory mobile DNA elements encode functions able to inactivate the toxic molecules or pump them out of cells.  Plasmids and other nomadic genetic elements harboring drug resistance genes eventually found their way into bacterial communities and multiplied in environments laden with antibiotics.  When humans first began deploying antibiotics, no one anticipated that some microbes had already solved the issues they posed and would pass the essential genetic information for resistance through the community.  It’s hard to foresee what you cannot imagine.  Worse, we have failed to learn from the numerous hard experiences of antibiotic treatment failures.

Human Vision vs. the Blind Watchmaker

Scientists have created a new technological approach to combat diseases and issues posed by invasive species; gene drives.  In principle these tools will enable humans to alter the genetics of wild organisms directly to achieve human goals.  Perhaps they will break the chain of malaria transmission by uploading genetic alterations that cause key mosquito vectors to go extinct.  Maybe gene drive overwrites of wild mouse genomes could prevent Lyme disease infections of humans and our companion animals.  These are laudable goals, will gene drive technology make them attainable?  Although the goals are simple, the situations are deceptively complex and a better question might be what makes us believe if we use gene drives we can now foresee the outcomes?    

  
The many systematic efforts to re-engineer ecosystem genetics to human needs employing antibiotics and pesticides never yielded lasting successes.  Instead, the ultimate outcomes demonstrated decisively that we do not comprehend the complex systems we attempted to transfigure to our own parochial specifications.  History proves our knowledge was too limited and our models too simplistic to reveal the future ramifications of our well-intentioned manipulations.  Anyone boldly imagining themselves qualified to permanently rewrite the genetics of ecosystems may be well advised to pay attention to the past.  Our future will be rooted there.  

 

(1) Matt Richtel and Andrew Jacobs.   A Mysterious Infection, Spanning the Globe in a Climate of Secrecy.  The New York Times, 6 April 2019.  https://nyti.ms/2G2C2jY

(2) Matt Richtel.   Candida Auris: The Fungus Nobody Wants to Talk About.  The New York Times, 8 April 2019.  https://nyti.ms/2FYlUPa

(3) Mitchell Cohen.   1992.  Epidemiology of Drug Resistance: Implications for a Post-Antimicrobial Era.  Science 257:1050-1055.  https://science.sciencemag.org/content/257/5073/1050

(4) Kai Kupferschmidt.   2016.  After 40 Years, the Most Important Weapon Against Mosquitoes May Be Failing.  Science, 13 October 2016.  https://www.sciencemag.org/news/2016/10/after-40-years-most-important-weapon-against-mosquitoes-may-be-failing

(5) Brad Spellberg and Bonnie Taylor-Blake.   2013.  On the Exoneration of Dr. William H. Stewart: Debunking an Urban Legend.   Infectious Diseases and Poverty 2:3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707092/#__ffn_sectitle

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And Yet We Saw It Move

Are mainstream scientists willfully blind to phenomena beyond the safe boundaries of orthodoxy?  Taking a fracas provoked by the discovery of interstellar object ‘Oumuamua (1l/2017 U1) (1) as a point of departure, an essay posted on The Daily Grail (2) offers evidence that closed-minded scientists might impede the discovery process.

Everyone a Skeptic, Everyone a Potential Target

Clearly, many scientists are decidedly unenthusiastic about certain claims regarding phenomena outside the customary boundaries of mainstream thought.  It must also be agreed that some approach fringe topics, and those promoting them, with disdain.   However, the ‘Oumuamua controversy demonstrates that even the most highly accomplished insiders such as Dr. Abraham Loeb will not escape scathing criticism for espousing assertions their colleagues deem based on flimsy evidence.  There is no doubt that ‘Oumuamua is a genuine anomaly, but extrapolating from strange observations to an alien creation is too great a leap beyond less exotic competing explanations.  To reach his ‘therefore, aliens’ conclusion, Dr. Loeb did not uncover something in the data no one else had seen, he added a colorful – non-falsifiable – explanatory hypothesis that caught eyes and unleashed ire.  

Next Steps

Dr. Loeb states he hopes to drive the scientific community to collect more data on the next interstellar object (2).  In fact, this would be a traditional approach to develop evidence supporting (or refuting) any hypotheses on the nature of interstellar objects.  Invoking Galileo’s tribulations and the evocative notion of giving voice to forbidden thoughts (2) will probably not get anyone’s grant proposal funded.  However, maybe a more conservative approach emphasizing the scientifically significant findings to be gained by establishing agreements to observe interstellar objects as early as feasible after first discovery could succeed.  Perhaps getting a good look at the next interloper will reveal unambiguous evidence of an alien craft.  Even if it doesn’t, we would still learn something about the Universe.

And Yet We Saw It Move

Do scientists refuse to see what they cannot explain (2)?  The ‘Oumuamua story puts that notion to rest.  This strange object was discovered using the Pan-STARRS 1 telescope working in the automated Spaceguard survey to find and track near-Earth asteroids (1).  Preconceived notions about typical asteroid orbital mechanics did not prevent the discovery of ‘Oumuamua, perhaps they actually helped flag it as something out of the ordinary.  Scientists recognized the anomalous nature of ‘Oumuamua and immediately organized a fast and nimble response to study it in as much detail as its small size and high velocity permitted.  This speedy attention yielded the first discovery of a bona fide interstellar object.

It is a pity ‘Oumuamua sped by so swiftly, but maybe Dr. Loeb’s advocacy will drive the scientific community to be better prepared if and when interstellar interlopers appear in the future.  In that event perhaps intense study will reveal their true nature.  Should it turn out that an interstellar object is an alien-constructed spaceship, I predict the scientists will recognize a Nobel Prize the instant they see it. 

 

(1) Calla Cofield.   NASA Learns More About Interstellar Visitor ‘Oumuamua.  National Aeronautics and Space Administration, 15 November 2018.  https://www.nasa.gov/feature/jpl/nasa-learns-more-about-interstellar-visitor-oumuamua

 (2) Greg. 2019.  Seeing the Spaceship: Why We Need to Pay Attention to Anomalies. The Daily Grail, 5 February 2019.  https://www.dailygrail.com/2019/02/seeing-the-spaceship-why-we-need-to-pay-attention-to-anomalies/

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Will “Cold Case Hammarskjold” Heat Up an AIDS Controversy?

A documentary film featured at the Sundance Film Festival 2019 (1) appears to have great potential to stoke more discord regarding the history of HIV/AIDS in South Africa (2).  Looking into the intrigue surrounding the death of U. N. Secretary General Dag Hammarskjold in an airplane crash, the documentary team is also unveiling explosive claims that a white South African militia group undertook active measures to deliberately spread HIV in the black population (2). 

Was Such a Thing Possible?

An article published in The New York Times reveals the basic assertion is that the South African Institute for Maritime Research (Saimar) used phony vaccinations to disseminate HIV to “wipe out the black population” (2).  Although there is no question that HIV is a deadly scourge, experts quoted in the Times article were decidedly skeptical that sufficient technical resources were available to support such an operation and surmount the many challenges working with that virus poses. 

A great deal of mystery surrounds the Saimar group and its leader, Keith Maxwell (2).  It appears he operated medical clinics in South Africa and expressed some strident opinions about the HIV/AIDS epidemic (2), but those scant facts do not establish charges a clandestine and opportunistic biowarfare campaign was waged against the black population are true.

The Birth of a New Conspiracy Theory?  

The New York Times article (2) makes it clear the claims of a former militia member featured in the documentary have not been corroborated and the investigation into the matter of a deliberate program to spread HIV remains incomplete.  The documentary creators have invited journalists to finish this work (2).   Unfortunately, this means viewers will be abandoned to bridge the gaps in the narrative and somehow reach their own conclusions. 

The holes remaining in the deliberate HIV infection story offer ample room to accommodate alternative interpretations.  It is possible to dispute the conclusions of the experts as to precisely how a nefarious program of racial biowarfare would (should) have been conducted and the attendant technical obstacles the perpetrators would have faced.  Indeed, a non-expert might have opted for a strategy the authorities would deem unthinkable.   The basic plan, the person(s) responsible for conceiving and actually executing the operation, its scale, and conclusions regarding its ultimate success or failure are all unknown.  Africa has been roiled by disinformation and conspiracy charges about the AIDS epidemic for decades (3, 4) and perhaps we are poised to witness yet another long-lived commotion as this highly publicized, but glaringly incomplete, documentary finds its audience.         

(1) Mads Brügger. Cold Case Hammarskjold. http://www.sundance.org/projects/cold-case-hammarskjold

(2) Matt Apuzzo.   Quest to Solve Assassination Mystery Revives an AIDS Conspiracy Theory.  The New York Times, 27 January 2019. https://nyti.ms/2HAHEF3

(3) Jasmine Garsd.   Long Before Facebook, The KGB Spread Fake News About AIDS.  NPR, 22 August 2018.  https://www.npr.org/2018/08/22/640883503/long-before-facebook-the-kgb-spread-fake-news-about-aids

(4) Adam B. Ellick and Adam Westbrook. Operation Infektion.  The New York Times, 12 November 2018.    https://www.nytimes.com/2018/11/12/opinion/russia-meddling-disinformation-fake-news-elections.html

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Bye, Bye Butterflies – Is Our Fate Foretold in the Stars?

Is `Oumuamua, the strange interstellar object discovered passing through our solar system last year, an operational alien device?  Conventional wisdom holds this is an asteroid on a unique trajectory, but speculation it is an alien probe aimed at us deliberately has come from some highly respected astronomers (1). `Oumuamua is small and moved fast, leaving scientists unable to photograph or discern much about it during its brief flyby, so it will remain an intriguing mystery.          

 A wide-ranging conversation with Dr. Avi Loeb about his decidedly distinctive deductions yielded some extremely interesting ideas (1).  One of them is his suggestion that, based on human stewardship of planet Earth, the presumed civilization that launched `Oumuamua is, as Dr. Loeb put it, “dead.”  Based on the speed this presumptive alien probe whizzed by us and the possibility it may now be only an artifact of a vanished society, we should not anticipate any further clarification from the manufacturers.       

N = 1

How many civilizations capable of interstellar communication could be in our galaxy?  A tough question, for the moment we know only of our own existence.  The Drake Equation (2) attempts to estimate broad parameters, but probably Professor Paul Davies has summarized the situation most succinctly; a Universe hypothesized to be crammed with planets and life is strangely silent (3).  Have our assumptions been too optimistic?   

One possibility is that the silence reflects the rarity of intelligent civilizations active at the specific – and brief – moment of time we happen to have been seeking them.  Humans are newcomers, maybe we just missed out as a consequence of bad timing.  The Drake Equation includes a term (L) to generally account for the fact that although the Universe is impressively old in human terms, civilizations may be comparatively transient. 

 N = R_* • f_p • N_e • f_l • f_i •f_c • L 

 Our sun is stable and long-lived, but it also has an innate lifespan which will constrain the time period our civilization will be safe on Earth.  The Universe can be violent, perhaps some civilizations have been terminated by virtue of being too close to supernovae or have suffered other catastrophes such as meteor strikes. 

N = 0, It Only Takes One 

Drawing again from the human experience, it seems possible that advanced civilizations are at some risk of technology-assisted suicide.  Our longstanding worry a nuclear conflict between hostile polities might effectively extinguish humankind has also been extrapolated to other worlds within the pessimistic ‘L’ term of the Drake Equation.  Could it be that our silent Universe signals the fact that civilizations are often aggressive and self-destructive?

Maybe this is projecting too much of ourselves into the science, meaning we must allow that some intelligent species have been able to dodge nuclear self-annihilation.  However, there may be more than one way to destroy a civilization.  Will our new-found capacity to re-jigger genetics lead to a better world or unanticipated misfortune?  Might our capacity to dominate the resources of our home planet lead to unsustainable overpopulation and lethal environmental degradation?  Maybe our fate is foretold in the stars.  It is sobering to think a silent Universe might reveal we are following the same perilous path that many journeyed before us. 

Humankind is taking our living planet into a new era of mass extinction whose ultimate outcome is uncertain (4).  Driven by multiple, concurrent factors such as climate change, pesticide use and development, biodiversity is fading into bio-impoverishment as both charismatic butterfly species (5, 6) and other insects essential for ecosystem function (6) begin to vanish.  Has Earth reached the tipping point of ecological collapse?  If we have, it may not be long before N =1 shifts to N = 0.       

Perhaps someone, somewhere in a habitable zone will spot one of our space probes passing by or intercept the Arecibo message beamed into space in 1974.  Scattered hardware and disseminated electromagnetic signals could be the sum total of dispersed evidence human civilization existed briefly in our galaxy.  So, bye, bye butterflies and your ecologically vital insect kin, collateral damage of the suicidal Anthropocene.  Our callous and ignorant unconcern for the living co-inhabitants of the Earth coupled with a spooky lack of evidence intelligent beings inhabit other worlds suggest that we, too, might march to oblivion soon.  The future of life on Earth is not necessarily us.

 

(1) Isaac Chotiner.   Have Aliens Found Us?  A Harvard Astronomer on the Mysterious Interstellar Object `Oumuamua.  The New Yorker, 16 January 2019.  https://www.newyorker.com/news/the-new-yorker-interview/have-aliens-found-us-a-harvard-astronomer-on-the-mysterious-interstellar-object-oumuamua

(2) SETI Institute. The Drake Equation. https://www.seti.org/drake-equation-index

(3) Paul Davies.   The Eerie Silence: Renewing Our Search for Alien Intelligence.  Houghton Mifflin Harcourt.

(4) Edward O. Wilson.   The Future of Life.  Vintage Books.

(5) Laura M. Holston.   With 86% Drop, California’s Monarch Butterfly Population Hits Record Low.  The New York Times, 9 January 2019.  https://www.nytimes.com/2019/01/09/science/monarch-butterfly-california.html

(6) Damian Carrington. Insect Collapse: ‘We Are Destroying Our Life Support Systems.’ The Guardian, 15 January 2019. https://www.theguardian.com/environment/2019/jan/15/insect-collapse-we-are-destroying-our-life-support-systems?CMP=twt_a-environment_b-gdneco

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Frankenstein’s Circle

The surprise announcement the first babies engineered by CRISPR-Cas9 genome editing had been born forced the scientific community to referee a tricky ethical fiasco.  Although some ambitious scientists may feel it is better to beg for forgiveness than ask for permission, this work was denounced by most peers as an unjustifiable rogue action (1-4).  The instigator of this effort, Dr. He Jiankui, clearly trampled ethical and professional norms of conduct to reach his personal goals and may now be under house arrest (5).

 A Familiar Shadow

Experiments using CRISPR/Cas9 for human germline editing are not permissible at this time and clandestine efforts that do not respect all the requirements for research involving human subjects will never be acceptable.  The CRISPR babies story is the latest news from the frontiers of science, but a good deal of it may sound familiar.  Perhaps you recognize the parallels with the well-known themes of arrogance, willful transgression of boundaries and abdication of responsibility conveyed in the Frankenstein tale written by Mary Shelley two centuries ago.

Aware of the enormous stakes, key scientific community opinion leaders reacted immediately to allay any fears that had been stoked by the unsanctioned CRISPR babies experiment (6).

 “Just because the first steps into a new technology are missteps doesn’t mean that we shouldn’t step back, restart and think about a plausible and responsible pathway for clinical translation.”

Dr. George Q. Daley (6)

One problem for anyone intent on clearing paths to clinical applications is that the new capabilities to undertake genomic alteration experiments are emerging quickly and the scientific community seems quite eager to use them.  Work can be done in ethically responsible ways with full respect for the wellbeing and autonomy of human subjects.  The vast majority of scientists will respect guidelines and norms as they go about perfecting the technical details of genome manipulation.  However, balancing the drive of scientists to experiment against the needs and desires of the larger public may be an underappreciated challenge.

Begging the Key Question?

Have scientists fallen into the logical trap of begging the question by assuming CRISPR genomic editing of humans is both inevitable and supported by the majority of citizens (7)?  Suggesting that some of the larger questions at hand are too weighty for scientists to decide alone, J. Benjamin Hurlbut reminds us how concerns over the potential dangers of recombinant DNA experiments were managed just over 40 years ago (7).  However, he warns colleagues anxious to continue the tradition of self-regulation not to disengage from the public and usurp the right to decide how best to proceed without substantive external input.  Notwithstanding the expressed hopes and desires of scientific community opinion leaders already envisioning paths into clinical applications, there is little evidence the general public shares their enthusiasm to blaze those trails.  Indeed, given the speed at which CRISPR-based genetic alteration technology has appeared and is evolving, it seems likely that most citizens will have little knowledge of how these procedures work, let alone a sense of their potential implications.  If that is the case assuming most people support the long-term plans of scientists might be wishful thinking.

Broadening the Small Circle

It is clear that enormously significant decisions lie ahead.  What may not be clear to the scientific community is that many of the choices and options must be determined outside the boundaries of laboratories and professional societies (7, 8).  The Asilomar experience where scientists spoke almost exclusively with other expert scientists and focused their decisions heavily on technical details of experiment safety may no longer serve when events having such far-reaching ramifications are racing forward so rapidly.  It is not a big surprise when researchers and their institutions unreservedly support more research.  However, there is no guarantee that even the strongest consensus forged within the scientific research community necessarily mirrors the opinions and desires of general society.  Dr. Hurlbut and others are working to stimulate some essential – and more inclusive – discussions regarding governance, safety and visions for the future (7).  Scientists anxious to leap the technical hurdles of genetic editing will be well advised to examine their unstated assumptions and take sincere actions to broaden their discussion circles.

When you have just re-enacted Frankenstein, you better do some fast talking.

(1) Christina Larson.   Gene-editing Chinese Scientist Kept Much of His Work Secret.  AP News, 27 November 2018.  apnews.com/13303d99c4f849…

(2) George Dvorsky.   Rogue Scientist Defends Gene-edited Babies – and Reveals a Second Pregnancy.  Gizmodo, 28 November 2018. gizmo.do/tZ7Hzjc

 (3) Pam Belluck.   Chinese Scientist Who Says He Edited Babies’ Gene Defends His Work.  The New York Times, 28 November 2018.  nyti.ms/2E5pxVd

(4) Sui-Lee Wee.   China Halts Work by Scientist Who Says He Edited Babies’ Genes.  The New York Times, 29 November 2018. https://nyti.ms/2zya3oN

(5) Elsie Chen and Paul Mozur.   Chinese Scientist Who Claimed to Make Genetically Edited Babies is Kept Under Control.  The New York Times, 28 December 2018.  https://www.nytimes.com/2018/12/28/world/asia/he-jiankui-china-scientist-gene-editing.html

(6) Second International Summit on Human Genome Editing. 2018. https://livestream.com/accounts/7036396/events/8464254/videos/184096639/player?width=640&height=360&enableInfo=true&defaultDrawer=&autoPlay=false&mute=false&t=1543422491964

(7) Benjamin Hurlbut. 2019.  Human Genome Editing: Ask Whether, Not How.  Nature, 2 January 2019.    https://www.nature.com/articles/d41586-018-07881-1

(8) Benjamin Hurlbut, Sheila Jasanoff and Krishanu Sana. 2018.  Hurlbut, Jasanoff, Sana: Chinese Gene-Editing Experiment was an Outrage, but Scientific Community Shares Blame.  Twincities.com, 2 December 2018.    https://www.twincities.com/2018/12/02/hurlbut-jasanoff-sana-chinese-gene-editing-experiment-was-an-outrage-but-scientific-community-shares-blame/

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A Question of Time

The unexpected announcement the first babies modified using CRISPR genetic editing procedures had been born left the scientific community struggling to respond (1).  This unsanctioned effort unquestionably violated norms for the conduct of research with human subjects and also raised concerns regarding the future health of the babies.  CRISPR genome editing of living cells has been perfected to a point where it is comparatively easy to use, but is an “immature” (1) technology in the sense that its use currently poses unknown consequential dangers.  The precision of CRISPR editing is uncertain; it is possible that the manipulations created only the changes in the early stage embryos the researcher intended.  However, these CRISPR interventions may have also generated additional mutations at other locations in one or more of the embryos.  So far, so good it seems, but these babies have a long developmental program ahead and whether any significant off-target genetic damage has been inflicted in one or both of them might not become apparent for quite some time in the future.

It Seemed Like a Good Idea

Another unfolding story underscores how long it can take to recognize the full spectrum of complications following medical treatments (2-5).  The specific issue at hand involves the consequences of a long-term human growth hormone supplement therapy protocol that was abandoned over 30 years ago.  Unfortunately, this effort precipitated a medical tragedy for more than 200 participants (2).

In order to help children with abnormally low growth rates, a large-scale program was devised to harvest growth hormone from the pituitary glands of human cadavers (2).  This material, c-hGH, collected at substantial effort from thousands of cadavers, was injected into these children to boost growth hormone levels.  However, this strategy which spanned decades and involved over 30,000 participants worldwide (4,) was terminated when it became apparent many young c-hGH recipients had been afflicted with a rare, invariably fatal, neurologic malady of the aged known as Creutzfeldt-Jakob disease (CJD). 

Retrospective analyses led to the stunning realization that a number of the donors serving as sources of c-hGH must have had the pathologic proteins – prions – that cause CJD lurking silently in them when they died (2).  These deceased donors never exhibited signs or symptoms of this neurologic disease because they had died well before the pathologic prions could normally accumulate to high enough levels to produce clinically-evident illness.  Unfortunately, a fraction of the c-hGH preps used to treat children were contaminated (4) and had transmitted a sufficient number of cryptic CJD prions to shift the time of clinical CJD emergence to far earlier ages than normal. 

It’s Not Over

Sporadic CJD is a rare affliction of the aged, but is transmissible by medical interventions such as transplants or neurosurgery.  It turned out that supplementation therapy using pooled tissue extracts from cadaveric pituitary gland donors posed the greatest threat to transmit CJD through medical procedures ever seen.  Once this tragic situation was recognized all use of cadaveric growth hormone sources ceased immediately, but whether any more of the still-living recipients will eventually develop CJD remains unknown.

This sad story has potential implications for Alzheimer’s disease (AD) and other neurologic conditions such as Parkinson’s disease (PD).  Post mortem examinations of brain tissue from several cadaveric hormone recipients who died from early-onset CJD revealed an additional pathologic complexity – amyloid deposits reminiscent of those observed in AD cases (2, 3).  This was another unanticipated observation because, just as for CJD emergence, amyloid deposits are not commonly seen in such young persons.  Additional experiments on surviving archived c-hGH preparations have confirmed the presence of specific amyloid peptides associated with AD and that injection of this material into experimental animals induces an accelerated-onset AD-like amyloid deposition (2-5).  Could it be that some of the cadaveric hormone preparations had transmitted the seeds for both CJD and AD-like amyloidosis simultaneously? 

One Bad Apple…

The pathologic hallmark of the distinct neurologic diseases such as CJD is a spongiform encephalopathy of the brain associated with the accumulation and spread of specific, abnormal proteins known as prions.  Prion proteins are present in normal cells, although their function(s) are mysterious.  The only known difference between normal prions and their deadly counterparts is a change in shape.  The disease process begins when a normal prion protein(s) somehow adopts the pathologic shape spontaneously and becomes locked in it permanently.  Once formed, these abnormally-shaped prions facilitate a rapid conversion of all their normal brethren into the pathologic type.  Like one bad apple in a barrel, a mis-folded prion protein acts as a seed to spread the ultimately fatal abnormality through autocatalytic templated reactions. 

The destructive amyloid deposits accumulated in AD patients have some notable similarities to the deadly prions of CJD.  Massive conglomerations of small protein fragments having unknown functions in normal health, these amyloid deposits frequently increase in step with increasing age.  Purified AD amyloid preparations extracted from demented humans can also seed amyloid pathology in experimental animals (4, 5).  The most significant known risk factor for AD development is also advanced age; could it be that spontaneous mis-folding events instigate the emergence of the amyloid deposits characteristically found in demented persons?  Perhaps one reason AD dementia becomes so prominent in the elderly is that these persons have been alive long enough to allow rare seeding events to occur and spread.   

A Nagging Worry

A group of deceased recipients of growth hormone therapy died of what was unquestionably an abnormally early-onset form of CJD (2).  A subset of them also had amyloid deposits reminiscent of AD, but did not have the full spectrum of lesions typically observed in persons with that dementia (3).  Although not the cause of their deaths, discovering amyloid deposits in such young subjects has raised some additional worries.

The growth hormone preparations injected into children were obtained by pooling and processing pituitary gland material from large numbers of deceased subjects, many of whom were probably elderly at the times of their deaths.  Amyloid deposits and CJD are both most prominent in the aged, perhaps some cadaveric hormone preparations contained a few pathologic CJD prions along with seeds promoting AD-like amyloid formation.  CJD prions may be transmitted by certain medical protocols and these new observations are worrisome because they suggest that under the proper circumstances it is possible medical interventions might pass along toxic amyloid seeds or perhaps full-blown AD, too.  At least some original cadaveric hormone preparations, despite having been archived for more than 30 years, accelerated the appearance of amyloid pathology when injected into the brains of experimental animals (2-5).  That suggests the structures responsible for amyloid seeding are resistant to inactivation (3), a general and problematic characteristic of CJD prions that facilitated their accidental spread by medical practices.       

The cadaveric growth hormone preparations were injected into the bodies of recipients, but these (presumably) few implanted toxic CJD prions and possible amyloid seeds still transmitted their respective pathologies into the brains of the deceased recipients with extraordinary speed.  Spontaneous CJD is a rare affliction of the aged and growth hormone preparation procedures seem to have increased toxic prion levels enough to spark its quick emergence.  In contrast, although AD pathology also develops over time by what might be an analogous autocatalytic mechanism(s), it is several thousands-fold more prevalent than CJD.  We see more AD cases than we did in the past and possibly this reflects the fact that far more people live to an age where dementia risks increase naturally.  But could now more routine medical interventions such as surgery, blood transfusions or other actions be transmitting just enough seeds to elevate the total incidence of AD or other brain diseases in the recipients?  Deadly disease agents such as hepatitis viruses and HIV have been transmitted by blood transfusions.  These agents may become apparent only after years or decades have passed since the receipt of the tainted blood products and perhaps we are just catching on to a new aspect of an old disease transmission problem.  At this point we do not know if finding AD-like amyloid deposits in human growth hormone recipients is cause for general alarm, a minor concern or nothing at all. 

Changes in neurosurgery protocols and source materials for transplants have controlled CJD transmission by these medical procedures.  Maybe additional work will lead to a conclusion that it might be best to take actions such as restricting blood donations to persons under a certain age to minimize the risk for incidental passage of AD pathology seeds.  It will take time to sort this out.

Back to the Future

Solidly justified and carefully executed medical research may sometimes yield unanticipated tragic outcomes.  As the long cadaveric growth hormone therapy chronicle reminds us, some consequences are unforeseeable and revealed only through the passage of time.  More than 30 years after termination, the full ramifications of this project are unknown and unpredictable.                                  

Hopefully, the newborn CRISPR-edited babies will enjoy long, healthy lives.  Given the uncertainty regarding the precision of this technique and near total lack of knowledge concerning the risk and consequences of any unintended off-target genetic alterations, the decision to proceed with this experiment on human subjects was premature and unconscionable.  The development of CRISPR technology has empowered scientists to perform once impossible feats of genetic manipulation in living cells with unprecedented ease and speed.  Scientists anxious to hasten the pace of human germline engineering may discover too late that the ultimate outcomes will become clear only after the passage of time.  

(1) The Editorial Board.   How to Respond to CRISPR Babies.  Nature, 5 December 2018.  https://t.co/GOtPMSnXLS

(2) Silvia A. Purro et al.   Transmission of Amyloid-β Protein Pathology from Cadaveric Pituitary Growth Hormone.  Nature 564:415-419.  https://www.nature.com/articles/s41586-018-0790-y

(3) Alison Abbot.   ‘Transmissible’ Alzheimer’s Theory Gains Traction.  Nature, 13 December 2018.  https://www.nature.com/articles/d41586-018-07735-w

(4) Tien-Phat Huynh and David M. Holtzman.   Amyloid-β Seeds in Old Vials of Growth Hormone.  Nature, 13 December 2018.  https://www.nature.com/articles/d41586-018-07604-6

(5) Madolyn Bowman Rogers.   Confirmed: Human Pituitary Extract Linked to Amyloidosis Contains Aβ Seeds.  AlzForum, 14 December 2018. https://www.alzforum.org/news/research-news/confirmed-human-pituitary-extract-linked-amyloidosis-contains-av-seeds

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Publishing the CRISPR Twins Research – Understanding the Audiences

An announcement that twins modified using CRISPR genetic editing had been born unleashed an immediate wave of condemnation from scientists.  With that event comes the big question – now what?  Much hinges on the scientific community answer.

Megan Molteni examined questions swirling around future formal publication of these experiments on human embryos (1).  One rationale to go forward with publication is utilitarian; the technical information might be useful to others in the future.  However, a strong counterargument is that allowing publication in the scientific literature rewards the blatantly unethical actions of a rogue.  The scientific community has grappled with the proper disposition of research results obtained through unethical practices since before the time of the Nuremberg trials.  Utterly shameful doings are one thing, are scientists managing to avoid the slippery slope when violations are not so obvious?

Whataboutism and a Focus on Technical Details

An article published in The New York Times (2) pointed out how the birth of CRISPR babies is not all that ground-breaking in one sense.  Genetically modified human beings, produced by different mechanisms than CRISPR, already exist.  An interesting facet of this story is that one of the seminal works (2), the birth of a 3-parent baby, sparked its share of controversy (3).  Stymied by F.D.A. regulations, this ambitious mitochondrial replacement therapy researcher relocated the project to a country admittedly selected because it lacked restrictive rules (3) and the results have been published in the scientific literature.  Perhaps that would not have happened if the experiment had been a tragic failure.  But could apparent success and the fact that genetically modified babies are technically old news make it easier to rationalize publishing the full details of the new CRISPR babies work?

No Harm, No Foul?

Unfortunately, medical research sometimes exposes human participants to hazards.  Investigators are required to inform subjects of the risks and potential adverse events as fully as possible.  In addition, scientists are expected to take actions to mitigate foreseeable problems.  Safeguarding the health and wellbeing of the research subjects is paramount, the needs of the investigators are secondary considerations.

Meticulous preparation prior to undertaking clinical trials is no guarantee the efforts will proceed as investigators hoped.  A trial of a promising drug candidate to combat Alzheimer’s disease (AD) had to be terminated after unanticipated, serious adverse events were observed (4).  Once the problems were recognized, the study was ended immediately.

As far as anyone knows the CRISPR twins are fine.  So, no harm, no foul?  If investigators have been permitted to publish in a high-profile journal the details of a failed drug trial that seriously injured many participants (4), why are there so many questions over doing that with the CRISPR babies data?  In one sense accounting for the difference in peer/community reaction is simple; the AD trial was conducted in an ethical manner and the welfare of the participants took priority over all other concerns.  The contrast with the work put forth by an apparently over-ambitious and unethical rogue could not be more stark.

One general issue with the 3-parent and CRISPR babies is no one will know with certainty whether or not the manipulations produced any adverse impacts for quite some time in the future (3, 5).  In the earliest public discussions of CRISPR genome editing, Nobel laureate David Baltimore suggested that a fundamental lack of knowledge regarding consequential impacts of alterations should discourage such efforts in humans for the time being (6).  The true potential tragedy of the CRISPR babies is that the news reports lead us to conclude there was no compelling medical need to perform the experiment.  A driven investigator may have secured his place in scientific history, but only the passage of time will reveal how much that achievement might ultimately cost the CRISPR babies. 

To Expunge or Not to Expunge?

The article by Molteni (1) points out that refusing to allow the CRISPR babies study to be published poses another dilemma.  She reminds us that publication serves two purposes, career building and knowledge accrual, leading to a concern that preventing the work from entering the written official record effectively throws away knowledge.  The scientific community has been grappling with the holes-in-the-official-record problem posed by failed – and therefore unpublished – clinical trials funded by private corporations.  Predicated on solid rationales that others might invoke as well, clinical trial data and approaches which did not achieve desired endpoints are still vitally important to future investigators because they may help prevent effort being wasted running down blind alleys that have already been traveled.  There are at least two ways to look at the CRISPR data publication dilemma – the study, or at least the manuscript describing it, is being characterized as “shoddy” (1), so its absence from the scientific record may not be a huge loss.  However, it might serve as an example of what not to do for future researchers, provided a person with demonstrated contempt for ethics deigns to convey his work and results truthfully.  Should a manuscript of suitable quality ever be produced, perhaps this would be a moment for a publisher to accept the work with the condition that a critique will appear alongside it.                     

Facing the Court of Public Opinion

It is important to recognize the current rules and guidelines for research involving human subjects have been refined over a period of decades and after some hard lessons.  And it seems true that now-notorious projects conducted in the past such as the Tuskegee study and Operation Sea-Spray (1) would probably never receive peer approval today.  We may take some comfort in that, but the legacy of prior transgressions still hangs over us.  The common thread between the work performed at Tuskegee and for Operation Sea-Spray was the deliberate use of human beings in an instrumental fashion to accomplish the goals of the scientists.  To anyone who maintains those days are long gone, take another look at the CRISPR babies story. 

Editing of the human germline will probably be done somewhere.  However, the work can – and must – be performed transparently and ethically, which will qualify it for publication in the scientific literature.  Citizens might not be interested in the deep technical details of this research, but will certainly comprehend what a mess the CRISPR babies debacle has exposed.  And they will definitely understand what it means if a utilitarian rationale is employed to justify the decision to publish such derivative, thoroughly unethical and probably substandard work. 

At this stage the most important audience for genome editing scientists is not their fellow research journal-reading colleagues, but the ordinary citizens who comprise the court of public opinion.  

       

 

(1) Megan Molteni.   How Do You Publish the Work of a Scientific Villain?  Wired.com, 11 December 2018.  https://www.wired.com/story/how-do-you-publish-the-work-of-a-scientific-villain/

(2) Carl Zimmer.   Genetically Modified People Are Walking Among Us.  The New York Times, 1 December 2018.  https://www.nytimes.com/2018/12/01/sunday-review/crispr-china-babies-gene-editing.html

(3) Sara Reardon. ‘Three-Parent Baby’ Claim Raises Hopes – and Ethical Concerns.  Nature, 28 September 2016.  https://www.nature.com/news/three-parent-baby-claim-raises-hopes-and-ethical-concerns-1.20698

(4) Rachelle S. Doody et al.   A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s disease.  The New England Journal of Medicine, 25 July 2013.     https://www.nejm.org/doi/full/10.1056/NEJMoa1210951

(5) David Cyranoski.   Baby Gene Edits Could Affect a Range of Traits.  Nature, 12 December 2018.  https://www.nature.com/articles/d41586-018-07713-2

(6) Nicholas Wade.   Scientists Seek Ban on Method of Editing the Human Genome.  The New York Times, 19 March 2015.   https://www.nytimes.com/2015/03/20/science/biologists-call-for-halt-to-gene-editing-technique-in-humans.html

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Dancing With Rogues

The creation of the first CRISPR babies immediately provoked harsh reactions from the scientific community (1).  Questioned at an informal meeting with some scientific peers, the scientist claiming this achievement was described as defiant and becoming agitated over negative reactions to his work (1).

Widely labeled a rogue, an interesting aspect of the reporting was that Dr. He Jiankui apparently believed he had complied with current ethical guidelines limiting human germline editing.  And a fascinating twist; He may feel his efforts model the work of in vitro fertilization (IVF) pioneer and paradigm-challenger, Dr. Robert Edwards.  Dr. Edwards was ultimately awarded a Nobel Prize for his investigations.

Who Will Publish This?

The editorial board of a leading scientific journal, Nature, is calling on the community to seize the initiative and establish clearly defined regulatory mechanisms to assure future efforts to modify the human germline proceed in a “more responsible” and transparent fashion (2).  The Nature editorial board may have its work cut out for it because the first nettlesome ethical issue could involve the journal directly.  The claims of Dr. He Jiankui, although clearly technically achievable, remain unsubstantiated by hard data.  Publication is the gold coin of the realm of science and researchers are anxious to have a look at these results.  A paper is being considered by a peer-reviewed journal (1) and that promises to create an extremely interesting situation. 

Dr. He Jiankui has been charged with acting unethically; lack of transparency, questions regarding whether proper informed consent protocols were followed and grave concerns that his actions exhibit a callous disregard for the health and wellbeing of the human subjects at the center of these experiments.  Here is the dilemma for would-be publishers of this study – how will such work ever pass an ethics review?  The scientific peers tapped to assess the technical aspects of this work will also need to point out any shortcomings regarding informed consent among other concerns.  What of the certifications that investigators must submit stipulating required institutional approvals were obtained and guidelines regarding the use of human subjects followed?  In light of the information reported by news organizations, if such documentation was submitted with the manuscript undergoing review, a case could be made that the author(s) have committed fraud.  Let’s be generous and assume that required certifications and stipulations were so vague as to be uninformative or ‘amended’ after the original submission.  The scientific publication peer review process is predicated on trust.  Would anyone trust researchers with such a lax approach to ethical conduct?  What reputable journal would want to touch this fiasco?

On one hand, unethical research cannot be published.  If investigators conducting ethically dubious work are rewarded with publication in a top-tier journal, it invites the criticism that turning a blind eye will encourage others to emulate sketchy, but successful, role models.  On the other hand, perhaps it will be argued that publishing the CRISPR baby data is a service to the community.  Doing so means the facts of the matter will be out there for all to see and judge.  Did Dr. He Jiankui achieve his historic goal?  If we can actually trust the data he submitted that question could be answered.  Perhaps the editors can proactively tamp down any criticisms by adding an ‘expression of concern’ or something. 

A Predatory Journal to the Rescue?

Dr. He Jiankui may find his hopes of publishing his ground-breaking work in a prestigious scientific journal summarily dashed on the grounds of questionable ethics.  However, that is not necessarily the end to this story.  In the era of predatory journals he will likely be able to get his study published in a pay-to-play journal.  Could this possibility that a now sensational study might appear in a fake journal end up as a perverse rationale for a mainstream publisher to put this manuscript into print?  It is hard to imagine a competition between two such utterly different publishing organizations, but we live in strange times. 

Hero Rogues?

Scientists value novelty and priority, the publication system rewards those who get there first.  Today, the first to capitalize on intellectual property can reap enormous fortunes as well as achieve fame.  Have these incentives warped our perspectives on ethics?  Probably most scientists would take offense at that question.

Science journalist Carl Zimmer published an interesting and balanced perspective on genetically modified humans (3).  It is noteworthy that two of the pioneers of human egg manipulations he highlighted were untroubled by cutting corners or deliberately dodging regulators to conduct their experiments (3, 4).  One question is whether the controversial, but apparently successful, ‘3-parent’ baby work reported in 2016 (4) paved the way for the British Human Fertilization and Embryology Authority to approve the use of mitochondrial replacement therapy in early 2018 (3).   

The scientific community must walk a fine line as it clearly promotes more research while remaining mindful that its ability to self-police has been exposed – repeatedly – as limited.  Some have paid a hefty price for crossing boundaries (1), yet others are cited as trail blazers.  Is the scientific community motivated to take steps to rein in would-be rogues?   

The CRISPR babies will ignite a new battle over the age-old dilemma of whether successful ends justify the means employed to achieve them.  The next conflicts will involve steps to be taken going forward should the first instances of human germline editing result in no detectable harm to the subjects of these experiments.  Perhaps we will see the spectacle of a scientific community gold rush to follow someone denounced today as a rogue.    

 

(1) Jon Cohen.   After Last Week’s Shock, Scientists Scramble to Prevent More Gene-Edited Babies.  Science, 4 December 2018.  https://t.co/wmV207SWbd

(2) The Editorial Board.   How to Respond to CRISPR Babies.  Nature, 5 December 2018.  https://t.co/GOtPMSnXLS

(3) Carl Zimmer.   Genetically Modified People Are Walking Among Us.  The New York Times, 1 December 2018.    https://www.nytimes.com/2018/12/01/sunday-review/crispr-china-babies-gene-editing.html

(4) Sara Reardon.    ‘Three-parent Baby’ Claim Raises Hopes – and Ethical Concerns.  Nature, 28 September 2016. https://www.nature.com/news/three-parent-baby-claim-raises-hopes-and-ethical-concerns-1.20698

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