Synthetic Genetic Shakespeares

Examining the implications of science and technology


Synthetic Genetic Shakespeares

The personal blog of Tyler Kokjohn. A partial list of my scientific publications may be found on PubMed. The opinions expressed in these posts are my own. I declare I have no competing scientific or financial interests regarding the topics examined in this blog.

Fighting Half-Fact Journalism


Will climate change release disease agents from melting permafrost and produce devastating epidemics?  An article (1) promoted on Twitter (19 June 2017) suggests this might happen.  Some of the material, dutifully cited by the author, appears to have been distilled from another, similarly slanted article (2).  Both works contain conceptual flaws and factual errors.  Watching myth information propagate and reverberate through the Twitterverse has been interesting and distressing. Responding  on Twitter has achieved only partial success.    

A recent anthrax outbreak was traced back to animals released from their permafrost tombs (1).  However, this disease is caused by a bacterium, Bacillus anthracis, not a virus.  Anthrax may be lethal, but it is antibiotic treatable and very difficult, if not impossible, to spread in a person-to-person fashion. Anthrax outbreaks are cause for concern, but the chance this disease is poised to leap from the melting permafrost and produce a human pandemic is essentially zero.  It is true that some bacteria, especially the spore-formers, persist for long periods under extremely harsh environmental conditions.  Unfortunately, some of the diseases they produce such as botulism and tetanus (2) are also not contagious on a person-to-person basis.  In addition, planet Earth has abundant reservoirs for these bacteria outside of the permafrost regions.  Realistically, none of these diseases has pandemic production potential and the threats posed by them have been with us for a long time.  Melting permafrost is not likely to dramatically increase the dangers they pose.       


The 1918 influenza virus, sometimes called the Spanish flu, produced a terrible pandemic a century ago.  However, infectious killer flu virus is probably not lurking in corpses buried in the Alaskan tundra.  To date, only fragments of 1918 flu genes have been recovered from such samples.  I cannot say there will never be an announcement that scientists have isolated infectious virus from a thawed cadaver.  But the evidence in hand does not suggest this prospect is likely.  

1918 fu

Blogger and Twitter user @Neuro_Skeptic has noted correcting errors in news articles can be challenging.  The good news is that the specific error regarding 1918 flu virus recovery was edited in the BBC paper although some overstated implications about tetanus and botulism still stand (2).  However, at the time this essay was posted (20 June 2017), the other article (1) had not yet been edited.  Do the authors and editors read Twitter comments?  I have no idea, but they have seen fit to correct some, but not all, of the problems pointed out in their articles.  

Where will this end?  Not all facts are equally reliable, but social media gives every one of them an equal opportunity to reverberate around the internet.  In light of the situation, journalists, editors and readers will be best served by actually evaluating references or investing the time to check facts.  For example, a cursory search through Wikipedia would reveal how botulism, tetanus and anthrax are, or are not, transmitted.  The last line of defense against half-fact journalism is an alert reader.    

(1)  D. Galeon.  2017.  Climate Change is Freeing Ancient Infections From Their Icy Prisons.  Futurism, 5 May 2017.

(2)  J. Fox-Skelly. 2017.  There Are Diseases Hidden in Ice, and They Are Waking Up.  BBC, 4 May 2017.


A CRISPR Kerfuffle

News and opinion regarding CRISPR genomic alteration technology often veers into extremes; this will either be the greatest tool ever or will entice humanity to ruin.  The prospect of immense financial rewards has induced the swift spawning of companies determined to exploit an extraordinary opportunity.  Developments are coming at a fast pace.

CRISPR genetic modification could be the key to controlling some diseases and a general sense of urgency has already propelled the technology into clinical trials.  However, questions as to whether researchers have gotten too far ahead of the data have been raised (1).  A controversial new study suggesting CRISPR editing may produce large numbers of untargeted DNA alterations has been met with a ferocious push back from eminent scientists and companies involved in developing the new technology (2, 3).  Disputing the methods and data and alleging faulty peer review, some have called for the journal to retract the paper.  For the involved publically-traded companies subject to market forces the stakes are high.  Stock valuations declined sharply in response to the publication of results highlighting the potential risks of CRISPR.

In one sense, the notion that CRISPR-Cas9 activity is imprecise is not controversial because investigators have been working for some time to improve the system (4).  However, right or wrong, the new findings were attention-grabbing and forcing a retraction of that paper may help companies minimize financial losses.  Although a retraction may satisfy pressing corporate concerns, it does not resolve the controversy surrounding off-target mutations generated by CRISPR therapy.  One problem is that not much published data can be cited to establish whether or not competing claims about genomic editing manageability are reliable.  This situation fuels a perception CRISPR technology is being rushed into the clinic based on sketchy information.  Perhaps companies will now be motivated to fill this information gap by publishing studies which establish the targeting efficiency and error induction rates of their genetic alteration systems.   

A troubling situation envisioned nearly 10 years ago by Nobel laureate Paul Berg may now have emerged (5).  Where academic scientists could once be counted on to act as honest brokers regarding the risk and benefits of new technologies, the situation we face today is much more complicated.  Many eminent scientists involved in CRISPR research and development have vested financial interests in the exploitation of this technology.  I feel sorry for the journal editors who must now adjudicate the issues swirling around a published paper that has offended some powerful persons and organizations.  At some point this particular dispute will be resolved.  For the sake of those volunteering for tests of CRISPR-based therapies it is vital to establish the scientific details supporting the clinical use of this technology with rigor and precision.  

Dead Mans

(1) A. King. 2017.  Fears that Gene-Editing Cancer Trails Are Premature.  Chemistry World, 9 January 2017.

(2) Antonio Regalado.   Gene Editing Companies Hit Back at Paper That Criticized CRISPR.  MIT Technology Review, 9 June 2017.

(3) I. Haydon. 2017. CRISPR Controversy Raises Questions About Gene-Editing Technique. The Conversation, 31 May 2017.

(4) H. Ledford. 2016.  Enzyme Tweak Boosts Precision of CRISPR Genome Edits.  Nature, 6 January 2016.

(5) P. Berg. 2008.  Meetings that Changed the World; Asilomar 1975: DNA Modification Secured.  Nature 455:290-291.



Propagating Myth-information


The producers of Ancient Aliens have done something unique.  In episode 6 of the current season, “The Science Wars,” aired 2 June 2017, they conducted a scientific investigation of an elongated skull purported to be from the Paracas region of Peru.  An eminent and highly qualified scientist, Dr. Todd Disotell, participated in the effort.  Jason Colavito has posted a review of the full episode (1). 

I give the producers of this episode credit for subjecting an artifact to laboratory examinations and seeking a competent scientist to advise them.  Unfortunately, instead of precise and systematic research I believe we witnessed the genesis of myth-information.  The DNA isolation effort was only partially successful and the results were characterized by Dr. Disotell as not definitive, but that did not inhibit wild speculation.  My concern is that although there was agreement more work is warranted, the necessary experiments might never be performed and published.  Instead, some half-baked presumptions based on a single, incomplete examination and findings that make “no sense whatsoever” will be allowed to stand as facts.

Fantastic claims regarding the nature of the Paracas skulls publicized outside peer-reviewed scientific journals are not new (2).  Perhaps the Ancient Aliens producers will provide enough support to enable Dr. Disotell to complete the essential experiments and produce a formal scientific publication to enable the independent evaluation of his methods and conclusions.  Have we witnessed a significant set of new discoveries or will the results turn out to be an embarrassing artifact?  We have assertions that some long-established ideas regarding human migration history and more might need to be re-evaluated.  Perhaps they do – let’s see the data.              

Is it possible the results in hand reveal the skull was from something that was not human?  Sure, that works provided you ignore the data actually in hand which shows the mother was human and choose to believe the complete lack of information confirms its father must have been an alien.  An absence of data inevitably invites speculation, but as Dr. Barry Starr demonstrates, extrapolation of incomplete mitochondrial genetic profile results may lead the unwary to absolutely absurd conclusions (3).  Imagine you had obtained a sample of mitochondrial DNA from President Barack Obama.  Conclusions based on it alone would suggest Mr. Obama is unequivocally Caucasian because mitochondrial DNA can reveal only the genetic lineage of his mother.  However, because we know his father was African, we immediately understand mitochondrial DNA testing results have some serious limitations. 

A scientific investigation that uncovers half a story is useless at best and misleading at worst.  Unfortunately, for this effort we do not even have half the story, but that may be enough to catalyze some enduring myths.



(1) Jason Colavito Blog, 6 June 2017.

(2) R. Chase. 2014.  Calm Down, the Paracas Skulls Are Not From Alien Beings.  Peru This Week, 13 February 2014.

(3) B. Starr. 2013.  DNA Ancestry Tests: Simultaneously Powerful and Limited.  KQED Science, 8 April 2013.


CRISPR Technology – When the Editor Errs


    Clinical trials using CRISPR-Cas9 in cancer patients are underway in China and anticipated to follow soon in the United Sates (1).  Is this technology being rushed into the clinic too soon?  A new set of experiments in mice (2) suggests that the gene editor may not be as precise as some investigators believed (3).

            The new study has raised some troubling concerns.  Intended to edit the T-cells of cancer patients to boost their capacity attack malignancy, few doubt the target DNA sequences will be hit successfully.  The problem is the editor may produce alterations at locations other than the intended target – perhaps many of them.  The CRISPR enzymes were designed to knock out T-cell proteins, but off-target mutations could end up inactivating other cell functions.  The problem is that no one will understand the functional implications of such changes until they become manifest and this may take time to sort out. 

            Investigators seeking to modify a single DNA base in two mice were able to achieve their goal.  However, along with their intended alteration they detected more than 1,600 additional untargeted mutations in those animals, a number shockingly higher than observed in previous CRISPR editing experiments.  Perhaps differences in methodology or conditions will ultimately explain why this extremely small scale mouse study produced so many off-target mutations.  Until it is possible to dismiss these new results as an experimental or procedural artifact or improve the precision of the CRISPR enzymes, Institutional Review Board (IRB) approvals for new clinical studies may decline.

            Should we demand CRISPR editing be perfect to permits its use in humans?  Current cancer therapies are often toxic and sometimes so mutagenic they are recognized to induce secondary malignancies in some patients (4).  If the true off-target CRISPR genome alteration rates lie somewhere between undetectable (3) and ‘alarming’ (2) we may have to calculate the risk-to-benefit ratio for given interventions and situations such as patients for whom standard therapies have failed.  Sometimes it may be necessary to resort to approaches that carry intrinsic risks.

            At the moment a great deal of basic work needs to be completed to make informed decisions about how best to harness CRISPR enzymes for medical treatments.  CRISPR evolved in bacteria, organisms with far smaller and structurally simpler genomes than human, animal or plant cells.  Intended to patrol small genomes to detect and eliminate invading viruses, the intrinsic error rates of these bacterial enzymes may be too high avoid producing large numbers of off-target mutations when they are forced to scan the enormously larger genomes of higher organisms.  It is also possible the physicochemical conditions prevalent in human cells may not allow CRISPR enzymes to function with optimal fidelity.  In addition, deploying CRISPR systems to engineer alterations that eliminate targeted sequences may demand extraordinary quality control measures.

            Additional factors may confound the easy clinical application of CRISPR genetic modification tools.  Our genomes are not totally stable.  The aging process itself – the combined impacts of environment, lifestyle, genetics and errors that creep in as DNA is replicated – may influence the emergence of diseases such as cancer (5).  This inherent mutability suggests that to some extent CRISPR manipulation of human genomes will exhibit idiosyncratic outcomes.  A protocol that succeeds in a young patient may yield greater numbers of off-target changes in older subjects.  Issuing a prognosis for success and assessing the threat of off-target changes may only be approximate for each person and situation. 

            Hopefully further work will reveal CRISPR genomic manipulation will provide a useful and safe tool to control disease.  Understanding how often the genomic editor errs and the long term consequences of those unintended changes is now critical. 



(1) A. King. 2017.  Fears that Gene-Editing Cancer Trails Are Premature.  Chemistry World, 9 January 2017.

(2). I. Haydon. 2017. CRISPR Controversy Raises Questions About Gene-Editing Technique. The Conservation, 31 May 2017.

(3) H. Ledford. 2016.  Enzyme Tweak Boosts Precision of CRISPR Genome Edits.  Nature, 6 January 2016.

(4) N. Hijiya et al. 2009. Acute Leukemia as a Secondary Malignancy in Children and Adolescents:  Current Findings and Issues.  Cancer 115(1):23-35.

(5) H. Ledford. 2017.  DNA Typos to Blame for Most Cancer Mutations.  Nature, 23 March 2017.


The Diverse Beasts of Dementia


When it comes to Alzheimer’s disease (AD) nothing is simple, not even counting how many persons are succumbing to it.  Using information from death certificates investigators noted an apparent substantial increase in AD mortality between 1999 and 2014 (1, 2).  This work is significant, but death certificate studies have some unavoidable limitations.  One issue is that it only reveals a fraction of the actual AD cases.  In addition, a formal diagnosis of AD requires post mortem neuropathologic confirmation and determinations based solely on clinical findings may confuse AD with other dementia-producing conditions.  Despite the problems, the death certificate study comports with prior work suggesting AD is a big, and growing, public health menace.    

AD Death rate    

Just over a year earlier reports emerged that dementia incidence was apparently dropping in some areas (3).  The findings encouraged us to believe it might be possible to stave off or prevent AD by controlling blood pressure, managing diabetes and encouraging healthy, active lifestyles.  Which reports should we believe?  Remarkably, it is possible that AD could be increasing while at the same time dementia could be decreasing in some situations.  The complication may reflect the fact that AD and dementia are different animals.  In fact, there are many biochemically distinct routes to brain malfunction and AD happens to be the most common of them.  AD subjects harbor abnormal deposits of amyloid-β peptides and tangles formed of the microtubule-associated protein tau.  However, other forms of dementia are linked to large deposits of tau alone, molecules such as α-synuclein or damage to the brain vascular system.  In fact, this complexity has confounded clinical trials of possible AD treatments.  The clinical signs and symptoms of dementia produced by different biochemical pathologies overlap which makes them hard to distinguish.  If you want to cure AD, but 20-30% of your demented trial participants actually have another type of unrelated dementia, it can be challenging to detect a beneficial impact from your treatments.  New imaging methods are now helping investigators better sort out prospective study subjects.  Again, with AD, simple answers are elusive as these new imaging protocols have also revealed our standard ideas as to how AD begins may need to be revamped. 

Perhaps the biochemical diversity of dementia allows us to rationalize how AD could be increasing while dementia might be decreasing in some circumstances.  Not all dementias come about in the same way and some may be more amenable to mitigation by managing lifestyle, diet or other interventions such as controlling blood pressure.  The bottom line is that dementia is a clinical finding, but most of the time no one is really sure what pathological changes in a particular patient’s brain have conspired to produce it.  The situations culminating in dementia are varied and complex.  AD is but one of many brain pathology-producing beasts scientists are attempting to subdue.                           

(1) G. D. Zakaib. 2017.  Alzheimer’s Deaths on the Rise.  Alz Forum, 27 May 2017.

(2) C. A. Taylor et al. 2107.  Deaths From Alzheimer’s Disease – United States, 1999-2014.   Morbidity and Mortality Weekly Report 66(20):521-526,

(3) B. Rogers. 2016.  Dementia Incidence in Britain Dropped, Mostly in Men.  Alz Forum, 21 April 2016.

(Web pages viewed 5/31/2017)


It is Alive


A group of high-powered biotech research and development leaders are meeting to hammer out a grand project (1).  Almost certainly this work will yield useful products and scientific insights.  However, the efforts will require massive financial support from a sponsor(s) able to make a long term commitment and tolerate some failures.  The specifics are being decided, but the overall plan is to launch a Moonshot style endeavor to develop technology to synthesize and manipulate large DNA molecules.  When these capabilities come on line, scientists will go from gene editing to literally being able to write entire genomes.                

GP write hand

This meeting is a second try to embark on the logical next phase of the Human Genome Project.  Despite the enthusiasm of an accomplished group of scientists, securing support from the U. S. government has been challenging.  One problem was that the promoters were not exactly clear about what they wanted to do.  Was this to be the Human Genome Project – Write, an effort with the audacious vision of synthesizing a complete human genome?  Or was the scope to be something less controversial such as perfecting the means to produce much longer DNA stands and other pilot projects (2, 3)?  The latest proposal is known as Genome Project – Write, a name reflecting a broader focus (1).

Proposing bold ideas like synthesizing human genomes incites criticism, but it can also generate public interest (1).  The science is intrinsically interesting to the scientists, but if the scope of work is not far-reaching enough and sufficiently relevant to human health it might be hard to win support of organizations like the National Institutes of Health.  During these times of fiscal uncertainty it will be challenging to secure funding for such an expensive, long-term program with uncertain deliverables.    

Researchers are drawing another new map to our future.  Their vision will, if it leads to action, change our lives.  However, at this stage we have to wait to see what they propose and how it is received by the persons controlling funding.  This is living, evolving science activism in action.  What will these talented persons cobble together?   And where will new capabilities to synthesize genomes take us?  Arguably one of the leading scientists involved in this effort, Dr. George Church, has summarized the future succinctly (4) –      

… I don’t know what the baby will grow up into.


(1) R. Cross. 2017.  Money Still Missing as the Plan to Synthesize a Human Genome Takes Another Step Forward.  Science, 8 May 2017.

(2) A. Pollack. 2016.  Scientists Announce HGP-Write, Project to Synthesize the Human Genome.  The New York Times, 2 June 2016.

(3) J. D. Boeke et al. The Genome Project – Write. 2016. Science, 2 June 2016.

(4) J. Abbasi. 2016.  Pioneering Geneticist Explains Ambitious Plan to “Write” the Human genome.  Journal of the American Medical Association 316(20):2074-2076.





You Discuss, DARPA Decides


Dr. Todd Kuiken published a hard-hitting article on some new programs being undertaken by the Defense Advanced Research Projects Agency, better known as DARPA (1).  These efforts involve utilizing breakthroughs in genetic engineering and synthetic biology to foster advances in practical applications.  As is often the case with DARPA work, some of the products promise to be amazing.  It is also fair to maintain that the new capacities could end up literally changing our world.  Scientists will create self-replicating gene drives that might alter entire wild ecosystems or perfect new ways to induce insects to perform useful tasks.  Dr. Kuiken opens his essay with a question; are we comfortable with all this?    



These projects may yield tremendous benefits and it seems important to have a capacity to defend against future weapons that come about as a consequence of the emerging technologies.  However, there are some risks.  One is that it is hard to separate work with a purely defensive purpose from research that might be used to develop weapons.  With the military funding and directing the programs it seems unlikely other nations will be reassured the U.S. has strictly benign intentions.  At the moment we seem to be heading toward a syn bio arms race by rushing to create countermeasures to weapons that do not yet exist.

Gene drive technology has also attracted significant DARPA interest.  Seeking to create reliable drives to modify the environment or thwart malfunctioning/nefarious tools, this work will provide a strong boost to those wishing to re-write ecosystem genetics.  The benefits of capacities such as genetically manipulating mosquito populations to halt disease transmission are obvious, but the risks of unanticipated consequences are essentially unknown (2).  However, if it proves possible to reverse gene drive manipulations or simply extrapolate any successes into broad assertions this can probably be achieved elsewhere, it may become easier to reassure the public new projects should go forward.  Might DARPA funding encourage gene drive researchers to reorient their focus to serve military objectives?  There is no way of knowing, but some groups do seem determined to use this remarkable technology (Stalking Horse).

Faced with furiously-developing biotechnologies such as CRISPR-Cas9 gene manipulation and synthetic biology advances, the scientific community has been forced to address ethical concerns and outline mechanisms for their judicious use (2, 3).  As issues come to the fore, a common action is for scientists to issue a call for public dialog (3).  Far easier said than done, but today it is becoming even harder to ensure ordinary citizens can make their voices heard.  While the scientific community is calling for discussions, DARPA has already made some key decisions as to what technologies will be pursued and how the work will be done. 

The issues of CRISPR-Cas9 gene manipulation and other advances may be new, but the problems of deploying novel technologies and dual-use research have been producing intense controversy in the scientific community for many decades (4). More recently worries over publishing sensitive information that could be exploited by terrorists (5), the wisdom of resurrecting the 1918 killer influenza virus (6) and see-saw battles over pathogen gain-of-function research (7) have not reassured the public the experts have matters well in hand.  Will these DARPA programs, the ones the public knows about and any others, be conducted safely?  What are the risks/benefits of these programs and how were they assessed?  The larger scientific community has not reached consensus on the matters involving the use of the new technologies, which experts did DARPA call on to help them decide how to proceed?  How many of them had direct conflicts of interest? 

DARPA managers understand the potential of the new biotechnologies.  They should also be aware of the how new advances are adopted and used by the scientific community has sometimes had a charged history.  It appears we in the civilian world can discuss, debate and plan as we like.  DARPA has already decided part of the future for us.    



(1) T. Kuiken. 2017.  DARPA’s Synthetic Biology Initiatives Could Militarize the Environment.  Slate, 3 May 2017.

(2) H. Ledford. 2016. Fast-Spreading Genetic Mutations Pose Ecological Risk.  Nature, 8 June 2016.

(3) D. Baltimore et al. 2015.  A prudent path forward for genomic engineering and germline gene modification.  Science 348:36-38.

(4) P. Berg. 2008.  Asilomar 1975: DNA Modification Secured.  Nature 455:290-291.

(5) E. Check. 2003.  U. S. officials urge biologists to vet publications for bioterror risk.  Nature 16 January 2003.

(6) P. A. Sharp. 2005.  1918 flu and responsible science. Science 310:17.

(7) B. Maher. 2012.  Bias accusation rattles U. S. biosecurity board.  Nature 14 April 2012.



A Resolute Faith in Science

Some of the headlines have been astonishing; essentially the blood of young animals restores the cognitive function of old animals (1).  But these were not click bait enticing readers to disappointment, the stories were about real experiments where a shot of young blood, or, more precisely, protein from human umbilical cord plasma, seems to have made old animals young again (1).  The work is at an early stage and the results were obtained in mice, but the potential implications for human health are huge.

Science and medicine are being challenged on several fronts by a skeptical public.  Climate change results and the risks vs. benefits of immunizations are some well publicized examples where expert opinion has been disputed or dismissed.  Perhaps we are now in an era where the judgment of the ‘elites’ no longer has the power it once did.  However, the masses may have soured on science in some ways, but the negative feelings are not universal.

Will young blood halt or reverse aging in human beings?  That is the question we really wish to answer.  Most scientists would probably tell you that many things remain to be established – details like precisely which protein in plasma is anti-aging (there are at least two candidates), how much young blood would it take to get detectable benefits and how long those improvements last.  Oh, and at what age does a person’s blood transition from fountain-of-youth elixir to death march juice?  You may be surprised to find out that despite the vagaries, a number of people are already participating in a trial to test the young blood hypothesis (2, 3).  In this study the blood of donors under age 25 is being transfused into test subjects.  Participants pay $8,000 USD for this privilege.  That is true faith.


Other examples of steadfast belief in science and advancing knowledge are available.  Persons pay to have their bodies or brains put in cold storage (4) awaiting a future technology-enabled resurrection.  Scientists have also taken note of the potential to develop novel products that appeal to a faith-based consumer logic.  How about drinking a probiotic concoction harboring the gut bacteria of elite athletes to boost your performance?  Developing such a product is being given serious consideration by a top research institute (5).  And if they put it out there I bet someone will buy the stuff and pound it down in hopes of becoming a champion.     

Over the last 400 hundred years scientists transitioned from questioning dominant religious authority to becoming an integral part of the secular power structure.  Proud of a tradition of challenging their own results, scientists are not as accustomed to contesting interpretations with outsiders.   The scientific data in hand revealing the possible age-mitigating powers of young blood proteins are intriguing, but at this stage the trial participants are taking an expensive leap of faith.  May their devotion be rewarded.  If it is, expect mass conversions to the religion of transhumanism.  



(1) S. Reardon.  2017.  Young Human Blood Makes Old Mice Smarter.  Nature, 19 April 2017.

(2) J. Kaiser.  2016.  Young Blood Antiaging Trial Raises Questions.  Science, 1 August 2016.  

(3) A. Maxmen.   Questionable ‘Young Blood’ Transfusions Offered in U.S. as Anti-Aging Remedy.  MIT Technology Review, 13 January 2017.

(4) The Alcor Life Extension Foundation.

(5) T. McNally.  2017.  Would You Drink a Probiotic with the Gut Bacteria of Elite Athletes?  The Huffington Post, 2 April 2017.…


A Gut Feeling About Cognitive Reserve and Alzheimer’s Disease

Why and how some people develop Alzheimer’s disease (AD) is not clear.  Although advancing age is a recognized risk factor, not all elderly persons succumb to AD.  The environmental and behavioral factors that seem to help guard against dementia are also understood only in vague terms.  Scientists are now making systematic efforts to assess the specific contributions of a feature loosely known as ‘cognitive reserve’ to successful brain aging (1).

Cognitive reserve is invoked to explain why certain people known to have harbored pathological changes linked to AD somehow resisted falling prey to dementia.  Ideally, scientists suspect it might be beneficial to figure out how to boost cognitive reserve, but first they will have to clarify what it is.  Educational attainment and continued intellectual stimulation are associated with cognitive reserve in that persons with greater levels of them tend to show slower mental declines, but that is about as precise as anyone can get at the moment. 

Physical exercise is also correlated with better brain health.  This could reflect the fact that exercise maintains vascular function which, in turn, would allow continued good brain perfusion.  Perhaps cognitive reserve represents a complex balance reflecting how neurons were trained and interconnected early in life, the functional demands placed on them after maturity combined with the capacity of the cardiovascular system to supply the brain with oxygen and nutrients.

Brain Connection Map

Image source

Dietary habits also play a key role in AD development with consumption of high levels of fat and sugar associated with a clearly greater threat of dementia.  Recent work has revealed that the brain is linked to complex feedback loops involving the digestive, immune and hormone systems (2).  Adding to the complexity, a diverse community of metabolically active microbes in the gut – the microbiome – makes substantial inputs into normal, and abnormal, brain function.  The mind-gut link is sensitive to what you eat and what the resident microbes in your gut make of it.

The cognitive reserve hypothesis is an attempt to explain the frustrating heterogeneity of AD.  How can equivalent levels of amyloid deposits and neurofibrillary tangles produce dementia in one patient while another remains functional?  This variability turns up even in persons carrying a genetically dominant point mutation which produces an early-onset form of AD (3).  Studies of a large group of persons carrying a mutation known as Paisa have revealed that the median age of dementia onset is around 49 years.  However, the range of onset varies between 30-80 years of age (3).  This variability among persons with the identical Paisa mutation has been long noted and suggests environmental or behavioral factors are somehow influencing the disease course (4).  Some members of this extended Paisa mutation kindred are now participating in clinical trials designed to prevent or delay AD onset (5).  In addition, extensive medical records are available for hundreds of Paisa-affected persons (3).  This may present an ideal opportunity to examine hypotheses as to whether the gut microbiome, dietary practices or lifestyles impact the onset of this specific form of AD or influence the attempted clinical trial interventions against it.

Cognitive reserve has been recognized as one of several factors that modify the risk for AD development.  No quick cure for AD is at hand, so exploring this factor could make significant contributions to the understanding as to how AD begins or might be evaded.  It will be interesting to see how big a role, if any, the gut microbiome plays in maintaining healthy brain function as we age.  This potentially important factor has received little attention from AD researchers.          


(1) AlzForum, Cognitive Aging Summit III.   NIH Summit Examines What Makes a Healthy Aging Brain, 25 April 2017.

(2) D. Gordon. 2017.  Gut Feeling. U Magazine, Spring 2017.

(3) J. I. Vélez et al. 2016.  A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer’s Disease.  Neural Plasticity 2016:9760314.

(4) F. Lopera et al. 1997.  Clinical Features of Early-Onset Alzheimer Disease in a Large Kindred with an E280A presenilin-1 mutation.  The Journal of the American Medical Association 277(10):793-799.

(5) Alzheimer’s Prevention Initiative.





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