Dreaming of a brighter futureFor centuries people have tried to lower incidence of common hereditary disorders, at least for generations to come. How could future be brighter and better, if according to Autism speaks the autism spectrum disorder already affects 1 in 50 children in US alone and this ratio continues to grow? The purpose of this project is to establish a framework of future social development in which incidence of complex and simple Mendelian disorders will be substantially lower than naturally occurring. Speaking in plain words, prevention of 90% of the Autism, 50% of diabetes type 1, 75% of diabetes type 2 and at least 60% of allergy cases could become a reality one day.
The project brief summaryBiomedical advances have led to a relaxation of natural selection in the human population of developed countries. In the absence of strong purifying selection, spontaneous and frequently deleterious mutations tend to accumulate in the human genome and gradually increase the genetic load; that is, the frequency of potentially lethal genes in the gene pool. Gradual increase in incidence of many complex disorders suggests deleterious impact of the genetic load on human well-being. Recent advances in in vitro fertilization (IVF) combined with artificial twinning and transgenerational embryo cryoconservation offer the possibility of preventing significant accumulation of genetic load and reducing the incidence of hereditary disorders.
Many complex diseases such as type 1 and 2 diabetes, autism, bipolar disorder, allergies, Alzheimer's disease, and some cancers show significantly higher concordance in monozygotic (MZ) twins than in fraternal twins (dizygotic, DZ) or parent-child pairs, suggesting their etiology is strongly influenced by genetics. Preventing these diseases based on genetic data alone is frequently impossible due to the complex interplay between genetic and environmental factors. We hypothesize that the incidence of complex diseases could be significantly reduced in the future through a strategy based on time-separated twinning. This strategy involves the collection and fertilization of human oocytes followed by several rounds of artificial twinning. If preimplantation genetic screening (PGS) reports no aneuploidy or known Mendelian disorders, one of the MZ siblings would be implanted and the remaining embryos cryoconserved. Once the good health of the adult MZ sibling(s) is established, subsequent parenthood with the cryoconserved co-twins could substantially lower the incidence of hereditary disorders with complex etiology and virtually eradicate simple Mendelian disorders.
The proposed method of artificial twinning has the potential to alleviate suffering and reduce the negative social impact induced by dysgenic effects associated with known and unknown genetic factors. Time-separated twinning has the capacity to prevent further accumulation of the genetic load and to provide source of isogenic embryonic stem cells for future regenerative therapies.
Project related materials
- Please open the complete presentation for more details. Truncated version of the slides was presented at the meeting of CAS senior international scientists and young fellows (2012).
- For more scientifically rigorous introduction to the project please refer to the poster.
- Yet to be published paper draft provides even more details.
- Future human evolution featured at whatwemaybe.org.
Why this is important and who cares?The failure of CuraGen and other similar startups (such as recent FDA class action lawsuit filed against 23andMe) demonstrated that prevention and cure of the complex diseases based on genomic information alone is elusive. Unlike simple Mendelian (single gene) disorders, many complex diseases are multi-locus, where minor compromises in multiple disease-associated genes combine through epistasis and trigger a disorder. Even though recently made studies demonstrated possibility of finding potentially causative de novo or inherited mutations in a small fraction of autistic children of unaffected parents (such as this, this, this, this, this or this), majority of autism cases remain unexplained. Moreover, complex diseases such as diabetes type 1 and 2, all sorts of autoimmune disorders (allergies), autism spectrum disorder (ASD) and many others have been documented to have a strong genetic component in their etiology and frequently run in the families.
Given the general tendency of incidence increase for the complex diseases in the developed countries, we speculate that the major driver of such rise is the accumulation of a genetic load, i.e. frequency of potentially lethal (damaged by a deleterious mutation) genes in the human gene pool. Please refer to the influential paper "Our Load of Mutations" published by Nobel Prize winner Hermann Joseph Muller back in 1950 that explains mechanism of accumulation and propagation of the deleterious mutations. Sixty two years after H.J. Muller's address the metropolis of Detroit lost more than half of the population, therefore many historical buildings stand abandoned and frequently in ruins. Given that the medical services provided by automakers (such as Packard and Studebaker) were extraordinary compared to many other places in US and across the World, it is reasonable to assume that excessive accumulation of the genetic load predicted by H.J. Muller could be one of the reasons leading to the city demise.
For example, celiac disease (CD) incidence has been documented to increase in USA 4.5 times from 1950 based on rigorous antibody measurements done by Mayo clinic. This conclusion has been drawn based on comparison of blood sera from 9,133 healthy young adults at Warren Air Force Base (WAFB) collected back to 1950s and modern days control group of 7,210 Minnesota residents who were the same age at sampling as WAFB subjects. According to this study, undiagnosed CD was associated with a nearly 4-fold increased risk of death compared to unaffected individuals. Research done in Italy finds that CD pairwise concordance is significantly higher in MZ (71.4%) than in DZ (9.1%) twins, providing evidence for a strong genetic predisposition in multifactorial CD. Such high concordance rate offers prevention odds of 3.47 for strategy based on time-separated twinning. According to http://www.celiac.com/ today more than 2 million Americans are affected by the disease (1 in 133, 0.75%) and its incidence continues to grow. If a person with the disorder continues to consume gluten (and many people are unaware of their adverse reaction to gluten or simply ignore doctor's recommendations), studies have shown that he or she will increase their chances of gastrointestinal cancer by a factor of 40 to 100 times that of the normal population.
Since 1980s incidence of autism in the United Stated have risen 600%, partially because of the elevated awareness and diagnostic at earlier age. For that reason many people argue that this raise is artificial and is associated with switch in classification criteria, which is currently DSM-V. Well, according to the following episode, DSM-IV criteria is quite restrictive and requires matching to six or more symptoms for autism diagnosis, such as self-stimulatory behavior patterns and lack of reciprocity. Special education is frequently cited as one of the most helpful early interventions alleviating severity of autism manifestation. Besides being expensive, such education only provides training in basic skills necessary for an autistic individuals to be less dependent when they reach adulthood (80% autistic adults in US are unemployed). Here is an example of both monozygotic twins being concordant on autism, one among many, with profound compromise in productive activity and life quality of affected families.
It is yet to be proven that the productivity compromises associated with the rising incidence of the above mentioned hereditary disorders contributed to the Detroit demise, or was it simply emigration of Detroit's elite to some other places that doomed the city. Regardless of the possible scenarios, one thing seems more certain. If only we could build a time tunnel and bring tenants of the old Detroit back to the empty city, the future of the city might not be without perspectives. Same observation refers to my personal life experience when I lived in Shadrinsk (Russia). Although possibility of building a time tunnel belongs to the domain of science fiction, artificial twinning combined with transgenerational embryo cryoconservation is well within our reach. One thing to remember, personality and IQ are highly heritable, with heritability ranging between 70-85% according to the various authors. IQ, in turn, is one of the best proxies defining self-sustained creative potential of an individual.
Advanced paternal age has been cited by renowned geneticist James Crow in his paper as one of the significant cause in many genetic disorders. It has been recently reported that 80% of de novo mutations are of paternal origin. Given that fathers of advanced age contribute higher number of de novo mutations, there is a massive evidence that these variants could be disruptive and cause higher predisposition to complex diseases and mortality that significantly correlates with paternal age. You may also want to check the WHO World Health Statistics from 2009 (page 14 Table 1) to see if mortality before age 5 in your country is by any means close to estimated 16% mortality before reproductive age mentioned in the James Crow paper (page 46 Box 2) as sufficient condition for purifying selection to keep the genetic load stable.
Time separated twinning paradigm offers possibility of not only incidence reduction of the complex disorders, but also the prevention of further accumulation of the genetic load that stems from the efficiency of the modern medicine. This technique also has capacity for improved catastrophic events (such as wars, epidemics and natural disasters) management, where population could be restored to its original pre-event structure relatively easy alleviating significant dysgenic effects and suffering frequently associated with such disasters.
This development is in line with Innovation 2020 program. In 2011 the program initiated pilot projects in 7 key areas: nuclear fusion and nuclear-waste management; stem cells and regenerative medicine; calculating the flux of carbon between land, oceans and atmosphere; materials science; information technology; public health and the environment.
Historical images of Detroit
- City Hall and Campus Martius, circa 1900 picture
- Tashmoo steamer in 1900 picture
- Tashmoo steamer in 1901 picture
- Woodward Avenue in 1910 (a shopper's paradise) picture
- Looking north on Woodward Avenue from the Maccabees Building, picture made in July 1942.
- Requiem For Detroit? documentary