Dreaming of a brighter futureFor centuries people have tried to lower incidence of common hereditary disorders, at least for the generations to come. How could future be brighter and better, if according to Autism speaks the autism spectrum disorder already affects 1 in 88 newborns and 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 occuring. 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 descriptionBiomedical advances have led to a relaxation of natural selection in the human population in 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. It is not possible to assess directly the negative impact of the genetic load on modern society because it is influenced by many factors such as constantly changing environmental conditions and continuously improving medical care. However, 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 improved 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 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 health of the adult MZ sibling(s) is established, subsequent parenthood with the cryoconserved twins could substantially lower the incidence of hereditary disorders with Mendelian or complex etiology.
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.
Poster presentationFor more scientifically rigorous introduction to the project please referer to the Poster.
Why this is important?The failure of CuraGen and other similar startups 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 de novo mutations in autistic children of unaffected parents (such as this and this this), no one can tell for sure if these variants found have something to do with the disorder. 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 Studebacker) 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 eat gluten (and many people are unaware of their diagnosis), 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.
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
- Woodward Avenue in 1910 (a shopper's paradise) picture
- Woodward Avenue in 1917 picture
- Tashmoo steamer in 1900 picture
- Tashmoo steamer in 1901 picture
- Soldiers' and Sailors' monument of Detroit in 1907 picture
- Same place in 1910 picture
- Same place in 1916 picture