by Frank Ryan
A European deal in June 2014 opened up the possibility of GM crops being grown commercially in any component state whose authorities decided to sanction this. The deal was supported by all of the member states other than Belgium and Luxembourg. Countries like France, which is said to oppose GM crops, will be free to eschew them, meanwhile England will be free to introduce them, even though other parts of the UK, including Scotland and Wales, may decide to oppose them. It is too early to speculate who is prudent and who is not.
The potential for future genetic modification of the human genome is even more likely to excite controversy and debate.
Most doctors would probably favor modification of the genome of people who are at high risk of genetically provoked serious, or potentially fatal, diseases—if and when such modification becomes available and safe. Who wouldn't wish to save young women the risk of developing breast or ovarian cancer, or a child from cystic fibrosis, hemophilia, or Huntington's disease? But once the technology to modify the human genome becomes more readily available, how far will the applications extend? We began this journey with the aim of confronting the mysteries of the human genome, but now this very trail, and the solutions it has provided, may have opened a Pandora's box for future scientists and society more generally.
Meanwhile, what of nature? Nature has no compunctions about changing genomes. So the question that is increasingly asked of scientists is as follows: Is the human genome still naturally evolving today?
Our modern human history has been accompanied by dramatic changes in environment and lifestyle. We have been bombarded by lethal infectious diseases, including malaria, tuberculosis, yellow fever, pneumococcal pneumonia, meningococcal meningitis, whooping cough, measles, poliomyelitis, and diphtheria. Many of these swept through populations on a regular basis, as did notorious everyday bugs such as the staphylococcus and streptococcus that cause boils, cellulitis, rheumatic and scarlet fever, and bone and dental abscesses. In my lifetime, I have treated human beings suffering from many of these illnesses. Susceptibility to diseases is one of the most powerful of external pressures for adaptive genomic change, most particularly affecting the evolution of the Major Histocompatibility Complex as well as the epigenetic portions of the genome. Meanwhile, the lingering presence of resident retroviruses and the hybridization-derived Neanderthal and Denisovan genomic introgressions will inevitably be still working at the level of the species gene pool.
In 2006, Voight and colleagues from the Department of Human Genetics at the University of Chicago developed a new analytical method for scanning for Snips in whole genome surveys that was capable of searching for recent evolutionary pressures. In three broad geographic populations—east Asians, northern and western Europeans, and Africans based on Yorubans from Ibadan, Nigeria—Voight and his team discovered widespread signals that denoted recent evolutionary change. These included genes related to malaria, lactose sensitivity, salt sensitivity in relation to climate, and genes involved in brain development. They also discovered signals of selective sweeps—so-called “genetic bottlenecks”—that appeared to be still in progress and were presumably related to disease liability.
So, dear me—no! I do not imagine for a moment that we humans have stopped evolving.
Evolution is intrinsic to life. New viral plagues such as AIDS, hepatitis A, B, and C, are sweeping through us. Natural calamities, including some that are man-made, are threatening us. We should recall that responsiveness to the environment is part of the way in which the epigenetic system evolves. And that epigenetic system is akin to an exquisitely sensitive and constantly changing software that governs how the genetic hardware works. A more subtle evolutionary pressure may be the massive increase in knowledge and lengthening period of education of our young coupled with the dramatic changes we have witnessed in just the last two decades in terms of how modern society works: think of the intrusion of computerized machines, social media, the global village, all maximally impacting on our young—a stage in which the human physiology, and epigenome, are still developing. Can we doubt that such overwhelming change is not already affecting our human evolution? How likely is it that such huge changes in behavior and systems of learning, brought about by the IT revolution, will affect future brain development?
Meanwhile there is another related development, a potential change that may be the most astonishing of all: this is the capability of future genetic engineers to create artificial life-forms.
Craig Venter, the scientist who founded Celera Genomics, produced the first commercially funded draft of the human genome in 2001, his team inventing several important innovations and developing the concept of ESTs and shotgun sequencing along the way. In a blunt and highly-entertaining autobiography, Venter declares that science has always set out to master life: “For centuries a principal goal of science has been, first, to understand life at its most basic level and, second, to learn to control it.” Venter anticipates a future in which scientists will engineer new life-forms, as well as modify the human genome, to suit human and societal needs. He has already taken what he sees as the preliminary steps to do exactly that.
By any stretch of the imagination, Craig Venter is an interesting individual. A man who took little interest in his early schooling in Salt Lake City, preferring to spend his time surfing and boating, he would subsequently put this down to his personal attention deficit disorder, which he had to struggle to overcome. Though opposed to the Vietnam War, he was drafted, enlisting into the US Navy, where he worked as an intensive care assistant in a field hospital. While in Vietnam, he attempted suicide by swimming out into the ocean, then changed his mind when more than a mile out. His experiences persuaded him to consider a career in medicine, but he subsequently changed course to biomedical research. Aggressively ambitious by nature, Venter proved to have a profoundly innovative gift as a scientist, combined with an irrepressible entrepreneurial spirit. In 2007 and 2008, he was listed in Time magazine's 100 most influential people in the world. Two years later he was listed fourteenth in the New Statesman's roll call of “the World's 50 Most Influential Figures.”
Venter was sacked by Celera in 2002, a year after the human genome was made public, reputedly because of differences in opinion with the main investor. He is currently President of the J. Craig Venter Institute, which has two main fields of enterprise. The first of these is to pioneer a discipline he labels “synthetic biology,” in which he and his colleagues aim to produce artificially engineered organisms designed to serve human and societal needs. He first began to work toward this goal with Synthetic Genomics, a company that he founded in the early 2000s. He moved on to explore the minimal genome necessity for cellular life before synthesizing the bare minimum of the genome of one of the smallest living bacteria, Mycoplasma genitalium, which causes urethral infections in humans. In essence, he reconstructed the minimal genome in stages, first in his computer and then in a laboratory synthesizer. Prior to this, the largest genomes ever artificially assembled in this way had been the much smaller genomes of viruses, the first being the polio virus assembled by Eckard Wimmer and his colleagues. The Mycoplasma genome was twenty times larger. Overcoming many obstacles, Venter's group succeeded in replacing the natural genome of a living bacterium with their own synthesized equivalent to create a living bacterial cell—a breakthrough Venter and his colleagues published in 2010. This paved the way to the deliberate creation of cellular life-forms to order.
The mystery has not ended, though. The extraordinary story of exploration of our mysterious human genome has, as ever, thrown up a new raft of very important questions.
Is Venter right in suggesting that science has always been determined not merely to understand life at its most basic level but also to learn how to control it? It's something one is obliged to think deeply about. I can't say that I am sure as to the answer, but I rather suspect that he is. Why then is this so? Is it because we humans are arrogant enough to just think that we can? Or is it because we think that there are i
mportant reasons why we should? If Venter is right, we have gone beyond the stage of musing about this question. It is much easier to genetically engineer a germ cell, or a newly fertilized embryo, than to modify the genome of a developed human being. We have already genetically engineered animals and plants in this way. In April 2015, the human embryo was deliberately engineered in a scientific experiment for the first time. I believe that this is as great a leap as the discovery of gravity by Newton, relativity by Einstein, and the extrapolation of Einstein's discovery to the atomic bomb. And just as with those epochal discoveries, it carries with it the potential for great good and great harm.
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Cavalli-Sforza, L. L. Genes, Peoples and Languages. London: Penguin, 2001.
Crick, F. What Mad Pursuit: A Personal View of Scientific Discovery. New York: Basic, 1988.
Darwin, C. The Descent of Man. London: John Murray, 1870. Prometheus edition, 1998.
———. The Origin of Species. London: John Murray, 1859. Penguin Classics reprint, 1985.
Dawkins, R. The Selfish Gene. Oxford: Oxford University Press, originally 1976, 1989 edition.
Dubos, R. J. The Professor, the Institute, and DNA. New York: Rockefeller University Press, 1976.
Duncan, D. E. Masterminds: Genius, DNA, and the Quest to Rewrite Life. London: Harper Perennial, 2006.
Friedberg, E. Sydney Brenner: A Biography. New York: Cold Spring Harbor, 2010.
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Frontispiece epigraph: Pauling, L.: 25.
Introduction
Bronowski, J.: 4.
Chapter 1: Who Could Have Guessed It?
Epigraph: Schrödinger, E.: 3.
The story of Dubos and his contribution to the antibiotic story: Ryan, F., 1992.
For more detail about Griffith, Arkwright, Dawson, Alloway, and so on: Dubos, R. J., 1976. Also Olby, R., 1994.
Avery and Dubos and the cranberry bog bacillus: Ryan, F., 1992.
Avery's paper: Avery, O. T., MacLeod, C. M., and McCarty, M. “Studies on the chemical nature of the substance inducing transformation of pneumococcal types. Induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III.” J Exp Med 1944; 79: 137–58.
The letter from Avery to his brother is reproduced in Dubos, R. J., 1976.
Chapter 2: DNA Is Confirmed as the Code
Epigraph: Deichmann, U. “Early responses to Avery et al.'s paper on DNA as hereditary material.” Historical Studies in the Physical and Biological Sciences 2004; 34(2): 207–32.
On Avery not getting the Nobel Prize: Portugal, F. “Oswald T. Avery: Nobel Laureate or noble luminary?” Perspectives in Biology and Medicine, 2010; 53(4): 558–70.
The Hershey and Chase paper: Hershey, A. D., and Chase, M. “Independent functions of viral proteins and nucleic acid in growth of bacteriophage.” J Gen Physiol 1952; 36: 39–56.
The warmer reception of Hershey/Chase experiment: Olby, R.: 318.
The bombshell of Griffith's 1928 paper: Dubos, R. J.: 132–33.
For Alfred E. Mirsky: Olby, R., 1994. Also Cohen, S. S. “Alfred Ezra Mirsky: A biographical memoir.” National Academy of Sciences.
Avery's response to Dubos, and Dubos's response to the death of Marie Louise: Ryan, F., 1992.
Chapter 3: The Story in the Picture
Epigraph: Maddox, B.: 60–61.
Watson's early life and confessions of innate laziness: Watson, J. D.: 21.
Watson's early interest in phages: Judson, H. F.: 49.
Hershey “drinks whiskey but not tea”: Judson, H. F.: 53.
Watson on Avery: Watson, J. D.: 13–14.
Chapter 4: A Couple of Misfits
Epigraph: BBC4 documentary, The Code of Life.
For more about Wilkins and Gosling: Wilkins, M., 2003.
Watson quotes: Watson, J. D., 1968.
“What Mad Pursuit”: This became the title of Crick's autobiography, 1988.
Bragg was infuriated by the upstart junior: Crick, F., 1988.
Chapter 5: The Secret of Life
Epigraph: BBC4 documentary, The Code of Life.
Crick—“Jim and I hit it off”: Crick, F.: 64.
Mering as “the archetypal seductive Frenchman”: Maddox, B.: 96.
Franklin working better with Jewish male colleagues: ibid.
Chargaff's scorn: Judson, H. F.: 142. See also Watson, J. D., 1968, and Crick, F., 1988.
Aaron Klug's comments about the terms of Franklin's appointment: Klug, A. “The discovery of the DNA double helix.” J Mol Biol 2004; 335: 3–26.
Stokes figuring out the likely X-ray diffraction of a helical structure: Maddox, B.: 152.
Obituary for Franklin: Bernal, J. D. Nature 1958; 182: 154.
Chargaff's paper: Chargaff, E. “Chemical specificity of nucleic acids and mechanism of their enzymic degradation.” Experientia 1950; 6: 201–209.
Duncan's conversation with Watson: Duncan, D. E.: 169.
The three Nature papers on DNA:
Watson, J. D., and Crick, F. H. C. “Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid.” Nature 1953; 171: 737–38.
Wilkins, M. H., Stokes, A. R., and Wilson, H. R. “Molecular structure of deoxypentose nucleic acids.” Nature 1953; 171: 738–40.
Franklin, R. E., Gosling, R. G. “Mole
cular configuration in sodium thymonucleate.” Nature 1953; 171: 740–41.
Chapter 6: The Sister Molecule
Epigraph: Judson, H. F.: 230.
For the chemical structure of DNA: Hartl and Jones, 2000.
For the background of DNA to protein, see Judson, H. F., 1995; Olby, R., 1974.
For biographical information on Sydney Brenner: Brenner, S., 2001; Friedberg, E., 2010.
For different types of mutations: Hartl and Jones, 2000.
Chapter 7: The Logical Next Step
Epigraph: Sanger, F. “Sequences, sequences, and sequences.” Ann Rev Biochem 1988; 57: 1–28.
Brenner paper on C. elegans: Brenner, S. “The genetics of Caenorhabditis elegans.” Genetics 1973; 77: 71–94.
Events of metamorphosis: Ryan, F., 2011.
Puberty and brain rewiring: Sisk, C. L., and Zehr, J. L. “Pubertal hormones organise the adolescent brain and behaviour.” Frontiers in Neuroendocrinology 2005; 26: 163–74.
Chapter 8: First Draft of the Human Genome
Epigraph: Shreeve, J.: 236.
More about J. Craig Venter: Venter, J. C., 2013.
Roger Highfield quote: The Daily Telegraph February 15, 2011: 4.
The Nature and Science papers:
International Human Genome Sequencing Consortium. “Initial sequencing and analysis of the human genome.” Nature 2001; 409: 860–921.
Venter, J. C., Adams, M. D., et al. “The sequence of the human genome.” Science 2001; 291: 1304–51.
Chapter 9: How Heredity Changes
Epigraph: Huxley, T. H., 1893. Chapter V, Mr. Darwin's Critics: 120.
Mutations and bat wings: Cooper, K. L., and Tabin, C. J. “Understanding of bat wing evolution takes flight.” Genes and Development 2008; 22: 121–24.