The sequence of the human genome.

2001.

First edition, journal issue in the original printed wrappers, signed by Craig Venter, of the first published announcement of Celera Genomics’ sequencing of the human genome. The problem of finding the order of the building blocks of the nucleic acids that make up the entire genetic material of a human was first proposed in 1985, but it was not until 1990 that the Human Genome Project (HGP) was officially initiated in the United States under the direction of the National Institutes of Health (NIH) and the U.S. Department of Energy with a 15-year, $3 billion plan for sequencing the entire human genome composed of 2.9 billion base pairs. Other countries such as Japan, Germany, the United Kingdom, France, and China also contributed to the global sequencing effort. Venter was a scientist at the NIH during the early 1990s when the project was initiated. In 1998 his company Celera announced its intention to build a unique genome sequencing facility, to determine the sequence of the human genome over a 3-year period. The Celera approach to genome sequencing was very different from the map-based public efforts. They proposed to use ‘shotgun sequencing’ (sequencing of DNA that has been randomly fragmented into pieces) of the genome, subsequently putting it together. This approach was widely criticized but was shown to be successful after Celera sequenced the genome of the fruit fly Drosophila melanogaster in 2000 using this method. The Celera effort was able to proceed at a much more rapid rate, and about 10% of the cost, of the HGP because it relied upon data made available by the publicly funded project. Venter announced in April 2000 that his group had finished sequencing the human genome during testimony before Congress on the future of the HGP, a full three years before that project had been expected to be complete. Venter’s article ‘The Sequence of the Human Genome’ was published in Science ten months later. The publicly funded HGP reported their findings one day earlier in Nature, thus preventing Celera from patenting the genetic information. Venter was listed on Time magazine’s 2007 and 2008 ‘Time 100’ list of the most influential people in the world, and in 2008 he received the National Medal of Science from President Obama. We are not aware of any other copy of this historic article signed by Venter having appeared on the market.

When the HGP was begun in 1990, it was far too expensive to sequence the complete human genome. The National Institutes of Health therefore adopted a ‘shortcut’, which was to look just at sites on the genome where many people have a variant DNA unit. The genome was broken into smaller pieces, approximately 150,000 base pairs in length. These pieces were then ligated into a type of vector known as ‘bacterial artificial chromosomes’, which are derived from bacterial chromosomes which have been genetically engineered. The vectors containing the genes can be inserted into bacteria where they are copied by the bacterial DNA replication machinery. Each of these pieces was then sequenced separately as a small ‘shotgun’ project and then assembled. The larger, 150,000 base pairs go together to create chromosomes. This is known as the ‘hierarchical shotgun’ approach, because the genome is first broken into relatively large chunks, which are then mapped to chromosomes before being selected for sequencing. Celera used a technique called ‘whole genome shotgun sequencing,’ employing pairwise end sequencing, which had been used to sequence bacterial genomes of up to six million base pairs in length, but not for anything nearly as large as the three billion base pair human genome.

Celera initially announced that it would seek patent protection on ‘only 200–300’ genes, but later amended this to seeking ‘intellectual property protection’ on ‘fully-characterized important structures’ amounting to 100–300 targets. The firm eventually filed preliminary (‘place-holder’) patent applications on 6,500 whole or partial genes. Celera also promised to publish their findings in accordance with the terms of the 1996 ‘Bermuda Statement’, by releasing new data annually (the HGP released its new data daily), although, unlike the publicly funded project, they would not permit free redistribution or scientific use of the data. The publicly funded competitors were compelled to release the first draft of the human genome before Celera for this reason.

Special issues of Nature (which published the publicly funded project’s scientific paper) and Science (which published Celera's paper) described the methods used to produce the draft sequence and offered analysis of the sequence. These drafts covered about 83% of the genome (90% of the euchromatic regions with 150,000 gaps and the order and orientation of many segments not yet established). In February 2001, at the time of the joint publications, press releases announced that the project had been completed by both groups. Improved drafts were announced in 2003 and 2005, filling in approximately 92% of the sequence.

In the publicly funded HGP, researchers collected blood (female) or sperm (male) samples from a large number of donors. Only a few of many collected samples were processed as DNA resources. Thus the donor identities were protected so neither donors nor scientists could know whose DNA was sequenced. In the Celera project, DNA from five different individuals was used for sequencing. Venter later acknowledged (in a public letter to Science) that his DNA was one of 21 samples in the pool, five of which were selected for use.

“The work on interpretation and analysis of genome data is still in its initial stages. It is anticipated that detailed knowledge of the human genome will provide new avenues for advances in medicine and biotechnology. Clear practical results of the project emerged even before the work was finished. For example, a number of companies, such as Myriad Genetics, started offering easy ways to administer genetic tests that can show predisposition to a variety of illnesses, including breast cancer, hemostasis disorders, cystic fibrosis, liver diseases and many others. Also, the etiologies for cancers, Alzheimer's disease and other areas of clinical interest are considered likely to benefit from genome information and possibly may lead in the long term to significant advances in their management.

“There are also many tangible benefits for biologists. For example, a researcher investigating a certain form of cancer may have narrowed down their search to a particular gene. By visiting the human genome database on the World Wide Web, this researcher can examine what other scientists have written about this gene, including (potentially) the three-dimensional structure of its product, its function(s), its evolutionary relationships to other human genes, or to genes in mice or yeast or fruit flies, possible detrimental mutations, interactions with other genes, body tissues in which this gene is activated, and diseases associated with this gene or other data types. Further, deeper understanding of the disease processes at the level of molecular biology may determine new therapeutic procedures. Given the established importance of DNA in molecular biology and its central role in determining the fundamental operation of cellular processes, it is likely that expanded knowledge in this area will facilitate medical advances in numerous areas of clinical interest that may not have been possible without them.

“The analysis of similarities between DNA sequences from different organisms is also opening new avenues in the study of evolution. In many cases, evolutionary questions can now be framed in terms of molecular biology; indeed, many major evolutionary milestones (the emergence of the ribosome and organelles, the development of embryos with body plans, the vertebrate immune system) can be related to the molecular level. Many questions about the similarities and differences between humans and our closest relatives (the primates, and indeed the other mammals) are expected to be illuminated by the data in this project.

“The project inspired and paved the way for genomic work in other fields, such as agriculture. For example, by studying the genetic composition of Tritium aestivum, the world’s most commonly used bread wheat, great insight has been gained into the ways that domestication has impacted the evolution of the plant. Which loci are most susceptible to manipulation, and how does this play out in evolutionary terms? Genetic sequencing has allowed these questions to be addressed for the first time, as specific loci can be compared in wild and domesticated strains of the plant. This will allow for advances in genetic modification in the future which could yield healthier, more disease-resistant wheat crops” (Wikipedia, accessed 4 June, 2018).

After high school, John Craig Venter (b. 1946) “joined the U.S. Naval Medical Corps and served in the Vietnam War. On returning to the U.S., he earned a B.A. in biochemistry (1972) and then a doctorate in physiology and pharmacology (1975) at the University of California, San Diego. In 1976 he joined the faculty of the State University of New York at Buffalo, where he was involved in neurochemistry research. In 1984 Venter moved to the National Institutes of Health (NIH), in Bethesda, MD, and began studying genes involved in signal transmission between neurons.

“While at the NIH, Venter became frustrated with traditional methods of gene identification, which were slow and time-consuming. He developed an alternative technique using expressed sequence tags (ESTs), small segments of deoxyribonucleic acid (DNA) found in expressed genes that are used as ‘tags’ to identify unknown genes in other organisms, cells, or tissues. Venter used ESTs to rapidly identify thousands of human genes. Although first received with scepticism, the approach later gained increased acceptance; in 1993 it was used to identify the gene responsible for a type of colon cancer. Venter’s attempts to patent the gene fragments that he identified, however, created a furore among those in the scientific community who believed that such information belonged in the public domain.

“Venter left the NIH in 1992 and, with the backing of the for-profit company Human Genome Sciences, in Gaithersburg, MD, established a research arm, The Institute for Genomic Research (TIGR). At the institute a team headed by American microbiologist Claire Fraser, Venter’s first wife, sequenced the genome of the microorganism Mycoplasma genitalium.

“In 1995, in collaboration with American molecular geneticist Hamilton Smith of Johns Hopkins University, in Baltimore, MD, Venter determined the genomic sequence of Haemophilus influenzae, a bacterium that causes earaches and meningitis in humans. The achievement marked the first time that the complete sequence of a free-living organism had been deciphered, and it was accomplished in less than a year.

“In 1998 Venter founded Celera Genomics and began sequencing the human genome. Celera relied on whole genome ‘shotgun’ sequencing, a rapid sequencing technique that Venter had developed while at TIGR … Celera began decoding the human genome at a faster rate than the government-run HGP. Venter’s work was viewed at first with scepticism by the NIH-funded HGP group, led by geneticist Francis Collins; nevertheless, at a ceremony held in Washington, D.C., in 2000, Venter, Collins, and U.S. President Bill Clinton gathered to announce the completion of a rough draft sequence of the human genome. The announcement emphasized that the sequence had been generated through a concerted effort between Venter’s private company and Collins’s public research consortium. The HGP was completed in 2003.

“In addition to the human genome, Venter contributed to the sequencing of the genomes of the rat, mouse, and fruit fly. In 2006 he founded the J. Craig Venter Research Institute (JCVI), a not-for-profit genomics research support organization. In 2007, researchers funded in part by the JCVI successfully sequenced the genome of the mosquito Aedes aegypti, which transmits the infectious agent of yellow fever to humans.

“JCVI scientists were also fundamental in pioneering the field of synthetic biology. In this effort, Venter was again in collaboration with Smith, who headed the organization’s synthetic biology and bioenergy research group. In 2008 Venter, Smith, and their JCVI colleagues created a full-length synthetic genome identical to the naturally occurring genome of the bacterium Mycoplasma genitalium. Two years later, Venter and his team created a synthetic copy of the genome of another bacterium, M. mycoides, and demonstrated that the synthetic genome was functional by transplanting it into a cell of the species M. capricolum. The recipient cell not only survived the transplantation procedure but also assumed the phenotypic characteristics dictated by the M. mycoides genome. While the synthetic research conducted by Venter and JCVI scientists was considered scientifically ground-breaking, it also raised significant concerns, particularly about the potential risks associated with the release of synthetic organisms into the environment. Nonetheless, Venter believed that synthetic organisms would ultimately prove beneficial, particularly as sources for alternative energy production” (Britannica).



Pp. 1304-51 in: Science, vol. 291, no. 5507, February 16, 2001. 4to, pp. 1155-1369. Original printed wrappers, signed by Venter on front wrapper, with the very large folding chart 'Annotation of the Celera Human Genome Assembly'.

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