Dei'ah veDibur - Information & Insight

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28 Shevat 5761 - Febuary 21, 2001 | Mordecai Plaut, director Published Weekly








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Significant Advance in Understanding the Human Gene
by Yated Ne'eman Staff

Possibly opening a new era in human biology and medicine, and certainly creating many pressing questions and controversial issues, two competing teams of researchers and scientists presented their first interpretations of the human genome, the set of DNA-encoded instructions that specify a person.

The Human Genome Project (HGP), an international goverment- funded research effort, and Celera Genomics, a private research group, are aiming to create detailed genetic and physical maps of the human genome, to determine the complete nucleotide sequence of human DNA, to localize the estimated 30,000-100,000 genes within the human genome, and to perform similar analyses on the genomes of several other organisms used extensively in research laboratories as model systems, as well as to examine the ethical, legal, and social implications of human genetics research.

Also on the HGP's agenda is to train scientists who will be able to utilize the tools and resources developed through the research to pursue biological studies that will improve human health.

The interpretation of the genome -- identifying the genes, their functions and controls, and how they relate to human physiology and disease -- is expected in time to revolutionize medicine by clarifying the mechanism of many diseases and generating new tests and treatments. However, it raises a far greater moral issue: who are we, mere mortals, to tamper with human genes?

The HGP realized that this question would nag at the minds of many, as the use of such genetic knowledge would have strong implications for both individuals and society and would pose a number of policy choices for public and professional deliberation. They have, therefore, included an analysis of the ethical, legal, and social implications of genetic knowledge, and the development of policy options for public consideration are another major component of the human genome research effort.

The issues involved in decoding the human genome became public in the mid-1980s, with the formation of the HGP and gained much press coverage and scientific analyses.

The Department of Energy (DOE) initially, and the National Institutes of Health (NIH) soon thereafter, were the main research agencies within the U.S. government responsible for developing and planning the project. By 1988, the two agencies formally combined efforts in the human genome research. In 1990, they published a joint research plan, "Understanding Our Genetic Inheritance: The U.S. Human Genome Project. The First Five Years FY 1991-1995."

Today, the HGP is a consortium of academic centers, mostly in the United States and Britain but with members in France, Germany, China and Japan. The U.S. National Institutes of Health and the Wellcome Trust of London are the main financers of the consortium.

Another research group has since been founded, however this one is privately run. Each team is highly critical of the other's approach, vying for the recognition as the most accurate decoder of the human genome. But the competition has proved enormously beneficial overall.

The government consortium was on a leisurely track to finish the genome by 2005 until Dr. J. Craig Venter, president of Celera Genomics, in Rockville, Md., a privately-run group of researchers and scientists, jumped into the race in May 1998, saying he would complete the genome by 2000. Now each group is fighting to be the first to clinch the discovery and present the data to the public at large.

Since last June, however, both have been observing a limited truce. On June 26 last year, when each side had finished assembling its version of the genome, a pact was made at the White House, calling for joint publication of their findings.

This "joint publication," which each side published in competing scientific journals in different continents, disclosed years of research to the public just last week.

The HGP's version of the human genome is described in a 62- page series of scientific papers in the February 15, 2001, issue of Nature, a London based magazine. The principal author is Dr. Eric Lander of the Whitehead Institute in Cambridge, Massachusetts.

Celera Genomics published their report in a 48-page article in Science, based in Washington.

Physically, the genome is minuscule -- two copies of it are packed into the nucleus of every ordinary human cell, each one of which is about a fifth the size of the smallest speck of dust the eye can see. But the genome is vast in terms of its informational content. Composed of chemical symbols designated by a four-letter alphabet of sugars -- A's, T's, C's, and G's -- the human genome is some 3.2 billion letters in length. If printed in standard type, it would cover over 150,000 pages of this newspaper.

The enormous task of decoding the genomic message began in 1990 and is now substantially complete, although both teams' versions of the genome are riddled with gaps.

Despite the two team's many differences, they largely agree on their findings about the human genome. Theirs is the first overall look at a genetic document of extraordinary strangeness and complexity. No one expected it to be comprehensible at first glance and the two teams have so far mapped only the principal features of its terrain.

The teams have uncovered much interesting data about the human genome. Celera Genomics has compiled a parts list of the proteins needed to make a person. The other team has discovered that human genes seem to have been derived directly from bacteria.

In a news conference on February 10th in Washington, the teams discussed their findings, confirming other oddities, too. They postulate that most of the repetitive DNA sequences in the 75 percent of the genome that is apparently useless ceased to accumulate many years ago, but a few of sequences, namely one specific family of repetitive DNA situated close to the core of the active genes, are still active and may do some good.

Their main discovery is how few human genes there seem to be. The number of human genes has long been thought to be around 100,000, but with the sequence of human DNA units in hand the two teams have found far fewer than expected. Dr. Venter says he has identified 26,588 protein-coding genes for sure and another 12,000 possible genes. The consortium says there are 30,000 to 40,000 human genes. Both sides favor the lower end of their range, since their methods of gene discovery tend to predict more genes than they believe exist.

The low number of human genes -- say 30,000 -- can be seen as good for medicine because it means there are fewer genes to understand.

However, this discovery reveals that the human genes don't number that much more than the roundworm's. The laboratory roundworm, sequenced in December 1998, has 19,098 genes and the fruit fly, decoded last March, owns 13,601 genes.

The roundworm, a minuscule creature that infests the intestines of humans and some animals, has a body of a total of 959 cells, of which 302 are neurons comprising its brain. Humans have 100 trillion cells in their body, including 100 billion brain cells.

Both teams discuss various possible solutions of how it can be that though people don't have all that many more genes than these simple creatures, yet they are, nonetheless, so much more complex.

Dr. Venter said he could find only 300 human genes that had no recognizable counterpart in the mouse. He then went on to deduce and speculate that the chimpanzee would have an almost identical set of genes as people, but possess variant forms of these genes.

Dr. William Haseltine, president of Human Genome Sciences, would not change his long-standing opinion that there are 120,000 or so human genes. Dr. Randy Scott, chief scientific officer of Incyte Genomics, predicted in September 1999 that there were 142,634 human genes. Last week, however, Dr. Scott said he accepted the rationale for the smaller number.

Dr. Haseltine, however, said last week that his company had captured and sequenced 90,000 full-length genes, removed all usual sources of possible confusion and he has made and tested the proteins from 10,000 of these genes. He believes that both research groups reached that low estimate through faulty methods.

Regardless of the number of genes a person body has, knowing how to recreate them can lead to drastic results. Dr. J. Craig Venter, president of Celera Genomics, concludes his article about the human genome with a warning against what he sees as the dangers of determinism, "the idea that all characteristics of the person are `hard-wired' by the genome." Dr. Francis Collins, leader of the public consortium and Celera's rival, said last week that "one of the greatest risks of this focus on the genome" is that people will draw the conclusion that their choices in life are "hard-wired into our DNA and free will goes out the window and we move into this mindset of genetic determinism."

It's easy to refute the advocates of genetic determinism, if any staunch ones exist, because it is obvious to scientists that human behavior is not completely specified by the genome. But the opposite position -- that biology has in no way shaped human behavior -- seems equally implausible.

Dr. Plomin, who discovered the first gene that affects human intelligence, describes the influence of genes on human behavior as "probabilistic rather than deterministic." Another expert said that nature has found it more effective to set loose prescriptions -- epigenetic rules, he calls them -- to guide those trying to survive in complex and hazardous jungle of human society.

When fully decoded, the human genome will have the potential to be the undeniable guide of both the good and bad side of human nature, which can manifest themselves in the creations and cruelties of the human mind.

Both teams' versions of the genome now seem to be in a good enough state to be of great use to biologists. The consortium's genome is available for free and Celera's through subscription. But Celera provides extra services, such as the ability to compare the human genome sequence with that of the mouse. Mouse DNA has retained a very similar sequence to human DNA both in its genes and in the DNA regions that control the activity of genes, but has diverged through mutation in all the nonessential parts of the genome.

The consortium, however, is also working on the mouse genome And plans to have that, as well as other important tools, available to the public.

Though both teams research is not yet complete and show many gaps in to genome's makeup, Dr. Venter included a comparison chart in his article that places his group in a more favorable light. According to his chart, the consortium's version of the genome has many more gaps than Celera's and the gaps are larger. But in an interview Dr. Venter complimented the consortium's efforts. "We are really impressed at how good the public paper is, given their input data," he said.

Dr. Lander rebutted this attack, saying Celera's strategy was a grand experiment that failed because it produced more than 100,000 assembled pieces that could not be attached to the genome sequence. Dr. Mark Adams of Celera returned that the company had assembled more than 95 percent of the genome into 2,845 large pieces and those were well anchored to the genome.

Disregarding their fierce competitiveness, both teams used information the other teams had uncovered. Dr. Venter used not only the snippets of DNA decoded by the consortium but also important information about their position generated by Dr. Robert H. Waterston of Washington University in St. Louis. The consortium copied Dr. Venter's method of linking DNA sequence data by "paired-end reads," and his reliance on heavy-duty computing to assemble data.

Experts are likely to debate which team's method for sequencing the human genome is better. But after all is said and done, which the scientists hope will be in the near future, the deep moral issues that are just up for discussion now will be on the forefront of every thinking person's mind. Unfortunately, for most people, these questions don't have definite answers and, like the frightening option of being able to choose to continue one's life or end it, the choice of creating a whole new life may become a commonplace decision.


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