Issue Brief

March 2001

The Human Genome - Part I

WHAT'S IT ALL ABOUT?     

"We've called the human genome the book of life, but it's really three books.  It's a history book.  It's a shop manual and parts list.  And it's a textbook of medicine more profoundly detailed than ever."  -- Francis S. Collins, Director of the National Human Genome Research Institute

I.  Introduction
On February 12, 2001 two teams of scientists held a news conference in Washington, DC to announce their success at producing a map of the human genome.  

If you have been watching television, reading newspapers, or listening to the radio in the last few months, you could not have missed at least one discussion of the human genome.  Yet most of us don't have the faintest idea what the genome is, why it needs to be mapped, or why the people involved are so excited about it.  This newsletter is an attempt to put this news in some perspective for those of us who are not scientists.

The term genome refers to the complete set of genetic instructions carried within the cells of an organism.  Every living thing has a genome and they can vary in size from quite small to extremely large.  The human genome is contained in twenty-three sets of chromosomes, which reside in the nucleus of each of the trillions of cells in the body.  Collectively these 23 pairs of chromosomes are called the human genome.    

II. History
Before getting into the details of the analysis of the human genome it is useful to know some of the history behind the current endeavor.   Scientists have been trying to understand the mystery of life for centuries, but the real beginning of today's efforts was made 48 years ago when James Watson and Francis Crick unraveled the basic structure of the molecule, deoxyribonucleic acid -- commonly known as DNA.

DNA is the chemical inside the nucleus of a cell that carries the genetic instruction for making living organisms.  (Genes are pieces of DNA.)   All the information needed to form and sustain life is contained in this one molecule.  DNA directs the formation of every single cell in the body from conception to death and coordinates all functions of every organ system, every tissue, every cell, and every molecule.  It is composed of four chemical bases (adenine, cytosine, guanine, and thiamine) that line up to form slender strands that contain the instructions for everything a cell does.  These long strands form pairs that coil around each other in the form of a twisted ladder, called a double helix.  This ladder folds compactly around other molecules and is called a chromosome.   Human beings have 23 pairs of chromosomes.

Soon after Doctors Watson and Crick published their work, it became clear that they were actually reporting the secret of life on earth.  At the time of their work, however, there was no way to uncover the actual order of genetic information contained in DNA so there were many things they couldn't figure out. 

A genome is all DNA contained in an organism or cell.  The human genome is often described using analogies to writing.  Rick Weiss writing in the Washington Post says, "it can be thought of as a huge encyclopedia that is written as a single enormously long sentence of 3.1 billion letters, with virtually no punctuation along the way...this six-foot-long rambling molecular sentence is folded inside almost every one of the body's 100 trillion cells.  Genes are individual portions of that run-on text, ranging in size from about 1,000 to 100,000 letters

Analyzing the human genome has involved massive efforts both by government and private business. The idea for a large DNA analysis project by the government first arose at Los Alamos and Lawrence Livermore National Laboratories where scientists were trying to determine whether the offspring of the survivors of Hiroshima and Nagasaki had mutations in their DNA as a result of their parent's exposure to radiation.  In the mid-1980's the Department of Energy (DOE) initiated a project to study the genome.  Later the National Institutes of Health (NIH) got involved and in 1988 they began working together formally on the Human Genome Project (HGP). 

The HGP is an international research program designed to construct detailed genetic and physical maps of the human genome as well as the genomes of several other organisms used in research.  In 1990 the HGP was formally launched and it is the largest coordinated biological research effort ever undertaken. 

International partners include the United Kingdom (largely through the Wellcome Trust of London), France, Germany, Japan, and China.

Congress initially funded efforts by DOE and NIH on a smaller scale but when they formally launched the HGP larger amounts of money were at stake.  That soon engendered opposition inside the biomedical community.  Fortunately, Congress had more foresight than many scientists and the endeavor proceeded. 

The HGP was originally planned to last 15 years and cost $3 billion . Three years ago the effort turned into a race when a private company-- Celera Genomics Corporation of Rockville, MD -- announced that it could do the job faster and more cheaply than the HGP.  This set off a raging controversy in the scientific community which is still going on but at the end of the day, both efforts came up with the map at the same time and described their findings jointly at a news conference on February 12, 2001.  The work of the HGP was published in the journal, Nature, on February 15 and the work of Celera was published in the journal, Science, on February 16.  The human genome has been successfully mapped four years ahead of schedule - a truly amazing feat.

What Watson and Crick discovered was the structure of the DNA molecule.  What the HGP and Celera did was identify virtually all of the 3.1 billion letters in the genetic code and place them in order on that molecule.

III.  Why do we want to study the Genome?
Why was Congress so willing to commit large resources to this endeavor? And, why was Celera Corporation also so willing to spend its money and talent to map the genome? 

Aside from "scratching some scientific itch" what did we have to gain?

Knowing the human genome sequence presents great scientific opportunities.  It provides scientists with a tool for genetics comparable to the Periodic Table of the Elements.  Once you have this information, you can learn how genes function, how they interact, and how they contribute to health and disease.  It also helps us understand our history in a unique way

A.  What scientific insights have we gained?
Among other things, we now know that all of the instructions for making a human being are contained in a surprisingly small number of genes.  Before this project was completed scientists speculated that human beings had 80,000 to 120,000 genes.   Now we know that people have only about 30,000 genes - about twice the number in a worm or a fly.

We know that there is little variation from person to person.  Individuals around the world are all about 99.9 percent genetically identical.   Analysis by the President of Celera, Craig Venter, strengthens the notion that race itself has no genetic basis.  Other analyses find that sperm cells are the main source of human genetic mutations  (That finding ought to contribute to the "battle of the sexes" for years to come.)

Much of the work on the genome is aimed at finding genes that contribute to disease.  There are some reports that scientists studying the genome map have discovered more than 40 previously unknown disease genes, including some for forms of epilepsy, deafness, color blindness etc.  Many more are expected to turn up in the next few years.

And perhaps one of the most surprising findings is that only a small amount of the human genome is directly devoted to making human beings.  An enormous amount of other biological activity occurs throughout the rest of the genome and we are once again learning how little we know about ourselves.

B.  What are the unique historical insights found in the genome map?
The genome is the fundamental raw material for evolution and, as such, contains messages from both our distant and recent past.  The task of identifying and organizing the information on the genome has been done.  Now, the challenge is to unlock its code and find out what it all means.   

The genome contains vast spaces between the 30,000 scattered genes that include many non-working genes and gene pieces.  They are integrated into the fiber of the human genome but they don't really seem to have anything to do.  New analysis shows that at least 45 percent of the human genome consists of genetic elements that appear to be just mooching off their human hosts.  By studying these pieces scientists are identifying some of the major genetic changes that correlate with key changes in human evolution.

Geneticists are dating and analyzing entities in the genome that are remnants of genes that were left behind by prehistoric viruses eons ago.  Some of these genetic remnants date back more than 500 million years.  

V. What the the Challenges and Risks
Recent polls show more than 40 percent of the American public opposes this work.  If it has so much potential to help us why are people against it.  I think the answer lies in the significant harm this type of knowledge can cause if it is used incorrectly or with evil intent.

There have always been two sides to scientific advances.  Unlocking the mysteries of the atom has given us vast new sources of power and great advances in health care at the same time it has given us the atomic bomb and the threat of nuclear winter.  Advances in chemistry help us fight disease and help produce biological weapons of great terror.

The genetic code is no different.  Genetic research poses the specter of human engineering and that makes it extremely frightening.  At the same time, it can be used to ward off life-threatening illnesses. 

Recognizing that genetics is not the only factor affecting human well-being, the HGP has devoted 5% of its budget to examining the ethical, legal, and social implications of genome research. In a unique partnership - the ELSI project -- biological and social scientists, health care professionals, historians, legal scholars and others have joined together to explore these issues.    According to an article that appeared in the October 23, 1998 issue of Science, "the ELSI program has generated a substantial body of scholarship in the areas of privacy and fair use of genetic information, safe and effective integration of genetic information into clinical settings, ethical issues surrounding genetics research, and professional and public education."  Obviously, the more we learn from the genome the more work we will have to do on the related ethical, legal and social issues.

V.  What comes next?
Now that the genome has been mapped a whole new set of challenges awaits us.  Many private businesses, academics, and medical researchers have already begun making practical use of our new-found knowledge. 

Scientists are also studying other genomes.  Recently, they have unraveled the mysteries of the rice genome.  Since rice is a staple food for much of the world's population this is an exciting development.  Scientists can now look for genes to improve yields and increase the nutritional quality of the grain.  They have also decoded the DNA of a very lethal strain of E.coli.  The differences between this genome and that of a very benign form of E.coli found in most human intestines have surprised scientists.  This advance could one day prevent thousands of illnesses and save many lives. 

But lawmakers and theologians will also have to enter the game.  The potential for abuse of this information is very grave.  The American Association for the Advancement of Science has urged the government to go slowly on human Inheritable Gene Modification (IGM).  The AAS raises many red flags about future genetic engineering of human beings.  While some argue that IGM offers the prospect of preventing the handing down in families of genetically-based diseases such as hemophilia, the AAS cautions that we can not do this safely yet. 

The AAS also expresses concern that positive use of these advances may be available only to the wealthy, further exacerbating discrepancies between the rich and the poor.

Some scientists express concern about businesses making propriety use of this information and closing it off from public use, thereby limiting our ability to learn from it.  Civil rights advocates fear genetic information may be misused to discriminate against people in employment or other areas of life.   

And it is not only the scientists and advocates who have weighed in on these questions.  With information on genetics in the media every day, the public is demanding its right to be heard.  Between the controversies surrounding genetically altered organisms, cloning, and genetic engineering, people want appropriate limits set on both scientists and businesses.  And they do not believe this should be left only to the experts.

The public debate on the future of genetics research may well prove to be more important than discussions in the scientific community.  The role of the NIHP is to further the understanding of health care and to employ informed and formal leadership in shaping practice and policy.  In my next newsletter I will discuss some of the public policies that are currently in place and other issues that will need to be addressed in the future as this work moves forward.

If you would like to learn more about genome research you can visit the National Human Genome Research Institute's web site at: www.nhgri.nih.gov.  You might also enjoy reading, Genome: The Autobiography of a Species in 23 Chapters, by Matt Ridley.