- Biology
101
Life On Planet Earth
18 February, 1998
1.
Methods in Genetics
2.
Single-Gene Inheritance
3. Complex Inheritance
4.
Chromosomal Inheritance
5.
The human genome project
6.
Medical Genetics Poses New
Medical and Ethical Dilemmas
A list of some symbols commonly used in human pedigree analysis
2.
Single-Gene Inheritance
Albinism is a rare condition that is inherited in a Mendelian manner as a recessive phenotype in many animals, including humans.
The human achondroplasia phenotype, illustrated
by a family of five sisters and two brothers. The phenotype is determined
by a dominant allele.
Pedigree of a dominant phenotype determined
by a dominant allele A.
Some rare dominant phenotypes of the human
hand.
Four siblings with testicular feminization syndrome. All four
subjects in this photograph have 44 autosomes plus an X and a Y, (so they
are genotypically MALES (!)) but they have inherited the recessive sex-linked
allele conferring insensitivity to androgens (male hormones).
3. Complex Inheritance
4.
Chromosomal Inheritance
With the significance of the work firmly established, the genesis of the human genome project is described. Apparently the idea of sequencing the entire DNA sequence for a "single" human being was first realistically proposed in 1985 by three different groups, who worked independently of each other. These groups all realized that the technology was quickly becoming available to achieve such a daunting task.
To give you an idea of the difficulty of the task - imagine that you were
to start reading the human genome, at one base every second. The
genetic information coding for you (and all other animals and plants) is
written down in a simple "text", just like this article. In the language
of DNA, there are only four "letters" - G, A, T, and C. To
read the DNA sequence of a human being would take about 140 years - if
you were to read one base a second, 24 hours a day, non-stop. The
(frustrating) fact is that you really would not know anything about the
person when you were done, except that they most likely had died (and had
to pay taxes!) several years before their DNA sequence had been read.
Obviously, one needs computers to handle this kind of information.
The best place for computers was at the National Laboratories in the U.S.
Southwest - mainly Lawrence Livermore & Los Alamos National Laboratories.
I had always thought that this was why the national labs had got involved
in the genome project. To be honest, I had often wondered how the
Department of Energy wound up financing the project. I was surprised
to learn that, in fact, one of the first groups to propose sequencing the
human genome was from Los Alamos. This was perhaps a "from nuclear
bombs to plowshares" type of philosophy. But in fact, there was a
bit more of a sinister twist to this plot. The U.S. military was
trying to study the effects of the atomic blasts on the Japanese survivors
from World War II. Furthermore, I know (from personal conversations
with scientists at Los Alamos during this time) that the U.S. military
was seriously operating under Ronald Reagan's philosophy of fighting and
surviving
(?) a nuclear
war. The result of all of this was that the human genome project
was funded initially by the Department of Energy; basically it was a military
project to ensure jobs for unemployed bomb makers (according to some of
the critics at the time).
The first "gene wars" aspect of this has to do with the politics of government funding. Really, the most logical place to fund this research would be the National Institute of Health (NIH), but many people were still feeling the pinch of less money for basic research at the time, and were quite afraid that the human genome project would steal money from basic grants. Furthermore, many scientists observed that, since roughly 98% of the human was "junk" (that is, it doesn't code for proteins), it would be a huge waste of money. Indeed, to try and use present or "old technology" to sequence the human genome WOULD be stupid - but the genome project was all about heavily investing in technology to improve speed of sequencing. In the 1960's, it was a very significant achievement to sequence 23 nucleotides (the equivalent of being able to read maybe 3 words in a sentence). In 1977, Fred Sanger (funded by the MRC in England) developed a sequencing technology that made it possible to read the entire sequence of a bacterial virus (about 5400 nucleotides long, or roughly the same as being able to read a short paragraph). This was significant enough to merit a Nobel Prize, shared with two Harvard scientists who had developed a different (slower) method for sequencing. By 1985, Sanger's technique had begun to be automated, such that a MACHINE could read the DNA sequence automatically - it now was possible to routinely sequence more than 10,000 nucleotides (this would be like being able to read a full page - with enough work it wouldn't be too difficult to put together an entire chapter). However, in 1985 the human genome project still was a pretty daunting task - at the present (1985) rate of sequencing, Jim Watson estimated that it would take about a thousand years to sequence the entire human genome!! (I should point out that if Fred Sanger had tried to sequence the human genome with his methodology from 1979, it would take close to a MILLION years to finish! So a "mere" thousand years is quite an improvement, but still not good enough.)
So the human genome project was set up to invest heavily in technology.
In fact, when the program finally was officially launched in October of
1990, it was a 20 year project, with the first 10 years invested mostly
into improved methods of sequencing, with most of the actual sequencing
of the genome being done in the last few years. In addition, the
genomes of smaller organisms were set up as intermediary goal posts along
the road. In the past two years, we have already seen the realization
of the early goals; the complete
sequence for the genomes of more than a
dozen bacteria are now available for research and comparison, and the
genome of the first
"animal" (simple yeast) was published earlier this year (1997).
Soon to come will be the
first worm (nematode), first plant, and first insect. It will
probably be another 4 or 5 years before the first mammalian genomes become
available.
The human genome project was initially set up to run from 1990 through
the year 2010. The annual budget is roughly $200,000,000 per year
(!) - of which about $120,000,000 is allotted to the NIH, and about $80,000,000
allotted to the DOE. At the suggestion of the first Director of the
Human Genome project (Jim Watson), about 5% of the budget is invested into
"ethical considerations of the human genome sequencing project".
As Cook-Deegan points out, there are many ethical considerations to consider.
There are the problems in dealing with knowledge about the future of someone's
life (for example, it is likely that this person will die of lung cancer
at the age of 20). There are also all the abortion related problems,
since now that we know how to screen for many diseases, pre-natal screening
now is much more predictive. Finally, there are many financial problems,
having to do with insurance, for example, as well as all the considerations
of patent rights.
In fact, a large part of the reason Jim Watson resigned as director was
related to his strong objections to the U.S. government policy of trying
to patent DNA sequences. Although Cook-Deegan takes a more "middle
of the road" approach, and tries to explain why the government wants to
regain money invested in research (which I think this SOUNDS fair enough...)
I really tend to agree with Watson. Imagine. You are living
a thousand years in the future, and no one speaks English anymore - in
fact, through years of neglect, it is almost a forgotten language.
Now you learn to read, and find one of Shakespeare's books. Suppose
you are the first person to read through part (not all, even) of one of
his plays. Does this mean that YOU have to right to charge anyone
else royalties who wants to read this or use it in the future? This
is in fact what was at issue at the "bioearth" summit in Brazil in 1992.
The U.S. did not want to sign an agreement forbidding the patenting of
DNA sequences, despite the agreement amongst all the other countries in
the world. I personally have no problems with patents - I think they
are wonderful, provided they are for something that you have created.
But I do have serious problems with patenting DNA sequences, because this
is just merely reading a text that someone else (God?
Nature?)
has already written.
In summary, this book is a good history of the beginning of the Human Genome project. For me, it was fun to see much fruit of this project in my own research. I think this is an essential reading for anyone who wants to understand what the human genome project is all about, in terms not only of the science, but also the development of government policies and the personalities of the scientists involved.
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6.
Medical Genetics Poses New
Medical and Ethical Dilemmas
There
have been several "ethical dilemmas" which have become more pronounced
recently, due to biotechnological advances in Medical Genetics:
Pre-natal
screening - as we determine the genetic
basis for more diseases, it is becoming easier to screen for these diseases,
even before a child is born. This can have potential health benefits,
but some people could use it to decide whether to have an abortion.
Should we curtail the knowledge that is available to the patient?
Who should decide this?
The
right to privacy. Do you really
want to know that there's a good chance you'll die at the age of 35 of
a heart attack? Should your insurance company know this? Should
your employer know this?
Gene
therapy. Presently we can do
"gene therapy" on somatic tissue, not on germ-line cells. Even with
this limitation, gene therapy will likely be applied to areas that are
ethically thorny in the near future. It is estimated that more than half
of all the genes in human genome (roughly 40,000 of the 70,000 total genes)
are expressed only in the brain. Thus, for example, gene therapy
could be applied brain cells, to modify behavior. There are several
questions about this: SHOULD we do this? Who will be the ones to
determine what "normal" behavior is?
Eugenics.
Presently, there are "human" cell lines which contain a "HAC", or human
artificial chromosome. Technically, it is possible to find a surrogate
mother and implant an embryo with 24 chromosomes (rather than the usual
23). Thus, you would have (from a biological point of view) a new
species, because this person could no longer interbreed. Or, at least
not unless she found a partner who ALSO had an additional 24th chromosome...
Should Bill Clinton introduce legislation to prevent this? Would
it be possible to enforce this?
Cloning.
Is it even possible to really
clone a human (e.g.,
make a xerox copy of a person?) (My
answer: not really - environment plays a more dominant role than hereditary!
However, you could certainly take a few skin cells from you and grow up
another person from those cells; this person would be very similar to you,
in many ways.)
Is it even possible
to prevent someone from doing
this?
(The answer: I don't
think so - it would certainly be very difficult, if not impossible.)
Should we try?
(The answer: I don't know!)
Human Cloning: Yesterday's Never Is Today's Why Not?
(from The New York Times, 2 December, 1997)
......But some experts said the real question was not whether
cloning is ethical but whether it is legal.
"The fact is that, in America, cloning may be bad but telling
people how they should reproduce is worse," Willadsen said.
In the end, Willadsen said, "America is not ruled by ethics.
It is ruled by law."
Patent
rights.
Should a person be allowed to get a "copyright" on a DNA sequence that
they have read?
A list
of books on the human genome project:
1990
Understanding
Our Genetic Inheritance,
The U.S. Human Genome Project , The First Five Years: Fiscal Years 1991-1995
(U.S. Government printing office, 1990) - click on this link (the
web site is:)
http://www.nhgri.nih.gov/HGP/HGP_goals/5yrplan.html
"Mapping
the Code : The Human Genome Project and the Choices of Modern Science",
Joel Davis, (John Wiley & Sons, New York, 1990).
"Genome : The Story of the Most Astonishing Scientific Adventure of Our Time - The Attempt to Map All the Genes in the Human Body", Jerry E. Bishop, Michael Waldholz, (Simon & Schuster, New York, 1990).
1991
"The
New Genetics : The Human Genome Project & Its Impact"
(Grand Rounds Pr Ser.), Leon Jaroff (Whittle Communication, 1991).
"The
Human Genome Project : Cracking the Genetic Code of Life",
Thomas F. Lee, (Plenum Press, 1991).
"The
Human Blueprint : The Race to Unlock the Secrets of Our Genetic Script",
Robert Shapiro, (St Martins Press (Trade), 1991).
"Exons,
Introns, and Talking Genes : The Science Behind the Human Genome Project",
Christopher Wills, (Basic Books, 1991).
"Mapping
Our Genes : The Genome Project and the Future of Medicine",
Lois Wingerson, (Rei Edition, Plume publishing company, 1991).
1992
"Gene
Mapping : Using Law and Ethics As Guides",
George J. Annas, Sherman Elias (Editors), (Oxford Univ Press, 1992).
"The
Code of Codes : Scientific and Social Issues in the Human Genome Project",
Daniel J. Kevles, Leroy Hood (Editors), (Harvard Univ Press, 1992).
"Human
Genome Project", McCun,
(Gem Publications; Publication date: June 1992, ISBN: 0865961344).
1993
"The
Human Genome Project",
Marianne Postiglione (Editor), (Itest Faith Science Press; Publication
date: March 1993, ISBN: 0962543160).
"Guide
to the Human Genome Project : Technologies, People, and Institutions" (Chemical
Heritage Foundation Publication, No. 11), Susan L. Speaker, M. Susan Lindee,
Elizabeth Hanson, Chemical Heritage Foundation; Publication date: February
1993, ISBN: 0941901106).
Human
Genome Diversity Project
: hearing before the Committee on Governmental Affairs, United States Senate,
One Hundred Third Congress, first session, April 26, 1993 (Published by
U.S. G.P.O. : For sale by the U.S. G.P.O., Supt. of Docs., Congressional
Sales Office; ISBN: 0160433347)
1994
"Are
Genes Us? : The Social Consequences of the New Genetics",
Carl F. Cranor (Editor), (Rutgers University Press, 1994).
"The
Human Genome Project : Deciphering the Blueprint of Heredity",
Necia Grant Cooper (Editor), (Univ Science Books, 1994).
"On
the New Frontiers of Genetics and Religion",
J. Robert Nelson, (Wm. B. Eerdmans Publlishing Company, 1994).
"Justice
and the Human Genome Project",
Timothy F. Murphy, Marc A. Lappe (Editors), (University of California Press,
1994).
"Genes
and Human Self-Knowledge : Historical and Philosophical Reflections on
Modern Genetics",
Robert F. Weir (Editor), Susan C. Lawrence, Evan Fales (Editor), ro Weir,
(Univ of Iowa Press, 1994).
"Perilous
Knowledge : The Human Genome Project and Its Implications",
Tom Wilkie, (University of California Press, 1994).
Department
of Energy's human
genome project issues arising from research :
hearing before the Subcommittee on Energy of the Committee on Science,
Space, and Technology, House of Representatives, One Hundred Third Congress,
second session, October 4, 1994 (Published by U.S. G.P.O. : For sale by
the U.S. G.P.O., Supt. of Docs., Congressional Sales Office; ISBN: 0160470382)
1995
"The
Global Human Genome Program by the OECD Forum Megascience",
(Published by O E C D; Publication date: October 1995, ISBN: 9264145753).
" The Book of Man : The Human Genome Project and the Quest to Discover Our Genetic Heritage", Walter Bodmer, Robin McKie (Scribner, 1995 - this first edition is hard to find - see 2nd edition, published in 1997).
1996
"Morality
and the New Genetics : A Guide for Students and Health Care Providers"
(Jones and Bartlett Series in Philosophy), Bernard Gert, (Jones &
Bartlett Publishers, 1996).
"The
Human Genome Project and the Future of Health Care"
(Medical Ethics Series), Thomas H. Murray (Editor), Mark A. Rothstein (Editor),and
Robert F. Murray, ( Indiana Univ Press, 1996).
The
Human Genome Project : Cracking the Code Within Us" (Impact-Science),
Elizabeth L. Marshall, (Franklin Watts, Incorporated, 1996).
"The
New Genetics : Challenges for Science, Faith, and Politics",
Roger Lincoln Shinn, (Moyer Bell Ltd., publisher, 1996).
"The
Lives to Come : The Genetic Revolution and Human Possibilities",
Philip Kitcher (Touchstone Books, 1997).
"The
Book of Man : The Quest to Discover Our Genetic Heritage",
Robin McKie, Walter Bodmer, (Oxford Univ Press, 1997, 2nd edition (first
edition was published in Jan. 1995, and is now hard to get.).
books in press: (As of 14 November, 1997)
"Controlling Our Destinies : The Human Genome Project from Historical, Philosophical, Social, & Ethical Perspectives" (Studies in Science & the humanities), Phillip R. Sloan (Editor), Brian H. Smith, (Univ of Notre Dame Pr; Publication date: December 1997, ISBN: 0268008183)
"Access
to the Genome : The Challenge to Equality",
Maxwell J. Mehlman, Jeffrey R. Botkin, (Georgetown Univ Pr; Publication
date: April 1998, ISBN: 0878406778).
For reviews,
reader's comments, and availability, click on the icon below:
A
few more links:
ELSI
Some
selected topics from this semester's Genetics
course:
A
Brief History of DNA
Exam # 4 - in particular, have a look at questions 6-10
Comments & corrections to Chapter 15 from Audesirk & Audesirk Biology 101 Text:
1.
Methods in Genetics
2.
Single-Gene Inheritance
3. Complex Inheritance
5.
The human genome project
6.
Medical Genetics Poses New
Medical and Ethical Dilemmas
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Last modified on: 19 February, 2000 by Dave Ussery