HUMAN GENOME PROJECT (HGP)

AND ITS
ETHICAL, LEGAL & SOCIAL
IMPLICATIONS (ELSI)
MBH-403: MICROBIAL BIOTECHNOLOGY
HUMAN GENOME PROJECT
• The Human Genome Project (HGP) is an international effort, coordinated by the United States
Department of Energy and National Institutes of Health, that aims to determine the sequence of
every nucleotide in the human genome and to identify all the genes contained within the genome.
Formally started in 1990, the project was intended to complete the working reference genome by
2005 but technical advances have decreased the timeframe to 13 years.
• The genome itself, at six billion nucleotides long, is far too big to sequence as a whole. The initial
approach was to break it into pieces, determine the order of the pieces, and then to determine the
nucleotide sequence for each piece. A private company split from the public project, however, and
began sequencing DNA segments in order to patent them. This forced the HGP to change its approach
to match that of the private company and to provide the nucleotide sequence of the pieces before
knowing the order of the pieces. The statement by President Clinton and Prime Minister Blair 26 June
2000 announced not only the virtual completion of the sequencing of the pieces, but also a truce
between the private and public projects. To obtain a reference copy of the human genome that is
99.99% accurate, and with all the pieces in order, would take another three or so years. Various
groups around the world had been working on individual chromosomes and the sequencing of these
is at different stages of completion. Chromosome 21, with the exception of three gaps 30,000
nucleotides in length, had already been completed to the final standard. Because this chromosome is
implicated in Down syndrome, some researchers had begun to sequence it before the start of the
Human Genome Project.
• The final, complete human genome sequence was described in a set of six papers in the April 1, 2022,
issue of Science.
HUMAN GENOME PROJECT

• One of the most significant aspects of the HGP is that it reverses the way in which science is
normally done. Usually, researchers approach a specific problem and then try to find its
causes, among which might be the DNA sequence of a gene or genes. The HGP will yield the
order of the nucleotides in the human genome, and identify putative genes, but will not
identify their functions. It will take many years, if not decades, before the gene products are
identified and many more years to understand how they interact with each other and the
environment in developmental, biochemical and physiological processes.
• The HGP has also involved the determination of the nucleotide sequence for the genomes of
other organisms, many of which have been used as laboratory models and so have many
well understood biochemical pathways and physiologies. Since their genomes have many
similarities to the human genome, knowing their sequences will help to identify genes and
the function of genes in the human genome.
ETHICAL, LEGAL AND SOCIAL
IMPLICATIONS OF THE HUMAN GENOME
PROJECT
• From the beginning, it has been understood that the Human Genome Project will have
profound ethical, legal and social (ELS) implications; thus, between 3 and 5% of its budget
has been devoted to the study of ELS issues. Ethical issues are generally defined as those
raising questions concerning what is moral or right. Legal issues are those concerning the
protections that laws or regulations should provide. Social issues are concerned with how
events may affect society as a whole and individuals in society. Clearly, these aspects of the
HGP and its possible outcomes are not independent of each other.
• Many of the ELS implications are not new. The gene for Huntington’s disease was
discovered in 1993, after a ten-year search following the localization of the gene to
chromosome 4 in 1983. A test for the disease was developed soon after. Many of the
questions currently being addressed by the ELS issues program of the HGP have, therefore,
been familiar for many years to families afflicted with Huntington’s. As a result of the HGP,
however, society as a whole will have to deal much more frequently with issues arising
from knowledge of the human genome. Moreover, the implications may be less clear in the
case of genes identified for diseases that have strong environmental aspects and involve
interaction with many other genes.
1. THE EXISTENCE OF GENETIC INFORMATION
• The existence of genetic information with respect to individuals and the human population as a
whole will have a profound impact on our day-to-day lives and may well change how we regard
ourselves and one another.
• The knowledge of predisposition to a certain disease and the ability to design "tailor made"
therapies may greatly help in the treatment of disease. Already a company in Great Britain has
applied for a patent on a device that can apparently detect different forms of over 2,500 genes
said to be associated with traits including behaviour and intelligence.
• It has been argued, however, that it is not proper, particularly at this juncture in history, to
search for such knowledge. For example, some have pointed out that science has often been
co-opted as a tool to accentuate racial differences and to defend racist practices. Given that
humans are far from resolving issues of race, it is thought that information from the HGP, and
such follow-up projects as the Human Genome Diversity Project, may have the potential to
inflame racism in an already overly racist world.
• Equally, some feel that if the goal of the HGP is to prevent disability and disease, increase life
spans, decrease infant mortality, and increase intelligence, the money would be far better spent
elsewhere. Given that we already know that environmental and social factors can influence
such diseases as diabetes in aboriginal populations and drug addiction among the socially
marginalized, some consider it unconscionable to dispense limited resources looking for genetic
causes for these diseases.
1. THE EXISTENCE OF GENETIC INFORMATION
• The legal aspects of knowledge of the human genome are enormous. Already DNA evidence is
being used as a powerful legal tool, particularly in exonerating wrongly accused individuals. Does
this mean that the criminal system should be able to keep a bank of DNA information on anyone
accused and/or convicted of a crime? Could the database be used for other purposes than simply
identifying and eliminating suspects? A DNA database could contain much more information on
individuals, both guilty and innocent, than does the current system of taking fingerprints.
• On a more hypothetical note, should genes leading to a propensity for criminal activity be found,
could they be used as prosecution or defence evidence in a trial? For instance, is a suspect who
knows that he or she has a genetic disposition toward criminal behaviour and does nothing to
avoid provoking such behaviour, guilty of a more serious crime than a suspect who is ignorant of
having such a propensity? On the other hand, could genetic disposition be used as a defence on
the grounds that the crime was really the fault of the gene, not the person?
• When a patient tests positive for a gene linked to risk of disease, does the physician (or the
patient) have a legal responsibility to inform the patients’ relatives of their own risks? Suppose a
patient finds out that she has a genetic propensity for breast cancer, but neither she nor her
doctor informs her relatives; would a relative who later developed that form of cancer be able to
sue, on the grounds that the genetic information had not been disclosed?
• Ensuring that the judge and jury in a trial are sufficiently educated to deal with these issues is yet
another problem with which the legal system will have to deal.
1. THE EXISTENCE OF GENETIC INFORMATION
• On a larger social scale, knowledge of the human genome could be used to emphasize the similarities
among all humans. The genetic differences between people within an identified group have already
been shown to be greater than the differences between groups. In other words, people within an
"ethnic" population are more different from each other than the group as a whole is different from
other "ethnic" groups. This fact is unlikely, however, to deter those who wish to emphasize any ethnic
differences that may be found.
• On a more individual level, the results of the HGP might encourage people to view themselves as
being wholly under the control of their genes. What has traditionally been viewed as the human
spirit might in future be seen as limited by pre-programming at birth. Thus, though we cannot predict
exactly how knowledge of the human genome will affect society, it could clearly have important
consequences.
• Individual decisions, such as choices with respect to mates and reproduction, could also be
influenced by knowledge of genetic makeup. Awareness of personal genetic differences from a
perceived norm might lead to confusion and uncertainty about the potential for disease, particularly
in the absence of adequate professional consultation. Genetic analysis might reveal a myriad of
genetic flaws that may or may not lead to disease, depending on what they are and how they interact
with the environment. How will individuals select from a debilitating array of lifestyle choices, none
of which has a certain outcome? Again, analysis of one’s own genetic makeup could reveal the
genetic makeup of parents and siblings, including, for example, unsuspected information about
paternity. How willing would people be to share this knowledge and, if they decided to withhold it,
how would they be affected by living with the secret?
2. OWNERSHIP AND COMMERCIALIZATION

• On 11 November 1997, UNESCO passed its Universal Declaration on the Human Genome
and Human Rights. Article 4 of the Declaration states that "The human genome in its
natural state shall not give rise to financial gains." In most countries, however, DNA, when
isolated from an individual, is not considered to be in its natural state and therefore can
give rise to financial gain. One of the benefits of the HGP and genomics research in general
is expected to be a thriving biotechnology industry with the potential, in the United States,
to be worth $45 billion (U.S) by 2009. In most technological industries, innovation has been
encouraged through the granting of patents on inventions.
• Researchers who devise an invention that is useful, new, and unobvious are given
approximately 20-year proprietary rights over its use. To be patentable, discoveries must
involve some human intervention and inventiveness. In return for these rights, the inventor
must make the invention public so that others may, at a price, use it to further their
research.
• For approximately 20 years, sequences of DNA that correspond to human genes have been
claimed in patents. Conceptually, the string of DNA molecules is considered no different
from other chemicals isolated from living organisms, such as penicillin, as long as it passes
the tests for patentability (being new, useful, and unobvious).
2. OWNERSHIP AND COMMERCIALIZATION

• For a number of reasons, some believe that human gene sequences should never be
patentable. A fundamental, philosophical reason is the belief that the human genome, as
an intrinsic part of every person, is a common heritage that all humans should share. This
line of reasoning has led the Parliamentary Assembly of the Council of Europe to
recommend that European Union countries renegotiate the agreed Directive that allows
the patenting of human genes that are isolated from the body and applicable to industry,
and specifically prohibit the patenting of human genes.
• The World Trade Organization’s Trade Related Aspects of Intellectual Property Agreement
includes some discussion on what member countries can exclude from patentability. Article
27(2) states that anything that is necessary to protect the "ordre public or morality" can be
excluded, as long as the exemption is not made simply because it is prohibited by law.
Section 27(3)(a) states that member countries may also exclude diagnostic, therapeutic and
surgical methods for humans and animals. No specific clause would seem to prevent a
member country from excluding the patentability of human genes. Canada’s Patent
Act does not have an "ordre public" clause.
2. OWNERSHIP AND COMMERCIALIZATION
• Some offer logistical reasons to explain why patents should not be extended to DNA
sequences. They suggest that such patents, particularly on partial gene sequences, would
inhibit innovation rather than encourage it, as the patent system is supposed to do. This
could arise in a scenario, dubbed the "tragedy of the anticommons," in which numerous
people and organizations held patents on different DNA sequences governing an overall
biochemical pathway that could be the target for a medical treatment. To research that
treatment, someone would have to negotiate for the rights to all the DNA sequences from all
the respective owners; this might be so costly and onerous as to make further research
unlikely. Pure researchers, who would not have the money, the time or the expertise for a
complex series of transactions, would be the most severely affected. Others, however, refute
this argument, citing the case of the computer industry. Patents on the various parts of
computers certainly do not seem to have impeded the growth of that industry, though some
might say that it has impeded innovation. Others point out that in the computer industry, the
free flow of information has been a driving force behind such innovations as the GNU-Linux
operating system.
• It has also been suggested that DNA does not pass the tests for patentability on the ground
that, since DNA exists in nature, knowledge of it is simply a discovery, not an invention.
Therefore, while drugs should be patentable, the DNA sequence upstream from the target of
the drug should not be. Moreover, it is said that many of the techniques used to isolate and
manipulate DNA are now routine, and therefore the inventions are too obvious to be
2. OWNERSHIP AND COMMERCIALIZATION

• In North America, the focus is more on what level of utility must be shown in order for
genes to be patented, rather than on whether they are patentable at all. The
Canadian Patent Act, as it is written, has for a long time been interpreted as meaning that
genes are patentable material. A problem has arisen because many private companies
have concentrated on sequencing genes in the hope of obtaining patents on a gene that
may one day prove to be useful. Most of the genes sequenced by the HGP and private
enterprises have as yet unknown functions; thus, applications are being made for DNA
sequences that have no genuine utility. Since the sequences do encode a protein, some
companies have gone so far as to claim that, at a minimum, the protein could be used for
animal feed or in a molecular biological technique as a DNA probe. In one well known case
in the United States, the company Human Genome Sciences obtained a patent on a gene
that was subsequently discovered by a different researcher to be an entry portal through
which the AIDS virus infects cells. Any future treatment of these cells that alters this entry
portal will require royalties to be paid to Human Genome Sciences. The U.S. Patent Office
has recently announced that it will increase the stringency of the utility requirement for
patenting DNA sequences.
2. OWNERSHIP AND COMMERCIALIZATION

• Searching for medically useful, and therefore potentially profitable, genes also raises many
ethical questions. Heritable disease patterns sometimes emerge in populations that have
not mixed extensively with other populations; as a result, private companies are doing
genetic exploration in such relatively isolated areas as Newfoundland, Iceland and certain
tropical islands. In Iceland, a company called deCODE has been given the rights to produce
a health sector database that will include genealogical, environmental, and molecular
genetic information, along with the combined anonymized patient records of the country.
In Newfoundland, political leaders are apparently coming to the conclusion that
Newfoundlanders should maintain control over their unique genome. How to regulate the
gene hunters without scaring off investment is a familiar problem to governments that
already have experience with charging royalties and regulating natural resource operations.
Gene "mining" companies, however, present a much more complex and emotional set of
ethical issues than does the natural resources sector.
3. GENETIC TREATMENT OF DISEASE
• From the outset, one of the defining goals of the HGP has been its potential for molecular
medicine. The concept is that, once the functions of genes are known and we understand the
effects of malfunctioning genes, we will be able to correct the problem either through the use
of designer drugs or by replacing the faulty gene. It is the latter option that has created the
most controversy.
• There are two routes to replacing a faulty gene. The first route, germ line therapy, has the goal
of replacing a harmful gene in a fertilized human egg with a properly functioning gene that
would be passed on to future generations. The other route, somatic gene therapy, aims to
replace the gene in target organs or tissues of an adult, so as to fix the symptoms in that
individual but not in the next generation. Germ line therapy has the more profound ethical,
legal and social implications.
• As yet germ-line therapy in humans is not possible and some have argued that it will continue
to be so for the foreseeable future. While this kind of therapy may be a long way off, it would
bring, on the one hand, the hope of eradicating some genetic diseases but, on the other hand,
the spectre of eugenics.
• The eradication of disease through germ-line therapy might not seem, by itself, to raise many
ethical questions. After all, humans have eradicated the smallpox virus from the world, why not
diseases with genetic components? Do doctors not have the moral obligation to provide the
very best treatment to their patients and would not the eradication of the disease be more cost
effective in the long run than continually treating adults with somatic gene therapy? The main
3. GENETIC TREATMENT OF DISEASE
• Some might say that eradication of a genetic disease for which there is no treatment and which is
always fatal, should be pursued with all means possible. Others say that this would be the start of a
slippery slope moving on toward the treatment of less obvious diseases and then to genetic
enhancement. Some argue that if the technology is advanced in order to eradicate some diseases, it
will inevitably be used by parents wishing to "enhance" their children, giving them the genes for
raven black hair and blue eyes or athletic prowess. It was serious ethical concerns about genetic
enhancement that prompted the Council of Europe to adopt the Convention for the Protection of
Human Rights and Dignity of the Human Being with Regard to the Application of Biology and
Medicine: Convention on Human Rights and Biomedicine. Article 13 of the Convention states that "an
intervention seeking to modify the human genome may only be undertaken for preventive,
diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the
genome of any descendants." Article 11 of the UNESCO Universal Declaration on the Human Genome
and Human Rights states that "practices which are contrary to human dignity, such as reproductive
cloning of human beings, shall not be permitted." It is left to individual states, however, to define
exactly what they believe these practices to be. Thus, while some countries, such as the signatories
to the European Convention, may prohibit germ-line therapy, others may not. It is the existence of
national differences in regulation of research on human embryos that has allowed controversial
research to be performed, for example, in Singapore. Regulation has thus slowed down the progress
of research but not prevented it.
• Another ethical consideration with respect to germ-line therapy is defining what is normal, what is a
disability, and what is a disease. Which of the genetic variations within a population ought to be
eradicated, if any? In trying to eradicate a certain variation, are we demeaning those in the
3. GENETIC TREATMENT OF DISEASE
• Somatic gene therapy has its own, less controversial, set of ELS implications. These may be less ominous
than eugenics but are of perhaps more immediate concern, given the more advanced state of the
technology. Effectively, gene therapy involves the introduction of a properly functioning gene into target
tissues in the hopes that it will be translated into a properly functioning protein, which will mask the
malfunctioning protein. Often the new gene is placed into a modified virus, which is then introduced
into a patient in the hope that the gene will be introduced into a tissue and properly expressed.
• Such types of therapy, after much research on laboratory animals, have now reached the clinical trial
stage. Unfortunately, what works for a mouse does not always work for a human being. In one highly
publicized case, a patient, Jesse Gelsinger, was given an injection of a virus in the hope of introducing a
protein into the liver. Mouse studies showed good absorption of the gene into the liver; however, the
mouse has a much higher concentration of viral receptors on its liver cells than do humans. The virus
did not absorb well into the human patient and, for still unknown reasons, created a massive immune
response, causing the patient to die. The original plan for the trials had been to use the virus only on
children in a coma caused by the lack of the particular liver enzyme; however, ethical and safety reviews
caused the researchers to change the trial direction and use adults only. Many questions are now being
asked regarding the ethics and scientific judgment of those performing such clinical trials. How well are
"volunteer" patients informed of the possible risks and benefits? How objective are investigators who
have equity in the companies that are funding the trials? One of the risks at this stage of gene therapy is
the excessive public anticipation, created in part by some researchers, with respect to future benefits.
This anticipation may turn to public distrust of science, if the benefits fail to be realized and problems
such as that in the Gelsinger case continue to occur. Some clinical trials have shown positive results, and
so there is still hope that somatic gene therapy will become a powerful medical tool.
4. DISCRIMINATION

• One of the problems some fear might result from knowledge of the human genome is the
emergence of a whole population of socially marginalized individuals, unable to obtain a
job, a family, insurance, or health care and stigmatized by the rest of society. Insurance
companies already insist that those identified at risk of Huntington’s disease must take a
genetic test. If the results are positive, insurance is frequently refused. Insurance companies
are on record as saying that if genetic information was available, they would use it in their
risk assessment. In countries without a public health insurance system, however, the plight
of such a non-insured person can be a nightmare. Care may be available but finding it is very
difficult. As more genetic tests become available, insurance is likely to be more and more
expensive for those carrying what the insurance companies deem to be risky genes. The
public insurance schemes may also start to feel the pressure for such genetic testing, and be
forced to make policy decisions based on the funding available and the knowledge of
genetic predisposition to disease within populations. Gene therapy is at the experimental
stage at this point but will certainly be very expensive when it first comes into regular use.
Who will pay for it? If not public insurance, will the therapy be available only to rich people,
thus creating an ever widening gap between groups in society, based on both money and
genetic inheritance?
4. DISCRIMINATION

• Employers may also want access to genetic information. Some genes might reveal a
susceptibility to environmental damage that was incompatible with a certain workplace
environment. Employers might choose to screen out workers carrying that gene rather
than trying to improve the environment. Individuals with genes associated with certain
behavioural traits might also be excluded from the workplace.
• Some action has already been taken to prevent the possibility of genetic discrimination. For
example, President Bill Clinton had signed an executive order prohibiting federal
departments and agencies from using genetic information in any hiring or promotion
action. He has also endorsed an Act, introduced in 1999 by a Senator and a member of
Congress, that would extend such protection to the private sector.