2012 Marek Vácha Engineering the engineer as well as the engine, we race our train we know not...

2012Marek Vácha

Engineering the engineer as well as the engine, we race our train we know not where.

Leon Kass

Gene therapy

somatic cells concerns one single individual

germ cells concerns plenty of individuals

LeRoy Walters:

What does it mean to be human? Adding a What does it mean to be human? Adding a occasional gene here and there is not going occasional gene here and there is not going to alter who we are as a human race. But if to alter who we are as a human race. But if we draw no line, if we accept that people we draw no line, if we accept that people have a right to make what they want of their have a right to make what they want of their lives, then we condone the right of humans lives, then we condone the right of humans to manipulate their genomes in the absence to manipulate their genomes in the absence of any real knowledge of what they are of any real knowledge of what they are doing. Might we add a gene here and alter a doing. Might we add a gene here and alter a gene there until we become a society of gene there until we become a society of chimeras, uncertain who wechimeras, uncertain who we are?are?

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

Oviedo, 4.IV.1997

Oviedo 1997:CONVENTION ON HUMAN RIGHTS AND BIOMEDICINE

Article 13 – Interventions on the human genome

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.

legally, there is no ban in the United States on germline engineering research

1996: New Jersey:the doctors took a client´s fertilized egg and added 5% of the cytoplasm (including mitochondria) from a donor egg to replace any malfunctioning units in the client´s egg.

Between 1996 and 2001, a reported 16 babies with the genetic makeup of three parents (the client mother and father and the female cytoplasm donor) were born

UNESCO: Universal Declaration on the Human Genome and Human Rights11 November 1997

= nonbinding declaration Article 24

The International Bioethics Committee of UNESCO should contribute to the dissemination of the principles set out in this Declaration and to the further examination of issues raised by their applications and by the evolution of the technologies in question. It should organize appropriate consultations with parties concerned, such as vulnerable groups. It should make recommendations, in accordance with UNESCO’s statutory procedures, addressed to the General Conference and give advice concerning the follow-up of this Declaration, in particular regarding the identification of practices that could be contrary to human dignity, such as germ-line interventions.

This declaration was signed by 186 nations.

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 - Interventions on the human

genomeAn 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.

Biological background

In vivo and Ex vivo gene therapy

The first definite success: a cure for X-linked severe combined immunodeficiency: X-SCID

nine of 11 treated patients were cured and enabled to lead a normal life

however, two of them have subsequently developed a leukemia almost certainly as a result of insertional activation of the LMO2 oncogene.

all trials involving retroviral transduction of large pools of lymphocytes were quickly suspended worldwide, pending full understanding of these tragic events.

Gene therapy

Somatic-cell gene therapy Germ-line gene therapy

Germ-line genetic modification

A therapeutic effect of a somatic-cell gene therapy would be limited to the treated patient a would not affect progeny

animals carrying foreign genes in their germ line (transgenic animals) have been produced using mice, rats, rabbits and some others.

Contemporary strategies

(A) Loss-of-function conditions. (B) Gain-of-function conditions.

miRNA1. An enzyme cuts each hairpin from

the primary miRNA transcript2. A second enzyme, called Dicer, trims

the loop and the single-stranded ends from the hairpin, cutting at the arrows (the fragment has about 20bp).

3. One strand of the double-stranded RNA is degradated; the other strand (miRNA) then forms a complex with one or more proteins.

4. The miRNA in the complex can bind to any target mRNA that contains at least 6 bases of complementary sequence.

5. If miRNA and mRNA bases are complementary all along their length

siRNAs

RISC = RNA-induced silencing complex

miRNAs and siRNAs

the same cellular machinery generates miRNAs and siRNAs and both can associate with the same proteins, producing similar results

the distinction between miRNAs and siRNAs is based on the nature of the precursor molecule for each while an miRNA is usually formed from single hairpin in

a precursor RNA, siRNAs are formed from much longer double-stranded RNA molecules, each of which gives rise to many siRNAs

it has been estimated that expression of up to one-third of all human genes may be regulated by miRNAs

Somatic Cell Gene Therapy

most scientists agree that treating a disease by inserting a corrected gene into a patient is not ethically different from using medicines to treat the disease.

most of the concerns: the safety of the procedures

(Gilbert, S.C., Tyler, A.L., Zackin, E.J., (2005) Bioethics and the New Embryology. Sinauer Associates, Inc. W.H. Freeman & comp. Sunderland, MA U.S.A. p. 200)

the boundary between treatment (for disease) and enhancement (for cosmetic or athletic purposes) can be indistinct is short stature a disease? is infertility a disease? is baldness a disease?

Myostatin„Schwazenegger mice“

studies in mice showed that if the gene for myostatin is absent, the mice grow into muscular rodents who are stronger and faster than their non-mutant littermates

individual muscles from myostatin mutants mice weighed 2-3 times more than muscles taken from normal mice

the increased muscle mass resulted from both an increased number of muscle fibers and an increased size of individual fibers

a human child has been found who is deficient in this gene

he has an exceptional musculature and is much stronger than other boys of his age

although he is healthy, physicians are watching him closely because the same gene is active in heart muscle, where such enlargement can be dangerous

Somatic gene therapy

A notable example is the trials conducted on patients suffering from cystic fibrosis, who inhale an aerosol spray of liposomes containing the gene that patients lack. if they were more promising, such therapies

might appear to be ethically unproblematical, because any changes induced would be limited to the patient and not passed on to their children

(Mepham, B., (2008) Bioethics. An Introduction for the Biosciences. Oxford University Press, Oxford, p. 139)

Germline Gene Therapy

= IGM = Inheritable Genetic Modification in laboratory animals, IGM has been

accomplished in two ways: by modifing the parental germ cells or the fertilized egg

such that a new genome is in every cell of the person´s body and is therefore transferred to the next generation through the germ cells

by modifying embryonic stem cells so that the adult body contains a high percentage of cells derived from these genetically altered blastomere

Germline Gene Therapy

Gregory Stock: the question is not if, but when.

given that IGM might be able to eradicate inhereited genetic diseases and enable us to expand our genetic repertoire, why should anyone be against it?

Some Comments

Gene therapy

Most human disease results from interaction of a born genetic factors with environmental influences.

Therapy only modifies the symptoms of disease, thereby giving the body an opportunity to heal itself

gene therapy: effective treatment should correct the underlying genetic defect itself and not just a symptoms

Genetic Engineering

= a proceess of inserting new genetic information into a cell with the intention of changing that cell´s function and ultimately modifying the phenotype of the organism.

Gene therapy = specific apllication of genetic engineering techniques with the primary objective of correcting defective genes to treat a genetic disorder.

The General Nature of Biological Engineering engineering = designing and constructing

of complex material artifacts for human use

up to the present, all technology has been concerned with lifeless material (most typically metals), shaping them into human artifacts for human use

man was the subject, „nature“ the object of technological mastery

Biological engineering: man becomes the direct object as well as the subject of the engineering art.

(Jonas, H., (1974) Philosophical essays: from ancient creed to technological man. Prentice-Hall)

Engineering:

man nature (metal)

Biological engineering:

man man

ENGINEERING from first element to final

product designing

maker is the sole agent vis-à-vis the passive material building

predictability is 100 % the engineer can accurately

predict the properties of his product

BIOLOGICAL ENGINEERING work on pregiven structure;

rather improvement than making de novo design alteration

modifier is a co-agent with the self active material intervention

number of unknown is immense prediction is reduced to

guessing, planning – to gambling

ENGINEERING experiments are performed

with substitute models which can be altered, tested and retested

everything in mechanical construction is reverisble

conventional engineering can always correct its mistakes in the planning and testing stages, even inthe finishing product automobiles f.e.) can be recalled to the factory for correcting of faults

BIOLOGICAL ENGINEERING the intended redesigning or

modification or improvement is in fact an experiment

for valid experiment, it must operate with the original itself the experiment is the real

deed modifications are

irreversible what is done is done (the

baby is born f.e.)

Genetic Engineering

= a proceess of inserting new genetic information into a cell with the intention of changing that cell´s function and ultimately modifying the phenotype of the organism.

Gene therapy = specific apllication of genetic engineering techniques with the primary objective of correcting defective genes to treat a genetic disorder.

Gene Therapy

is it true that… the natural is good and the unnatural is

History

Gene therapy

The first approved gene-therapy protocol began on September 14, 1990, in NIH, Maryland

within a few weeks after gene therapy began, her immune system showed improvement, and after several months she began living a relatively normal life

a four-year-old girl suffering from adenosin deaminase (ADA) deficiency was given back her own immune cells (specifically her blood T lymphocytes) that had been corrected by inserting a normal copy of ADA gene

W. French Anderson, 1990

In the treated children, a sample of their own (ADA-deficient) immature lymphocyte stem cells was cultured. The functioning ADA gene was inserted into the genome of a harmless virus, which was then allowed to „infect“ the cultured precursor cells. These cells incorporated the corrected gene and were injected back into the patient. The treatment has been successful in several cases; the patients´immune system function was restored, although they undergo continual medical treatment

later other patients received similar treatment, with up to 10-12 treatments per patients

several patients reported dramatic clinical improvements however, all the patients continued also to

receive treatment with an enzyme preparation, making it uncertain how much of their improvement was due to the gene therapy

X-linked SCID was the first unambigous success

the treatment was ex vivo, using a retroviral vector encoding the γc chain of cytokine receptor gene IL2R

bone marrow cells expressing CD34, a marker of hematopoietic stem cells, were incubated for 3 days with the retroviral vector…

…and then returned to the patient

„The Bubble Boy“

David Phillip Vetter (September 21, 1971 – February 22, 1984)

he suffered SCID at the age of 12, he died

after hematopoietic stem cell transplantation

„The Bubble Boy“

What was wrong?

pros cons

effort to save the life doing everything is

possible

career of the researchers publications popularity for the

researches

giving too much hope to the parents

Celý životopis JG sepsaný jeho otcem Paulem Gelsingerem je na http://www.jesse-gelsinger.com/

Jesse Gelsinger

born 18/06 1981 at the age of two, Jesse Gelsinger was first diagnosed

with a disease called OTC deficiency (ornithine transcarbamylase deficiency syndrome) OTC protein is a part of the urea cycle that is used to

remove excess nitrogen if the urea cycle doesn´t work, the nitrogen from the proteins

accumulates in the form of ammonia that builds up in the blood and brain

high levels of ammonia can cause damage especially to cells in the nervous system

permanent brain damage can result almost half of the patients die before the age of five years

Jesse Gelsinger

Treatment for JG: low-protein diet and cca 32 pills per day

the day he turned eighteen he left to Pennsylvania and gave the informed consent with the gene therapy

Jesse Gelsinger

on September 13, 1999, JG was sedated and a dose of the gene therapy agent was administred he received 6x1013 recombinant adenoviral

particles by intra-hepatic injection Within hours after doctors shot the normal OTC gene

attached to a therapeutic virus (adenovirus) into his liver, Jesse developed a high fever. His immune system began raging out of control, his blood began clotting, ammonia levels climbed, his liver hemorrhaged and a flood of white blood cells shut down his lungs.

Jesse Gelsinger

he was pronounced dead on September 17, 1999 His death was the first reported death ever directly

attributable to a gene therapy experiment There were questions about the quality of informed

consent at University of Pennsylvania and accusations that the university had failed to report toxic side effects earlier that could have shut down the study.

Jesse Gelsinger

the announcement of Jesse´s death made for headlines, shocked the public and terryfied the scientific community

gradually, increasing numbers of articles suggested, that his death had been avoidable

there were 18 participants in this OTC gene therapy trial, JG was the youngest why JG did die when others who received the same

treatment did not is not known in the aftermath of this tragedy, the gene therapy

institute in Pennsylvania has stopped working with human subjects and returned to work on animal model system

Arguments for

Gene TherapyArguments FOR

Isolating a disease-inducing aberrant gene looks fairly continuous with isolating a disease-inducing intracellular virus

Suppllying diabetics with normal genes for producing insulin has the same medical goal as supplying them with insulin for injection

Germe-line therapyarguments for

it solves the problem once and for all. Why leave the patient´s descendants at risk of a disease if you could equally well eliminate the risk?

Arguments against

Nontherapeutic genetic modificationethical issues

a child is not able to give an informed consent

goals: surely not to create man – man is already here to create better man? – but what is standard of

better? but better adapted to what... ... these questions all converge into one: in

what image?

Germ cells gene therapyobjections

present men have the power over the future men, who are the defenseless objects of antecedent choices by the planners of today

there is no right to existence for hypothetical individuals not yet conceived

but though not the right of merely imagined offspring, the right to offspring of the hindered progenitor is involved.

it coul lead to people being viewed as products capable of being manufactured, with the result that people could be „made to measure“.

our actions might come to be viewed as genetically determined rather than a matter of free will

germ line therapy is not necessary. Candidate couples would most likely have dominant or recessive Mendelian disorders (recurrence risk 50 % and 25 % respectively). Given a dish containing half a dozen IVF embryos from the couple, it would seem crazy to select the affected ones and subject them to an uncertain procedure, rather than simply to select the 50 % or 75 %of unaffected ones for re-implantation

Germ-line TherapyObjections

there are several alternative procedures prenatal genetic diagnosis gamete donation embryo selection adoption

...these are currently available and would not evoke the issues involved in germline manipulation

it is not safe when altered genes are inserted into the genome,

they may disrupt presently functional genes this has certainly been encountered in laboratory

mice. In one case, the disruption of single gene resulted in mice who were born without eyes, semicircular ear canals, or a sense of smell

some effects may take several generations to manifeste themselves - and any mistakes made will be permanent

it is not safe IGM is not a drug that can be discontinued if

the side effects are disastrous ...but we may one day use artificial

chromosomes to add genes that could be induced to lose their centromeres by a signal from exogenous factor. Once the signal was administered, such chromosomes would not survive meiosis or mitosis and would not be passed on to the next generation.

we know that there are genes that affects height and muscle mass, so we could conceivably make our offspring taller and stronger

if genes involving intelligence were found, those who could afford this procedure might enhance themselves in the hopes of producing highly intelligent offspring

Lee Silver (1998) envisions a world where, due to such economic inequality, the genetic haves and have-nots are far apart in their abilities: genetic engineering would convert economic differences into inherited biological differences.

some question a consequence if a trait chosen in one generation falls out of fashion in the next or becomes particulary ill-suited to a change in the environment one genration preffering a certain hair color, height

or organ endowment if parents were to select genes for height and

body musculature, they might then pressure their child to succeed at aports, regardless of whether the chilod wants to play the game

a genetic engineering could convert a child into a commercial product with expected parameters of normality and function

...and people who fell short of some technically achievable ideal would be seen as "damaged goods", increasing prejudices and discrimination

Gene TherapyArguments AGAINST

"Still harder will it be for most people to live easily and wisely with less certain information - say, where multigenic traits are involved or where the predictions are purely statistical, with no clear implication for any partictlar "predisposed" individual

The recent case of a father who insisted that ovariectomy and mastectomy be performed on his ten-year-old daughter because she happened to carry the BRCA-1 gene for breast cancer dramatically shows the toxic effect of genetic knowledge"

(Kass, L.R., (2002) Life, Liberty and the Defense of Dignity. Encounter Books. New York, London. p. 125)

Hans Jonas: "knowledge of the future, especially one´s

own, has always been excepted /from the injunction to "Know thyself"/ and the attempt to gain it by whatever means (astrology is one) disparaged - as futile superstition by the enlightened, but as sin by theologians; and in the latter case with reasons that are also philosophically sound"

C.S.Lewis: "In reality (...) if any one age really attains, by

eugenics and scientitfic education, the power to make its descendants what it pleases, all men who live after it are the patients of that power. They are weaker, not stronger" for though we may have put wonderful machines in their hands we have pre-ordained how they are to use them..."

because the technology is imprecise, any errors in the therapy (e.g. involving the insertion of a gene in the middle of another gene, disrupting its

expression) would also be inherited outcomes are unpredictable, for examle eradicating

the gene for sickle cell anaemia might increase the susceptibility of some carriers of the gene (e.g. in tropical Africa) to malaria, against which the gene confers resistance

manipulating of the embryo is seen as intrinsically ethically objecionable

present men have the power over the future men, who are the defenseless objects of antecedent choices by the planners of today

there is no right to existence for hypothetical individuals not yet conceived

but though not the right of merely imagined offspring, the right to offspring of the hindered progenitor is involved.

Religions

Footnote: catholicism

there is no problem with gene therapy of somatic cells

gene therapy of germ cells: in the present state of research, it is not morally

permissible to act in a way that may cause possible harm to the resulting progeny. In the hypothesis of gene therapy on the embryo, it needs to be added that this only takes place in the context of in vitro fertilization and thus runs up against all the ethical objections to such procedures. For these reasons, therefore, it must be stated that, in its current state, germ line cell therapy in all its forms is morally illicit.

Judaism

The older and comforting belief that human nature remains the same and that the image of God in it will assert itself against all defacements by man-made conditions, become untrue if we "engineer" this nature genetically and be the sorcerers (or sorcerer´s apprentice) that make the future race of Golems

Jonas, H., (2001) Contemporary Problems in Ethics from a Jewish Perspective in Yaffe, M.D., (ed.) Judaisms and Environmental Ethics. Lexington Books. Lanham. p. 259)

Judaism

The jewish posture should be, in the briefest formula: education - yes; genetic manipulation - no. (...)

We have not been authorized, so Jewish piety would say, to be makers of a new image (...)

The protest should always be against turning men into things

Jonas, H., (2001) Contemporary Problems in Ethics from a Jewish Perspective in Yaffe, M.D., (ed.) Judaisms and Environmental Ethics. Lexington Books. Lanham. p. 259)

Enhancement

Nontherapeutical gene modifications

Nontherapeutic genetic modificationethical issues The same tools and techniques being

developed for the therapy of human disease are also available for nontherapeutic genetic manipulation of human beings

therapy is aimed at severe disorders that are universally viewed as errors that provide no benefit to the patient and are to be treated whenever possible

scientific, theological and metaphysical tradition of both Western and eastern worlds accept that human disease is to be fought.

The alleviation of suffering caused by human disease is generally considered a moral good and even moral imperative

but medical intervention is already practiced for the enhancement of a variety of non-disease related human traits. Plastic surgery is generally not condemned as unethical or unacceptable

Nontherapeutic genetic modificationethical issues Will the same attitude pertain to genetic

approaches to the modification of non-disease related human characteristics?

Genetic component have certainly characteristics like: size skin color intelligence

Nontherapeutic genetic modificationethical issues Issue of eugenic - are we allowed to

make hereditary „improvements“? Slippery slope - might we slide into a new

age of eugenic thinking by starting with small genetic improvements?

an immunization is an enhancement an immunization is most definitely an

enhancement, as it leads to the proliferation of certain clones of immune cells, and even rearrangemets of DNA (Collins, F., (2006) The Language of God. Free Presss, New York, p. 265)

body building, hair dyeing or plastic surgery is improvement as well, and we do not see in these examples any ethical dilemmas

IGF-1 shows great promise in animal studies to increase muscle mass, and would be very difficult to detect by current monitoring systems. Most would consider this just as unacceptable as steroids in the atletic setting

but IGF-1 appears potentially able also to slow down the aging process

If that turns out to be true, would this use alo be immoral? (Collins, F., (2006) The Language of God. Free Presss, New York, p. 266)

Nontherapeutic genetic modificationethical issues What distinguishes a serious disease from

a“minor“ disease or from genetic variation? Should an adolescent whose parents are both 150 cm tall be provided with a growth hormone gene on result?

If the gene transfer extends one day to allowing a normal individual to acquire, for example, a memory-enhancing gene?

since more and more scientists believe that all traits of personality have at least a partial biological basis, how will we distinguish the biological "defect" that yields "disease" from the biological condition that yields shyness or melancholy or irascibility?

everyone would welcome a gene therapy to alleviate muscular dystrophy and to reverse the debilitating muscle loss that comes with old age.

But what if the same therapy were used to improve athletic performance?

researches have developed a synthetic gene that, when injected into the muscle cells of mice, prevents and even reverses natural muscle deterioration. The gene not only repaires wasted or injured muscles but also strenghtens healthy ones

suppose that muscle-enhancing gene therapy turned out to be safe - or at least no riskier than a rigorous weight-training regimen. Would there be a reason to ban its use in sports?

it might be argued that a genetically enhanced athlete, like a drug-enhanced athlete, would have an unfair advantage over his unenhanced competitors...

...but it has always been the case that some athletes are better endowed than others, and yet we do not consider this to undermine the fairness of competitive sports

(Sandel, M.J., The Case Against Perfection. The Atlantic Monthly (April 2004): 51-62 in (Pierce, J., Randels, G., (2010) Contemporary Bioethics. Oxford University Press, NY, Oxford. p.599)

Runners

researches have produced smart mice by inserting extra copies of a memory-related gene into mouse embryo. The altered mice learn more quickly and remeber things longer than normal mice.

The extra copies were programmed to remain active even in old age, and the improvement was passed on to offspring.

.. we are now looking for "a Viagra for the brain"

there are 81 million Americans over fifty, who are beginning to encounter the memory loss that comes naturally with age

such use would straddle the line between remedy and enhancement

unlike the treatment for Alzheimer´s , it would cure no disease...

...but insofar as it restored capacities a person once posessed, it would have a remedial aspect

Finasteride and Propecia

there is a very fine line between treatment and enhancement the drug finasteride stops the prostate from enlarging and is

medically prescribed to men with this serious condition in smaller doses, the same drug will retard male pattern

baldness both prostate growth and pattern baldness result from the

metabolizing of testosterone to a more potent steroid hormone, and finasteride blocks that metabolism

those men who can afford the drug can impede baldness by using it, and it is widely marketed for this purpose under the brand name Propecia

Germinal Choice Technology (GCT)

GCT could be accomplished by adding auxiliary human chromosomes (numbers 47 and 48), which will carry artificial genes for characteristics promoting attributes like increasing intelligence and longevity

each successive generation could have a genetic update, rather as you currently update your computer!

If we could make our baby smarter, more attractive, a better athlete or musician, or keep him of being overweight, why shouldn´t we? (Gregory Stockis)

(Mepham, B., (2008) Bioethics. An Introduction for the Biosciences. Oxford University Press, Oxford, p. 150)

Genetic Enhancement

Beacause memory is good, can we say how much more memory would be better?

If sexual desire is good, how much more will be better?

Life is good, but how much extension of the lifespan would be good for us?

Only simplistic thinkers believe they can easily answer such question

Kass, R.L., (2002) Life, Liberty and the Defense of Dignity. Encounter Books, New York, London. p. 132

Candidates for gene therapy

Single gene disorders: ADA deficiency, cystic fibrosis, hemophilia, familial hypercholesterolemia, alpha-1 antitrypsin deficiency

diseases that result from the faulty interactions of several genes: diabetes, hypertension, arteriosclerosis, most forms of cancer

Gene Therapy of Germ Cellsarguments against

it coul lead to people being viewed as products capable of being manufactured, with the result that people could be „made to measure“.

our actions might come to be viewed as genetically determined rather than a matter of free will

Playing God

"Even at his most powerful, after all, man is capable only of playing God"

Kass, R.L., (2002) Life, Liberty and the Defense of Dignity. Encounter Books, New York, London. p. 129)

2012 Marek Vácha Engineering the engineer as well as the engine, we race our train we know not...

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