Toward Bantam-Size Mammals
Don Platt
Introduction
This report is intended to
summarize a recent literature survey on the genes that regulate cell, organ and
animal size and offers recommendations for the best path to pursue for further
research and experimentation into developing bantam mammals – mammals with
about 1/8th (12.5%) to 1/10th (10%) the size of wild-type
mammals but with typical behaviors and proportional body size.
Possible reasons to work
towards developing the capability to miniaturize mammals might include
microlivestock, small pigs that can easily be maintained in a laboratory to
test organ-transplant procedures, small dogs or cats as pets where otherwise
they would not be allowed and ultimately, miniature humanoids.
Overview
A literature review has been
conducted of recent research in the areas of cell size, organ size and body
size regulation. Within the last five
years much research has been conducted to identify how cell, organ and body
size is regulated. Much of this work has
been concentrated on developing transgenic mice, flies (Drosophila) and worms (C. Elegans).
Controls of
Cell, Organ and Body Size
The size of a cell can vary
dramatically with cell type, neurons for example, can be 1,000 times larger
than epithelial cells. Another factor is
the number of genome sets, or ploidy. A
haploid Drosophila cell is only half the size of a diploid cell (Hafen, 2003).
There has also been evidence
for a cell size checkpoint in yeasts, which keeps cells from moving from one
phase of the cell cycle to another before they reach a threshold size. However, in multicellular organisms there
does not appear to be a need for a cell size checkpoint mechanism (Conlon and
Raff, 2003). It seems that mammalian
cell growth is linear and there may not be as great a need for a cell size
checkpoint.
Changes in organ size are
only partly due to changes in cell size.
Mutations in genes coding for insulin signaling components that mediate
a starvation response have been demonstrated to affect body and organ size by
reducing cell size and cell number. In
Drosophila, modifications in the insulin pathway have a large effect on the
final size of an organ without changing the pattern or proportion of the organ
(usually the imaginal disc, the larvalstructures from which all of the adult
epidermal structures of the fly are derived).
It also appears that individual organs are “programmed”
differently. For instance, multiple
transplanted fetal thymus glands each grow to their normal size, while fetal
spleens grow a total of one spleen size (Hafen, 2003).
There is also a competition
effect in mammalian cells. Cells that
are slow to grow are eliminated when they are near cells growing at a normal
rate. The slowly growing cells are
“outcompeted” because they are not efficiently using resources. A gradient mechanism may also be at work, a
small organ with few cells will see a large gradient of signaling molecules but
as the organ grows and cells divide, the gradient becomes smaller until it
reaches a threshold and the cells stop growing.
Also, a secreted growth-promoting factor accumulates in the growing organ;
its function is counteracted, or antagonized, by an inhibitor accumulating
slowly. As the growth factor is used up
or the inhibitor builds up, organ growth slows and eventually stops.
Body size is controlled by
growth hormone and subordinate insulin-like growth factor (IGFs). Figure 1 shows the insulin/PI-3-kinase
(phosphoinositide 3-kinase) signaling pathway.
Insulin or insulin-like growth factors (IGF’s) bind to and activate the
intrinsic tyrosine kinase activity of insulin and IGF receptors (R’s). When they are activated, the receptors
phosphorylate insulin receptor substrate proteins (IRSs), leading to
Weak loss-of-function
mutations in the insulin/IGF receptor gene in Drosphila, Inr and the Drosophila
homolog of Akt, dAkt produce small flies with small cells. Also small organs
and cells occur when genes that modulate the activity of dAkt1 or Dp110 (the
Drosophila PI-3-kinase) are mutated.
These are evident in fly wing and eye development. Overexpression of DPTEN (the Drosophila PTEN
homolog, which is a tumor suppressor in humans) produces small flies that also
have small cells.
Figure 1 The Insulin/PI-3-Kinase
Signaling Pathway (Coelho C, Leevers, S. (2000) )
Size
Gene Experiments
As was stated before, there
have been many experiments to modify genes controlling size in flies, worms and
mice in recent years. In this section a
review of some of this work will be presented.
Drosophila Experiments
The entire Drosophila genome
has been mapped and much of the genetics of the fly have been shown to be
conserved to mammals and specifically humans. For this reason, work done with
Drosophila has direct applications with human genetics.
Analysis of mutant DPTEN
clones in the eye and wing of Drosophila indicated that DPTEN regulates cell
number and cell size (Goberdhan, et. Al, 1999).
Overexpression of a dominant negative form of Dp110.PI-3-kinase and
mutants in
To identify genes involved in
regulating imaginal disc growth, a gain-of-function genetic screen was
conducted (Hipfner, et. Al. 2002). They
found a gene locus they called bantam (ban) which influences tissue growth
rates. It seems to coordinately regulate
cell growth and cell division for normal tissue growth. Bantam flies are 15% smaller than normal,
wild-type flies. Almost all bantam flies
are sterile (only 2.5% are fertile) compared to 95% of wild-type females. Viable mutants of Drosophila myc and certain
components of the insulin/PI-3-kinase signaling pathway have been identified
and discussed elsewhere in this report.
They have all shown to produce small, normally patterned adult flies. Flies lacking the product of the cdk4
(cyclin-dependent kinase-4) gene are also reduced in size. In this case though the size deficit is the
result of fewer adult cells. Hipfner
described that the ban mutant fly wings were smaller by 9-13% but not due to a
decrease in cell size.
Montagne and colleagues
(Montagne, et. Al, 1999) showed that Drosophila deficient in the S6 kinase gene
(sS6k) exhibited extreme delay in development and a severe reduction in body
size. These flies also has smaller
rather than fewer cells. In mammals the
S6 kinase is p70S6 kinase, also called S6k1.
Loss of the Drosophila dS6k function induces female sterility, a strong
developmental delay, a severe reduction in growth, and often death. Growth deficit for adult flies was about 30%
with flies homozygous for partial loss of function dS6k displayed an
intermediate cell size. In dS6k mutants,
the decrease in rate of proliferation is most likely from a reduction in
ribosomal protein synthesis and the effect on cell size may be because of the
absence of S6 phophorylation and an altered pattern of translation. Cell cycles times were 12.5+/-1 hours and
24+/- 4 hours for wild-type and mutant wings respectively.
Drosophila dPTEN plays an
essential role in the control of cell size, cell number, and organ size. In mutants, dPTEN- cells
proliferate faster than their heterozygous siblings and show an increase in
cell size with larger organs (Gao, et. Al, 2000). It appears that dPTEN acts
through the PI-3-kinase signaling pathway to regulate translation. Over-expression of dPTEN results in opposite
phenotypes, such as reduced organ size, compartment size and organism size (53%
reduction). Examination revealed that in fly wings, 18% of the reduction was
due to a decrease in cell number, and the rest due to a decrease in cell size. Gao found that manipulation of dPTEN activity
can override the intrinsic control mechanism that regulates both compartment
and organ size. Overexpression of dPTEN
was accomplished by a ubiquitously (whole organism) expressed armadillo driver
(arm-GAL4). Most of these mutants died
as larvae and pupae. The few that
survived eclosed after a 6-day delay and showed a reduction in body size. They
also found that PTEN and PI-3-kinase antagonize
each other in regulating size. Studies
in flies have now demonstrated that one way in which PTEN inhibits growth is by
keeping the cellular response to insulin in check.
In the Drosophila imaginal
disc, overexpression of the cell cycle activator dE2F accelerates the pace of
cell divisions without affecting cell growth, thus leading to decrease in cell
size. Overexpression of the
dE2F-inhibitor RBF slows the cell cycle without affecting cell growth, thus
increasing cell size (Raisin, et. Al, 2003).
This suggests that the cell cycle machinery can be activated independently
of the cell growth machinery and growth does not depend upon cell
division.
Mouse Growth Control
Many genes
with growth-promoting functions such as
growth hormone, the insulin-like growth factors and some of their receptors
lead to smaller mice when inactivated in developing embryos (Hockedlinger, et.
Al, 2000). Some of these genes are
subject to genetic imprinting which is unique to mammals. These imprinted genes are often marked and
made distinguishable by a methylation signal during parental gametogenesis. This ensures that these genes are expressed
in a parental-specific manner in embryos and adults.
A comprehensive analysis of
dwarfing phenotypes of mutant mice lacking GH receptor, IGF1 or both
demonstrated that both GH and IGF1 promote postnatal growth (Lupu, et. Al,
2001). They found that the body weight
of double Ghr/Igf1 mutants (nullizygotes) is only 17% of wild-type and an
absolute magnitude of about 5 grams.
They concluded that the growth control pathway in which the components
of the GH/IGF1 signaling systems participate constitutes the major determinant
of body size.
During mouse development, the
growth process starts in early embryogenesis (blastcyst stage) and lasts until a
steady state (a balance between proliferation and apoptosis, cell death) is
reached postnatally when a mouse attains a programmed body size of about 30
grams at 4-5 months.
Growth factors are produced
by many tissues and exert local effects that predominate during embryo
development, whereas hormones act systemically away from where they are
produced. IGF2 is essential for normal
embryo growth while IGF1 is a ligand that has continuous function through
development. IGF1 mutants, if they
survive, have about 60% wild-type body weight at birth and about 30% at steady
state. Growth hormone receptor does not
operate during embryogenesis although it is present so its manipulation does
not affect prenatal growth.
In most mouse strains, the
growth of the GH-deficient spontaneous mutants, Snell (dwarf, dw),
Lupu and group defined the
GH/IGF1 relationship as follows: GH is involved in the production of hepatic
IGF1, which reaches circulation and acts as a hormone. Whole body growth is the sum of variable
effects of these components in various tissues.
The IGF system is the major determinant of both embryonic and postnatal
growth that is modulated in the postnatal period by GH.
In rodents, unlike humans,
insulin does not participate in embryonic growth late gestation. The growth retardation of mice lacking IGF1
and /or insulin receptors is due to reduced cell number, resulting from
decreased proliferation (Nakae, et. Al, 2001).
The phenotypes of insulin receptor gene mutations in human and mice show
important differences in the development roles of insulin and its receptors in
the two species. Embryo development is
much different between the two species as well with rodents being born at a
stage corresponding to the 26th week of human gestation. In mice both IGF1 and IGF2 contribute to
prenatal growth, but only IGF1 is needed for postnatal growth. IGF2 is not expressed after birth in mice
while in humans it is expressed throughout life. IGF1 knockouts have similar features in both species
however, suggesting that IGF2 expression cannot alone compensate for lack of
IGF1 in human postnatal growth.
There are at least nine
different genes encoding insulin-like peptides: IGF1, IGF2, Relaxin, and four
unsulin-like peptides: Insl3, 4, 5 and 6.
At least three receptors interact with the ligands: insulin receptor,
IGF1 receptor, and IGF2 receptor. IR-related
receptor has also been identified but has not been extensively tested.
In contrast to Igf1 mutants,
Igf1r-deficient mice invariably die within minutes of birth, probably as a
result of respiratory failure caused by impaired development of the diaphragm
and intercostals muscles ((Nakae, et. Al, 2001). Below is a table of growth retardation
phenotypes presented by Nakae.
Table 1 Growth Retardation in Mice with insulin/IGF mutations (Nakae, et. Al, 2001) IUGR = intrauterine growth retardation
|
Genotype |
Growth (% birth weight) |
Phenotype |
|
Ins1+Ins2 |
80-85 |
Diabetes |
|
Igf1 |
60 |
Prenatal and postnatal
growth retardation, infertility |
|
Igf2 |
60 |
IUGR |
|
Ir |
90 |
Diabetes |
|
Igf1r |
45 |
IUGR |
|
Igf2r |
140 |
Perinatal death, organ
abnormalities |
|
Irs1 |
60-80 |
Prenatal and postnatal
growth retardation and insulin resistance |
|
Irs2 |
100 |
Insulin resistance, b-cell failure, infertility |
|
Irs3 |
100 |
|
|
Irs4 |
80 |
Prenatal and postnatal
growth retardation |
|
Igf1+Igf2 |
30 |
IUGR (nonviable) |
|
Igf1+Igf1r |
45 |
IUGR |
|
Igflr+Igf2r |
100 |
|
|
Igf2+Igf2r |
65-75 |
IUGR |
|
Igf2+Igf1r |
30 |
IUGR |
|
Igf2+Igf1r+Igf2r |
30 |
IUGR |
|
Ir+Igf1r |
30 |
IUGR |
|
Igf2+Ir+Igf1r |
30 |
IUGR |
|
Igf1+Ghr |
17 |
Prenatal and postnatal
growth retardation |
Lack of IGF1 leads to
infertility in both males and females.
In males testosterone levels are reduced to 18% of normal and are
associated with reduced size of testis,
epididymus, and distal regions of the spermatic duct. Infertility appears to be due to impaired
mating behavior, since the ability of capacitated spermatozoa to fertilize eggs in vitro is
normal. Females show hypoplastic uterus
and anovulation. However, Igf1r-deficient
mice are fertile which suggests that IGF1 signaling through IR is sufficient to
restore reproductive function.
It has been shown that IGF1
deficiency in humans and mice causes severe intrauterine and postnatal growth
retardation, perinatal lethality, and developmental defects in the bone,
muscle, and reproductive systems. In a
study by Liu and LeRoith (Liu and LeRoith,
1999), viable IGF1 null pups weighed 65%
of wild-type and 30% of wild-type as adults. IGF1 null pups were born with a
frequency 18.5%, which is lower than the expected 25%. From 2 weeks on, the IGF1 null mice grow more
slowly and delayed onset of prepubertal growth and do not undergo pubertal
change. Their final body weight becomes
approximately one-third and body length two-thirds of wild-type.
A way to stop cell proliferation is through the production of
extarcellular inhibitory signals. Mice
that are deficient in the CDK inhibitor p27/Kip1 (p27) are 30% larger than
normal, with more cells in all organs that have been examined. It appears that p27 is part of a timing
mechanism that limits cell proliferation and helps the precursor cells exit the
cell cycle and terminally differentiate at the appropriate time (Conlon and
Raff, 1999).
It has been demonstrated that
cell cycle progression in response to mitogens requires activation of
cyclin-dependent kinase (CDK). Then for
the cell to proliferate , it has to up-regulate the biochemical machinery to
direct cell growth. Recent studies
demonstrate that the translational up-regulation of transcripts is mediated in
part by p70S6k/p85S6k.
Three-week old p70S6k homozygous mutant mice were reduced in
size compared to wild-type by 20% for both males and females (Shima, et. Al,
1989). Weights of all organs were proportional to the reduction in body weight
at 3.5 weeks. Analysis of body weight
over an 11-week period following birth showed up to about 5 weeks of age both
homozygous males and females grew more slowly than their wild-type
littermates. Somewhere between 5 and 6
weeks the growth rate for all mice slowed down and became equivalent up to 11
weeks.
In a typical litter at 14.5
days of gestation, homozygous mutants were distinctly smaller size. Shima and co-authors demonstrated that
S6k-deficient mice are viable and fertile but significantly smaller than
wild-type. They also found a new S6
kinase that functionally overlaps S6k1 and whose transcripts are up-regulated
in S6k1-deficient mice. In the case of S6k1-deficient mice, the smaller size of
homozygous mutants is consistent with a defect in translational capacity. S6k1
has been shown to be involved in the regulation of 5’TOP mRNAs expression at
the translational level.
A key role in regulating the
activity of a group of insulin and growth factor –stimulated protein kinases
has been identified as a function of 3-phosphoinositide-dependent protein
kinase-1 (PDK1) (Lawlor, et Al, 2002). These kinases belong to the AGC
subfamily of protein kinases. These include isoforms of protein kinase B (PkB,
also known as Akt), p70 ribosomal S6 kinase (S6k) and p90 ribosomal S6
kinase. Once activated, these enzymes
mediate many of the diverse effects of insulin and growth factors on cells by
phosphorylating key regulatory proteins that play important roles controlling
processes such as cell survival, proliferation, nutrient uptake and storage.
There is only a single gene
encoding PDK1 in mammals. Knocking out
PDK1 homologs in worms, yeast and flies have shown that PDK1 is required for
the normal development and viability of these organisms. Lawlor’s group generated and analyzed the
phenotype of both PDK1 knockout mice and PDK1 hypomorphic mutant mice that
express markedly lower levels of PDK1 in all tissues. They generated mouse embryonic stem (ES) cell
lines called PDK1fl/fl. These
cells were hypomorphic for PDK1 expression, as they had markedly lower levels
of PDK1 protein and PDK1 kinase activity compared with PDK+/+ ES
cells. The heterozygote PDK+/fl ES cells possessed a normal level of
PDK1 protein and kinase activity. The ES cells for each mutant were injected
into murine blastocysts to generate mice possessing these genotypes using
standard procedures.
The PDK1+/-
heterozygote mice were healthy and displayed no obvious phenotypes. These mice were mated in an attempt to generate
complete PDK1 knockout mice. No PDK1-/- postnatal mice were ever
recovered. It is concluded that this
genotype is embryonic lethal. Indications were that these embryos died and were
reabsorbed after E9.5 (embryonic day 9.5). Below is a table of mice mating and resulting
genotypes as observed by Lawlor’s group.
Table 2 Mice Mating Table from Lawlor et. Al (2002)
|
Cross |
Stage |
Genotype |
Total |
|
PDK1+/- x PDK1+/- |
E7.5 |
PDK1+/+(25%)
PDK1+/-(45%) PDK1-/-(30%) |
20 |
|
PDK1+/- x PDK1+/- |
E8.5 |
PDK1+/+(27%)
PDK1+/-(50%) PDK1-/-(23%) |
26 |
|
PDK1+/- x PDK1+/- |
E9.5 |
PDK1+/+(23%)
PDK1+/-(52%) PDK1-/-(25%) |
61 |
|
PDK1+/- x PDK1+/- |
Weaning |
PDK1+/+(34%)
PDK1+/-(66%) PDK1-/-(0%) |
81 |
|
PDK1+/fl x PDK1+/fl |
Weaning |
PDK1+/+(32%)
PDK1+/fl(47%) PDK1fl/fl(21%) |
106 |
|
PDK1fl/fl x PDK1+/- |
Weaning |
PDK1+/fl(63%)
PDK1-/fl(37%) |
78 |
|
PDK1fl/fl x PDK1fl/fl |
Weaning |
PDK1fl/fl(100%) |
27 |
|
PDK1-/fl x PDK1-/fl |
Weaning |
PDK1-/fl(30%)
PDK1fl/fl(70%) |
20 |
The PDK1fl/fl mice
were viable and born at a slightly lower than Mendelian frequency (about
5%). Viable PDK1-/fl mice
were also obtained at a frequency of 25% lower than expected. Both groups were fertile. In all tissue investigated, PDK1fl/fl mice
had 3-to 5-fold lower PDK1 kinase activity than PDK1+/+ mice. PDK1-/fl mice had 5- to 10-fold
lower PDK1 kinase activity.
Both male and female
hypomorphic PDK1fl/fl mice were about 30% smaller than PDK1+/+
and PDK1+/fl littermates and they remained smaller throughout their
adult life. In the case of males, the
difference in weight between the PDK1fl/fl and PDK1+/+
mice increased to about 45% by 6 months of age while the female difference
remained at 30%. The male and female
PDK1-/fl mice were 45-50% and about 35%, respectively, smaller than
their PDK1+/+ littermates.
The zona fasciculata of the
mice’s adrenal gland was analyzed and they found that
PDK1-/fl cells
were 45% smaller than PDK1+/fl cells. The size of the nuclei was not significantly
different however and the number of cells was essentially the same. These was also no noticeable difference in
the rate that the cells multiplied in these groups. Smaller cell size must be due to a reduction
in cytoplasmic volume. They believe
there is another pathway that regulates nuclear size.
Growth Control in Humans
While developing, mammalian organisms increase in size until a limit is reached which is mainly determined by the rate and duration of cell divisions, increasing total cell number. A human weighing 70 kg has a 3,000 fold increase in mass compared to a 25 g mouse. This is mainly from cell number not cell size (Hockedlinger, et. Al, 2000).
In humans, about 15% of
imprinted genes have been identified and genes such as IGF2, H19,
CdkNIcC(P57,KIP2) and INS (insulin) map to an imprinted domain on human
chromosome 11p15.5. When paternally
expressed imprinted genes, such as IGF2, when inherited from the father act as
growth promoters, while maternally expressed imprinted genes, such as IGF2r,
when inherited from the mother, are mainly growth suppressors.
A human case of IGF1 knockout
has been documented. The patient was
born of consanguineous parents and displayed poor fetal growth (1.4 kg birth
weight), and reached only 23 kg at age 15.
The patient had sensorial deafness and mental retardation. Cases of human IGF1R mutations have shown
multiple dysmorphic abnormalities, including a characteristic facies,
bi-lateral clinodactyly, café-au-lait spots, and mental retardation (Nakae, et.
Al, 2001).
A quasi-human homolog of the
lit mouse mutation has been identified in a group of people in Pakistan (Maheshwari,
et. Al, 1998). They identified 18 dwarfs (15 male, 3 female), all members of a
consanguineous kindred, ranging in age from newborn to 28 yr. Body proportions
and habitus were normal. DNA sequencing revealed a nonsense mutation (Glu50Stop)
in the extracellular domain of the GHRH-R. This mutation predicts a severely
truncated GHRH-R Mean height was 7.2 SD below the norm, with mean adult heights
of 130 cm for males (about 75% of average) and 113.5 cm for females. Insulin-like growth
factor I (IGF-I) and IGF-binding protein 3 were low (5.2 +/- 2.0 ng/mL and 0.42
+/- 0.13 microg/mL, respectively; mean +/- SD) but rose normally with GH
treatment. Parents of affected subjects
reported that pregnancy, birth size, and breast feeding were normal and that
growth retardation became apparent during early childhood. No symptoms of hypoglycemia could be elicited
and intelligence appeared normal. One
subject was the offspring of two dwarf parents.
This child proves that fertility is possible, in both sexes, in the
absence of a GHRH-R.
Figure 2 Dwarfism of Sindh Patients as
Documented by Maheshwari et. Al, 1998
Head size is significantly
smaller than that observed in conventional GH deficiency, and there is no facial
hypoplasia or frontal bossing. This contributes to the "normal, but
miniature adult" aspect of these patients.
Known genetic causes of
proportionate dwarfism in humans are mutations in the GH-N gene, the Pit-1
gene, the Prop-1 gene, or the GH receptor gene. The former three manifest
themselves in GH or combined pituitary hormone deficiency, the latter in GH
resistance.
Other Developments
Several other developments
have taken place that offer other clues to organ size and ultimately body size
of organisms. Undifferentiated or
partially developed kidney precursor cells derived from early embryos and fetal
tissue (human and porcine) was transplanted into mice. The result was functional miniature human or
porcine kidneys in the mice that produced diluted urine (Reisner, et.
Recent studies suggested that
tissue-specific stem cells can differentiate into lineages other than the
tissue of origin (Jiang, et. Al 2002).
For instance, when injected into a mouse blastocyst, neural stem cells contribute
to a number of tissues of the chimaeric mouse embryo (
Research Recommendations
It appears that PTEN and the
insulin signaling pathway it controls are involved in developing embryos of all
higher organisms. This signaling system
plays a role in telling cells to what size they will grow, and at what point
they will divide. It also helps to keep
different organs in proportion with each other.
It can also control the size to which whole animals grow.
The research summarized in
this report demonstrated some previous paths that have been covered and
possible fruitful paths to follow and possible dead ends.
Actual cases of human
dwarfism show that genetic mutations can decrease size of the human body
significantly. Also, experiments
conducted with other animals such as flies, worms and mice have demonstrated
many genes responsible for size control in animals. Many
of these genes are conserved in humans and it seems reasonable that some of this
work could be transferred to humans.
Mice only 17% of wild-type
size have been created by modifying the genes responsible for growth hormone
reception in the GH-IGF pathway. Most of
these mutations have detrimental effects on fertility. However, recent work in the PTEN and PDK
functional pathways have demonstrated small mice with small cells that seem
viable and fertile. A combination of
gene mutations to modulate PTEN to increase its function and a decrease in PDK1
function seems a reasonable place to start.
First experiments with mice could begin fairly soon.
Other work that can be
investigated is how much differentiation various adult stem cells can actually
produce inside a mouse blastocyst.
Perhaps even a porcine stem cell line can be tested in a mouse
blastocyst to see if a mouse sized pig will develop.
Applications
While research and recent
developments indicate it is possible to change the size of an organism by
several different techniques, the question remains – Why do it? There are several
applications and reasons why this research may be pursued.
Experiments with mammals to
decrease their size can lead to beneficial mutations such as very small pigs,
cows, and other animals that can be used as microlivestock. Microlivestock offer developing countries and
other disadvantaged groups a less expensive, less environmentally impacting
alternative to traditional animals as a natural resource (Panel on
Microlivestock, National Research Council, 1991). A herd of 8 inch tall cattle
would take considerably less land than a full-size herd yet produce meat and
perhaps some milk for a small family in a developing country where both natural
and human resources may be limited.
Initial investment for the farming family would also be considerable
less.
Pigs have similar physiology
as humans and much research has been conducted testing the capability of using
porcine organs as human transplants.
Also, pigs have been used to test therapies and medicines before their
use on humans because of the similar physiology. However, pigs are relatively large animals
and therefore are difficult to use in the laboratory. Miniature pigs have been developed which are
about 50% full-size animals to develop and test organ transplant therapies for
humans (adult weight around 50 kg). This
makes the porcine organs more similar in size to human organs (Panepinto and Phillips, 1986). Small pigs and other mammals also offer good
pets for people with limited space and/or resources to look after an animal.
If there does come a time
when because of natural disaster or, regrettably, war, part of Earth becomes
uninhabitable, smaller human size may be beneficial. They use fewer resources
and require less area to live. If
humanity is to move out into the cosmos and populate other regions, first of
the solar system and then eventually beyond, smaller size will also be
beneficial. Less propellant would be
required to transport much smaller people as well as life support and other
resource requirements. These people
could even live on a small asteroid or inert comet. It is possible that smaller size may actually
be required for our survival if something happens to our Earth.
Conclusion
Much recent research has
caused an explosion in the organism size control field. Many applications have been identified and it
seems more reasonable now than ever that size can be controlled in many
different kinds of organisms.
Several different research
thrusts have been identified in this report.
Growth hormone and IGF have been shown to regulate size. Mice and human GH-deficient, viable
individuals have been identified. This
line produces body size about 50% below normal.
PTEN and PDK have been
identified to control cell size more than cell number. This seems to be a productive avenue since
viability seems to be improved as well as fertility if cell number is not
decreased as size gets smaller.
A modulation of increased
PTEN and decreased PDK as well as perhaps GH and IGFI/II should be looked at as
a possible research thrust. Experiments
can be conducted with mice although some physiological differences make some
results not directly transferable. Perhaps human organ size growth can be
tested in mice in experiments similar to those of Reisner’s team.
The capabilities of stem
cells, even adult stem cells also needs to be looked it. It has been found that adult stem cells can
be made to differentiate into many different tissue types in the right
environment. Injection of stem cells
into blastocysts is an important research thrust.
Overall, a literature review
has been conducted and several recommended future work paths have been
identified. The next few years offer
great potential for more breakthroughs.
References
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in the way a mammalian cell and yeast cells
coordinate cell growth and cell-cycle progression. Journal of
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