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Despite the challenges, the process ect will succeed or fail based on the abil- cist, Alexander S. Serebrovskii of Mos-
of engineering a disease-fighting, trans- ity to drive that transgene into the wild cow University, and a British biologist,
genic mosquito is not merely an aca- population—even if it makes its bearers Frederic L. Vanderplank of the Tangan-
demic exercise. The Bill and Melinda less fit. A practical system to meet this yika (Tanzania) Research Department,
Gates Foundation recently contributed need is still far away, but it is possible. sowed the intellectual seeds for this
more than $35 million to the Founda- Using the rules of population genetics, a approach in the 1940s. The two men
tion for the National Institutes of Health number of research groups are harness- realized independently that in certain
for the purpose of developing trans- ing so-called selfish DNA, which spreads circumstances, competition between
genic mosquitoes as a weapon against without regard to the overall fitness of two interbreeding insect strains doesn’t
insect-borne diseases, and governmen- its host, giving the illusion of turning favor the fitter group. This dynamic
tal agencies and other philanthropies in natural selection on its head. involves the genetic property that sci-
the United States and abroad have also entists call underdominance, which can
funded this research. Strain Replacement actually cause the strain with greater
Regardless of what the anti-pathogen The idea of designing a gene that ac- fitness to die out.
transgene turns out to be—an antiviral or tively spreads through a pest popula- To explain underdominance, it’s
antiprotist gene, a lethal gene, or some- tion without conveying some fitness helpful first to know the terms domi-
thing else not yet developed—the proj- advantage is not new. A Soviet geneti- nant and recessive, which describe the
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that produce 20 eggs, then the average
��
egg production by female offspring
from the A strain will be (0.80 × 20) +
(0.20 × 100) = 36, and the average for
strain B offspring would be (0.20 × 20)
�� + (0.80 × 50) = 44. Even though strain A
is more fit, strain B produces offspring
with higher average fitness. Over time,
�� strain B would replace strain A.
Vanderplank did exactly this experi-
ment in the late 1940s with two sexu-
� ally compatible species of tsetse flies,
� �� � the insects that transmit the parasite
������������� that causes sleeping sickness. Mating
the two species yielded offspring with
Figure 2. Frederic L. Vanderplank (top left) low fitness. Working in an area that had
and Alexander S. Serebrovskii (lower left) been abandoned because of disease risk,
pioneered concepts of genetic control of pest Vanderplank released high numbers of
species in the 1940s, but neither received rec-
one species into the habitat where the
ognition for his efforts. Serebrovskii’s peers
second was more fit. Over time, the first
in the Soviet Union rejected his work be-
cause of the Lysenko-era policy of dismiss- species outcompeted the second, send-
ing Darwin’s theories as unsubstantiated ing its numbers plummeting. Within
bourgeois science. Vanderplank never pub- two years or so, the introduced spe-
lished his findings. The concept of under- cies (which was not well adapted to the
dominance, critically important to the work habitat) had largely died off, leaving the
of both scientists, describes the condition area free of sleeping sickness and en-
when a mating between strains (labeled A abling local people and cattle to inhabit
and B in the bar chart above) results in prog- the region.
eny (AB) that are less fit than either parent.
Serebrovskii worked out the theory
(Vanderplank photograph courtesy of John
for a type of mutation called a balanced
Vanderplank; Serebrovskii photograph re-
printed from Medvedev 1969.) chromosomal translocation, in which a
piece of one chromosome breaks off and
inheritance of traits. Consider a case other words, those offspring have a becomes attached to another chromo-
with two purebred parents from dif- lower evolutionary fitness.) some. Serebrovskii calculated that even
ferent, interbreeding strains: Many fea- Still, the idea that the less-fit strain less-fit insects with the translocation
tures of their offspring will favor one B could outcompete the more-fit strain could replace the wild-type—the normal,
parent or the other. For example, sup- A doesn’t seem to make sense accord- nonmutant strain with higher fitness—
pose that parent A comes from a strain ing to basic Darwinian theory. But because some of the grandchildren of
that produces 100 eggs and parent B Vanderplank, Serebrovskii and others the cross between mutant and wild-type
comes from one that produces 50 eggs. realized this is exactly what happens parents don’t inherit a complete set of
If the offspring from the mating of A when two conditions are met: when chromosomes (a lethal condition). Chris-
and B each generate 95 eggs, a biolo- the offspring of a mating are less fit topher F. Curtis at the London School
gist would typically say that the high- than either parent (underdominance), of Hygiene & Tropical Medicine later
egg-production trait was dominant. If, and when the less-fit parental strain pointed out that if the strain with the
instead, the offspring laid only 55 eggs, is more abundant. Under these condi- translocation carried a desirable gene
then a biologist would classify the trait tions, adults of the less common strain (such as one that conferred malaria re-
as recessive. But if offspring from the A A are more likely to find and mate with sistance) on the translocated chromo-
× B mating produced fewer eggs than adults from the more common strain some, then the translocation would also
either parent (here, fewer than 50), B, thereby producing less-fit offspring. sweep the desirable gene into the popu-
then egg production would be consid- For example, if strain A makes up 20 lation. The scientists needed only to in-
ered underdominant. In most crosses percent of the insects in a certain habi- undate the natural pest population with
between strains, traits do not show un- tat and strain B makes up 80 percent, such a translocation.
derdominance, but sometimes a mat- then (all else being equal) four out of Several research teams conducted
ing between distantly related strains five individuals from strain A will en- lab and field-cage experiments in the
yields offspring that don’t survive or counter a mate from strain B, but only 1970s to test Serebrovskii’s and Curtis’s
reproduce as well as either parent. (In one out of five individuals from strain theories. The teams made some prog-
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ress with the translocation studies, but
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this line of investigation ultimately ��
failed: Rearranging a mosquito’s chro- �
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mosomes left it unfit to survive in the ���
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field. The products of classical genetics � ��
�
proved too crude for the job, and inter-
est in this approach waned. ��
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A Two-Transgene Technique � ��
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The disinterest didn’t last long. Soon af- � � � � �
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ter the first successful addition of foreign
�����
DNA to the fruit fly Drosophila melano-
gaster, biologists began to explore the � �� ����
potential for genetic manipulation of �
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pest species. The growing sophistication ����� � � � �
��
of molecular biology has enabled them �����
to make genetic changes with much
greater precision than before. For exam-
�
ple, Stephen Davis and his colleagues
at the University of New South Wales
����������������������� ��������������������
in Australia developed a novel idea for
a two-transgene system that uses un-
derdominance to spread new genes into ���
a population. They envisioned the cre-
ation of two distinct pieces of DNA, or ����������������������� ��������������������
constructs, that were spliced into different ��
chromosomes. Each construct contained
�������������������
���
an on/off switch and a gene that en-
codes a biological toxin. The switch was ��
� �
“on” by default. Construct I also carried � � � �
��
a gene that turns off the toxin produc-
tion in construct II, and construct II had �� ����
�������������������
a gene that turns off toxin production �
���������
��
from construct I. Thus, individuals with ����� � � �
�� � � � �
both constructs (or neither) survived. �
�����
Having just one of them was lethal.
� �� ����
In this model, a cross between a wild-
� �
type strain and a strain that was ho-
���������
mozygous for both constructs (meaning �����
Figure 3. In a mating between two insect strains, underdominance
��
� frequen-
can change the
that each construct was present on both cies of the strains; under some� conditions, it can cause the less fit strain to outcompete the
�����
halves of a chromosome pair) would more fit strain, in seeming opposition to the laws of natural selection. This example shows a
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yield progeny heterozygous for both hypothetical interaction between a strain producing on average 100 offspring (A) and another
�
constructs. (In other words, they would yielding 50 (B). When a strain A (blue) male mates with a strain A female their offspring
carry only one copy of construct I and (top right, bar 1) are more fit (that is, they leave more progeny) than those from a mating of a
strain B (orange) male and female (lower right, bars 1−4). However, in this example, strain A
one copy of construct II.) This genera-
makes up only 20 percent of the population (left). Thus, four out of five of A’s matings occur
tion would survive. But many of the with individuals of strain B. These hybrid matings produce progeny with low fitness (striped
second generation would die because bars). In contrast, even though strain B is itself less fit than strain A, its high abundance in the
they inherited only one of the two con- population results in rare mating encounters (only one out of five) with strain A, so few of its
structs (similar to the effect seen in Sere- offspring are low-fitness hybrids. On average, strain A offspring in this situation leave 36 of
brovskii’s translocation model). their own progeny compared to an average of 44 from strain B. Thus, after one cycle of mating
This engineered form of underdom- the frequency of strain B increases.
inance is superior to a translocation
because it can enable the transgenes field conditions. And as Curtis noted even lower—if the mutant strain were
to spread even if the number of mu- in the similar case of translocations, homozygous for two independent in-
tants released is less than 30 percent an anti-pathogen gene included in the sertions of construct I and two inde-
of the population (the exact propor- constructs would also spread through pendent insertions of construct II. Our
tion depends on how much of a fitness the population. Having the anti-patho- research team has modeled the effects
cost is associated with the transgene). gen gene on both constructs provides of different fitness costs and different
Furthermore, because the engineered a backup in the event that a random numbers of transgenes and found that
strains only differ from native strains mutation disables one copy. multiple insertions of a construct can be
by two inserted genes (instead of a Theoretically, the chance of suc- more efficient than a single insertion as
full chromosome rearrangement), the cess would be even higher—and the long as the cost per insertion is below
transgenics should be more fit under number of engineered insects needed 10 percent. These models can predict
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Figure 5. The random insertion of transgenes can have different effects on evolutionary fitness (as measured by the number of offspring) depend-
ing on the genomic insertion site. A normal gene appears at the top, with regions of DNA that encode protein (purple bars) separated by noncoding
DNA (thin lines). Insertions into the noncoding portions usually cause less disruption of gene function than insertions into the coding regions.
The four lower rows show hypothetical examples of various insertions in the same gene (orange dot) on the same part of the insect’s three chro-
mosomes (upright gray bars). In addition to the disruption caused by random insertion, transgenes can also decrease fitness by coding for novel
proteins or altering the timing or abundance of other native proteins, thereby compromising cellular and physiological functions.
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����� ����
� a ����������
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���� ������������
� b
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����
� c
������������������������������ ������������
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� d e
Figure 7. One of the strategies for driving anti-pathogen genes into a population uses a pair of transgenes (a). Both carry a gene that encodes a
lethal toxin (red), and each transgene also codes for a unique repressor that acts on the other (purple and green). The desired anti-pathogen gene
(orange) has it’s own promoter that isn’t affected by these repressors. If a mosquito inherits either transgene singly, then the toxin gene remains
active and kills the individual (b and c). But when both transgenes are present, the reciprocal block of toxin production allows the insect to live (d).
The pattern of inheritance and mortality with this arrangement (e) resembles that of Alexander S. Serebrovskii’s chromosomal translocation.
a kind of intracellular bacteria called males. And because infected females talizing to consider. But as with the
Wolbachia, which is passed through the pass on the Wolbachia infection to male other approaches, several challenges
female line only (similar to mitochon- and female offspring (regardless of the must be met before this system could
dria) and can manipulate the repro- infection status of their mate), the fre- be deployed. Most fundamentally, mo-
ductive success of its insect hosts. One quency of Wolbachia in the population lecular biologists need to learn how
type of Wolbachia causes cytoplasmic increases over time. to genetically manipulate Wolbachia, a
incompatibility, in which the progeny of A group led by Stephen L. Dobson at process that is more difficult because
Wolbachia-infected males and uninfect- the University of Kentucky transferred the bacteria live within the cells of an-
ed females are nonviable. However, this type of Wolbachia into Aedes aegypti other organism.
infected males breed normally with in- mosquitoes and found that the para-
fected females. This situation provides site spread from 20 percent to 100 per- Simple Eradication
a reproductive advantage to infected cent of a laboratory population within These strategies are designed to spread
females, which can mate successful- eight generations. A strain of Wolbachia an anti-parasite gene that would inter-
ly with either infected or uninfected carrying an anti-pathogen gene is tan- rupt disease transmission but leave
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