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NOBEL PRIZES 2020
PHYSICS · PHYSIOLOGY OR MEDICINE · CHEMISTRY
Black Holes – Exotic Bottomless Pits in the Universe
Smiles Mascarenhas
PHYSICS
Roger Penrose Reinhard Genzel Andrea Ghez
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COVER STORY
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December 2020 | Science Reporter | 11
THREE Laureates share this year’s Nobel Prize in Physics for
contributing to our understanding of one of the most enigmatic and
tantalizing phenomena in the Universe, the Black hole. The work of
Roger Penrose is purely theoretical – he devised mathematical
models that showed how the General theory of relativity leads to
the formation of Black holes. Reinhard Genzel and Andrea Ghez led
two independent teams of observational astronomers who discovered
that an invisible and extremely heavy object govern the orbits of
stars at the centre of our Galaxy. A supermassive Black Hole is the
only object that explains their observation.
One half of the prize money goes to Penrose and the other half
is shared by Genzel and Ghez. Roger Penrose is from the University
of Oxford, U.K., Reinhard Genzel is from the Max Planck Institute
for Extraterrestrial Physics, Garching, Germany and Andrea Ghez is
from the University of California, Los Angeles, USA.
Black holes are super dense objects with a phenomenal
gravitational field from which not even light can escape. Because
of this, they are expected to be dark but matter in the
neighbourhood can form an accretion disc around it emitting X-rays
in the process. Observational astronomers were actually looking for
such objects in the Universe. Little did they realize that Black
holes would be the foundation for all the galaxies in the
Universe.
It is speculated that Black holes can range in size from tiny
micro Black holes to supermassive Black holes. It is generally
believed that the concept of Black hole sprung up after Albert
Einstein published his General Theory of Relativity in the year
1915. The first theoretical description of what we now call a Black
hole came just a few weeks after the publication of the General
Theory of Relativity. The German astrophysicist Karl Schwarzschild
was able to provide Einstein with a solution that described how
heavy masses can bend space and time.
Later studies showed that once a Black hole has formed, its
boundary is defined by an event horizon. Nothing within the event
horizon can escape and the Black hole remains forever hidden inside
it. The greater the mass, the larger the black hole and its
horizon. For a mass equivalent to the Sun, the event horizon has a
diameter of almost three kilometres and, for a mass like that of
the Earth, its diameter is just nine millimetres.
The first calculation of the collapse of a massive star was made
at the end of the 1930s, by physicist Robert Oppenheimer. When
giant stars, more than ten Solar masses, run out of fuel, they
first explode as supernovas and then collapse into extremely
densely packed remnants, so heavy that gravity pulls everything
inside. Not even light can escape from it. Einstein himself
suspected if such objects could really exist or can be objects of
mathematical curiosity. Only after his death in 1955, a series of
milestone discoveries on General relativity opened up the
possibility of the existence of Black holes. These came in the form
of ‘singularity theorems’ starting with the work of the Indian
physicist A.K. Raychaudhuri and culminating with the classic 1965
paper of Roger Penrose.
The question of the existence of Black holes was again revived
in 1963, with the discovery of quasars, the brightest compact
objects in the far corners of the universe. For almost a decade,
radio astronomers were puzzled by radio waves from mysterious
star-like sources, such as 3C273 in the constellation of Virgo.
Doppler measurements in visible light finally revealed that 3C273
is over a billion light years from the Earth. If the light source
is so far away, it must have an intensity equal to the light of
several hundred galaxies. It was given the name ‘Quasar’ (from
Quasi Stellar Radio object, since it resembled a star).
Astronomers soon found quasars that were so distant they had
emitted their radiation during the infancy of the universe. How did
quasars produce such incredible energy in a compact dimension?
There is only one way to obtain that much energy within the limited
volume of a quasar – from matter falling into a massive black hole.
To explain the effect, Penrose toyed with the idea of trapped
surface. Trapped surface forces all rays to point towards a centre,
regardless of whether the surface curves outwards or inwards. Using
trapped surfaces, Penrose was able to prove that a black hole
always hides a singularity, a boundary where time and space end.
Its density is infinite and, as yet, there is no theory on how to
approach this strangest phenomenon in physics. Trapped surfaces
became a central concept in the completion of Penrose’s proof of
the singularity theorem. He introduced differential geometry and
topological methods in the study of our curved universe.
Coming to the observational part of this year’s Nobel Prize,
even though we cannot see the Black hole, it is possible to
establish its properties by observing how its colossal gravity
directs the motions of the surrounding stars.
One hundred years ago, the American astronomer Harlow Shapley
was the first to identify the centre of the Milky Way, in the
direction of the constellation of Sagittarius. A serendipitous
discovery by Karl Jansky in 1931 showed a strong source of radio
waves in that direction, opening up the exciting field of Radio
Astronomy. This source was given the name Sagittarius A*. Towards
the end of the 1960s, it became clear that Sagittarius A* occupies
the centre of the Milky Way, around which all stars in the galaxy
orbit.
For more than fifty years, physicists have suspected that there
may be a black hole at the centre of the Milky Way. Ever since
quasars were discovered in the early 1960s, physicists reasoned
that supermassive black holes might be found inside most large
galaxies, including the Milky Way. However, no one can currently
explain how the galaxies and their Black holes, between a few
million and many billion solar masses, were formed.
German astronomer Reinhard Genzel and US astronomer Andrea Ghez
each led separate research groups that explore the centre of our
galaxy, the Milky Way. Shaped like a flat disc about 100,000 light
years across, it consists of gas and dust and a few hundred billion
stars including our Sun. From our vantage point on Earth, enormous
clouds of interstellar gas and dust obscure most of the visible
light coming from the centre of the galaxy. Infrared and Radio
telescopes first allowed astronomers to see through the galaxy’s
disc and image the stars at the centre. Using the orbits of the
stars as guides, Genzel and Ghez have produced the most convincing
evidence that there is an invisible supermassive object hiding
there. A black hole is the only possible explanation.
It was not until the 1990s that bigger telescopes and better
equipment allowed more systematic studies of Sagittarius A*. Genzel
and Ghez each started independent projects to attempt to see
through the dust clouds to the heart of the Milky Way. Along with
their research groups, they developed and refined their techniques,
building sensitive instruments and committing themselves to
long-term research.
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Only the world’s biggest telescopes will suffice for gazing at
distant stars. Genzel and his group initially used NTT, the New
Technology Telescope on La Silla Mountain in Chile. They eventually
moved their observations to the Very Large Telescope facility on
Paranal Mountain, also in Chile. With four giant telescopes twice
the size of NTT, the VLT has the world’s biggest monolithic
mirrors, each with a diameter of more than 8 metres.
Andrea Ghez and her research team use the Keck Observatory,
located on the Hawaiian mountain of Mauna Kea. Its mirrors are
almost 10 metres in diameter and are currently among the largest in
the world. Each mirror is like a honeycomb, consisting of 36
hexagonal segments that use adaptive optics to better focus the
starlight.
With large telescopes we suffer from the problem of
scintillation of starlight. Large bubbles of air above the
telescope, which are hotter or colder than their surroundings, act
like lenses and refract the light on its way to the telescope’s
mirror, distorting the light waves. This is why the stars twinkle
and also why their images are blurred. The advent of adaptive
optics
was crucial in improving observations. The telescopes are now
equipped with a thin extra mirror that compensates for the air’s
turbulence and corrects the distorted image.
For almost thirty years, Genzel and Ghez have followed their
stars in the distant stellar jumble at the centre of our galaxy.
They continue to develop and refine the technology, with more
sensitive digital light sensors and better adaptive optics, so that
image resolution has improved a lot. They are now able to more
precisely determine the stars’ positions, following them night
after night.
The researchers track some thirty of the brightest stars in the
multitude. The stars move most rapidly within a radius of one
light-month from the centre, inside which they perform a busy dance
like that of a swarm of bees. The stars that are outside this area,
on the other hand, follow their elliptical orbits in a more orderly
manner. One star, called S2 or S-O2 completes an orbit of the
centre of the galaxy in less than 16 years. This is an extremely
short time, so the astronomers were able to map its entire orbit.
We can compare this to the Sun, which takes more
than 200 million years to complete one lap around the Milky
Way’s centre. This duration is called a Cosmic year. During the
last lap of the Cosmic year, dinosaurs were dominating the surface
of the Earth.
The agreement between the measurements of the two teams was
excellent, leading to the conclusion that the Black hole at the
centre of our galaxy should be equivalent to around 4 million solar
masses, packed into a region the size of our solar system.
We may soon get an image of Sagittarius A* mapped. This is next
on the list because, just over a year ago, the Event Horizon
Telescope astronomy network succeeded in imaging a supermassive
black hole thousand times more massive than Sagittarius A*. This is
at the core of the galaxy known as M87 which is at a distance of 55
million light years from us. I am proud to add that one of the
members of that team was my former student.
Prof. K. Smiles Mascarenhas was formerly a Scientist at the
Millimeter wave Astronomy Lab of the Raman Research Institute,
Bangalore. Email: [email protected].
PHYSIOLOGY OR MEDICINE
Nobel Recognition for Solving a Mystery
Biju Dharmapalan
Harvey J. Alter Charles M. RiceMichael Houghton
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December 2020 | Science Reporter | 13
IN a year when the whole world has been held hostage by a minute
virus, the Nobel Prize for Physiology or Medicine going to
scientists who discovered the hepatitis C virus seems to be a
morale booster for researchers working on the COVID-19 virus.
The 2020 Nobel Prize in Physiology or Medicine has been awarded
to Harvey J. Alter from the US National Institutes of Health in
Maryland, Charles M. Rice from Rockefeller University in New York,
and Michael Houghton, a British virologist at the University of
Alberta in Canada, for discovering the liver-ravaging hepatitis C
virus, a breakthrough that led to cures for the deadly disease and
tests to keep the scourge out of the blood supply.
“For the first time in history, the disease can now be cured,
raising hopes of eradicating hepatitis C virus from the world
population,” the Nobel committee said in a statement.
In the 1940s, it became clear that there are two main types of
infectious hepatitis. Hepatitis A is transmitted by polluted water
or food and generally has little long-term impact on the patient.
Hepatitis B virus virus is transmitted through blood and bodily
fluids and represents a much more serious threat since it can lead
to a chronic condition, with the development of cirrhosis and liver
cancer.
In the 1960s, Baruch Blumberg determined that one form of
blood-borne hepatitis was caused by a virus that became known as
Hepatitis B virus, and the discovery led to the development of
diagnostic tests and an effective vaccine. Blumberg was awarded the
Nobel Prize in Physiology or Medicine in 1976 for this
discovery.
Even after the discovery of Hepatitis B, scientists were
intrigued by the existence of another deadly form of Hepatitis.
This intriguing deadly virus, later identified by this year’s Noble
laureates as Hepatitis C, has affected around 150 million people
globally.
Harvey J. Alter was working in a blood bank at the US National
Institutes of Health during the 1960s when hepatitis B was
discovered. He was studying the occurrence of hepatitis in patients
who had received blood transfusions. Although blood tests for the
newly-discovered Hepatitis B virus reduced the number of cases of
transfusion-related hepatitis, a large number of cases still
remained. Tests for Hepatitis A virus infection were also developed
around this time, and it became clear that Hepatitis
A was not the cause of these unexplained cases.
In 1978, Alter showed that plasma from patients with unexplained
hepatitis could cause disease when transferred to chimpanzees,
indicating it was caused by an infectious agent. In additional
experiments using chimpanzees, Alter and his colleagues showed the
disease was likely caused by one or more viruses. Alter’s
methodical investigations had in this way defined a new, distinct
form of chronic viral hepatitis. The mysterious illness became
known as “non-A, non-B” hepatitis.
Michael Houghton was a young researcher at Chiron Corporation,
an American pharmaceutical company (now part of Novartis), when he
began searching for the Hepatitis C Virus (HCV)
in 1982. Houghton, along with colleagues Qui-Lim Choo and George
Kuo collected RNA from the serum of infected chimps and used the
RNA to make a new cDNA collection. They put that collection into
bacteria that could produce the proteins encoded by the DNA
snippets. Finally, they used serum from an infected patient — which
they assumed would carry antibodies to the virus — to identify any
bacterial colonies that might produce a viral protein. Out of 1
million bacterial colonies they screened, one coded for a protein
from a virus. The researchers described their seminal work in 1989
in a paper published in Science in which they named the disease
hepatitis C.
Houghton’s work led to the development of a diagnostic test to
identify the virus in blood, enabling doctors and
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researchers for the first time to screen patients and blood
donors. This allowed blood donations around the world to be
screened, which dramatically reduced the number of newly infected
people.
The University of Alberta recruited Houghton in 2010 and he
moved to the Edmonton area shortly thereafter where he became the
director of the Li Ka Shing Applied Virology Institute.
The discovery of Hepatitis C virus was pivotal; but one
essential piece of
the puzzle was missing: could the virus alone cause hepatitis?
To answer this question the scientists had to investigate if the
cloned virus was able to replicate and cause disease. Charles M.
Rice, a researcher at Washington University in St. Louis, along
with other groups working with RNA viruses, noted a previously
uncharacterized region in the end of the Hepatitis C virus genome
that they suspected could be important for virus replication. Rice
also observed genetic
variations in isolated virus samples and hypothesized that some
of them might hinder virus replication.
Through genetic engineering, Rice generated an RNA variant of
the Hepatitis C virus that included the newly defined region of the
viral genome and was devoid of the inactivating genetic variations.
When this RNA was injected into the liver of chimpanzees, virus was
detected in the blood and pathological changes resembling those
seen in humans with the chronic disease were observed. This was the
final proof that Hepatitis C virus alone could cause the
unexplained cases of transfusion-mediated hepatitis. This work was
also published in the journal Science in 1997. It also set the
stage for work that would lead to the development of drugs, which
can now cure most people who are infected with hepatitis CProf.
Satyajit Mayor, Director, NCBS
Prof. Sudhir Krishna, NCBS
Dr Ranabir Das
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December 2020 | Science Reporter | 15
In the midst of the current pandemic, Professor Rice’s work
reminds us of how challenging viral diseases are to eradicate and
how revealing basic biological mechanisms of disease is critical to
designing treatment. The 68-year-old currently works at Rockefeller
University in New York.
The prize announcement has also created heated debate in India.
India contributes a large proportion of this HCV burden. The
prevalence of HCV infection in India is estimated at between 0.5%
and 1.5%. “In the medicine Nobel, it’s always related to some
fundamental questions and impact on amelioration of a deadly
disease. How this choice is made is an interesting question?
Putting money into research on
emerging viral diseases is paramount (as is putting money into
science in general).” says Prof. Satyajit Mayor, Director, National
Centre for Biological Sciences (NCBS).
“India is weakly positioned in virus research,” says Dr Ranabir
Das, also from NCBS. “The financial support for these kinds of
research work is minimal. Unless India commits to improve the basic
infrastructure and give financial long-term commitment on virus
research, we will be found wanting in a future situation when a
virus specific to the Indian sub-continent hits us.”
According to Prof. Sudhir Krishna from NCBS, “India needs to
build a virology network encompassing
CHEMISTRY
Chemistry Nobel Prize for Molecular Genome Editing Tool
M.S.S. Murthy
Emmanuelle Charpentier Jennifer A. Doudna
ON October 7, 2020, The Royal Swedish Academy of Sciences
awarded the Nobel Prize in Chemistry 2020 jointly to Dr Emmanuelle
Charpentier of Max Planck Unit for the Science of Pathogens,
Berlin, Germany and Dr Jennifer A. Doudna, University of
California, Berkeley, USA, “for their
veterinary medicine, human medicine and even plant research and
should provide training to build capacity building. The Nobel
Committee often recognizes basic science that has laid the
foundations for practical applications in common use today. All
these Nobel prizes stress on the need to focus on basic science
research.”
Mr Biju Dharmapalan is Assistant Professor & Head, School of
BiosciencesMar Athanasios College for Advanced Studies Tiruvalla
(MACFAST), Kerala-689101. E-mail: [email protected]
[email protected]
development of a method for genome editing”. The method is known
as CRISPR-Cas9.
Why edit genes? Genes regulate every function in our body and
determine the basic characteristics like height, weight, skin
colour, intelligence, etc. This complete set of instructions known
as
genome is present in the form of 24 pairs of chromosomes in
every cell of our body, while the germ cells, the sperms and eggs
have one chromosome of each pair.
We inherit them from our parents, one set from the father and
one from the mother, and pass them on to our children. Any changes
in these genes, known as
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mutations, generally alter their functions which, many a times
cause diseases. If such changes are produced in the germ cells,
they are passed on to our offspring as inherited diseases. The only
possible way to handle such problems is to edit such genes – either
to inactivate or replace them with unmodified ones. This approach,
known as gene therapy, which has been a dream all these years is
becoming possible because of the tool created by the awardees for
editing the genome. There are many more applications for gene
editing.
CRISPR-Cas9 has been adapted from the natural immune system of
certain types of bacteria. In the 1980s, bacteriologists discovered
that widely different bacteria contain in their genetic material
“DNA sequences that are surprisingly well preserved; the same code
appears over and over again.” These repeat sequences of constant
length, about 30 nucleotide long, were partially palindromic. They
read the same way backwards and forwards like the words “mom”,
“race car”, etc.
Their observations also revealed that the repeat sequences were
interspersed with unique, non-repetitive nucleotide sequences that
differ from each other. They called this Clustered Regularly
Interspersed Short Palindromic Repeats (CRISPR).
Another interesting observation that came later was that the
unique non-repetitive sequences in the CRISPR
showed homology, that is they were matched with parts of genetic
codes of various viruses that generally invade bacteria.
Subsequently, bacteriologists identified another group of genes
adjacent to the CRISPR region in the bacterial genome, which they
called CRISPR associated genes (Cas genes). These genes code for
proteins called nucleases, which specialize in unwinding and
cutting DNA strand. So, the thinking at that time was that CRISPR,
together with Cas genes was part of an ancient immune system, that
protected bacterial from the invading viruses.
Putting all this information together, bacteriologists proposed
a scheme for bacterial defence system. If a bacterium survived a
virus infection, it grabs a piece of viral DNA and adds it to its
own genome at the CRISPR region as a memory. When the virus attacks
again, the bacterium copies the genetic material in the CRISPR
region into an RNA, which now contains a sequence that matches with
the viral DNA as well as the repeat sequences. Cas proteins attach
themselves to the CRISPR RNA. As the RNA seeks and binds to the
viral DNA, the Cas proteins cleave the two strands of the viral DNA
at corresponding positions, creating a double strand break, which
is enough to destroy the virus. In fact, these spacers appeared to
evolve in time, adding new spacers.
Each infection which the bacteria survive is like a vaccine shot
for future protection. While mapping the entire CRISPR-Cas system
in the bacteria Streptococcus thermophilus, Dr Jennifer Doudna
found that it is a complex machinery requiring many different Cas
proteins to disarm a virus.
In 2009, Emmanuelle Charpentier, working at Umea University at
Sweden, was interested in gene-regulating RNA molecules in the
bacteria Streptococcus pyogenes. During her investigations she
found one type of small RNA molecules that existed in large numbers
with genetic code partially complementary to the CRISPR RNA.
Intrigued by this finding her team mapped the CRISPR region in S.
pyogenes and found out two important aspects.
First, she showed that the small unknown RNA molecules she had
identified earlier, which she called trans-acting crispr RNA
(tracrRNA), had a decisive role in the bacterial defence system.
When the bacteria produced the CRISPR RNA in response to a viral
attack, it would be a long molecule containing all the repetitive
as well as the unique viral sequences. This was precursor CRISPR
RNA (pre-CRISPR RNA).
To function as a part of the defence mechanism, it was necessary
to convert it to an active form by cleaving it into smaller units.
This is brought about by
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December 2020 | Science Reporter | 17
the tracrRNA. When tracrRNA pairs with this precursor CRISPR
RNA, the long molecule is cleaved by an RNase III enzyme into
smaller units, each containing a single spacer and a partial repeat
sequence, constituting what is called crRNA. She called it a
process of maturation. It was also found that Cas9, the Cas protein
found in S. pyogenes, was more versatile than the Cas proteins
worked out by Doudna and the system required just one Cas9 protein
to cleave any viral DNA.
At this stage Charpentier realised that she had hit upon
something extraordinary and decided to collaborate with Doudna for
further work. In its natural form, the CRISPR-Cas9 system works on
viral DNA. Charpentier and Doudna wanted to design a programmable
gene scissor that could cut any DNA at predetermined locations even
in other types of cells, enabling genome editing.
To test their concept, they picked up a DNA sample stored in the
freezer and selected five locations where it should be cleaved.
Based on these locations, they synthesized tracrRNA and crRNA in
the laboratory and fused them into a single module called ‘guide
RNA’ and complexed it with Cas-9 protein. When the system was
mixed with the DNA molecule in a test tube, it was spliced in
exactly the intended locations. Thus, was born the molecular
genetic scissor, a simple two component system that could be easily
programmed for sequence specific cleavage of target DNA in any type
of cell.
How does gene splicing lead to gene editing? When a cell
undergoes DNA damage like a double strand break, there are two ways
in which the cell can repair the break. The broken ends of the DNA
strands can be ligated, in a process called non-homogenous end
joining, to form a continuous strand. However, this process is
prone to produce errors by either deleting certain bases
(Deletions) or adding new bases (Additions) that are originally not
part of the gene. In either case, the reconstituted gene sequence
is altered and this may turn off the gene. In such cases, the
protein product is not formed.
Alternatively, the repair system can use a sequence in the
genome that is homologous or highly similar to the cut sequence as
a template to repair the break (Homology directed repair). A
researcher can hijack this system by introducing copies of DNA that
are homologous to the target sequence and also containing a stretch
of new sequence or modifications that he desires. During repair,
this modified sequence can get precisely incorporated to the genome
at the spliced region.
CRISPR-Cas9 is not the first gene editing tool. There are others
like Zinc finger and TELENE which are in use for some years now.
However, these are highly cumbersome to program, time consuming and
expensive. In all these aspects CRISPR-Cas9 beats them. Hence, soon
after Charpentier and Doudna published their results in 2012,
several research groups adapted the system to edit genes in plants,
insects, animals and humans. It has revolutionised agriculture by
producing drought resistant, salt resistant, nutrition rich crops;
modified insects like mosquitoes from spreading malaria, dengue.
Animal breeders have adopted this system to breed animals with
desirable characteristics.
More recently, in the face of the COVID-19 pandemic researchers
have adapted the CRISPR-Cas9 gene editing tool for rapid
coronavirus diagnostic tests. The Council of Scientific and
Industrial Research in India which has also developed such a test
known as Feluda test, says it can deliver results in 45 minutes to
one hour.
Health researchers have been trying to develop new therapies for
cancer, which are due to mutations that lead to uncontrolled cell
division in tissues. They have already been using this technique to
make the dream of curing inherited diseases come true by
experimenting on sickle cell anaemia and beta thalassemia. These
diseases arise from a single mutation in the beta globin gene that
encodes for the protein haemoglobin, the oxygen carrying molecules
in the red blood cells. The defective haemoglobin turns the red
blood cells from their usual doughnut shape to sickle shape. They
not only have reduced oxygen carrying capacity, but also get jammed
in blood vessels causing pain, organ damage and often premature
death. In the experimental treatment the doctor removes the
patient’s bone marrow cells, treats them with CRISPR-Cas9 system,
repairs the defect and transfuses the cells back to the patient.
There are more than 6000 genetic diseases for which specific causal
mutations in humans have been identified.
These therapeutic efforts involve editing somatic cells. The
tool can also be used to edit germ cells – the egg and sperm cells
or the cells in the early embryo to fix disease-causing mutations,
which otherwise will be inherited by the offspring. However, it is
also possible to attempt to create what geneticists call the
“Designer babies”, wherein selected characteristics such as sight,
skin colour, intelligence, etc. can be introduced in yet unborn
babies. Since these attempts alter the genome of future
generations, they raise ethical considerations and social
issues.
Though CRISPR-Cas9 has been found to be a versatile gene editing
tool, there are a few safety aspects in its widespread use. Some
genes have multiple functions and editing them to correct one
problem may affect the other functions of the gene. This is
particularly important in while editing germ cells and embryos.
Furthermore, some studies have shown that the system may induce
off-target cuts, at locations other than intended. These clearly
will have undesirable consequences. Researchers are working out to
improve the system and make it safer.
Mr M.S.S. Murthy, I-Block, #304, Mantri Alpyne Apartments,
Vishnuvardhana Road, BSK 5th Stage, Bengaluru-61. Email:
[email protected]