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- BBC News

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What will the


Doctor order?
By Melissa Hogenboom

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Our quest to understand how our genes work started in earnest in the mid-19th
Century when a biologist and monk called Gregor Mendel came to a startling
conclusion about the traits of plants. He crossed purple flowered pea plants with
white ones, and found that all the resulting offspring were purple. However, he
noticed that the third generation produced both colours.

This revealed that a characteristic such as colour


can be inherited, with one trait more dominant than
another. In a way, Mendel had figured out what
genes did, but not what they were, or even looked
like.

This came much later. It was only in the following


Maurice Wilkins and century that the very structure of DNA was
Rosalind Franklin discovered. Building on the work of Rosalind
Franklin and Maurice Wilkins, in 1953 James
Watson and Francis Crick discovered that our DNA is formed in a double helix.

This was a breakthrough. Knowing this structure


helped unlock more secrets. When DNA is
replicated, this helix splits in two - it "unzips".

This means mutations can be introduced as our


cells divide. Even a small genetic error can cause a
devastating disease.
Francis Crick
In other words, the unique book of letters that makes
up each of us can be printed or rewritten with mistakes. But we now have the tools
- including the ability to analyse large data sets - to both read our book quicker,
cheaper and even tinker with it.

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Let's start with the people who are interested in doing that tinkering. Scientists are
now able to edit genes from organisms. Gene editing has already been used for
some devastating illnesses - with great success. However, it is often lengthy and
costly.

Only five years ago a form of gene editing was


discovered with great fanfare. It is called CRISPR
Cas9, or CRISPR for short. Simply put, CRISPR
uses "molecular scissors" to alter a very specific
strand of DNA – either cutting it out, replacing it or
tweaking it.

It is now used in labs all over the world, altering and


manipulating the genes of plants and animals with
the idea that it can soon be used to treat numerous human diseases.

"The question that the public are very interested in is the possibility of using
CRISPR gene editing for therapeutic purposes," says Prof Robin Ali of the
European Society for Gene and Cell Therapy. This could happen within the next
decade if early studies show promise.

The first human trials are already under way in


China and have been given the go-ahead in the US.
These trials injected patients with modified cells
which had first been removed, rather than editing
cells inside the patients directly. If cells were directly
modified within the body, many more genetic
disorders could be treated.

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Still, scientists remain excited about the technology as it could provide effective
therapies for conditions that are currently untreatable, such as Huntington's disease
and cystic fibrosis, to name but two. In theory CRISPR could provide treatments
quickly, taking days or weeks rather than months.

"There are very few examples where new technology has swept across labs around
the world, where it's implemented to do things that were extremely difficult to do,"
says Prof Ali. The use of CRISPR will not, however, be "instant" he warns. It will
take a number of years for the technology to be used clinically.

Intellia Therapeutics is one of several companies developing the technology for use
in humans. The company's CEO, Nessan Bermingham, believes that CRISPR has
the potential to completely revolutionise healthcare.

The eventual hope is that it could target both diseases caused by only one
defective gene as well as diseases caused by more than one genetic mutation.
"This technology has the potential to allow us to target multiple regions of DNA at
the same time," says Bermingham.

Intellia has shown, he explains, that a single injection into an animal can slow down
a toxic protein from being produced by 97%.

Before it can be used in humans, any drugs will


have to be extensively trialled and regulated by the
relevant authorities. Until then its use will mainly be
as a research tool in the lab. "Without doubt, the
power [of CRISPR] is how easy it is to edit
genomes," says Prof Ali.

This is Many scientific questions still have to be answered


unprecedented in before Intellia can seek approval for clinical trials on
our industry." humans. For this reason Bermingham is hesitant to
propose a specific timeline.
Nessan Bermingham, Intellia
The money though is already flowing. Although
Intellia is currently caught up in a battle for the
CRISPR patent, Bermingham says this has not deterred investors. "From an
investors' standpoint, from a scientific standpoint, people are looking at these
discoveries and saying 'now we have the tool, we're ready to go.'"

Genome editing also comes with its own scientific controversies. It immediately
brings up the question of designer babies. Though it's important to note that altering
an individual's DNA will only change the specific genes being edited. The change
won't be passed onto their offspring – a process called somatic editing.

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It is editing single-celled human embryos that would


have an impact on all future generations if they
resulted in pregnancy. Trials on human embryos are
already taking place, but only for research purposes.

As for Intellia, they are focusing on somatic gene


Potential revolution for editing. "Any discussion about germ line editing –
healthcare at Intellia where those cells or those edits get passed onto
your children and their children's children – is
premature," says Bermingham.

We will soon see how successful further human trials are, only then will we
understand whether CRISPR will be as big a game changer for human disease as
it has been predicted to be.

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While CRISPR can be used for a range of genetic diseases, including cancer, there
are many other companies targeting specific types of cancer. There are over 200
forms of it, making it a very difficult disease to treat.

One emerging technology to treat cancer uses a patient's own immune system to
fight it. Our immune system is very efficient at fighting infections. Some of these
infection-fighting "machines" in our blood are white blood cells called t-cells, which
specifically look for signs of infection. If they spot a virus they multiply and attack.

The problem is that t-cells do not recognise cancerous mutations as invasive


enemies, as they are mutated versions of the patient's own cells. "Medical science
has long wanted to redirect them from killing virally infected cells to killing cancers,"
explains Dr Martin Pule of University College London. He and colleagues have now
been able to do just that, by genetically altering t-cells to recognise and attack
cancerous ones.

One such therapy, called CAR-T, has already been licensed for use in the US, at a
cost of $475,000 per patient. The personalized treatment is extremely effective. It
treats children and young people with acute lymphoblastic leukaemia and has an
83% remission rate from a single dose, according to Novartis, the company that
manufactured the drug. "There has been nothing like it in a generation," says Dr
Pule.

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These are actually Dr Pule sees this type of treatment as the future of
living cells and they oncology, with nine clinical trials currently under way
go into the patients' at University College London. Several businesses
cells and graft, they are also now working on treatments harnessing the
divide, and do all
power of t-cells, these include Autolus and
the things they
Immunocore, both in the UK, and Novartis in the US.
normally do for an
infection, killing
infected cells."

Dr Martin Pule

Immunocore, a company based just outside Oxford, uses a technology called TCR
therapy – where a small molecule attracts the t-cells and the cancerous ones. Once
both cells are connected, it allows the t-cells to release toxins to kill the cancer.

This molecule has been developed to target a rare type of eye cancer which can
quickly spread to the liver. When it does so, the patients do not have long to live.
This drug therefore targets these liver tumours. Immunocore has treated 180
patients with promising results.

Eva-Lotta Allan, Immunocore's chief business officer


hopes clinical trials can begin in the coming two
years. "We have increased the survival rate after
one year of treatment by almost four times,
compared to other [treatments] out there today," she
says. If effective, the technology could also be used
to treat infectious diseases such as HIV, TB and
Eva-Lotta Allan, Immunocore
autoimmune diseases.
We have an
opportunity to Immunocore's investors, which include the Bill and
really extend Melinda Gates foundation and several
patients' lives." pharmaceutical companies, have made it possible
for them to spend many years working on a drug for
Eva-Lotta Allan such a rare cancer, Allan says. Only about 4,000
patients are diagnosed each year, which could
inhibit investment from some quarters. "Major
pharmaceutical companies from a commercial perspective may not think it is fruitful
to do so."

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While genetic mutations can cause a range of diseases, so too can foreign
invaders. Malaria for instance kills almost half a million people each year across the
globe. There are several forms of the malaria parasite and they are all extremely
good at outwitting treatments by constantly mutating.

To understand how the malaria parasite evolves


drug resistances, scientists look to the parasite's
genetic diversity. It's now possible to do so in remote
areas with a handheld sequencing device called the
Nanopore MinION. Dr Jane Carlton, adjunct
professor at NYU's Department of Microbiology,
uses one to help her understand how malaria
outsmarts treatment.
Tombatu in Sulawesi,
Using only a laptop and the MinION, which is about
Indonesia: surrounded by
the size of a mobile phone and costs $1,000 for a
plantations and mosquitoes
starter set, Dr Carlton can sequence a malaria
parasite's genome in a few hours. That's compared
to the washing machine-sized sequencing machines she uses in her lab in the US,
which require a lot more maintenance, not to mention transporting samples back to
her lab.

This technology enables her to quickly understand whether or not the parasite will
be resistant to certain antimalarial drugs. Using the device, Dr Carlton has been
able to identify drug resistant mutations the same day that patients were diagnosed
with malaria.

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The MinION can be used to sequence any living


organism, making it extremely useful for quickly
studying devastating diseases outside the lab. It has
helped scientists understand more about the Ebola
and Zika viruses. It has even been used to
sequence the human genome.

Another researcher who has benefited from the


MinION is Dr Kim Judge, a senior stat scientist at
The MinION, helping to
the Wellcome Trust Sanger Institute. She says it is
understand malaria's
invaluable out in the field because it is so portable.
resistance to drugs
The technology is currently only licensed for
It means that this research purposes, but trials are under way to see
next level of how it could diagnose illnesses more quickly than
personalised existing methods.
medication is not
just available to Professor Yutaka Suzuki of the University of Japan
people who are in is one researcher who spotted the potential for the
reach of a teaching MinION as a tool for developing countries, and he
hospital is available and his team have been taking it to clinics and
to everybody, hospitals in the Indonesian province of North
everywhere." Sulawesi.

Dr Kim Judge, Wellcome Trust He says it can do in five hours what previous
Sanger Institute sequencers needed five days to do, enabling
doctors to make a rapid and accurate diagnosis.
“Usually the patient cannot wait, especially when
infected with the dangerous pathogens..immediate
reactions are needed for the patients,” he says.

“And the treatment strategies may be different


depending on the pathogens or whether they are
drug resistant or not.”

Professor Yutaka Suzuki of


the University of Japan who
saw the potential of MinION

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These are but a handful of the biotech companies which have jumped on the
rapidly advancing knowledge of genetics. Investors are keen to cash in on
innovative treatments, but profits are not guaranteed and many start-ups will fail in
the early rounds. Many companies doing early-stage research, like Immunocore,
will not see any returns for many years to come. So why do people invest in
medical sciences in the first place?

To start with, if a company's drug or product is successful, the returns can be


extremely lucrative, says Hitesh Thakrar, partner at life sciences venture fund,
Syncona. Take gene editing. Estimates suggest that CRISPR treatment could cost
up to $1m per patient. The UK government also offers tax breaks to invest in
qualifying businesses under the Enterprise Investment Scheme. "I invest in start-
ups as more innovation is happening from bottom up," says Thakrar.

Monetary goals may be the only factor for some, but Thakrar is also excited by
following cutting-edge advances in medicine. "For the first time in the history of
medicine we are on the verge of curing people – that's quite an exciting time to be
exposed to companies that are curing disease rather than symptoms," he says.

When businesses profit from science it can have other impacts. That so much
money is at stake can take funding away from blue-sky research – the pursuit of
knowledge where unexpected and ground-breaking discoveries can be made.
Some see this shift in research agendas as concerning.

"It's a slightly different pursuit," says Dr Timothy Weil, a molecular biologist at the
University of Cambridge. "Many start-ups and venture capitalists are looking to
solve a problem, searching for the answer to a known unknown. One of the most
exciting aspects of basic, blue-sky research is the prospect of the unknown
unknowns," he asserts.

History tells us that Another issue is that when patents are involved,
just because money scientific discoveries are not always shared with
is thrown at a other scientists, despite the fact that it is often
problem, it doesn't university researchers who make vital, early
guarantee you're
discoveries.
going to figure it
out." Funding for academic research, however, can be
time consuming and competitive. Dr Pule splits his
Dr Timothy Weil, University of time between academia and business. He therefore
Cambridge says that "industrial investment allows the rapid
application of large sums of money towards very
focused goals." For him, CAR-T is an example
where technological and clinical development has advanced really quickly. "It is a
good example of the power of capitalism."

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What is clear is that investment in emerging technology is growing at a rapid pace.


This is why Prof Ali believes that there has never been a more exciting time to be
working in biotech. "The influx of investment and establishment of many new
companies just demonstrated how much confidence there is that the technology is
going to deliver."

It also shows that advances in medicine can and do come from many different
areas. "These are generational challenges and the more ways of approaching the
problem, the better chance we have to find solutions," says Dr Weil.

It's a long way since Mendel and his pea plants. Rapidly advancing knowledge of
the human genome means that these companies - and others like them - will help
humans enter into a world where personalised medicine, tailored to individual
genomes, will become the norm.

Credits

Author Melissa Hogenboom


Series producer Philippa Goodrich
Video producers Adrienne Murray
Rebecca Fordham
Video editor Sara Hegarty
Online production Harpoon Productions

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Production team Rafki Hidayat, Haryo Bangun Wirawan (Indonesia)


Ian Cartwright (USA)
Peter Page, Tracey Langford (UK)
Graphic artist Sue Bridge
Editor Robb Stevenson
Commissioning Mary Wilkinson
editor
Pictures BBC
Getty Images
Intellia
Publication date 19.12.17
Built with Shorthand
All images subject to copyright

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