NEWS & VIEWS RESEARCH
magnetic flux far down the jets, as would be
expected if the electromagnetic jet-launching
mechanism referred to above is at work. The
authors’ results thus provide direct observa­
tional evidence that this is the case.
Theoretical simulations3,4 of accretion disks
have shown that, under certain conditions, the
magnetic flux in the vicinity of the black hole
naturally reaches a maximum equilibrium
value. When this happens, forces exerted by
the magnetic field dominate in the inner part
of the disk. Disks for which this is true are
called magnetically arrested disks, or MADs3,4.
Zamaninasab et al. find that the derived slope
of the linear correlation between the accretion-
disk luminosity and the jet magnetic flux is
precisely the value predicted for such disks,
strongly suggesting that this MAD scenario is
operating in the hearts of AGN.
These results indicate that the jets of AGN
are launched electromagnetically by magnetic
fields twisted by the black hole’s spin, that these
magnetic fields have a dominant role in deter­
mining the dynamics of the disk and jets in the
vicinity of the central black hole, and that this
may remain true at least out to VLBI scales,
several parsecs from the black hole. It will
therefore be important to consider the influ­
ence of the magnetic field, for example, when
inferring the properties of the central black
hole and accretion disk from high-resolution
studies made with millimetre-wavelength,
ground-based VLBI5–7, or with ‘space VLBI’,
in which one or more antennas orbiting Earth
are used with ground antennas8,9.
Zamaninasab and colleagues’ findings also
radically change the way astronomers view
the jets emanating from the centres of AGN.
These jets are not just outflows of matter car­
rying tremendous amounts of energy, but are
also intrinsically magnetic structures. Many
of their properties are probably determined
by the magnetic fields embedded in them and
travelling outwards with them. The twisting
of the central magnetic fields that launches
the jets should give rise to helical jet mag­
netic fields, which may be manifest in the
jets’ magnetic-field structure and morphol­
ogy10,11. Because a fundamental relationship
exists between magnetic fields and electrical
currents, jet outflows should be regarded
as systems of magnetic fields and currents.
This is essential if we are to understand these
enormous structures: how they propagate,
why they remain so narrow as they traverse
enormous distances, and how they inter­
act with the mater­ial through which they
are moving.
As the jets travel beyond their host galaxy
and into intergalactic space, effects other than
magnetic forces will probably also come into
play, making the jets and the surrounding gas
more turbulent and reducing the magnetic
field’s effects. Further detailed studies of the
jets of AGN and their magnetic fields, from
VLBI scales out to the ends of the jets many
thousands of parsecs from the central black Mon. Not. R. Astron. Soc. 418, L79–L83 (2011).
hole, should help to determine whether such a 4. McKinney, J. C., Tchekhovskoy, A. & Blandford, R. D.
Mon. Not. R. Astron. Soc. 423, 3083–3117 (2012).
transition occurs, and where. ■ 5. Dexter, J. & Fragile, P. C. Mon. Not. R. Astron. Soc.
432, 2252–2272 (2013).
Denise Gabuzda is in the Department of 6. Doeleman, S. S. et al. Science 338, 355–358
Physics, University College Cork, (2012).
7. Johannsen, T. et al. Astrophys. J. 758, 30 (2012).
Cork, Ireland. 8. Kardashev, N. S. et al. Astron. Rep. 57, 153–194
e-mail: d.gabuzda@ucc.ie (2013).
9. Takahashi, R. & Mineshige, S. Astrophys. J. 729, 86
1. Zamaninasab, M., Clausen-Brown, E., Savolainen, T. (2011).
& Tschekhovskoy, A. Nature 510, 126–128 (2014). 10. Molina, S. N. et al. Astron. Astrophys. (in the press);
2. Blandford, R. D. & Znajek, R. L. Mon. Not. R. Astron. preprint at http://arXiv.org/abs/1404.5961 (2014).
Soc. 179, 433–456 (1977). 11. Gabuzda, D. C., Cantwell, T. M. & Cawthorne, T. V.
3. Tchekhovskoy, A., Narayan, R. & McKinney, J. C. Mon. Not. R. Astron. Soc. 438, L1–L5 (2014).
H EPATI TI S C
Treatment triumphs
A stampede of recent clinical studies suggests that we are on the cusp of
developing well-tolerated, orally delivered drugs that can effectively eradicate
hepatitis C virus from most, if not all, infected individuals.
CHARLES M. RICE & MOHSAN SAEED been treated by intravenous injections with
type I interferons — secreted cellular proteins
T
he story of hepatitis C began in the that elicit potent antiviral responses12. The
1970s, when it was recognized that success rates for interferon-based regimens
something other than hepatitis A or improved from single digits in the 1970s to
hepatitis B infections was causing liver inflam­ around 50% by 2002, accomplished by increas­
mation following blood transfusions1,2. In ing dose, lengthening treatment, chemically
1989, the troublemaker was identified as a stabilizing the interferon (by PEGylation) and
small RNA virus, named hepatitis C (HCV)3. adding ribavirin, an RNA-nucleoside analogue.
Although there are now effective diagnostic Ribavirin has poor anti-HCV activity when
procedures that allow a safe blood supply in used alone but significantly increased treat­
most developed countries, intravenous drug ment success when combined with interferon
abuse continues to lead to new infections. An (by mechanisms that are still unsettled). How­
estimated 185 million people are chronically ever, this treatment required a 24- or 48-week
infected with HCV and are at risk of develop­ course and was plagued by awful side effects,
ing life-threatening liver diseases, including including nausea, depression and anaemia.
cirrhosis and cancer4. But a recent series of clin­ Hence, the goal remained to develop highly
ical trials, reported in the New England Journal effective, orally administered and well-toler­
of Medicine5–11, demonstrate drastic increases in ated regimens that work for all patient groups.
the effectiveness of anti-HCV drugs. Two enzymes encoded by HCV that are
Historically, HCV-infected patients have essential for viral replication — a serine
1980s 1989 2002 2011 2014
Mystery HCV identified, PEG-IFN + PEG-IFN + All-oral
virus diagnostics developed ribavirin ribavirin + DAA DAA
~5% ~50% ~75% >95%
cure cure cure cure
Figure 1 | HCV trajectory.  In the 1980s, mysterious cases of liver inflammation following blood
transfusions that were not explained by hepatitis A or hepatitis B viral infections were treated using type I
interferon proteins, with a success rate of around 5%. The cause of these infections was identified in 1989 as
RNA virus hepatitis C (HCV). The combination of PEGylated interferon (PEG-IFN) and ribavirin, approved
in 2002, improved cure rates to around 50%. By 2011, drug cocktails containing HCV-specific direct-acting
antivirals (DAAs) were being used to treat patients, with around 75% cure rates, and recent clinical trials5–11 of
all-oral, interferon-free, DAA-based regimens have increased treatment success rates to more than 95%.
5 J U N E 2 0 1 4 | VO L 5 1 0 | NAT U R E | 4 3
© 2014 Macmillan Publishers Limited. All rights reserved
 RESEARCH NEWS & VIEWS
protease (NS3-4A) and an RNA polymerase
(NS5B) — are attractive drug targets. In the
2000s, inhibitors of these enzymes and of
another non-enzymatic but essential HCV
protein (NS5A), referred to as direct acting
antivirals (DAAs), emerged as the lead targets
for HCV drug development. In late 2011, two
NS3-4A protease inhibitors were approved for
human use in combination with PEGylated
interferon and ribavirin, raising treatment suc­
cess to more than 70% for patients with HCV
genotype 1 (there are six highly divergent and
variable genotypes of the virus).
However, euphoria over this advance was
short-lived. Patients with advanced disease
were treated but many others were not, owing
to the additional, often severe, side effects of
this drug combination and the emergence of
viral resistance. In the meantime, and continu­
ing into the present, dozens of new compounds
were being tested in the clinic. In 2013, more-
potent DAAs, in combination with PEGylated
interferon and ribavirin, were approved, as was
the first all-oral regimen, consisting of a NS5B-
targeting DAA combined with ribavirin alone.
The recent clinical studies5–11 present the
next wave of interferon-free, all-oral, DAA-
based regimens, which are likely to be approved
in the near future for HCV treatment. Without
delving into details and trade names, several
key points about these trials emerge. First, they
include multiple all-oral combinations that can
achieve success rates of more than 95%. ‘Suc­
cess’ for HCV treatment means no detectable
virus 12 weeks after stopping treatment. Unlike
drug treatments for hepatitis B and HIV, most
HCV researchers believe that this endpoint
represents a durable cure that lowers the risk
of progressive liver disease. Second, these
treatments are effective in patients who are
in greatest need and are most difficult to treat
— those with advanced fibrosis and cirrhosis,
those who are co-infected with HIV, and even
liver-transplant candidates and recipients. Also
noteworthy is that the new drug combinations
promise shorter treatment times (12 weeks and
possibly even less) and minimal side effects; as a
result, fewer people are expected to discontinue
their treatment.
So from a mystery virus and a 5% treatment-
success rate, we have come to an era of cure
rates of more than 95% (Fig. 1). Game over,
right? Not quite. What about viral resistance
to the drugs? With nearly 200 million infected
individuals, 6 diverse viral genotypes and
around 1 trillion viral variants being gener­
ated per day per infected person, it is likely
that HCV will have some tricks up its sleeve to
develop resistance. However, some of the new
DAAs, in particular sofosbuvir, which targets
the active site of NS5B, have an extremely
high barrier to resistance, and there have
been only rare glimpses of resistant variants in
clinical observations with multiple viral geno­
types13. Combining potent DAAs, each with
lower resistance barriers, can still be highly
4 4 | NAT U R E | VO L 5 1 0 | 5 J U N E 2 0 1 4
effective at avoiding the build-up of resistance.
Nonetheless, resistance will undoubtedly
occur and should be taken into account to
guide treatment decisions. The current drugs
are also less effective against genotype 3 HCV,
which is common in South Asia, although pan-
genotype drugs are in development.
Another barrier is identifying those
infected. Most people are unaware of their
HCV infection14, and only a small minority has
been treated15. Although some health agen­
cies have recommended universal screening
of high-risk groups, implementing such poli­
cies is challenging and time-consuming. And
once infected individuals are identified, how
will society pay for their treatment? The cur­
rent price tag for cutting-edge HCV treatment
in the United States is more than US$80,000
for a 12-week course. Competition among
pharmaceutical companies may lower this
price, but most people infected with HCV live
in countries that cannot afford the new treat­
ments. Fortunately, there is movement in the
pharmaceutical industry to provide for low-
cost drug production in certain countries, such
as Egypt, where an estimated 10% of the pop­
ulation is infected. Finally, getting rid of the
virus does not always erase the risk of future
liver-related problems — patients still need to
be monitored routinely for liver function and
cancer, particularly those whose infection had
led to cirrhosis.
With the new drugs that are in hand or on
the horizon, we have the means to eradicate
this virus, possibly without needing a vaccine.
However, the challenge now is to extend these
N EUR O LO GI CA L DI S OR DE R S
Quality-control
pathway unlocked
A modified ubiquitin protein has been identified by three independent studies
as the missing link in a cellular quality-control pathway that is implicated in
Parkinson’s disease. See Letter p.162
ASA ABELIOVICH
P
arkinson’s disease, a progressive neuro­
degenerative disorder, has long been
hypothesized to be caused by defects in
organelles called mitochondria, which power
mammalian cells through the production
of ATP molecules. An accumulation of dys­
functional mitochondria may lead not only
to a cellular energy crisis, but also to excessive
production of toxic by-products. Two enzymes
implicated in Parkinson’s disease, PINK1 and
parkin1,2, are thought to be involved in the
disposal of defective mitochondria, but how
© 2014 Macmillan Publishers Limited. All rights reserved
great medical advances on a national and
global scale to those in need — something that
has not been terribly effective in the past. We
can hope that implementing these transforma­
tive HCV advances will help to create a model
for success, for this and other widespread
human diseases. ■
Charles M. Rice and Mohsan Saeed are
in the Center for the Study of Hepatitis C,
Laboratory of Virology and Infectious Disease,
The Rockefeller University, New York,
New York 10065, USA.
e-mail: ricec@rockefeller.edu
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(suppl. 1) 1–4 (2014).
the two proteins interact has been unclear. A
trio of studies (by Kane et al.3, writing in the
Journal of Cell Biology; by Kazlauskaite et al.4,
in the Biochemical Journal; and by Koyano
et al.5, on page 162 of this issue) now report
that phosphorylated ubiquitin protein is the
link between PINK1 and parkin, provid­
ing insights into a complex system of parkin
regulation.
Kinase enzymes such as PINK1 alter the
behaviour of target proteins through the addi­
tion of phosphate groups, a process called
phosphorylation. PINK1 is imported to mito­
chondria and, in healthy cells, undergoes