In a recent analysis of Essential Science
Indicators data from
Thomson
Reuters, the journal Metabolic Engineering
was singled out as having the highest number of
citations among journals in the field of
Biology &
Biochemistry upon entering the database. The
journal's current record includes 255 papers cited a
total of 3,173 times between January 1, 1998 and
October 31, 2008. Metabolic Engineering was
founded in 1999 and is published by Academic Press, an
imprint of Elsevier.
In the interview
below, ScienceWatch.com correspondent Gary Taubes
talks with editor Dr. Greg Stephanopoulos, about the
journal's history and growing influence in its
field.
What is metabolic engineering, precisely, and can
you tell us a little about the history of the field?
The field of metabolic engineering began to emerge in the early 1990s with
the advent of recombinant DNA technology and the realization that microbes
could be genetically engineered to become, in essence, little chemical
factories for the production of fuels and chemicals. However, the idea of
engineering microbes for fuels and chemicals production did not get a lot
of attention for about a decade after that because most of the focus was on
medical applications. With the change in the landscape of energy supply and
production three or four years ago, now there’s a lot of interest in
using microbes for utilization of renewable resources and making fuels and
chemicals from them.
When was the journal Metabolic Engineering
founded, and were you the founding editor?
It was started in 1999 and I was one of the three founding editors
(Professor A. Sinskey and M. Yarmush were the other two). There had been a
series of events leading up to this: one was a conference that used to be
called something like "Applications of Recombinant DNA Technology." I was
asked to chair that conference back in the mid-1990s and I thought about it
and decided that this title didn't make a lot of sense. The natural title
for the conference was "Metabolic Engineering." So I contacted the
stakeholders of the conference and they agreed to change the conference
title, and this is how the Metabolic Engineering conference series got
started. It’s now a biannual event and we’re currently in the
eighth edition.
Once the field started getting a lot of attention, we thought about
starting a journal. We talked to the people at Academic Press and they were
very enthusiastic about it. Then in 1998 I published a book on metabolic
engineering and all the pieces were in place.
How would you account for the excellent impact factor of
your journal?
"…metabolic engineering does
not go unnoticed any
longer."
I have an interesting story to tell you here. Like all journals, this one
was not listed in the main indices for the first two, three years. And
despite my insistence, there had been a lapse on the part of the publisher
to apply for listing the journal with Journal Citation
Reports® and the main indexing services. This is a lengthy process
and takes close to a year. Then after the journal is listed, the formal
process for accounting for citations gets into place and the journal
eventually gets an impact factor.
In our case, at the end of the year prior to the year that Metabolic
Engineering got its first impact factor, I had a discussion with the
publisher, pushing them to apply for these indices, but there were some
glitches in the system. We finally got them resolved, and we were going to
apply, when I was contacted by people from Clarivate, telling me they
had observed unusual traffic of citations for the journal, therefore they
decided to include it in their databases, and in just six months we would
have an impact factor. So all it happened automatically and we never
actually had to apply and provide all the supporting materials, etc. And,
nowadays, of course, if you’re not listed in these services, you
don’t have an impact factor and it’s very difficult to attract
good-quality papers.
What do you think caused that unusual traffic?
A few reasons. The first, I think, is that there was a lot of metabolic
engineering-kind of work going on. Namely, following some key developments
in applied molecular biology, people began to apply genetic modulations
very broadly, knocking out genes, deregulating genes, doing lots of
molecular, genetic level manipulation, with the goal, always, of improving
cellular properties for a particular purpose, such as overproducing a
useful product. The possibilities were suddenly infinite, and as a result,
there was a lot of metabolic engineering research going on. In that
environment, it is only natural that people wanted to know what happens
when you do these kinds of changes in cells, particularly people in
industry.
A second observation is that before we had even obtained our impact factor,
we noticed an unusually high rate of downloads per paper, compared with the
other journals in the Academic Press database. That download rate actually
continues to be very high and, unfortunately, it’s not quite captured
by impact factors, because we suspect many of the people downloading papers
are in industry and those people don’t write subsequent papers; they
write patents.
The most-cited papers from Metabolic
Engineering date to 2001 and are on the subject of C-13 metabolic
flux analysis. Do you think these could have been a driving
factor?
That’s a very likely possibility. Indeed, the use of isotopic tracers
like glucose labeled with carbon isotopes—C-13, for example—is
a very important method that people use to probe metabolic pathways. If you
are looking at a metabolic pathway, from a biochemistry book, it gives you
the impression of a street map. As such, it indicates what route you can
follow to go from point A to point B but you have no idea how long
it’s going to take to do so. Such maps are very static. Your travel
time depends very much on traffic, and the map doesn’t show traffic
rates.
It's the same with metabolic pathways; when you’re looking at these
diagrams, you have no idea how efficient a pathway is in converting
compound A into compound B. But if you have a flux map, which is a map of
the rates of individual reactions, it’s like having a traffic map.
And that will tell you whether a particular pathway plays an important role
for converting a precursor to a product in a particular organism or whether
you should try a different pathway because a particular reaction is too
slow. You can get that kind of information by doing C-13 flux analysis and
by using other stable isotopic tracers. This is now one of the tools of
metabolic engineering. So these papers by Wiechert et al. were
very important contributions to the journal and to the field, and there are
many papers in that area that we’ve published since.
Was it difficult to convince Wiechert and his colleagues
that they should publish such important work in such a relatively new
journal?
Not really, because he’s one of the people who fit very naturally in
the community of metabolic engineering and also in the constituency of the
audience of the journal. He’s one of the natural readers and
contributors. In general, the large majority of the papers we publish are
submitted unsolicited.
Have there been specific developments in the fields
served by your journal that may have contributed?
I would think the current interest in renewable fuels is a major external
factor, which brings metabolic engineering to the forefront. Metabolic
engineering is the enabling technology for the production of these fuels
from renewable resources. Another one is synthetic biology, which is simply
a method for making synthetic DNA for constructing synthetic pathways in
microbes. As such, the main application of synthetic biology is in
modifying and optimizing metabolic pathways, which is the goal of metabolic
engineering. A lot of metabolic engineers nowadays use genes that have been
made synthetically.
People often confuse synthetic biology and metabolic engineering. The best
way to view these two areas is that synthetic biology provides synthetic
DNA for pathway construction; metabolic engineering provides the strategic
directions for pathway modification and gene targeting by analyzing and
assessing such pathways. It is important to remember that metabolic
engineering preceded synthetic biology by two decades in the context of
pathway modulation for product synthesis. The ideas of cell factories and
microbes as product formers have been around a long time before the ability
to synthesize DNA became a mail-order laboratory function.
How do you see the field of metabolic engineering
evolving in the next few years?
First of all, I think metabolic engineering will continue to get more and
more recognition. A lot of life scientists are becoming more aware of the
field and biofuels is a good catalyst for that, but only one of many. In
just 15 years this field has had some tremendous successes: microbes have
been engineered to make fuels, amino acids, biopolymers, pharmaceuticals,
different types of chemicals. So metabolic engineering does not go
unnoticed any longer. People pay attention.
"…there’s a lot of
interest in using microbes for utilization of
renewable resources and making fuels and
chemicals from them."
As for where it’s likely to go from here, I think the prospects are
very bright. The production of renewable fuels from renewable resources is
very promising indeed despite current oil price gyrations, and
microorganisms are very well suited to do this kind of work and to compete
very well with chemical methods. So this area will be growing by leaps and
bounds. I have been getting lot of telephone calls about using microbes to
convert biomass into major chemical products. That has a bright future.
Yet another big area where people are just scratching the surface is in
medical applications of metabolic engineering. Diabetes and obesity are
essentially metabolic diseases, and so mapping the flux landscape in these
diseases will be very important to do if we’re to have hope of
understanding them.
What do you mean by the flux landscape?
If you compare, for example, the flux maps of liver cells from a normal
individual to liver cells from a diabetic, you may find different patterns
of glycolysis, glycogen production, respiration, etc. And, if they’re
different, are all diabetics different in the same way?
Even more important, you can consider cancer a metabolic disease. If you go
back to Otto Warburg's work at the beginning of the 20th
century, he noticed that cancer cells grow faster than other cells in the
organism and, if they’re growing faster, they must be consuming a lot
of glucose and oxygen—their metabolism must be different. He made
some very beautiful observations along these lines.
In the 1980s and 1990s, with the avalanche of research on oncogenes,
signaling cascades, etc., we got totally away from the metabolism of the
cancer cells. Now we’re having a return to the concept of cancer as a
metabolic disease. If we take tumor cells and study them with the methods
of metabolic engineering, we can discover significant variations compared
to the metabolism of normal cells. This might give us clues to what may be
going wrong in a cancer cell vs. a normal cell, and this kind of analysis
is now allowed by the very high resolution with which we can dissect the
fluxes and the internal metabolism of these cells, again using isotopic
tracers.
You can see the importance of studying the flux landscape when people come
to suspect that a particular metabolite may be an important precursor in
the production of a useful product. Say someone hypothesizes that some
pathway is ATP limited, for example. To test this hypothesis one may do an
experiment aiming to increase the supply of ATP followed by a measurement,
typically of ATP concentration, to determine whether the experiment
succeeded or not. What is often found is that the level of metabolite is
virtually unchanged, because the organism compensated with a lot of other
mechanisms. The level of ATP may have stayed unchanged, however, its rate
of supply may have changed by an order of magnitude. Only flux measurements
can assess accurately the success or failure of these hypotheses.
The point is that just knowing the level of the metabolite tells you
absolutely nothing about the rate at which the metabolite is formed or
depleted. That is such a simple point, but you'll see this
misinterpretation frequently. People look at the level of ATP and they see
that it’s constant and so they say, "OK, my efforts failed." Again,
here is when flux analysis is critical and comes into the limelight.
What role do you see for your journal in the coming
years?
I’d like it to become the premier place for publishing the kind of
work where people modulate genes cells and then do the difficult job of
describing the result of that genetic modification. While it’s nice
to be driven by a hypothesis or by a good model, in many cases that will
not be possible. So, besides the rational approaches of metabolic
engineering we would also like to cover combinatorial methods that have
been shown to have a lot of potential.
I’d also like Metabolic Engineering to rise up in the impact
factor game. Right now the field of biotechnology is in a not very pleasant
situation: you have the very high-impact journals and then nothing until
you reach an impact factor of 2-3. This is really not good, as it
undermines the importance of many journals and concentrates attention on
the top few. So I’d like Metabolic Engineering to be the
high-tier journal that attracts the best work out there.
What plans, innovations, or improvements would you like
to implement for the journal in the coming years?
I do have lots of plans. What I don’t have is the time to implement
them. That’s my problem—too many things on my plate. I
certainly would like to pay more attention to getting good reviews in the
journal, organizing some special issues in critical areas for metabolic
engineering. There is one in the field of biofuels that will be coming out
soon, for example. That’s one area I think we should try to cover
very well.
But it’s important to keep in mind that this journal, like many
others, is basically based on volunteers. We don’t have the staff to
assign them functions to do special reporting, to write special features,
all the things you see in the top journals. Those journals have large
staffs that they can use for this purpose. We have to do the best we can
with volunteers.
What would you like to convey to the general public
about the work of Metabolic Engineering?
To pay more attention to the field of metabolic engineering. This is the
field that codifies the enabling technology for using the tremendous power
of biology as an alternative to chemistry. In essence, metabolic
engineering is a new type of organic chemistry. Instead of synthesizing
things in test tubes, we synthesize them inside microorganisms. We use them
as little chemical factories, and the potential for very efficient and very
clean processes is just enormous. We are only scratching the surface in
this regard.