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Last month, in an extraordinary dispute before the US Patent and Trademark Office (USPTO), university lawyers laid out their clients' legal strategies for claiming patents that cover the celebrated gene-editing technology CRISPR–Cas9. Over the next year, the USPTO will receive volumes of evidence centred on who first invented the technology.

Battles over scientific priority are as old as science itself. But the CRISPR–Cas9 patent dispute is unusual because it pits two leading research institutions against one another for the control and industrial development of a foundational technology: the University of California, Berkeley (UC Berkeley), and the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

As scientific institutions increase their involvement in the commercialization of research1, it is worth considering the potential consequences for science if more institutions follow the path of UC Berkeley and the Broad Institute.

High stakes
In May 2012, researchers at UC Berkeley, led by Jennifer Doudna and her collaborator, Emmanuelle Charpentier (then located at the University of Vienna in Austria) filed a patent application in the United States for CRISPR–Cas9. Seven months later, Feng Zhang, a researcher at the Broad Institute, filed a competing application that covered similar uses of the technology. After Zhang's lawyers requested that his application be fast-tracked, the USPTO awarded one patent to Zhang in April 2014, followed by a dozen more in the subsequent 12 months. Meanwhile, the application made by Doudna and her colleagues languished.


How the US CRISPR patent probe will play out
Last April, Doudna's lawyers requested that the USPTO conduct a specialized legal trial, known as a patent interference, to determine the ownership of the US patents that cover the CRISPR–Cas9 system. This January, the USPTO formally agreed to carry out the proceeding.

One conspicuous aspect of this case, in my opinion, is the degree to which UC Berkeley and the Broad Institute have weighed in on what is essentially a dispute over scientific priority.

The Broad Institute has produced press releases, videos and a slick feature on its website that stress the importance of Zhang's contributions to the development of the CRISPR–Cas9 technology. And earlier this year, the central positioning of Zhang's work in a historical perspective of CRISPR published in Cell2 by the president and director of the Broad Institute, Eric Lander, prompted a storm of angry responses from scientists, including Doudna and Charpentier. Meanwhile, at UC Berkeley, a press release that discussed the potential of CRISPR described Doudna as “the inventor of the CRISPR–Cas9 technology”.


CRISPR everywhere
The financial stakes are high. The CRISPR–Cas9 patents are widely viewed to be worth hundreds of millions, if not billions, of dollars. Both organizations have invested directly in spin-off companies that were co-founded by their researchers — the Broad Institute in Editas Medicine, co-founded by Zhang, and UC Berkeley in Caribou Biosciences, co-founded by Doudna. A report submitted by Editas in January to the US Securities and Exchange Commission lists the Broad Institute and other Harvard-affiliated institutions as owning a major equity stake in the company: about 4.2% of its common shares.

Different times
Efforts to commercialize the research output from universities played out differently in the past. Since 1980, US universities have been able to patent the inventions of their researchers, thanks to the Bayh–Dole Act — legislation that determines the ownership of intellectual property arising from federally funded research. But for the most part, institutions have kept their distance from disputes over scientific priority. In fact, after factoring in the costs of filing patents and staffing, university technology-transfer offices have generally been money losers for their institutions3.

“Efforts to commercialize the research output from universities played out differently in the past.”
Even in the case of lucrative patents, commercial development has frequently been left to venture capitalists and the researchers themselves. Take the Cohen–Boyer patents, which covered early gene-splicing technology and netted Stanford University and the University of California, San Francisco (UCSF), both in California, hundreds of millions of dollars in licensing fees during the 1980s and 1990s. In this instance, Genentech, the company in South San Francisco, California, that was formed to commercialize the underlying technology, sprung from the efforts of Herbert Boyer, one of the founding researchers, and the financier Robert Swanson. The company was neither owned by, nor an exclusive licensee of, Stanford or UCSF.

Research institutions in general are starting to play a bigger part in shepherding their researchers' projects through the commercialization process. A 2014 report from the Association of University Technology Managers in Oakbrook Terrace, Illinois — an organization that supports managers of intellectual property at academic research institutions, non-profit organizations and government agencies worldwide — documented that universities are increasing equity investments in their researchers' start-up companies. Of the patent licences granted by universities in 2014, 10% were tied to such investments1, compared with 6.7% in 1999 (ref. 4).


Genome editing: 7 facts about a revolutionary technology
I am concerned that such involvement in commercialization has the potential to clash with the broader, educational mission of research institutions.

Universities worldwide have long strived to foster a culture of scientific collaboration. Even when universities have obtained broad patents, as the Carnegie Institute of Washington in Washington DC did in the early 2000s for a gene-expression control technology known as RNA interference, licences have been cheap and easy for researchers to obtain5. In other cases, scientists have simply ignored patents that cover fundamental technologies6.

Academic research institutions now seem less shy about taking each other to court for patent infringement. In 2011, the University of Utah in Salt Lake City sued the Max Planck Society for the Advancement of Science in Germany over claims to a patent that covered a technology called short interfering RNA, which inhibits gene expression (see go.nature.com/vyujnp). And over the past four years, Stanford University and the Chinese University of Hong Kong in Sha Tin have engaged in a heated patent litigation over prenatal genetic diagnostic blood tests, a market that was worth US$530 million in 2013.

MIT senior Ava Soleimany knows the value of determination in the lab, and on the tennis court. The major in course 6-7 (Computer Science and Molecular Biology) is an award-winning researcher, as well as a captain of the MIT Women’s Tennis Team.
While to some these two sides of her identity might seem unrelated, Soleimany has found that her experience as an athlete has, in many ways, impacted her growth as a researcher.
“In tennis, not every practice is going to be your best practice, and not every match is going to be your best match. In research, like in sports and in a lot of other things, the ball is not always going to bounce your way. It’s about being as prepared as you possibly can to make sure that when the uncertainties do arise and things don’t go as expected, you will be able to handle it,” she says.
When she’s not in the lab or working on her forehands and backhands, Soleimany channels her energy into helping others succeed. This June, the California native will graduate with a concentration in education. She is also a teaching assistant for biochemistry, a counselor for the Freshman Leadership Program, and the co-managing director of the Leadership Training Institute.
Soleimany knew before she arrived at MIT that she wanted to do something within biological sciences, but it was not until after her freshman fall that she found herself interested in computer science. “I took 6.0001 [Introduction to Computer Science and Programming in Python] during IAP [Independent Activities Period], and that was amazing to me because I never had experience with computer science before. I realized that computer science was a very powerful thing that pushed me to think in new ways.”
She discovered in computer science a way to complement her knowledge of biological science, and also to grow as an academic. “I decided to learn more to gain skills to improve my research in biology, but I mostly recognized studying computer science as a way to exercise my analytical thinking and problem-solving skills.”
Course 6-7 allowed Soleimany to explore biology and computer science simultaneously, as well as the intersections between the two fields. The curriculum, offered jointly by the Department of Electrical Engineering and Computer Science (EECS) and the Department of Biology, gives 6-7 students a solid footing for careers in areas like pharmaceuticals, bioinformatics, and computational molecular biology.
Building bacterial computers
Much of Soleimany’s time at MIT has been spent doing research in synthetic biology. Since her sophomore year, Soleimany has worked in the Synthetic Biology Group of Timothy Lu, associate professor of electrical engineering. Her junior year research was supported through EECS’s SuperUROP program, which allows students to work on year-long research projects under the supervision of a faculty member. During this time, Soleimany worked with graduate student Nathaniel Roquet on building finite state machines, a model of computation, in living cells.
“Just like you can use circuit elements to engineer logic into an electronic circuit, you can use gene regulatory parts to build a gene circuit that executes some type of logic,” she explains.
The project, for which Soleimany received the 2015 SuperUROP Outstanding Research Award, took “engineering logic” a step further by building state machines in E. coli.
“With these bacterial machines, we’re able to detect all orders and identities of several chemical inputs, and systematically program gene expression patterns. This project can provide a new way to study natural systems where the timing and combination of environmental events is important, like biofilm development,” Soleimany says. “It enables living diagnostics that could detect orders of disease-relevant markers, for example in microbiome applications.”
She recalls that, when working on this project, there was a period of time in which all of her experiments were failing. She later discovered that only a very small mistake in a protocol had been preventing her from moving forward. She says that the persistence she gained through tennis helped her handle her frustration and navigate the situation with more ease.
“In tennis and in science you have to be determined and willing to learn from your mistakes,” she says.
Domino effect
Soleimany has been playing on the women’s varsity tennis team since her freshman year, and for the past two years she has been a captain of the team. “Outside of academics, it’s by far the biggest part of my experience at MIT,” she says.
Her role as a captain has given her skills that go beyond the tennis court. “It’s taught me a lot about leadership, and how to bring a group of very different people together to work towards a common goal. Being a captain has given me the opportunity to help my teammates become better players and better leaders themselves.”
Soleimany also works as a counselor for MIT’s Freshman Leadership Program (FLP), a five-day pre-orientation program for incoming freshmen.
At FLP, counselors facilitate activities and discussions centered on different aspects of identity and social justice. The program creates a space for conversation about topics like prejudice, gender, sexuality, privilege, culture, and religion.
“I think it’s amazing to help someone else discover themself,” she says. “At FLP we give people space to really think about who they are and learn from the experiences of others.”
Soleimany also is the co-managing director of MIT’s Leadership Training Program (LTI), which turns MIT students into mentors for Boston area high school students interested in leadership and service. Through LTI, each high schooler comes up with an idea for a community service project, and develops it with help from their MIT mentors.
“It’s all about enabling people to go out and make an impact, setting a domino effect into motion. That’s a goal I have for myself in everything that I do,” she says.
After graduation, Soleimany will be pursuing a PhD in biophysics at Harvard University. She hopes to be involved with teaching and outreach, and to keep growing as a leader and as a scientist. As she looks back on her time at MIT, she says that it’s the people she has met and worked with that have made the experience for her. “I’ve become a much more resilient, compassionate, and empathetic person thanks to MIT, and that’s meant the world to me.”

Guest editors Jordi Garcia-Ojalvo, Ahmad S. Khalil and John McCarthy introduce the Biological Insights from Synthetic Biology themed issue of Integrative Biology.
Biological Insights from Synthetic Biology

The combination of synthetic and systems biology is a powerful framework to study fundamental questions in biology and produce chemicals of immediate practical application such as biofuels, polymers, or therapeutics. However, we cannot yet engineer biological systems as easily and precisely as we engineer physical systems. In this review, we describe the path from the choice of target molecule to scaling production up to commercial volumes. We present and explain some of the current challenges and gaps in our knowledge that must be overcome in order to bring our bioengineering capabilities to the level of other engineering disciplines. Challenges start at molecule selection, where a difficult balance between economic potential and biological feasibility must be struck. Pathway design and construction have recently been revolutionized by next-generation sequencing and exponentially improving DNA synthesis capabilities. Although pathway optimization can be significantly aided by enzyme expression characterization through proteomics, choosing optimal relative protein expression levels for maximum production is still the subject of heuristic, non-systematic approaches. Toxic metabolic intermediates and proteins can significantly affect production, and dynamic pathway regulation emerges as a powerful but yet immature tool to prevent it. Host engineering arises as a much needed complement to pathway engineering for high bioproduct yields; and systems biology approaches such as stoichiometric modeling or growth coupling strategies are required. A final, and often underestimated, challenge is the successful scale up of processes to commercial volumes. Sustained efforts in improving reproducibility and predictability are needed for further development of bioengineering.

In a Berkeley Lab-led study, flexible double-helix DNA segments (purple, with green DNA models) connected to gold nanoparticles (yellow) are revealed from the

Biotechnology applications require engineering complex multi-genic traits. The lack of knowledge on the genetic basis of complex phenotypes restricts our ability to rationally engineer them. However, complex phenotypes can be engineered at the systems level, utilizing directed evolution strategies that drive whole biological systems toward desired phenotypes without requiring prior knowledge of the genetic basis of the targeted trait. Recent developments in the synthetic biology field accelerates the directed evolution cycle, facilitating engineering of increasingly complex traits in biological systems. In this review, we summarize some of the most recent advances in directed evolution and synthetic biology that allows engineering of complex traits in microbial systems. Then, we discuss applications that can be achieved through engineering at the systems level.

ello PLOS Synbio community! Our online forum is growing! Last month we welcomed the addition of a new editor, Sam Million-Weaver, and now I get to introduce myself as a regular contributor. My name is Aaron Dy and I’m a PhD student at MIT in Biological Engineering. I’ll be adding to the conversation with posts a couple of times a month on news, events, and hot topics in the field of synthetic biology. I hope to go beyond rambling on my own expertise and actually engage with more of you on what excites you in synthetic biology.

A new exhibition at San Jose's Tech Museum explores the present and future of synthetic biology.

Liver diseases leading to organ failure may go unnoticed as they do not trigger any symptoms or significant discomfort. We have designed a synthetic gene circuit that senses excessive bile acid levels associated with liver injuries and automatically produces a therapeutic protein in response. When integrated into mammalian cells and implanted into mice, the circuit detects the onset of liver injuries and coordinates the production of a protein pharmaceutical which prevents liver damage.

Synthetic biology aims to take the rational design principles of engineering and apply them to the modification and manipulation of living organisms. This strategy has resulted in the construction of increasingly complex genetic circuits and rewired pathways, although the manual construction of these circuits can often be a time-intensive task with fiddly optimization required