Amidst the frenzy that strikes graduate students as they scramble to collect last-minute data and write up committee reports, there exists an escapist outlet that occurs only once a year. This realm—also known as the realm of annual holiday parties— allows graduate students to temporarily commiserate their year’s worth of struggles before consuming a bounty of free sugar cookies and seasonal libations. After the students’ bellies are full, they, for a moment, forget about their anxieties and past failures and instead come together in warm friendship and optimism for better days. Of course, this hopefulness only lasts until the next day. But luckily, because there is a stream of holiday parties in the month of December, the perpetual cycle of brief elation and pleasant distractions continues. This week I’ve attended numerous holiday parties and despite my reluctance at first to attend them, I’m glad I got to build a better rapport with my peers and relieve the weight of end-of-year expectations. Whether it be the GSC holiday party, a departmental holiday party, a college-alumni party, or even a biotech networking event, I highly encourage students to accommodate these events into their schedule because they can make the last month of the year much more bearable. So let’s cheer to the annual holiday parties!
In the wake of hurricanes Harvey and Irma, I feel compelled to understand what cleantech strategies are currently available to tackle climate change. California’s cleantech industry was an obvious thought that came to mind. Over the past decade, California’s institutions and companies have been leaders in the U.S. market for producing clean energy and biodegradable materials. This past summer, the Joint BioEnergy Institute (JBEI) in the Bay Area received federal funding for innovation in biofuels and bioproducts. Since its inception, JBEI has yielded several startups that are committed to engineering microbes and crops to convert sugars into high-value renewable fuels. But where does Massachusetts stand in the cleantech industry? Fortunately, we’re not too far behind.
The nation’s largest cleantech startup incubator actually exists right here in Massachusetts. The Somerville incubator Greentown Labs hosts more than 100 startup companies and has raised over $200 million in investor funding since its founding. There is an emphasis on solar, wind, and wastewater technology in this incubator that is very unique. For example, the startup WrightGrid has developed a single solar-panel-based charger for robust cell phone charging in rural areas. Furthermore, SolChroma has developed full-color reflective digital billboards that reduce light pollution and energy costs in big cities. The company Sistine Solar can come to your home and design personalized solar panels in all aesthetic shapes and colors, enticing homeowners to switch to solar energy. One company that piqued my interest was Spyce, a startup intersecting food and technology. The company has developed a robotic kitchen that can serve meals with fresh ingredients in less than five minutes. The robotic kitchen is compact and reduces the amount of space and manpower that is typically needed at restaurants to prepare meals.
For the global market, Greentown Labs hosts Promethean Power Systems, a company that manufacturers rural refrigeration systems in off-grid and partially electrified areas of developing countries. In the same vein, Ivys Energy Solutions provides renewable hydrogen fuel cells to the international market. For the agrigulture sector, Raptor Maps fuses drone-based imaging technology to detect pest and weed infestation so to reduce water usage and nutrient management. Multisensor Scientific has also developed imaging capabilities to visualize and quantify in real-time methane leaks from natural gas infrastructures, thus reducing harmful methane emissions that are driving climate change. In the materials sector, Alkemy Environmental recycles industrial waste into lightweight concrete. For water management, Aquafresco is reinventing how we do laundry through a wastewater recycling invention that reduces the amount of water we use by 95%
Just a week ago, Tufts University collaborated with Greentown Labs to support cleantech solutions. The agreement between the parties will allow them to share their expertise, resources, and networks. The collaboration is also exciting because it allows for startups run by Tufts affiliates to directly become members of Greentown Labs. Currently Greentown Labs is tight on space but they are opening up a new building in Somerville next month to host more startups. The expansion of Greentown Labs is very promising for the future of cleantech in the Boston area. Just like Kendall is synonymous with biotech, in the next few years Somerville will be synonymous with yuppies, hipsters, and, perhaps, cleantech.
Often touted as a “miracle therapy” for certain cancers, CAR-T treatment has created a lot of buzz in the immuno-oncology field. There are over a hundred CAR-T clinical trials open in the U.S. and the first commercial CAR-T could possibly be approved by the end of this year. Initially, the advent of the therapy in 2012 had some warranted safety concerns. The technology is inherently aggressive and can become unruly if not it’s not properly monitored. For this reason, the first clinical trials of CAR-T created damaging side effects and in some cases the therapy was associated with patient deaths. However, therapy design has been revamped over the past five years and researchers are finding ways to dampen the level of toxicity the therapy produces. Despite the risks associated with CAR-T, clinical trials have shown to be effective at treating the targeted cancer. Recently, clinical trials have shown remissions rates of up to 94% and as a result the therapy has attracted millions of dollars from investors. Although the technology is not perfect, there is optimism in the field that CAR-T can radically improve cancer patient care.
CAR-T treatment involves the infusion of transgenic T-cells that express a Chimeric Antigen Receptor (CAR) on their cell membrane into the patient. The most common procedure involves isolation of the patient’s own T-cells, which are then genetically modified and expanded in vitro. These transgenic T-cells are then infused back into the patient to specifically target tumor cells. The CAR-T receptor of the transgenic T-cell contains three domains: (1) a target-binding domain externally exposed to the extracellular environment, (2) a transmembrane domain, and (3) an activation domain that is intracellular contained. The target-binding domain is engineered to recognize a specific tumor antigen; it is structurally different than endogenous T-cell receptors because it recognizes antigens independent of major histocompatibility complex (MHC). The antigens CAR-T recognizes are instead proteins, carbohydrates, and gangliosides on the tumor cell surface. The transmembrane domain and activation domain of the CAR-T receptor are more structurally similar to endogenous T-cell receptors—they are responsible for activating and triggering T-cell proliferation when the receptor binds to its target antigen. When activated, the T-cells mediate killing of tumor cells by two mechanisms: (1) secretion of granzymes and (2) activation of death receptor signaling in the tumor cell. These killing strategies are potentiated by additional signaling receptors on the T-cells that can improve T-cell proliferation and cytokine release. As of now, research teams have designed third-generation CAR-Ts that contain costimulatory receptors that ameliorate antitumor activity and proinflammatory cytokine secretion.
The high success rate of CAR-T therapy in clinical trials has prompted several companies to compete for commercialization and introduction of the therapy into the market. At the moment, Novartis is leading in the race of clinical development and commercialization. In November, the company successfully completed Phase II trial of the CAR-T candidate for B-cell acute lymphoblastic leukemia (ALL) and Novartis is currently preparing to submit applications to the FDA this year. Kite Pharma also recently completed their Phase II clinical trials for CAR-T therapy against lymphoma and Kite Pharma have also started regulatory submissions with the FDA. Both companies have created a lot furor and excitement around their respective CAR-T therapies. However, some researchers are skeptical that FDA approval will be granted to these companies because severe side effects still exist and deaths have been reported in the clinical trials. Juno Therapeutics, a company that was initially in the stiff CAR-T race, terminated their research and development program for this very reason—5 patients died of cerebral edema caused by the therapy. Alternatively, companies like Cellectis and Bellicum Pharmaceuticals have taken the approach to mitigate harmful CAR-T side effects. Cellectis has developed a CAR-T therapy with a switch control system that only activates the transgenic T-cells when rampamycin is present. This therapy is currently in Phase I clinical trails and has already shown a lot of promise after saving two infants from leukemia. Bellicum Pharmaceuticals is also developing a similar technology that requires rimiducid to be present for CAR-T cell activation.
A technical limitation of CAR-T technology is that it is challenging to target solid tumors. The therapy is most effective against hematological cancers. However, in other cancers that have solid tumors, there is low T-cell infiltration and additionally an immunosuppressive environment prevents the immune system from attacking the solid tumor. To solve this problem, the company Celyad is developing a CAR-T that expresses Natural Killer Receptors (NKR) that can bind ligands of solid tumors. The company is currently beginning clinical trials with these NKR expressing CAR-Ts. Researchers have also suggested combining the checkpoint inhibitor drugs such as PD-1 with CAR-T therapy as a multi-pronged method to attack solid tumors; however the side effects of this combination therapy are unknown.
From a patient’s and physician’s point of view, another limitation of CAR-T therapy is that it expensive and lengthy process because the CAR-Ts are developed from the patient’s own cells. Cellectis and Celyad are offering a solution to the expense of CAR-T by developing an allogeneic CAR-T therapy—that is, the T-cells are derived from a healthy donor and are immediately available when they are needed. This technology is still at its early stages and is scientifically challenging to develop since foreign donor T-cells can be readily attacked by the patient’s immune system. Additionally, the manufacturing, transportation, and banking of the allogenic CAR-T would also prove to be tricky. The plethora of different CAR-Ts in clinical trials has given hope to patients, physicians, and investigators that the therapy will be introduced to the market fairly soon. Although several limitations exist for CAR-T, ongoing research and clinical development continues to refine the therapy and encourage the public that CAR-T has the potential to revolutionize the immuno-oncology field.
Yu et al. Journal of Hematology & Oncology (2017) 10:78
GSC Career Paths Committee
On February 13, 2017, the GSC Career Path’s Committee kicked off the year with a workshop learning the basics of the Prism Graphpad software. In the past, students had expressed interest in analysis of data using statistical software as well as graphing the data in a presentable fashion. Therefore, the GSC thought a workshop on PRISM would not only be very useful but also have a significant impact on the students’ research careers. The workshop was kindly guided by Dr. Dan Cox, a professor in the Neuroscience department, and it took place in the computer room in the Sackler library. There workshop was well-received, according to GSC representatives Vaughn Youngblood and Roaya Alqurashi. “(The workshop) was a successful one and from who attended they loved it too. The attendees loved how Dr. Cox explained each application you will need to use in Prism with an active learning experience” Roaya said. Vaughn mentioned “the Prism workshop was helpful! It taught the fundamentals of using Prism along with how to represent different types of data. Hopefully, we can bring Dr. Cox in for another session with another statistical program like R.” If time permits this year, the GSC Career Path’s Committee hopes to hold several more workshops like this with different analysis softwares (R, SAS, etc.).
At the moment in the USPTO office, a fierce battle is occurring between two scientific teams over patent rights associated with core CRISPR/Cas technology. On one side of the dispute is Jennifer Doudna’s team from UC Berkeley. On the other side is Feng Zhang’s team from the Broad Institute of MIT and Harvard. Both teams were one of the first labs to demonstrate that the Cas9 enzyme can be directed to cut specific sites in isolated DNA. It will be intriguing to find out who is finally the victor of this contentious debate.
The story of the patent dispute has been lengthy and drawn-out. Jennifer Doudna’s team first filed for patent rights over CRISPR/Cas technology back in May of 2012. Feng Zhang’s team subsequently filed their patent in December of that same year. Interestingly, Zhang’s team beat Doudna’s team to the punch because in October of 2013 they submitted their patent for expedited review. Expedited review required the Broad to undergo “accelerate examination,” where they were required to respond quicker to questions asked by the USPTO office. Due to the expedited reviewing process, the patent was ultimately awarded to Zhang’s team in April of 2014. Shortly after this award, eleven other CRISPR-related patents were additionally filed under the Broad Institute. To counter-attack the Broad’s prompt monopoly over CRISPR-related patents, Doudna’s team requested a patent interference against all CRISPR-related patents filed by the Broad. The USPTO office finally granted the interference request in January of 2016.
Historically, an interference request has been a procedure to resolve disputes between two parties over who was the “first to invent.” However, in March of 2013 the USPTO altered the patent system from “first to invent” to “first to file.” Under these rules, Doudna’s team would have won the CRISPR patent rights because the team was the “first to file” their patent claiming rights over CRISPR/Cas technology. But since both parties filed their patents before March 2016, the interference procedure defaults under the outdated “first to invent” rules.
The “first to invent” rule has blurred the lines of who is the true proprietor of the patent rights. For over nine months, both parties have been providing evidence claiming they were the “first to invent.” The Broad asserts that Zhang’s team was the first group to demonstrate that CRISPR/Cas technology has applications in editing genes in mammalian cells. Furthermore, they argue that Doudna’s team only described using CRISPR/Cas in bacteria, not in eukaryotes. This distinction is important for patentability because some of CRISPR’s most lucrative, future applications will be in gene therapeutics for hospital patients. Doudna’s team countered the Broad’s argument by claiming that although her team only demonstrated the use of the technology in bacteria, transferring the technique to mammalian cells was “obvious” and any “person of ordinary skill,” such as a postdoc, could have made that inference. This observation is also important because one of the hallmarks of patentability is that it cannot be obvious to a person of ordinary skill. The Broad subsequently counter-argued that scientists in the biological field are far from being considered “ordinary” and the shift from bacteria to mammalian cells was “anything but obvious.” This type of back-and-forth between the USPTO, UC Berkeley, and the Broad has been continuing for the last nine months and updated details of the case can be viewed on the Broad’s CRISPR Patent Interference Updates webpage (reference is listed below).
Patent interference cases can last up to two years before appealing to the Federal Circuit. Due to the intense, ongoing clash between the two academic teams, attorneys expect the end date of the CRISPR patent interference case to be sometime in 2017. However, a recent twist in the interference case may close the case completely by the end of this year. This past week, UC Berkeley attorneys submitted a 2013 email to the USPTO office. This email was from Feng Zhang to Jennifer Doudna describing his team’s first, published CRISPR paper and mentioning that he has been “very inspired” by her team’s work. This is enough evidence to imply that Zhang’s team had adapted from Doudna’s team’s work. The Broad understands that it’s difficult to counter this piece of evidence. Since the submission of this email, the Broad has asked patent officials to remove four CRISPR-related patents from the interference case in hopes that they can demonstrate novelty of the patents in other ways that are separate from the initial Zhang team’s CRISPR patent. If the Broad can separate these patents from the interference case, then both UC Berkeley and the Broad can walk away with some intellectual property. We will see in the forthcoming weeks how the case plays out.
Although intellectual property was at stake for the two scientific teams, the interference case has been rather unusual in nature. Why has the fight been so bitter and acrimonious? One explanation could be that it’s not the academic institutions that are footing the legal bill for the case but the biotechnology companies that are relying on the license of the patent. Both Doudna and Zheng have started up genome editing companies and if one of those companies has proprietary rights over the CRISPR/Cas technology, that company can collect huge patent royalties. Perhaps another reason why the dispute has been rancorous is because Doudna and Zheng have their eyes set on Nobel Prize. CRISPR/Cas technology will and is revolutionizing the way we do basic science research, the way we treat diseases, and the way we practice agriculture. For these reasons it’s only inevitable that the scientists behind the technology will receive a Nobel Prize. Regardless of the uncertainty that surrounds the outcome of the patent interference case and the Nobel Prize, the scientific community is certain of one thing: CRISPR has definitely made its mark in history.
- CRISPR Patent Interference Updates. Retrieved from https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crispr-patent-interference-updates
- Begley, S. (2016, August 16). CRISPR patent fight: The legal bills are soaring. Retrieved from https://www.statnews.com/2016/08/16/crispr-patent-fight-legal-bills-soaring/
- Cohen, J. (2016, October 5). Dramatic twists could upend patent battle over CRISPR genome-editing method. Retrieved from http://www.sciencemag.org/news/2016/10/dramatic-twists-could-upend-patent-battle-over-crispr-genome-editing-method
- McCall, A. (2016, June 5). The CRISPR Clash: Who owns the groundbreaking, DNA altering technique? Retrieved from http://www.ipwatchdog.com/2016/06/05/crispr-clash-dna-technology/id=69650/
- Ledford, H. (2016, September 21). The Titanic clash over CRISPR patents turns ugly. Retrieved from http://www.nature.com/news/titanic-clash-over-crispr-patents-turns-ugly-1.20631
Photo from abc.net.au