Opinion: Clearing the Air About Unenforceable Policies

Opinion: Clearing the Air About Unenforceable Policies

by Kristina Victoreen

Is a policy without enforcement really a policy, or is it just an aspiration? That question has been on my mind lately, in two different contexts, both related to the air we breathe. First, there’s Penn’s new “Tobacco-free Campus” policy. I first noticed the signs in November, when they quietly popped up here and there around campus. As someone who has spent many a lunch hour going from bench to bench all around campus in an often-vain attempt to find a place to sit and eat my lunch without having to breathe second-hand smoke, I was really excited to see those signs. But I confess I was much less excited when I went online and read the actual policy, particularly the section on enforcement. You can read it here.

What it seems to say is that there is no enforcement, and if you have any questions, ask the person you report to or your Dean. In other words, Penn wants you to not smoke but if you do, probably nothing will happen. This idea that the policy won’t be enforced, was confirmed in Rahul Chopra’s December 3rd DP article, in which Frank Leone, Director of the Comprehensive Smoking Treatment Program at Perelman School of Medicine, was quoted as stating that "There's not going to be enforcement or an effort to corral smokers." So Penn’s idea is to try to change the norms, and also provide supports for those who are trying to quit, perhaps partly by removing some of the triggers. For example, the smoking pole outside Van Pelt Library has been removed and replaced with a sign, with the expectation that folks won’t just stand where the pole used to be and drop their cigarette buts on the ground. I’m definitely not an expert on smoking cessation or behavioral economics principles and I know lots of research and some testing went into choosing this approach. Presumably robust baseline data have been collected on smoking behaviors, so that the success of the program can be measured with real outcomes, and I will be very interested to see the results, (and to enjoy a smoke free outdoor lunch when the weather gets warmer.) Certainly it’s no longer unusual to use "nudge" techniques to try to elicit desired behaviour changes, and such policies are popular because they are non-coercive and can be very cost effective. The alternative would be to have the campus police enforce the tobacco policy, and I’m guessing that this may be viewed by the Administration as much more trouble than it's worth, perhaps alienating the people the policy targets, and diverting resources from campus police who have other more pressing concerns. 

In Philadelphia, diesel and other vehicles are subject to several anti-idling laws, enforced (in theory) by different agencies. You can see them all in one place at this helpful site from Pennsylvania Diesel Difference. For example, you can be issued a ticket for $101 by the Philadelphia Parking Authority for excessive idling, and the Department of Health’s Air Management Services can issue a citation to the operator of a heavy duty diesel truck, bus or other vehicle under a separate law, for idling over 2 minutes. There are many exceptions, having to do with things like ambient temperature, (look here for the details) which make the laws incredibly difficult to enforce even if any agency were inclined to enforce them. In addition to Philadelphia’s laws, Pennsylvania has a separate diesel idling law that can be enforced by the State Police. Confused yet? Here’s an experiment to try. Next time you see a PPA agent giving out tickets, try to report an idling vehicle. You might get a quizzical look. I tried this only once, but the PPA officer I asked did not seem to have heard of the anti-idling law. There are a few No Idling signs here and there, but you have to look hard to find them. Thanks to the Clean Air Council, there is a web site where anyone can report an idling vehicle. But it’s doubtful that citations will be issued on the basis of only a citizen complaint, especially without a video to show how long the vehicle idled, and the citizen needs to know the law and be willing to do the reporting.

In short, there are many laws, little enforcement, and no incentive for compliance. So what’s the solution? Should the City be employing nudge methods, and/or trying to change the culture around idling? What would it take to do that? Should the PPA be issuing tickets? I am guessing that a $100 ticket may be seen as a reasonable cost of doing business for the operator of even a small fleet. What about higher fines? According the the New York State web site, there you can be fined up to $18,000 for a first offense with certain idling violations. It seems that steep fines might generate funds to pay for some grants for replacing older engines and doing clean diesel retrofits, but you still need enforcement in order to collect those fines. So at least in the case of vehicle emissions, it appears that policies without enforcement sometimes amount to little more than hope, and as Rudy Giuliani famously said, hope is not a strategy.

UPenn Scientists Are Investigating Better Treatments for Sarcoma Tumors

by Adrian Rivera-Reyes and Koreana Pak

Soft tissue sarcomas (STS) are rare cancers of the connective tissues, such as bone, muscle, fat, and blood vessels. Soft and elastic, sarcoma tumors can push against their surroundings as they grow silent and undetected. Residing in an arm, torso, or thigh, it can take years before a sarcoma begins to cause pain. By the time a patient presents their tumor to a doctor, amputation may be unavoidable¹.

In 2017, it is predicted that 12,390 Americans will be diagnosed with sarcoma, and approximately 5,000 patients will die from these tumors². But the vast majority of these patients aren’t dying from the first tumor in their arm or leg—the real danger is metastasis, which is responsible for more than 90% of cancer-related deaths^3-5.

Metastasis occurs when tumor cells leave their original site and colonize a new area of the body, such as the lungs, liver, or bones^3-5. The current treatment options for sarcoma—surgery, chemotherapy, and radiation—are not very effective against metastases^6,7. Only 10-25% of STS patients respond to chemotherapy, leaving surgery as the best option for many^6,7. However, tumor cells can spread to other parts of the body even in early stages of sarcoma, long before the first tumor is even noticed. By the time the tumor is surgically removed, metastases have usually developed in other parts of the body.

As a sarcoma tumor grows, it becomes increasingly starved of oxygen and nutrients. Under these conditions, cancer cells are driven to metastasize. Moreover, tumor hypoxia, or low oxygen levels, are an important predictor of metastasis and low survival in sarcoma patients^8-10. In other words, the more tumor hypoxia, the lower a patient’s chance of surviving.

But how does this actually work? How does hypoxia drive sarcoma cells out of a tumor and into other organs, such as the lungs? Surprisingly, UPenn scientists have found it has a lot to do with collagen¹¹!

Metastasizing tumor cells (pink) associated with collagen (blue). Image taken by Koreana Pak.

Collagen is the most abundant protein in the human body, but you’ll know it best as the substance that makes your skin flexible and elastic¹². This elastic material has many uses, and you can find it in gelatin, marshmallows, surgical grafts—and hypoxic tumors. In STS tumors, the low oxygen levels cause collagen to form sticky, tangled fibers.  Sarcoma cells will actually hijack this disorganized collagen and use it as a “highway” over which they can migrate out of the tumor and into other organs¹¹.

If these hypoxic collagen “highways” were disrupted in patient tumors, cancer cells could be prevented from metastasizing. But how?

In an effort to make this therapy a reality, UPenn scientists used models of human sarcoma and metastasis in which they could disrupt collagen. By deleting the hypoxia factors HIF-1 and PLOD2, they could restore normal collagen in tumors, which reduced tumor metastasis. Excitingly, they also found that minoxidil, a drug usually used to treat hair-loss, also reduced tumor collagen and halted metastasis¹¹.

Whether minoxidil could be used for human patients is unclear; nevertheless, drugs that reduce hypoxic targets like PLOD2 could serve as promising anti-metastatic therapies.

In a follow up study, these scientists looked at another hypoxic factor, called HIF-2¹³. While related to HIF-1, this protein actually plays a very different role in sarcoma. Elimination of HIF1 is important because it reduces metastasis¹¹. But when it comes to primary sarcoma tumors, the expression of HIF-2 can help reduce cancer cell growth¹³.

Again using a model of human sarcoma, the authors found they could increase tumor size when they eliminated HIF-2. They also used a clinically approved drug, Vorinostat, to treat these tumors, and saw that HIF-2 increased and as a consequence the tumors to shrank¹³.

Sarcoma Treatment: Going Forward

The diversity of STS, which comprises about 50 different types¹, as well as the low incidence of cases, makes it very challenging to develop better treatments for sarcoma. Clinical trials often combine patients with different types of sarcomas into a single study, even though the trial may not be a good fit for all the patients. A more specific approach is needed to treat the different types of sarcomas.

Through their research on hypoxia in sarcoma, UPenn scientists hope to improve current treatments. Their observation that HIF-1 and HIF-2 play opposing roles in different cancers is of particular importance, because HIF inhibitors are already being developed for cancer therapy^11,13. Doctors can also use markers like HIF-2 to predict how well patients will respond to different treatments. For example, patients with tumors that have low levels of HIF-2 will respond well to treatments with Vorinostat. Unfortunately, such predictive markers are rare in STS, and the identification of additional markers should complement the development of new treatments.

Complementing standard chemotherapy with new sarcoma-specific therapies would greatly improve current treatment options. However, treating the primary tumor alone is not sufficient, as metastasis remains primarily responsible for patient death^6,7. For this reason, further study into HIF-1/PLOD2 and the role of collagen in metastasis is needed. Through the development of drugs like minoxidil, which target harmful tumor collagen, we see exciting potential for the future of sarcoma therapy and patient survival.

References

1. Cancer.Net Editorial Board. (2012, June 25). Sarcoma, Soft Tissue – Introduction. Retrieved on April 4, 2017 from: http://www.cancer.net/cancer-types/sarcoma-soft-tissue/introduction

2. The American Cancer Society medical and editorial content team. (2017, January 6). What Are the Key Statistics About Soft Tissue Sarcomas? Retrieved on April 4, 2017 from https://www.cancer.org/cancer/soft-tissue-sarcoma/about/key-statistics.html

3. Mehlen, P., & Puisieux, A. (2006). Metastasis: a question of life or death. Nature Reviews Cancer, 6, 449-458.

4. Monteiro, J. & Fodde, R. (2010). Cancer stemness and metastasis: therapeutic consequences and perspectives. European Journal of Cancer, 46 (7), 1198-1203.

5. Nguyen, D.X., Bos, P.D., & Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer, 9, 274-284.

6. Linch, M., Miah, A. B., Thway, K., Judson, I. R., & Benson, C. (2014). Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat. Rev. Clin. Oncol. 11(4), 187-202.

7. Lorigan, P., Verweij, J., Papai, Z., Rodenhuis, S., Le Cesne, A., Leahy, M.G., Radford, J.A., Van Glabbeke, M.M., Kirkpatrick, A., Hogendoom, P.C., & Blay, J.Y. (2007). Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastaic soft tissue sarcoma: a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Journal of Clinical Oncology 25 (21), 3144-3150.

8. Shintani, K., Matsumine, A., Kusuzaki, K., Matsubara, T., Santonaka, H., Wakabayashi, T., Hoki, Y., & Uchida, A. (2006). Expression of hypoxia-inducible factor (HIF)-1 alpha as a biomarker of outcome in soft-tissue sarcoma. Virchows Arch. 449 (6), 673-681. 

9. Nordsmark, M., Alsner, J., Keller, J., Nielsen, O.S., Jensen, O.M., Horsman, M.R., & Overgaard, J. (2001). Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br. J. Cancer 84 (8), 1070-1075. 

10. Rajendran, J.G., Wilson, D.C., Conrad, E.U., Peterson, L.M., Bruckner, J.D., Rasey, J.S., Chin, L.K., Hofstrand, P.D., Grierson, J.R., Eary, J.F., & Krohn, K.A. (2003). [(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism, and VEGF expression. Eur. J. Nucl. Med. Mol. Imaging, 30 (5), 695-704.

11. Eisinger-Mathason, T.S.K., Zhang, M., Qiu, Q., Skuli, N., Nakazawa, M..S., Karakasheva, T., Mucaj, V., Shay, J.E., Stangenberg, L., Sadri, N., Puré, E., Yoon, S.S., Kirsch, D.G., & Simon, M.C. (2013). Hypoxia dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discovery, 3 (10), 1190-1205.

12. What is collagen? Retrieved on April 4, 2017 from http://www.vitalproteins.com/what-is-collagen.

13. Nakazawa, M.S., Eisinger-Mathason, T.S., Sadri, N., Ochocki, J.D., Gade, T.P., Amin, R.K., & Simon, M.C. (2016). Epigenetic re-expression of HIF-2 alpha suppresses soft tissue sarcoma growth. Nature Communications, 7, 10539

Event Recap: Intellectual Property Panel “From Research to Patent”

by Adrian Rivera-Reyes

On November 10^th, the Penn Science Policy Group and the Penn Intellectual Property Group at Penn Law co-hosted a panel discussion focused on intellectual property and how to patent scientific research. The panel included Peter Cicala, Chief Patent Counsel at Celgene Corp.; Dr. Dora Mitchell, Director of the UPstart Program at the Penn Center for Innovation (PCI) Ventures; and Dr. Michael C. Milone, Assistant Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania (HUP), and Assistant Professor of Cell and Molecular Biology at Penn Medicine.

The event started with the introduction of both groups by their respective presidents and was proceeded by Kimberly Li giving an introduction of the panelists. Next, Peter gave a short PowerPoint presentation with a general introduction of intellectual property. Below are some key points to understand intellectual property/patent law ^1,2:

1) In general, patents provide a “limited monopoly” that excludes others from making an invention, using, offering for sale, selling, or otherwise practicing an invention, but it does not confer upon the patentee a right to use the said invention. Thus, patents serve as a form of protection for the owner.

2) A single invention can only be patented once; once the patent on that invention expires, others may not file to patent the same invention again.

3) In order to confer a patent, the United States Patent and Trademark Office ensures that inventions of patentable subject matter meet the following legal requirements: i) inventions must be novel, ii) inventions must be useful, and iii) inventions must be non-obvious.

4) Utility patents only last for 20 years from the date of filing. After 20 years, anyone can make, use, offer for sale, sell, or practice the invention. A single invention cannot be re-patented after the time is done. In contrast, trademarks or trade secrets last forever, and copyrights last for the lifetime of the author.  

5) The United States Patent and Trademark Office follows the ‘first to file’ rule. Thus, the first person or entity to file a patent is the assumed owner.

6) Patents can be invalidated by the United States Patent and Trademark Office.

A clever example discussed by Peter Cicala was the patenting of a new car feature. If X company has submitted and received a patent for a car and Y company makes a new feature for the car, they can patent the new feature (as long as it meets the legal requirements introduced above). Once the patent for the new feature is conferred to Y company then they can produce that one feature, but not the car that was patented by X company, unless a license is provided by X company to Y company. Thus, the patent for Y company only gives them the power to prevent others from making that new feature.

Conferring Patents in the US and Internationally

First, there has to be an invention of some sort. Once there is an invention, a patent is filed. Patents are drafted free-hand, unlike a tax application where one has a specific form to fill. For patents, one has to start from scratch. Patents are usually long (some can reach 500 pages in length) and there are many legal requirements on what to say in the application and how to say it. Eventually, when one files a patent application it will go to the patent office. A patent examiner will, as the name suggests, examine it and deliberate with the patent office over the course of 3-5 years as they point out sections that need further editing, clarification, or justification. There is a lot of back and forth, until the examiner agrees that the invention has satisfied the patent requirements. Then, one pays fees and the patent is awarded. Fun fact: In the US, patents are granted only on Tuesdays.

On a global basis, one files a single international patent and the designated patent offices around the world examine it locally. If an office grants a patent, such patent will only be valid in that jurisdiction. That is why submitting patents cost so much, because one files and pays legal fees for each jurisdiction. For example, if a patent is filed in Japan for a compound, a different entity can manufacture the compound freely in the US, but not in Japan. This is one reason why companies and universities are very careful when filing patents.

Intellectual Property in Industry

Pharmaceutical products start with a great idea, but for every product in the market there are about 10,000 that fail. Therefore, companies file many patents even though many of those patents may not have any commercial value in 5-6 years. It costs about $500K to file (including filing and attorneys’ fees) and receive a single issued patent, which means companies spend a lot in patents (i.e. 10,000 patent submissions each worth $500K)! Out of those 10,000 patents, typically one will make the company about an estimated $5 billion a year in returns.

A student asked, “Is submitting a patent the same price for a university as it is for a company?” In essence, no! The patent office makes a distinction between large and small entities. Small entities, based on requirements provided by the patent office³, pay half the fees, but attorneys charge a fixed price. In the end, small entities save just a small percentage of money. Another question asked by an audience member was “what is patentable in the pharma business?” If one patents a molecule, no one else can infringe or use that molecule itself. That is how companies patent drugs or their associated components. One can also patent dosing regimens, formulations, modes of administration, etc. The compound claim gives the most protection, because it is very hard to make a knock-off of a molecule.

Intellectual Property in Academia

A student raised the issue that there is a lot of communication that occurs in science, especially at conferences, symposia, or amongst colleagues, classmates, etc. That seems to be a big risk in the context of protecting one's intellectual property, but doing so is an unavoidable risk when one does scientific research.

Dora, patent analyst from PCI Ventures, then proceeded to discuss the issues brought up from an academic perspective. She said, “The question raised here is that when one works in an academic institution the work is knowledge based and disseminated to others.... How does one draw the line from all that to protect something valuable?” What most, if not all, academic/research institution do is have their lawyers work very closely with faculty, so that anytime they are about to publish a paper, go to a conference, attend grand rounds, or any other such public appearance, the lawyers will hustle and get an application submitted before such events.

In addition to these more public forums, problems can arise from talking with friends who are not directly associated with the work. An example of this pertains to OPDIVO®, a drug patented by Ono Pharmaceuticals and the Kyoto University in the 90’s, which later was exclusively licensed to Bristol-Myers Squibb who launched the drug. Recently, Dana Farber Cancer Institute sued Ono Pharmaceuticals and Bristol-Myers Squibb because the principal investigator at Kyoto University had periodically consulted a colleague at Dana Farber for his advice. The professor-consultant at Dana Farber would send some data he thought was helpful and consult with them. Dana Farber sued both companies, claiming that the now-retired professor from its institution should be included as an inventor in the patent. Because an inventor of a patent is part-owner, Dana Farber is actually claiming ownership of the patent and will receive compensation from the sales of products under the patent^4,5.

Michael, Penn Med professor who works intimately with a team of lawyers from PCI because he regularly files patents, said that balancing confidentiality with science communication is a difficult task. He commented, “I think it comes down to how important one thinks the invention is and a lot of the times the patent will not get developed if it will not bring any money to the owner (company/institution).” Moreover, there has to be a conversation with the university because the university pays for the patent, so it decides what to file. It also depends on the resources of the university. Regarding the work of graduate students or postdoctoral fellows, there are more considerations. Students and postdocs want and need to publish, go to conferences, and present their work in order to move forward with their careers; thus patents can be a rather limiting step for them.

From the industry perspective, Peter clarified that the rule at Celgene is that no one can talk about anything until the patent application is filed. Once the patent application is filed, employees are free to talk to whomever they wish without causing a situation like the one with Dana Farber and Bristol-Myers Squibb, since the patent application has been filed prior to any communication.

Thus, a clear difference between industry and academia is that in industry, things are kept under wraps and then a patent is filed, whereas in academia patents are filed early to make sure that the institution does not lose the rights of patenting by making the information public. Because universities file very early, there is a lot to deal with afterwards. The costs of prosecution are high, and sometimes the application does not make it through the full process, because universities cannot afford to throw $500K for an application if they are not confident on getting a return on the investment. The reason to file for some universities might be purely strategic.

Ownership vs. Inventorship

Another interesting topic discussed, was that of ownership vs. inventorship. There is the notion that ownership follows inventorship. In most cases, people do not file patents on their own; they work for companies or universities. Usually, an employment contract will state that if an employee invents something while employed by that entity, then ownership to a resultant patent will be assigned to the employer. Thus, the person is the inventor but not the owner of the patent; the entity is the owner. For academic research, the Bayh-Dole act was enacted to allow universities to own inventions that came from investigations funded by the federal government⁶. Dora explained that, “Government officials got together and agreed that they awarded so much money into research and good stuff came out of it, which the government would own but not file patents or do anything with it commercially."

A preliminary list of inventors is written when the patent is filed, but legally the inventors are the people that can point to a claim and say: "I thought of that one." Inventors have to swear under oath that they thought of a particular claim, and need to be able to present their notebooks with the data supporting a claim of inventorship. Inventors are undivided part-owners of the patent, which means that any inventor listed in the patent can license that patent in any way, without accounting for any of the other inventors. Additionally, there is a difference between the people that think about the claims and the people that actually execute the subject matter of the resulting claim. If a person is only executing experiments without contributing intellectually to the idea or procedure, then that person is not an inventor. For those in academic research, this often differs from how paper authorship is decided – usually performing an experiment is sufficient.

Summary

The discussion prompted the researchers in the room to be on the lookout for ideas they have that can result in patents, and to be careful when discussing data and results with people outside of their own research laboratory. Also, the discussion exposed key differences between intellectual property lawyers working for universities and industries, as opposed to law firms that have departments working on intellectual property. Ultimately, students felt they gained a basic understanding on how intellectual property works, the rules to file patents, and some intrinsic differences between academic and industry research.

References:

1) United States Patent and Trademark Office – (n.d.) Retrieved December 11, 2016 from https://www.uspto.gov/patents-getting-started/general-information-concerning-patents

2) BITLAW – (n.d.) Retrieved December 11, 2016 from http://www.bitlaw.com/patent/requirements.html

3) United States Patent and Trademark Office – (n.d.) Retrieved December 20, 2016 from https://www.uspto.gov/web/offices/pac/mpep/s2550.html

4) Bloomberg BNA – (2015, October 2) Retrieved December 11, 2016 FROM https://www.bna.com/dana-farber-says-n57982059025/

5) United States District Court (District Court of Massachusetts). http://www.dana-farber.org/uploadedFiles/Library/newsroom/news-releases/2015/dana-farber-inventorship-complaint.pdf

6) National Institute of Health, Office of Extramural Research – (2013, July 1) Retrieved December 11, 2016 from https://grants.nih.gov/grants/bayh-dole.htm

Event Recap: Anonymous Peer Review & PubPeer

by Ian McLaughlin 

On the 24^th of October, the Penn Science Policy Group met to discuss the implications of a new mechanism by which individuals can essentially take part in the peer review process.  The group discussion focused on a particular platform, PubPeer.com, which emerged in 2012 and has since become a topic of interest and controversy among the scientific community.  In essence, PubPeer is an online forum that focuses on enabling post-publication commentary, which ranges from small concerns by motivated article readers, to deeper dives into the legitimacy of figures, data, and statistics in the publication.  Given the current state of the widely criticized peer-review process, we considered the advantages and disadvantages of democratizing the process with the added layer of anonymity applied to reviewers.

PubPeer has been involved in fostering investigations of several scandals in science.  Some examples include a critical evaluation of papers published in Nature 2014 entitled Stimulus-triggered fate conversion of somatic cells into pluripotency [1].  The paper described a novel mechanism by which pluripotency might be induced by manipulating the pH environments of somatic cells.  However, following publication, concerns regarding the scientific integrity of published experiments were raised, resulting in the retraction of both papers and an institutional investigation.

  
Subsequently, the publications of a prolific cancer researcher received attention on PubPeer, ultimately resulting in the rescission of a prestigious position at a new institution eleven days before the start date due, at least in part, to PubPeer commenters contacting faculty at the institution.  When trying to return the professor’s former position, it was no longer available.  The professor then sued PubPeer commenters, arguing that the site must identify the commenters that have prevented a continued career in science.  PubPeer, advised by lawyers from the ACLU working pro-bono, is refusing to comply – and enjoy the support of both Google and Twitter, both of which have filed a court brief in defense of the website [2]. 

                  
Arguably at its best, PubPeer ostensibly fulfills an unmet, or poorly-met, need in the science publication process.  Our discussion group felt that the goal of PubPeer is one that the peer review process is meant to pursue, but occasionally falls short of accomplishing. While increased vigilance is welcome, and bad science – or intentionally misleading figures – should certainly not be published, perhaps the popularity and activity on PubPeer reveals a correctable problem in the review process rather than a fundamental flaw. While the discussion group didn’t focus specifically on problems with the current peer review process – a topic deserving its own discussion [3] – the group felt that there were opportunities to improve the process, and was ambivalent that a platform like PubPeer is sufficiently moderated, vetted, and transparent in the right ways to be an optimal means to this end.

                  
Some ideas proposed by discussion participants were to make the peer-review process more transparent, with increased visibility applied to the reasons a manuscript is or is not published.  Additionally, peer-review often relies upon the input of just a handful of volunteer experts, all of whom are frequently under time constraints that can jeopardize their abilities to thoroughly evaluate manuscripts – occasionally resulting in the assignment of peer review to members of related, though not optimally relevant, fields [4].  Some discussion participants highlighted that a democratized review process, similar to that of PubPeer, may indeed alleviate some of these problems with the requirement that commenters be moderated to ensure they have relevant expertise.  Alternatively, some discussion participants argued, given the role of gate-keeper played by journals, often determining the career trajectories of aspiring scientists, the onus is on Journals’ editorial staffs to render peer review more effective.  Finally, another concept discussed was to layer a 3rd party moderation mechanism on top of a platform like PubPeer, ensuring comments are objective, constructive, and unbiased.

                  
The concept of a more open peer review is one that many scientists are beginning to seriously consider.  In Nature News, Ewen Callaway reported that 60% of the authors in Nature Communications agreed to have publication reviews published [7].  However, while a majority of responders to a survey funded by the European Commission believed that open peer review ought to become more routine, not all strategies of open peer review received equivalent support.

[7]

                  
Ultimately, the group unanimously felt that the popularity of PubPeer ought to be a signal to the scientific community that something is wrong with the publication process that requires our attention with potentially destructive ramifications [5].  Every time a significantly flawed article is published, damage is done to the perception of science and the scientific community, and at a time when the scientific community still enjoys broadly positive public perception [6], now is likely an opportune time to reconsider the peer-review process – and perhaps learn some lessons that an anonymous post-publication website like PubPeer might teach us.

References

1) PubPeer - Stimulus-triggered fate conversion of somatic cells into pluripotency. (n.d.). Retrieved November 25, 2016, from https://pubpeer.com/publications/8B755710BADFE6FB0A848A44B70F7D 

2) Brief of Amici Curiae Google Inc. and Twitter Inc. in Support of PubPeer, LLC. (Michigan Court of Appeals). https://pubpeer.com/Google_Twitter_Brief.pdf

3) Balietti, S. (2016). Science Is Suffering Because of Peer Review’s Big Problems. Retrieved November 25, 2016, from https://newrepublic.com/article/135921/science-suffering-peer-reviews-big-problems

4)Arns M. Open access is tiring out peer reviewers. Nature. 2014 Nov 27;515(7528):467. doi: 10.1038/515467a. PubMed PMID: 25428463.

5) Jha, Alok. (2012). False positives: Fraud and misconduct are threatening scientific research. Retrieved November 25, 2016, from https://www.theguardian.com/science/2012/sep/13/scientific-research-fraud-bad-practice

6) Hayden, E. C. (2015, January 29). Survey finds US public still supports science. Retrieved November 25, 2016, from http://www.nature.com/news/survey-finds-us-public-still-supports-science-1.16818 

7) Callaway E. Open peer review finds more takers. Nature. 2016 Nov 10;539(7629):343. doi: 10.1038/nature.2016.20969. PubMed PMID: 27853233

New Research shows how to make Human Stem Cell Lines divide equally

by Amaris Castanon

For the first time, scientists have generated haploid embryonic stem (ES) cell lines in humans, as published in Nature. This could lead to novel cell therapies for genetic diseases – even color blindness (Benvenisty et al., 2016)

The study was performed by scientists from the Hebrew University of Jerusalem(Israel) in collaboration with Columbia University Medical Center (CUMC) and the New York Stem Cell Foundation (NYSCF).

The newly derived pluripotent, human ES cell lines demonstrated their ability to ‘self-renew’ while maintaining a normal haploid karyotype (i.e. without chromosomal breakdown after each generation) (Benvenisty et al., 2016).

While gamete manipulation in other mammalian species has yielded several ES cell lines (Yang, H. et al., Leeb, M. & Wutz, A.), this is the first study to report human cells capable of cell division with merely one copy of the parent’s cell genome (Benvenisty et al., 2016).

The genetic match between the stem cells and the egg donor may prove advantageous for cell-based therapies of genetic diseases such as diabetes, Tay-Sachs disease and even color blindness (Elling et al., 2011).

—

Mammalian cells are considered diploid due to the fact that two sets of chromosomes are inherited: 23 from the father and 23 from the mother (a total of 46) (Wutz, 2014; Yang H. et al., 2013). Haploid cells contain a single set of 23 chromosomes and arise only as post-meiotic germ cells (egg and sperm) to ensure the right number of chromosomes end up in the zygote (embryo) (Li et al., 2014; Elling et al., 2011).

Other studies performed in an effort to generate ES cells from human egg cells reported generating solely diploid (46 chromosome) human stem cells, which is a problem (Leeb, M. et al., 2012; Takahashi, S. et al., 2014). This study, however, reported inducing cell division in unfertilized human egg cells (Benvenisty et al., 2016).

The DNA was labeled with a florescent dye prior to isolating the haploid stem cells and scattering (the haploid cells or the cells) among the larger pool of diploid cells. The DNA staining demonstrated that the haploid cells retained their single set of chromosomes, while differentiating to other cell types including nerve, heart, and pancreatic cells demonstrates their ability to give rise to cells of different lineage (pluripotency) (Benvenisty et al., 2016).

Indeed, the newly derived haploid ES cells demonstrated pluripotent stem cell characteristics, such as self-renewal capacity and a pluripotency-specific molecular signature (Benvenisty et al., 2016).

In addition, the group of researchers successfully demonstrated usage of their newly derived human ES cells as a platform for loss-of-function genetic screening. Therefore, elucidating the genetic screening potential of targeting only one of the two copies of a gene.

These findings may facilitate genetic analysis in the future by allowing an ease of gene editing in cancer research and regenerative medicine.

This is a significant finding in haploid cells, due to the fact that detecting the biological effects of a single-copy mutation in a diploid cell is difficult. The second copy does not contain the mutation and therefore serves as a ‘backup’ set of genes, making it a challenge for precise detection.

The newly derived haploid ES cells will provide researchers with a valuable tool for improving our understanding of human development and genetic diseases.

This study has provided scientists with a new type of human stem cell that will play an important role in human functional genomics and regenerative medicine.

References:

Derivation and differentiation of haploid human embryonic stem cells. Sagi I, Chia G, Golan-Lev T, Peretz M, Weissbein U, Sui L, Sauer MV, Yanuka O, Egli D, Benvenisty N. Nature. 2016 Apr 7;532(7597):107-11.

Elling, U. et al. Forward and reverse genetics through derivation of haploid mouse embryonic stem cells. Cell Stem Cell 9, 563–574 (2011).

Leeb, M. et al. Germline potential of parthenogenetic haploid mouse embryonic stem cells. Development 139, 3301–3305 (2012)

Leeb, M. & Wutz, A. Derivation of haploid embryonic stem cells from mouse embryos.Nature 479, 131–134 (2011)

Li, W. et al. Genetic modification and screening in rat using haploid embryonic stem cells. Cell Stem Cell 14, 404–414 (2014).

Takahashi, S. et al. Induction of the G2/M transition stabilizes haploid embryonic stem cells. Development 141, 3842–3847 (2014)

Wutz, A. Haploid mouse embryonic stem cells: rapid genetic screening and germline transmission. Annu. Rev. Cell Dev. Biol. 30, 705–722 (2014).

Yang, H. et al. Generation of genetically modified mice by oocyte injection of androgenetic haploid embryonic stem cells. Cell 149, 605–617 (2012)

Penn Science Spotlight: Learning how T cells manage the custom RNA business

Chris Yarosh

This Science Spotlight focuses on the research I do here at Penn, the results of which are now in press at Nucleic Acids Research¹. You can read the actual manuscript right now, if you would like, because NAR is “open access,” meaning all articles published there are available to anyone for free. We’ve talked about open access on this blog before, if you’re curious about how that works. 

First, a note about this type of science. The experiments done for this paper fall into the category of “basic research,” which means they were not designed to achieve an immediate practical end. That type of work is known as “applied” research. Basic research, on the other hand, is curiosity-driven science that aims to increase our understanding of something. That something could be cells, supernovas, factors influencing subjective well-being in adolescence, or anything else, really. This isn’t to say that basic research doesn’t lead to advances that impact people’s lives; quite the opposite is true. In fact, no applied work is possible without foundational basic work being done first. Rather, the real difference between the two categories is timeline and focus: applied research looks to achieve a defined practical goal (such as creating a new Ebola vaccine) as soon as possible, while basic research seeks to add to human knowledge over time. If you’re an American, your tax dollars support basic research (thanks!), often through grants from the National Institutes of Health (NIH) or the National Science Foundation (NSF). This work, for example, was funded in part by two grants from the NIH: one to my PhD mentor, Dr. Kristen Lynch (R01 GM067719), and the second to me (F31 AG047022). More info on science funding can be found here.

Now that you've gotten your basic research primer, let's talk science. This paper is primarily focused on how T cells (immune system cells) control a process called alternative splicing to make custom-ordered proteins. While most people have heard of DNA, the molecule that contains your genes, not everyone is as familiar with the RNA or proteins. I like to think of it this way: DNA is similar to the master blueprint for a building, specifying all of the necessary components needed for construction. This blueprint ultimately codes for proteins, the molecules in a cell that actually perform life’s work. RNA, which is “transcribed” from DNA and “translated” into protein, is a version of the master blueprint that can be edited as needed for different situations. Certain parts of RNA can be mixed and matched to generate custom orders of the same protein, just as you might change a building’s design based on location, regulations, etc. This mixing and matching process is called alternative splicing (AS), and though it sounds somewhat science-fictiony, AS naturally occurs across the range of human cell types.

While we know AS happens, scientists haven’t yet unraveled the different strategies cells use to control it. Part of the reason for this is the sheer number of proteins involved in AS (hundreds), and part of it is a lack of understanding of the nuts and bolts of the proteins that do the managing. This paper focuses on the nuts and bolts stuff. Previous work2 done in our lab has shown that a protein known as PSF manipulates AS to produce an alternate version of a different protein, CD45, critical for T cell response to antigens (bits of bacteria or viruses). PSF doesn’t do this, however, when a third protein, TRAP150, binds it, although we previously didn’t know why. This prompted us to ask two major questions: How do PSF and TRAP150 link up with one another, and how does TRAP150 change PSF’s function?

My research, as detailed in this NAR paper, answers these questions using the tools of biochemistry and molecular biology. In short, we found that TRAP150 actually prevents PSF from doing its job by binding in the same place RNA does. This makes intuitive sense: PSF can’t influence splicing of targets it can’t actually make contact with, and it can't contact them if TRAP150 is gumming up the works. To make this conclusion, we diced PSF and TRAP150 up into smaller pieces to see which parts fit together, and we also looked for which part of PSF binds RNA. These experiments helped us pinpoint all of the action in one region of PSF known as the RNA recognition motifs (RRMs), specifically RRM2. Finally, we wanted to know if PSF and TRAP150 regulate other RNA molecules in T cells, so we did a screen (the specific technique is called “RASL-Seq,” but that’s not critical to understanding the outcome) and found almost 40 other RNA molecules that appear to be controlled by this duo. In summary, we now know how TRAP150 acts to change PSF’s activity, and we have shown this interaction to be critical for regulating a bunch of RNAs in T cells.

So what are the implications of this research? For one, we now know that PSF and TRAP150 regulate the splicing of a range of RNAs in T cells, something noteworthy for researchers interested in AS or how T cells work. Second, we describe a mechanism for regulating proteins that might be applicable to some of those other hundreds of proteins responsible for regulating AS, too. Finally, PSF does a lot more than just mange AS in the cell. It actually seems to have a role in almost every step of the DNA-RNA-protein pathway. By isolating the part of PSF targeted by TRAP150, we can hypothesize about what PSF might do when TRAP150 binds it based on what other sections of the protein remain “uncovered.” It will take more experiments to figure it all out, but our data provide good clues for researchers who want to know more about all the things PSF does.

A map of the PSF protein. Figure adapted from Yarosh et al., WIREs RNA 2015, 6: 351-367. doi: 10.1002/wrna.1280

Papers cited:

1.) Christopher A. Yarosh; Iulia Tapescu; Matthew G. Thompson; Jinsong Qiu; Michael J. Mallory; Xiang-Dong Fu; Kristen W. Lynch. TRAP150 interacts with the RNA-binding domain of PSF and antagonizes splicing of numerous PSF-target genes in T cells. Nucleic Acids Research 2015;

doi: 10.1093/nar/gkv816

2.) Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell 2010,40:126–137.

Welcome!

Welcome to the Penn Science Policy Group.  We are a group of scientists interested in the relationship between science and public policy, examining how both domains affect each other to shape our society.  

Our mission is:

1) To educate scientists about the process of science policy, namely how research and public policy can inform and guide each other.

2) To advocate for research and improve communication of science to the public.

3) To provide resources and training for scientists interested in developing a career in science policy.


We achieve these goals by discussing current issues in interactive monthly meetings, receiving career information from speakers and info sessions, and refining relevant skills through written and oral public communication.  

Whether you are planning a science policy career, or simply looking to stay abreast with important issues, we are here to help you learn about and navigate the field of science policy. 

For more information, please email penn.science.policy@gmail.com.

Thanks,
PSPG