Negotiation Strategies for Scientists II: Making the Counter Offer

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Source: http://www.someecards.com/users/profile/crazy4tzus

In this second installment of Negotiation Strategies for Scientists, we will feature advice provided at a FASEB Career Center session led by Dr. Debra Behrens of the University of California, Berkeley.

Question:

When you propose a counter offer, the employer’s main concern is…

  1. your experience/education level.
  2. salary equity within the organization.
  3. the market-value of your position.
  4. how much s/he wants you to say yes.
  5. whether you will need to relocate/commute a great distance.

 

Answer: C

It is important to know your market value!

When making a job offer, Dr. Behrens stated that employers consider all of the above options, but the position’s market value is the most important. Employers consider the internal salary structure of the organization, compensation for similar positions in the industry, and what the market will bear given the supply and demand for labor.

When the dreamed-for job offer arrives, how do you go about making your counter offer? First, ask if this is a firm offer and for an email or fax of the terms. Then, ask for a time frame for your reply. This typically ranges from a few days to a week, which underscores the importance of doing your research early. You can also ask if the position is negotiable. While most employers expect you to negotiate, it may make you feel more confident to know for certain that a counter offer is acceptable.

Your counter offer is typically made over the phone, or if you are lucky, in person. Use email as a last resort, as this form of communication does not allow you to capture the emotional context of the speaker or allow for immediate clarification. Talk to your future colleagues about what is negotiable and what you should be asking for, and select one or two key issues to negotiate before calling. Leverage those requests by reminding your prospective employer of your strengths and how you can meet needs within the organization or department. Dr. Behrens encouraged maintaining a win-win perspective in which together, you and the employer approach the job offer as a problem solving process. If you have developed a rapport with your potential employer, working together toward the same objective of fair compensation will facilitate the process.

Dr. Behrens advised job seekers to anticipate the challenges that may occur in response to their counter offer and outlined the steps of win-win negotiation, also known as interest-based negotiation, as outlined by Fisher & Ury in the book, “Getting to Yes.

  1. Separate the people from the problem. Do not take disagreements as personal attacks. Focus on the facts, not the emotions associated with them. You can handle people problems by identifying different perceptions and looking at the issue from the other party’s side. Acknowledging the emotions of the other party and trying to be understanding of their feelings can do a lot to develop trust. Establishing clear communication and a common understanding of the facts at hand are also key to separating people from the problem.
  2. Focus on interests, not positions. In other words, identify the interests, needs, and concerns of the other party rather than viewing them as an adversary. When you come to a conflict, you can then work together to find a solution rather than digging in to your position.
  3. Generate many options. Brainstorm possible compromises with which you could be satisfied, so that you have options if your first suggestion is not feasible.
  4. Use objective standards. If asking for a higher than typical salary for your position, establish with your prospective employer the circumstances in which they could meet your counter offer.

At an Impasse

If your counter offer is not positively received, Dr. Behrens gave the following tips. Clarify the facts of the situation, issues at hand, and the players affecting the decision-making process. Explore and generate options using the possibilities that you brainstormed earlier. When searching for options, move to the positive with the other party by asking questions to better understand why certain terms of the counter offer cannot be met, and under what circumstances they could be achieved. Remember to be enthusiastic, polite, and professional during the process. The world of scientific research can be quite small, and you never know the interactions you may have in the future.

Dr. Behrens provided examples of common mistakes she has observed in people negotiating job offers. One is accepting the offer too quickly, without taking the necessary time to digest the terms of the offer and determine whether it is appropriate for you. Another frequent mistake is not knowing what you want in an offer. If you have not taken the time to establish what is important to you for your research productivity and quality of life, how are you to know if the job offer will set you up for success? Similarly, not preparing adequately for the negotiation is another common error. For example, if you have been observant during your interview and identified the needs of the department or organization, you can use that knowledge during the negotiation process. In Dr. Behrens’ perspective, preparation for the offer negotiation requires just as much attention as the job search itself.

 Remember that your prospective employer may not have the authorization to grant your request and may need to communicate with upper level administrators. Once you have agreed on terms, make sure that the new offer is documented. Cover your bases by reviewing any verbal agreements that were not on the printed offer in an email to the employer with a summary of the negotiations. That way your terms have been documented, since not all departmental and division level items are written in the offer letter. Finally, remember that it is not real until it’s in writing on letterhead.

Dr. Behrens likened learning to negotiate to ice-skating. You you fall down a lot at first, but once you learn it appears easy. With these tips in mind, don’t be afraid to ask for what you need. I like the advice given in Nora Roberts’ book, Tears of the Moon:

“Girl, if you don’t go after what you want, you’ll never have it. If you don’t ask, the answer’s always no. If you don’t step forward, you’re always in the same place.”

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Negotiation strategies for scientists: Preparing your counter offer

You finally did it! You got an interview for the job of your dreams. For years you have been working for this- first, persevering through five years of graduate school while your friends were beginning their careers and making money; then another five years of postdoctoral fellowships where you were not quite a student, but not faculty either.

The interview goes well, and you think this might be it. The chair of the department offers you the position, along with a salary amount, and asks if you think it is adequate. It’s much more than you made as a postdoc, but it’s difficult to know your own self-worth. You may be applying for a position outside of academia or in a slightly different field. In addition, you have been a trainee for such an extended period of your life that it is difficult to toot your own horn. Should you make a counter offer? And if so, how?

Negotiation skills are important for science careers, yet few scientists are trained to in this area. Further, women are less likely to negotiate than men, and receive lower salaries. According to a study at Carnegie Mellon University of graduating masters’ candidate salary offers, men were more likely to negotiate than women. The salary offers for men were 7.6% higher than for women.

At the FASEB Career Center on Saturday, Dr. Debra Behrens gave two sessions on Negotiation Strategies for Scientists. Dr. Behrens, a PhD counselor at the University of California, Berkeley, provided key strategies to determine the appropriate salary for your position and how to leverage your strengths to negotiate for your needs.

Learning to negotiate well has benefits beyond establishing a salary. Preparing to negotiate allows you to evaluate yourself: your financial needs, what you require for professional productivity, and the strengths and abilities that you can provide for the employer. This won’t be the only time you will need negotiation skills in life, so it pays to prepare for the first position. In addition, future salaries are often based on your previous pay.

Dr. Behrens outlined 5 strategies for effective negotiation.

  1. Preparation

Research the position and its typical salary range. For academic positions, you can visit The Chronicle for Higher Education and search by discipline and position for average salaries. AAUP, ACS, Association of American Medical Colleges, and The Scientist also provide salary information. At public institutions, it is a requirement that faculty salaries are made freely available, and can be found on the institution’s website. If you are currently affiliated with a university, you may be able to access their subscription to Vault, a career information website which contains employee surveys and career guides to individual industries.

Salary surveys, as well as federal research are available for private industry positions. Professional organizations are also a good resource for salary information in industry. When searching for salary information, make sure to factor in the region where the position is located, as cost of living will vary across the country.

It is often thought that negotiating your salary is not possible for jobs in the government and public sector. While the salaries for these positions are not as flexible, they may be more negotiable that you would think, as there are differences among agencies. Dr. Behrens shared a pro tip for career advancement in government: when considering your place in career grade and step, it is better to begin at the bottom of the pay grade. Even if the positions are similar in pay, there is more possibility for advancement by increasing your steps within a pay grade than to level up from on pay grade to the next.

During the interview, you may be asked what you would expect for a salary before you have actually been offered the job. It is in your best interest to wait to answer this type of question until you have an actual offer, when you have the most power. If you accept a salary offer during the interview, it locks you in early before you have a full understanding of what you can leverage during the negotiation process.

If they ask you during the interview what you would expect for salary before stating an offer, it is to your best advantage to wait until you have an actual offer. You could respond by saying, “At this point, I’m focused on learning more about the position and telling you about what I have to offer first before discussing salary.”

  1. Effective listening

During your interview, be observant for cues about the needs of the department or company. Consider how you can fill those gaps and use that knowledge as a leveraging tool during the negotiation period. In addition, pay attention to facial cues during your interview. If someone looks confused, it is better to stop and ask if you need to elaborate than run the risk that your future employers do not know your strengths and what you require from them for success.

  1. Big picture perspective

It is important to create a list of the must-haves and deal breakers when negotiating a job offer. However, it is also just as critical to keep the grand scheme of things in mind. What are the things you are willing to concede in order to achieve a higher goal? Dr. Behrens cited a concept called “firm flexibility” in which you remain firm about your goals, but flexible about the way you achieve them (Fisher & Ury, Getting to Yes 1991).

  1. Interactive exchange

Treat the job negotiation as an interactive, not a static exchange. In other words, it’s a lot of give and take. First, developing a rapport with your employer during the interview will build trust that you can utilize during the negotiation process. Second, it’s ok to ask questions such as, “What would it take to resolve X?” “Would it be feasible to do Y?” or “Under what circumstances might you consider Z?” By keeping the exchange interactive, you are able to gain key insight into the rationale behind your job offer and what accommodations are actually possible. Other valuable questions include, “What issues do you foresee with this request?” and, “What might be other ways we could go about this?”

  1. Win-win outcome

Finally, focus on a win-win outcome. Both sides of a job offer have the same objective of fair compensation. Indicate how fulfilling your needs will benefit the organization, making it easy for them to say yes. If you have received a job offer, the employer really does want you. As in the movie Jerry Maguire, your employer is really saying, “Help me help you,” though hopefully without all the melodrama and sweating.

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Source: http://imgur.com/XEN9a7x

When negotiating a job offer, you have more power than you likely ever will with the organization. Knowing that, remember that employers expect you to negotiate. Finally, know that there is more to negotiate than salary. You can negotiate things such as housing benefits, course release, the size and location of your lab space, and many more items listed below that contribute to your quality of life.

Money isn’t the only issue

  • availability of dual career programs (check out Stanford’s website on dual career programs).
  • housing benefits for new faculty
  • moving expenses
  • sabbaticals/vacation
  • tuition reimbursement
  • summer research stipends
  • intellectual property/patent rights
  • teaching load/ course buy out
  • use of teaching assistants/readers/graders
  • advising, theses and committee work
  • work schedule
  • telecommuting
  • on-site childcare
  • parking
  • start up package
  • size and location of office/lab space
  • lab equipment
  • computing/software
  • research assistants
  • conference and travel funds
  • intramural research funds
  • grant-writing support
  • journal subscriptions/books

In part two of Negotiation Strategies for Scientists, we will learn how to make the counter offer and how to navigate an impasse in the negotiation.

 

 

 

 

 

 

 

Investigating the links between alcoholism, impulsivity, and neurogenesis

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A model of impulsivity in humans. http://xkcd.com/1466/ 

Impulsivity is defined as behavior performed with little or insufficient forethought. Another more technical description is disinhibition of reward-driven behavior that is not appropriate for the current demands. Impulsivity has strong correlations with substance abuse, including alcohol addiction. People with impulsive behavior may be more at risk for addiction, and degeneration due to chronic alcohol abuse can increase impulsivity, progressing severity of the disorder. Understanding the connection between impulsivity and addiction may lead to better treatments for substance abuse. However, their relationship is relatively unknown. In this post, we will follow the work of two scientists who demonstrate the persistence and curiosity required for biomedical discoveries.

Scientists can recreate alcohol addiction using transgenic mice. These mice lack a particular transporter known to function in alcohol consumption called ENT1, or equilibrative nucleoside transporter 1. After drinking alcohol, this transporter is inhibited. Mice without this transporter protein are less affected by alcohol and tend to consume more than normal mice, mimicking alcohol addiction in humans.

Normally, ENT1 transports adenosine, a neuromodulator that has an inhibitory effect on the central nervous system. When ENT1 can’t transport adenosine, it is unable to regulate excitation in the brain and tell it to “slow down.” In other words, alcohol keeps the foot off the brakes, possibly promoting impulsivity.

Alfredo Oliveros is a Mayo Graduate School PhD candidate in the lab of Dr. Doo-Sup Choi at the Mayo Clinic College of Medicine. He is using these transgenic ENT1 negative mice to discover exactly how alcohol addiction alters adenosine levels in order to cause impulsive behavior.

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So, how do you measure impulsivity? A famous example of impulsivity in humans is the marshmallow test. In this test, children are told they could have one marshmallow now, or wait and receive more marshmallows later. The more impulsive kids are unable to wait for more marshmallows, and instead eat the one and receive instant gratification.

Oliveros translated the marshmallow test for mice to test their impulsivity. Mice were trained to get food from a receptacle only when a special sound-cue is played. However, if they were impulsive (i.e. were unable to wait for the next sound-cue) and checked the receptacle, their next opportunity for the reward was delayed. Impulsive mice would check the food receptacle frequently, while less impulsive mice were able to wait. He also used a test, which differed in that the reward was only provided when a certain pattern of lights was illuminated, adding a cognitive aspect to the test.

Oliveros found that the alcohol preferring ENT1-negative mice were more impulsive than normal mice and checked the food receptacle frequently. Since ENT1 transports adenosine, he then studied the involvement of adenosine as the next step between alcoholism and impulsivity. To promote impulsive behavior, adenosine binds to a particular receptor on neurons involved in inhibitory behavioral control. Oliveros used a drug to antagonize that receptor, blocking any downstream effects. Once again, he saw that impulsivity was increased, suggesting that adenosine is the brake that controls impulsivity.

If ENT1 regulated adenosine levels to promote addiction and impulsivity, what did adenosine regulate? You can see that scientists are never content with one answer. They are always asking, “why,” tunneling further and further toward the truth. Oliveros and Choi knew that the adenosine receptor activated a protein called ERK. Was ERK also responsible for enhanced impulsiveness in alcoholism? To test this question, the scientists used a drug to inactivate ERK and examined the mice for impulsive behavior. Sure enough, mice with inactive ERK demonstrated more impulsivity.

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ERK plays many roles in the brain, one of which is cell proliferation. Normally, brain cells do not divide. However, it has been discovered that neurogenesis, or the creation of new neurons in the brain, does occur. The function of neurogenesis is still unclear, though current studies implicate neurogenesis with learning and memory. Could modulation of impulsivity be a novel function of neurogenesis via ERK?

Interestingly, neurogenesis was reduced in the ENT1 negative mice that displayed alcoholic and impulsive behavior. It appears that alcohol addiction promotes impulsivity by inhibition of adenosine, which inactivates ERK. ERK caused a reduction in neurogenesis, suggesting a new role for neurogenesis in alcohol addiction and impulsivity. How do altered levels of neurogenesis cause these behaviors? The questions continue, and Oliveros and Choi will continue to follow the trail.

By mapping out the connections between addiction, impulsivity, and neurogenesis, Oliveros and Choi provide potential targets for therapeutics to treat alcohol addiction. Scientists such as these who persist, continuing to ask “why,” are the key to future drug discoveries and improved lives.

 

References

Choi, D.S., et al. (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nature Neuroscience. 7: 855.

Nam, H.W., et al. (2013) Adenosine Transporter ENT1 Regulates the Acquisition of Goal-Directed Behavior and Ethanol Drinking Through A2A Receptor in the Dorsomedial Striatum. Journal of Neuroscience. 33: 4329.

Verdejo-García, A., et al. (2008) Impulsivity as a vulnerability marker for substance-use disorders: Review of findings from high-risk research, problem gamblers and genetic association studies. Neuroscience and Biobehavioral Reviews. 32: 777.

 

Glycoprotein-130 and Chitosan-Coated Nanoparticles: Two Keys to Bladder Cancer Treatment

Studies show that glycoprotein-130 may hold the key to bladder cancer treatment. Inhibition of this IL-6 cytokine receptor can reduce bladder cancer cell proliferation and tumor volume in mice, as shown in a study performed by Dr. Darryl Martin, an Associate Research Scientist working with Dr. Robert Weiss at Yale University in the Department of Urology.

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Darryl T. Martin, courtesy of http://medicine.yale.edu/about/profiles/darryl_martin-1.profile

In the search for bladder cancer targets, the Weiss lab found that the cytokine IL-6 was overexpressed in several bladder cancer cell lines. Unfortunately, inhibition of IL-6 expression did not alter cancer cell proliferation–but the scientists were not discouraged.  The IL-6 receptor is located at a central point between 3 important pathways involved in cancer regulation: JAK/STAT, PI3K/AKT and ERK/MAPK. Perhaps greater success would be found by studying the IL-6 receptor. Glycoprotein-130, or GP-130, is a critical component of the IL-6 receptor, important for activation of downstream targets stimulated by IL-6 binding.

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Courtesy of Tawara et al. (2011) Cancer Manag Res. E3: 177-89.

To begin, Martin evaluated GP-130 expression in human bladder cancer specimens by immunohistochemistry and found that levels of GP-130 protein were correlated to tumor grade. He also looked at GP-130 levels in cell lines derived from human bladder cancers. Cell lines from high grade tumors showed elevated GP-130, while a cell line from a low grade papillary tumor showed less protein as seen by Western blot.

Martin then began experiments knocking out GP-130 in vitro. siRNA for GP-130 caused a 60% decrease in cell viability and 50% reduced migration in the scratch assay. Crystal violet staining of cells showed a reduced number of cells. This showed promise for GP-130 as a target for bladder cancer treatment.

To explore the mechanism by which GP-130 regulates cell proliferation and viability, the effects of GP-130 knockdown on the PI3/STAT pathway were investigated. Western blots showed reduction of AKT by 20% and a 50% decrease in mTOR, suggesting that GP-130 indeed utilizes this pathway, but that others may be involved, as well.  ERK1/2 and other pathways are currently being explored.

In his final set of experiments, Martin evaluated the effectiveness of GP-130 inhibition in vivo. Heterotransplant tumors were formed by subcutaneous injection of UMUC3 bladder cancer cells in nude mice. Upon tumor formation, GP-130 siRNA encapsulated in chitosan-coated nanoparticles was injected into tumors. Martin and Weiss developed this delivery system in collaboration with Drs. W. Mark Saltzman and Jill Steinbach in the Department of Biomedical Engineering at Yale in an attempt to enhance the amount of siRNA delivered to the cancer site. By delivering siRNA within nanoparticles, its stability is increased, and lower doses are required. One issue with cancer treatments instilled in the bladder is that the drugs do not always penetrate the urothelial wall. The coating of chitosan, a mucoadhesive polysaccharide, allows greater penetration of this bladder permeability barrier.

When the tumors were observed following treatment, tumor volume was significantly decreased in the siRNA-treated mice compared to the control mice.  In addition, levels of the GP-130 protein were reduced, as well as those of the CK20 protein, a marker correlated with advanced tumor stage. The success of this experiment was a critical step for the advancement o f GP-130 as a bladder cancer target, as tests in animals are required before clinical trials may begin.

Future experiments will include injection of cancer cells into the bladder to create a model more similar to bladder cancer in humans. This would also allow Martin to evaluate the effectiveness of the chitosan nanoparticle to penetrate the urothelial wall, inhibit GP-130 expression, and tumor growth.

The anti-obesity drug Belviq® may be repurposed for treatment of cocaine abuse.

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Image courtesy of stockimages and David Castillo Dominici at FreeDigitalPhotos.net.

Belviq®, an anti-obesity drug that acts on serotonin receptors in the brain, shows signs of dampening the rewarding and reinforcing effects of cocaine in rhesus macaques. Dr. Gregory Collins of the University of Texas Science Center at San Antonio and the South Texas Veterans Health Care System San Antonio is working with Dr. Charles France to determine if this drug could be safely repurposed for the treatment of cocaine addiction.

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Dr. Gregory Collins, Courtesy of http://pharmacology.uthscsa.edu/facultyresearch/collinsg.asp

Belviq®, also known as lorcaserin, is an anti-obesity drug developed by Arena Pharmaceuticals that was approved by the FDA in 2013. It works by activating the serotonin receptor 5-HT2c in the brain hypothalamus to induce satiety. However, activation of the 5-HT2c receptor can also dampen dopaminergic neurotransmission, which has important implications for cocaine abuse. Cocaine leads to the increased release of dopamine in the brain, a neurotransmitter which activates the reward pathways of the brain. Drs. Collins, Lisa Gerak, and France are studying whether the activation of 5-HT2c receptors could counteract the increase in dopamine caused by cocaine, reducing the rewarding and reinforcing effects of the drug. “There have been a lot of preclinical studies looking at 2c receptor agonists and 2a receptor antagonists as phamacotherapies for cocaine abuse but since this one is actually in the clinic it should be pretty easy to repurpose it for a different indication if we can find effects in the lab,” stated Collins.

Drug repurposing, or the study of a drug currently used for one disease or condition for its use in other diseases, is a strategy which can speed the time it takes for a drug to travel from the lab to the clinic. By beginning with a drug which has already been proven safe for humans with one disease, the success rate is greatly increased for its use in another. The NIH National Center for Advancing Translational Sciences developed a program in 2012 to support drug repurposing, which can be read about here.

In order to repurpose lorcaserin, Collins needed to determine the effectiveness of the drug to reduce cocaine self-administration in animals, to confirm that the dose was still safe, and to determine that tolerance to lorcaserin didn’t develop. For his experiments, Collins used the rhesus macaque, a species of monkey with behavioral responses to cocaine very similar to that of humans.

In the first set of experiments, the possibility of negative behavioral effects was tested in monkeys. This allowed them to determine a safe and pharmacologically active range of lorcaserin doses. Importantly, they observed that lorcaserin treatment induced yawning in monkeys, a behavioral response that is characteristic of 5-HT2c activation, indicating that the scientists were maintaining receptor specificity with their treatment method.  They also evaluated the effects of lorcaserin on food-maintained responding, a test that was used to confirm that the changes in animal response to cocaine were actually due to the lorcaserin treatment, and not just a general disruption of the animals’ behavior. This test showed only modest changes in food-maintained responding, allowing Collins to proceed to testing the effects of lorcaserin against cocaine.

In the next phase of research, Collins and colleagues measured blood levels of lorcaserin in monkeys to determine the point at which lorcaserin is highest in the body following treatment. This information is important for identifying the appropriate pretreatment time to study the effects of lorcaserin against cocaine. In behavioral treatments, Collins was then able to treat the monkeys with cocaine at a point in which lorcaserin levels were highest.

Finally, the key experiment for lorcaserin was performed. Would treatment with the drug decrease the monkeys’ interest in cocaine? To determine this, Collins and colleagues used a cocaine self-administration assay in which the monkeys were trained to press a lever to self-inject cocaine. Normally, monkeys will respond at high rates to earn injections of cocaine. However, if the rewarding and reinforcing effects of the drug are reduced by lorcaserin, the monkeys should start to reduce this cocaine-taking behavior.

Amazingly, when the monkeys were pre-treated with lorcaserin, their preference for the lever delivering cocaine was significantly reduced. In fact, this effect was consistent over 14 days, suggesting that the monkeys did not develop a tolerance to lorcaserin. In addition, the effects of lorcaserin treatment were also observed with larger doses of cocaine, suggesting that the monkeys were unable to surmount the effects of lorcaserin by taking more cocaine.

This is excellent news for Dr. Collins and the France lab, suggesting great promise for lorcaserin in the treatment of cocaine abuse. As investigations of the anti-cocaine effects of lorcaserin move into human cocaine-abusers, Drs. Collins, Gerak, and France are now beginning to assess the effectiveness of lorcaserin against other stimulants of abuse such as methamphetamine.

To learn more about the France Lab, click here.

Reynold Spector Award in Clinical Pharmacology Lecture by Dr. Scott A. Waldman

Dr. Scott A. Waldman received the Reynold Spector Award in Clinical Pharmacology at this year’s national ASPET meeting at Experimental Biology. Dr. Waldman gave a presentation regarding his award-winning scientific achievements titled, “Bench-to-Bedside Translation in Clinical Pharmacology: From Knowledge Generation to Healthcare Delivery.” Dr. Waldman outlined the history of his research on the gastrointestinal receptor guanylyl cyclase C, or GCC, from the initial characterization of its overexpression in colorectal cancer to its use as a biomarker and therapeutic target for the disease.

Colorectal cancer is the 4th leading cause of cancer in the United States and the 2nd cause of cancer-related death. It is typically caused by the sequential accumulation of mutations that cause normal intestinal epithelial cells to transition to a hyperproliferative state, followed by the formation of adenoma and final progression to carcinoma.

Guanylyl cyclase C is a receptor localized to the intestine. The molecules which bind the GCC receptor include the hormones guanylin and uroguanylin. Interestingly, this receptor also mediates the symptoms of Traveler’s Diarrhea by binding to the enterotoxin released by harmful bacteria.

One theory behind the initiation of colorectal cancer is that of paracrine hormone insufficiency. The hormones guanylin and uroguanylin are the most commonly lost gene products in colorectal cancer. This reduction occurs during the early phases of cancer. When these hormones are lost, the receptor GCC is silenced. Studies have shown that loss of GCC results in an increased incidence of colorectal cancer in rodents, leading to its identification as a tumor suppressor. Therefore, Waldman hypothesized that hormonal replacement therapy could prevent the occurrence of colorectal cancer recurrence. By maintaining homeostatic levels of guanylin and uroguanylin, perhaps the silencing of the receptor could be avoided and carcinogenesis prevented. Fortuitously, since the GCC receptor is exposed to the lumen of the small intestine, hormone therapy can be delivered orally, making it amenable to clinical use. When tested in mice, hormone replacement therapy eliminated tumorigenesis. Currently, Dr. Waldman is collaborating with the NCI Division of Chemoprevention, Ironwood Pharmaceuticals, and the Mayo Clinic to test paracrine hormone replacement therapy in humans.

Dr. Waldman’s lab then investigated the use of GCC as a biomarker for colorectal cancer. GCC is only found in the small intestine and colorectum normally. However, they found that it can also be detected in colorectal cancer cells. Could GCC be used as a marker to test for colorectal cancer metastasis? Indeed, upon further research his lab proved that RT-PCR analysis of extraintestinal tissues can indicate the presence of metastatic cancer cells, as well as the harder to detect micrometastases. Dr. Waldman is also investigating the use of GCC as a biomarker to differentiate tumor stage and risk of recurrence. Currently, clinical trials are underway to determine whether chemotherapy, a treatment typically reserved for metastatic cancer, will be effective for patients who are not categorized with metastatic cancer by current staging guidelines, yet have extraintestinal sites of GCC-positive cells, indicating micrometastases.

The third area of research which Dr. Waldman has pursued is the development of GCC-based vaccines to prevent colorectal cancer recurrence. He hopes to direct the immune system to metastatic cells expressing GCC.  The mucosal and systemic systems have different lymphoid organs and separate effectors, providing a dual immune system with minimal cross talk. Waldman is taking advantage of this to immunize the systemic compartment against GCC-expressing cancer cells, without inducing a response in the mucosal compartment where GCC is normally localized. In fact, a vaccine containing GCC elicited antibody and killer T cell responses in mice, preventing metastatic tumor formation without creating or exacerbating inflammation. Currently, Dr. Waldman is testing a GCC-based vaccine in a Phase 1 trial of stage I and II colorectal cancer patients. So far, positive antibody and killer T-cell responses have been observed.

The advances in cancer research that Dr. Waldman has accomplished is the dream of many scientists. To discover the basic mechanisms of a disease and use that information to not only diagnose, but also treat the disease is a feat that few scientists ever accomplish, and Dr. Waldman is indeed worthy of the Reynold Spector Award in Clinical Pharmacology for his research. Throughout his presentation, Dr. Waldman also took the time to highlight scientists who have acted as mentors and friends, supporting him throughout his career. “I think it’s a rare opportunity that we get to thank our mentors in public,” Waldman said. “These are the people that set our feet on the path for our careers and shaped us… For me these are the people on whose shoulders I’m standing, trying to catch a brief glimpse of the horizon in the distance.”

During his doctoral training at Thomas Jefferson University, Dr. Waldman worked in the lab of Dr. Ken Chepenik.  “He is the one that instilled in me a love of science and research,” said Waldman. He also expressed appreciation for the friendship he has maintained with Dr. Chepenik through the years. “While he taught me many things scientifically, the more important gift that he gave me was his enduring friendship.”

In 1979, Dr. Waldman began a postdoctoral fellowship in the lab of Ferid Murad, co-winner of the 1998 Nobel Prize in Physiology or Medicine. “He taught me how to do big science,” stated Waldman. “The most important thing that he taught me was actually a passion for translational research. He is the quintessential physician-investigator. Every day it was, ‘What are we going to discover today that we can translate to better manage a patient tomorrow?’” In addition to the science he taught Waldman, their families have remained close friends for 35 years.

Dr. Waldman also thanked his colleague Dr. Andre Terzic, whom he met as a junior faculty member at Thomas Jefferson University. Waldman expressed gratitude for several lessons in personal and professional development. “There’s no ‘I’ in team,” said Waldman of advice gained from Dr. Terzic. “When you are working on something, you are doing it for the betterment of the institution and organization, not for the betterment of the individual. In every interaction, always take the high road, and I’ve tried to do this throughout my career.” Waldman and Terzic have produced a textbook together in basic and clinical pharmacology, and have been the co-editors of Clinical Pharmacology and Therapeutics for ten years. “While scientifically and professionally he’s given me a lot, more importantly he’s given me his friendship, which is of paramount importance,” said Waldman.

Lastly, but most importantly, Dr. Waldman credited his success to his loving family. “All the mentors and all the science is great, but at the end of the day there’s got to be something that inspires you. My inspiration, the thing that gets me up every day, is my family,” said Waldman. “Of all the things that I’ve ever done, of all the cool science that I’ve done and the projects that I’ve been a part of and the people who I’ve met, it’s all wonderful, but truly my family is probably the most important thing I’ll ever do in my life.”

The Reynold Spector Award in Clinical Pharmacology was established in 2014 by ASPET in recognition of Dr. Spector’s dedication and contributions to clinical pharmacology. The award recognizes excellence in research and/or teaching in clinical pharmacology. This award is made possible by an endowment to ASPET from Dr. Reynold and Mrs. Michiko Spector.

Is Optogenetics Too Good to Be True?

Optogenetic Light Alters Gene Expression in Wild-type Microglia

New research indicates that the use of optogenetic light for cell-selective control may have effects on surrounding cells, an important consideration for the use of this recently popularized neuroscience technique. Kevin Cheng, a graduate student in the lab of Dr. Jyoti Watters at the University of Wisconsin-Madison discovered this phenomenon while performing research with microglia.

For those unfamiliar with optogenetics, this technique utilizes the ability of light-responsive proteins to control cells. By targeting these transporters to certain cells, scientists can activate cells of their choosing by exposure to blue and other wavelengths of light. This also allows cells to be turned on and off at the researcher’s choosing. This technique was originally used to excite or inhibit neurons, though it has now expanded to various cell types and can also be used to control other functions of the cell such as GPCR activity.

To learn more about the basics of optogenetics and why it is so cool, check out this clip by Nature Video

Originally, Cheng was trying to transduce microglia cells with the construct for the light-responsive protein. They expected that optogenetic light would alter gene expression in the optogenetic protein-containing cells without effects on the wild-type cells lacking the light-responsive transporter. However, what they found was very different. When exposed to the light, control microglia lacking the light-responsive protein showed changes in gene expression. “The first time that I brought this to our weekly lab meeting, they laughed. Do you think it is possible that this is happening?” asked Cheng. “And they said no, it’s not.” After rigorous experimentation, Cheng was able to prove to his labmates that indeed, there were side effects of optogenetic exposure in normal cells.

To prove his hypothesis, Cheng utilized a black-walled 96-well plate aligned with an LED array. This setup allows for control of light duration and intensity in each well. Microglia were grown on the plate, then exposed to blue light at 450 nm, a common wavelength used for optogenetic experiments. Following exposure, pro-inflammatory gene expression was determined by quantitative RT-PCR.

Since the inflammatory response within the central nervous system is mediated by activated microglia, Cheng compared gene expression in both basal and LPS-activated microglia. He also evaluated the difference between a single bolus of light and a light pattern commonly used in optogenetics.

Of the pro-inflammatory genes measured, COX-2 expression was induced in basal cells exposed to both bolus and optogenetic light patterns. In LPS-activated cells, the genes IL-1b, iNOS, COX-2, IL-10, IL-6, and VEGF were decreased and IGF-1 was increased after bolus light exposure. Further, IL-1b, iNOS, COX-2, and IL-10 also exhibited decreases in gene expression following light with LPS activation. To make sure the energy dose delivered was not harmful to the cells Cheng also measured the potential for blue light to induce cell death and DNA damage in microglia, and found no effect. This suggests that wild-type microglia respond to blue light and that it may exert a surprisingly anti-inflammatory effect.It also demonstrates that optogenetic patterened light exposure can have effects on wild-type cells near the cells of interest.

To date, this is the first report of non-specific effects of optogenetic light. This study has important implications on the field of optogenetics, a technique which has named “Method of the Year” in 2010 by Nature Methods. Cheng plans to expand his experiments to include other cell types and to explore the mechanism behind this unexpected phenomenon.

For the abstract of this work, visit here.

To learn more about research in the Watters Lab, click here.