Thought Experiments – Genetics and Synthetic Biology, A Report

Image from the Infinity Box Theater

FOSEP members and other guests had a great time at the Thought Experiments with Infinity Box Theater. The four plays were:

• Editors by Holly Arsenault, directed by Susanna Burney
• Frivolous Natura by Kelly Mak, directed by Roy Arauz
• Anomie by Courtney Meaker, directed by Teresa Thuman
• Solace by Bryan Willis,  directed by Tyrone Brown

After the play, there was a lively discussion, followed by a Happy Hour and conversation at Schultzy’s Sausage. The plays touched on issues like whether it was better to intervene (scientifically and genetically) or let things develop “naturally” (using a metaphor of genetically engineered tomatoes that were efficient but didn’t taste good, and making and developing music); enhancement using genetic engineering and making / creating better people (which could result in “mistakes” for some people), security and biological hacking, and replacing bad genes using technologies like CRISPR in the near future to inject DNA into people (but only those who were more privileged).

In the discussions during the intermission with my seatmates and FOSEP members, I was pleased to see that not everyone in our group had the same interpretation of what we saw – we each layered our experience on top of what we saw.  I find I often want to know what something means *before* I attempt to interpret it, but that maybe I need to talk about how I respond to the art emotionally first. The purpose of the plays was for each of us to engage with the material in our own way – to have our own “thought experiments” with the material.

Why this may not be Dr. Lefkowitz's last Nobel Prize

Scientist Robert Lefkowitz, along with his former student Brian Kobilka, was awarded the 2012 Nobel Prize in Chemistry on Wednesday. His research pertaining to a family of receptors called G-Protein Coupled Receptors (GPCRs) lead to the award, but current work in Dr. Lefkowitz’s lab has the potential to change the way we think about medication even further.

Dr. Lefkowitz graduated from Columbia University with an M.D. degree in 1966. He is currently the James B. Duke Professor of Medicine at Duke University and has been a Howard Hughes Medical Investigator since 1976. In the 1980s, Dr. Lefkowitz’s laboratory was a major contributor to the cloning of several GPCRs, and this research lead to the discovery that all GPCRs have similar structure.

There are upwards of 800 known GPCRs in the human body, the largest family of receptors to date. GPCRs are proteins that loop back and forth across the membrane of a cell seven times. One tail of the receptor sticks out into the outside of the cell (extracellular space) and the other tail of the receptor is located inside of the cell (intracellular space). A multitude of chemical signals, such as hormones, taste molecules, and neurotransmitters, bind to and activate these types of receptors. These receptors are located throughout the body, from the brain to the heart to the reproductive organs. Importantly, about half of currently approved medications target these receptors, thus understanding how they work is crucial to future drug development.

With the help of Dr. Lefkowitz, we now understand that GPCRs and the molecules that bind them act as a sort of lock (GPCR) and key (molecule). When a molecule binds to the extracellular tail of a GPCR in the correct way (ie the key fits the lock), the GPCR will change shape in a way that affects the proteins that are already bound to the intracellular tail of the GPCR. The proteins bound to the intracellular tail are called G-proteins (hence the name G-Protein Coupled Receptor), and can become activated in response to the change in shape of the GPCR. Activated G-proteins can then un-attach from the intracellular tail and go on to activate additional downstream intracellular proteins, leading to a cascade of events inside the cell.

In addition to his work in the early 1980s on understanding how GPCRs work, Lefkowitz’s laboratory has also been seminal in the discovery that other proteins, besides the G-proteins, can interact with GPCRs and lead to downstream effects. The two main types of these proteins are G-protein coupled receptor kinases and beta-arrestins. There proteins were originally thought to regulate the trafficking and silencing of GPCRs, but more recently it has become appreciated that they can also act as signaling molecules themselves, similar to the actions of the activated G-proteins. Thus, when a molecule binds to a GPCR, it can activate multiple pathways (via the G-proteins and also via arrestin), or it can activate just a subset of pathways.

This type of signaling is now known as ‘ligand directed signaling’ or ‘biased agonism.’ In this type of signaling, the unbiased ligand (molecular key), usually the natural receptor ligand, activates multiple pathways via G-proteins and also via arrestins.  A biased ligand would then be a molecule that directs the signaling pathway in a specific direction via the activation of either the G-protein or the arrestin. Ligand directed signaling has gained appreciation for it’s potential to reduce the unwanted side effects of prescription drugs. Imagine you have a drug like morphine that produces pain relief but also has the unwanted side effects of tolerance and later dependence and subsequent addiction liability. Morphine works in the body by activating the mu opioid receptor (MOR), a GPCR. Now imagine that following MOR activation, one downstream pathway controls the pain relief and one pathway controls the tolerance and addiction liability. The potential to design a drug that activates just the pain relief pathway of the MOR receptor has huge implications for medicine.

Currently, many patients take prescription drugs to block or decrease the unwanted side effects of other prescription drugs. These drugs used to block side effects of other drugs may also have unwanted side effect, and on and on and on. This circular problem increases the number of prescriptions and the cost for patients around the world. There in lies the power of ligand directed signaling. If researchers can understand how to target only specific effects of receptor activation they can then better treat patients and decrease or even eliminate these unwanted side effects. Imagine a world where a patient can be treated for chronic pain without the risk of addiction to that pain medication.

Dr. Lefkowitz is only one of a multitude of researchers working on understanding ligand directed signaling, and only six Nobel laureates have received more than one prize, but with the multitude of posts and news articles discussing mainly his early work, I think it would be remiss not to discuss the groundbreaking work Lefkowitz and his team is currently conducting.

Go here for the Nobel Prize in Chemistry 2012 Information for the Public sheet. The information sheet contains a great write-up of the early work conducted by Dr. Lefkowitz and Dr. Kobilka.

Go here  for Dr. Lefkowitz’s most recent review regarding ligand directed signaling (warning, subscription required).

Go here for a recent scientific publication investigating ligand directed signaling at the mu opioid receptor.

Seattle Researchers Among NIH Tissue Chip Awardees

Researchers in Seattle, WA, lead by Dr. Jonathan Himmelfarb, have recently been awarded part of a $70 million research grant to develop 3 dimensional chips that mimic living organs such as the lung or heart. The Seattle group is among 17 such awards, and their project will focus on the kidney. A main goal of the research is to develop chips that mimic the function of an organ system so that they can be used for drug safety testing prior to preliminary testing in humans.

From the UW press release, “The NIH pointed to studies that show that more than 30 percent of promising medications have failed in human clinical trials because the drugs were found to be toxic, despite pre-clinical studies in animal models. Tissue chips may offer more accurate predictions of the side effects of potential therapeutic agents because they contain human cells.”

The Seattle project is titled, A tissue-engineered human kidney micro physiological system. From the NCATS website, ”There is a critical need to be able to model human organ systems, such as the kidney, to improve understanding of drug efficacy and safety, as well as toxicity, during drug development. The goal of this project is to develop a model system that predicts drug handling (especially drug excretion and kidney toxicity) in the human kidney, emulating healthy and disease-related conditions.” In addition, the 3-D chip may also prove useful for understanding how toxins and infections diseases produce kidney injury.

Dr. Jonathan Himmelfarb is a professor within University of Washington’s Department of Medicine, Division of Nephrology,  and is the director of the Kidney Research Institute.  The project will combine biology, engineering, and computer science. Interdisciplinary in nature, the research team will range from physicians and pharmacists, to bioengineers and computer programmers, and bring together multiple colleges and schools across the UW campus. For this project, the UW researchers will partner with the biotechnology start-up company Nortis.

The award is funded by the new National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health in a collaboration with the Defense Advanced Research Projects Agency and the U.S. Food and Drug Administration. 10 awards will focus of development of 3-D tissue chip systems that each represent a specific human organ system. 7 other awards will focus on developing a cellular source that can be used to populate these tissue chips. NCATS’s mission: “…to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions.”

UK scientists and government collaborating to eliminate maternal genetic mutations through new reproductive techniques

Recently in Britain, renewed talk of banned legislation regarding advances in an in vitro fertilization (IVF) technique has commenced. The controversial procedures would save children from inheriting certain genetic diseases but would also result in a child with three genetic parents and the destruction of a fertilized egg. The new IVF techniques obviously raise ethical and legal concerns, but should Britain pass this legislation they would be the first in the world to test these procedures in humans.

Mitochondrial DNA (mtDNA) is inherited from the mother and is the source of numerous devastating neuromuscular and neurodegenerative disease. Mutations in mtDNA passed on from mother to child are responsible for diseases such as muscular dystrophy, diabetes mellitus, deafness, and myoclonic epilepsy and affect around 1 in 5000 people. Now Britain has initiated steps towards clinical trials investigating a break through IVF technique that combines the nuclear DNA of the mother with mutation-free mtDNA from a donor egg.

UK’s Human Fertilization and Embryology Authority (HFEA) announced on January 19^th a public dialogue regarding this emerging IVF technique in order to gauge public opinion of the possible use in a clinical setting. The Secretary of State of Health together with the Secretary of State of Business, Innovation, and Skills jointly asked HEFA to form this task force, a necessary first step to bringing this potentially life-saving technique to clinical trials. The public dialogue will begin later this year and be guided and overseen by a panel of experts. Additionally, the biomedical charity Welcome Trust has promised funds for preclinical safety experiments and the Nutffield Council on Bioethics has started an independent review. Here seems to be a perfect case where scientists, government, and policy experts are working together instead of just talking past or at each other.

There are two procedures currently under development: pronuclear transfer and maternal spindle transfer. In the first an egg with mutated mtDNA is fertilized in vitro, then the resulting pronucelus is removed and transferred to a donor egg that has had its pronucleus removed. The second technique involves chromosomes (DNA) taken from an unfertilized egg with mutated mtDNA being added to an unfertilized donor egg lacking a nucleus, then fertilization occurs in vitro. Pronuclear transfer has been successfully preformed on defective human eggs and maternal spindle transfer has been used to produce two healthy rhesus monkeys. Additionally, HEFA released a review in early 2011 finding the techniques not unsafe, although they did determine numerous additional studies would be required prior to beginning clinical trials.

These proposed IVF techniques, techniques that would produce children with three genetic parents, raise many important legal and ethical questions and issues. In the US federal funds cannot be used for research involving human embryos. Additionally, these procedures were banned by the British government in 2008 for safety, ethical, and research related reasons. But importantly, legislation was also put in place for a streamlined mechanism to legalize the techniques should scientific advances be made.  Now, based on recent technical advances the British government has decided to take another look at the legislative ban. Chair of HFEA, Lisa Jardine, said in a recent press release, “This is an issue of great importance to families affected by mitochondria disease and it is also one of enormous public interest. The decision about whether this research technique should be made available to treat patients is one for the Secretary of State and, ultimately, Parliament. We will work hard to stimulate a rich and varied public debate, to help him make an informed decision.”

FOSEP partners with the Center for Biological Futures

Yesterday, UW Today highlighted the new UW initiative Biological Futures in a Globalized World. This initiative, hosted by the UW Simpson Center and working in collaboration with Dr. Roger Brent and the Center for Biological Futures at the Fred Hutchinson Cancer Research Center (FHCRC), strives to bring together scientists and humanists to discuss the ethics surrounding biological futures.  The collaboration hopes to bring ethics training to (e.g.) non-medical scientists through seminars, workshops, classes and colloquia- one of which was held on November 7^th in the Simpson Center.* The initiative will focus on ethical training by placing emphasis on “ethical obligations that certain scientists and engineers have … that are specific to the scientific enterprise.”

FOSEP has two events in the works in collaboration with this initiative and the Center for Biological Futures, including a discussion group scheduled for Wednesday, November 30^th at the Simpson Center (Communications 202/204) at 4:00pm. Dr. Brent will give a short presentation on the Center, and Dr. Alison Wyile will talk about the Biological Futures in a Globalized World Ethic Research Project, followed by an informal discussion. If you are interested in enhancing your science ethics training, want to hear more about the CBF and its mission and/or would like to learn more about what “biological futures” entails, stop by! All FOSEP members are welcome.

*The third CBF/Simpson Center colloquium will take place on January 9th at the Simpson Center.

To read the entire UW Today article (written by Nancy Wick), click here: “Biological futures initiative aims to bring larger ethical issues into non-medical science”

Two Big Court Rulings Last Week

I’m a little slow getting around to this, but just got back from vacation and while catching up on news saw there were two court rulings last week in cases I’ve been interested in. First, last Wednesday in a district court Judge Royce Lamberth ruled against two scientists who had filed a lawsuit to prevent federal funding of embryonic stem cell research. Then on Friday an appeals court reversed an earlier ruling and upheld a patent Myriad Genetics had involving the BRCA gene sequence as a test for breast cancer risk. Despite some of the headlines I’ve been seeing there’s a bit a nuance in this ruling that will be interesting to see how it is followed up.

Blurring Lines of Genetic Modification

One comment I’ve heard frequently in discussions about transgenic plants is how the description “genetically modified” is a misnomer given how much we’ve modified the genetics through traditional breeding. Some proposed changes to how the EPA may regulate the use of this technology serve as a good example of how the distinction between old and new methods of modification may not be that important.

These proposed changes would relax the restrictions on some classes of crops that have been modified. One group called “cisgenic” modification would involve the transfer of gene between plants that can naturally interbreed. The example that introduced this concept was the American chestnut which is sensitive to a blight, while the related Chinese chestnut has developed resistance. It may be possible to cross these two plants to provide resistance in the American plants, but this would involve all the messiness of trying to get the right chromosomes into the new plants and hoping other undesirable traits don’t come along for the ride. On the other hand if we knew exactly which genes are responsible we could isolate them and transfer the genes, without having to worry about other genes interacting in unwanted or unexpected ways. According to the article, Charles Maynard and his group at the State University of New York is possibly close to identifying the genes responsible, getting us closer to being able to use the technology in such a way.

Alternatively, intragenic (inside the gene) modifications can be done that remove parts of DNA to change expression of traits, but wouldn’t need to have any new DNA being inserted.

However modifying the DNA in a lab instead of the field by crosses would mean these crops would have to go through the additional regulatory processes as transgenic organisms that have foreign DNA inserted into the genome. The proposed changes would allow cisgenic and possibly intragenic modification to bypass some of the requirements that transgenic crops have to go through. Not too surprisingly this has met resistance from those who think these kinds of plants should be more regulated rather than less. But it has also been opposed by people in support transgenic crops who think the change would create an artificial distinction based on the source of a gene, which really says very little about any actual effects of the changes that have been made. That this is an issue is a good demonstration of how the current regulatory system seems more focused on technology being used rather than actual properties of these plants.

Saturday Morning at AAAS – Privacy and Personal Medicine

I’m slowly working my way through posting about the AAAS conference, finally made it to the second day.  While my title would probably make for a good topic itself, this is actually two separate panels I made it to last Saturday morning.

The day started off with the panel titled “Balancing Security and Privacy”, which I’ll end up going through in the reverse order of their presentations. I think the final speaker Bruce Schneier made a good point by saying it’s a false dichotomy with plenty of security protocols that don’t involve sacrificing privacy, using the example of a lock being a lot more effective than having a guard asking for the ID of anyone trying to enter a room. Similarly he pointed out the most effective significant changes to air travel since 9/11 were locking cockpits and the change in mindset where passangers will fight back – two things that have nothing to do with the additional searches and identification we have to go through. The other main theme Schneir made was how many people have a poor sense of how much privacy they are keeping, given that our way of thinking about social interactions developed in a more limited context, and new technology has let us share info with large numbers of people very quickly.

The second speaker, Jeremy Pitt dealt more with balancing privacy and utility rather than privacy and security. He went over a variety of different technology that is being developed that can have benefits, but would also cost us the ability to give up information. He also warned about how most of this technology requires us to trust it is being used in the way we’re told. While we may be protected in some ways, it’s also in the interest of many companies to get us to reveal as much as possible.

The first speaker was Stephen Lechner who was there to provide a European perspective on privacy, and quickly made a convincing case that there is less a “European” perspective than each country having different views on what is important to think about privacy. Given the setup of the EU, even if there is an attempt to standardize rules it is up to each individual country to determine how to implement it. Lechner also had a good example of how protections of privacy may be implemented in theory but offer little actually benefit. This was a standardized form that people had to sign before getting a cell phone that was supposed to inform people of the way the company may be storing information. However this form merely referred to the relevant laws without even explaining what they were.

I went from that panel to  “Personalized Medicine: Moving Forward or Backward” which was more of a typical science talk than many of the other sessions I attended this year. It mainly focused on ways to personalize medicine other than the obvious genetic sequencing that is starting to become feasible. The first speaker was Susan Sumner from RTI International, who has been developing ways to look at persons metabolome – the small molecules that are produced in our bodies as part of our metabolism. Specifically she was looking at what markers may be associated with different states of health. One example was a study to look at how the biochemistry may differ in a two groups of obese adolescents with different ability to lose weight after attending a healthy weight camp. Another study she described was able to identify metabolites in pregnant women during the second trimester that seem correlated with a risk for premature birth.

The second speaker Karen Nelson from the J. Craig Venter Institute who dealt with similar ideas of looking for other indicators of disease states, but in this case by looking at what different microbes may be living inside our bodies. This was done with a similar approach that was previously done where the Venter Institute isolated DNA from ocean samples and used sequencing to identify what microbes where living in different environments. They found less than 1% of organisms were those that we have been able to culture but by sequencing the DNA from these samples they have found entire new classes of microbes. They have begun publishing the results of using the same technique to identify what microbes may be correlated with different health issues. For instance they have found a particular microbe that was associated in people with esophageal cancer, which may be useful to identify cancer in earlier stages. They have also seen another microbe that is missing in people with Crohn’s Disease, and could be administered as an alternative treatment to surgery.

The final talk of the morning was Willie May from the National Institute of Standards and Technology, where he has been involved with developing different standards when measuring samples such as in the previous talks. While it would be great to simple take some relatively easy to get sample and test for different components that may be associated with a health problem, this will only work if the tests can give reliable results. Right now this is difficult to do, one example Dr Mays described was testing for the amount of the protein troponin as a measure of a damage after a heart attack. Three kits made by different manufacturers gave results in a range over 20 fold difference. These issues with reproducibility are also important for the consistency of results from different labs that are sharing data to identify these kinds of markers. I think this last speaker was the most interesting one of the panel. While the others gave some insight into different things we may be able to look for, the nature of the AAAS audience meant they didn’t go into enough detail to really judge how useful these techniques are. On the other hand Dr. May gave some idea of where the limitations of this kind of technology are right now. As the moderator said in her introduction, the title of the panel was meant to refer to how we may have to step back first in order to make sure we’re using the right tools.

AAAS Friday – "GM Crop Regulations: Safety Net or Insurmountable Obstacle"

The panel on genetic food was another one I had to miss part of due to overlaps with other interesting ones; this time I came in just after Kate left. A major theme I got from the remaining speakers was that the current way of regulating GMO food is overly restrictive, and inappropriate for the relatively low risk scientific evidence would support.

This started with Roger Beachy from the USDA (I think, missed the name, but that was the name the person in the abstract with that affiliation which I did catch), who went through the process he has been involved with developing a strain of plums that are resistant to Plum Pox Virus (PPX) since 1990. This is accomplished by inserting a piece of DNA that will produce RNA complementary to the viral genome, turning off protein expression through RNAi. This process of protecting crops was also used to protect papyas in Hawaii, one of the few forms of genetic modification that has been deregulated so far. This mechanism was only recently identified however, which partially explains the slow progress in developing the PPX resistant plums. It has been cleared by Animal and Plant Health Inspection Service (APHIS) and the Food and Drug Administration, and is expected to be approved by the EPA soon. Dr. Beachy was especially critical of the EPA as being more difficult to work with than other agencies. One particular complaint was the fact that the current regulations require the EPA to regulate this modification as a Plant Incorporated Pesticide, despite the fact that no proteins are produced and it acts through silencing viral proteins instead. This requires a lot of additional studies to show safety that are clearly not applicable to this sort of protection from a virus.

The second speaker was Drew Kershon, who started by pointing out that he is lawyer rather than a scientist and would focus on policy. Despite this disclaimer he referred to scientific evidence pretty frequently, though it was accurate as far as I understand. He started by quoting a report form the National Academies written in 1987 that said there were “no unique risks” to GMOs compared to other forms of producing new strains of plants, and the science since then hasn’t changed the support for that view. He specifically looked for a report from Europe given the more precautionary stance over there, and quoted one saying there have been “very few unexpected results” from modified organisms, with most of the “unexpected results” referring to benefits from the crops protecting non-modified crops that were grown nearby. Mr. Kershon went on to say it could make sense to have a series of tiers with different levels of restriction with each form of modification being treated individually, since some modifications deserve more scrutiny than others. However most crops have ended up being left with the most restrictive regulations in place. He argued that this is not for science reasons, but based on market considerations, which go beyond the authority of agencies like the FDA and EPA to have a say over.

There was a fair bit of overlap between the final two speakers, Hector Quernada speaking about the challenges of developing transgenic crops by the public sector and Allen McHughen describing the difficulties in developing “orphan crops” that may be of limited economic value to a private company, but have significant benefits to particular areas. The overlap coming from these crops generally being developed by academics with public funding. Since this is the case, as taxpayers we have made a significant investment in developing this crops, but have gained little from this investment due to the difficulties in bringing them to users. Right now only three have been approved that didn’t have the backing of private companies. Dr. McHughen went over results from a recent paper looking at the areas that seemed plausible bottlenecks – technical problems, intellectual property issues, safety, and regulatory hurdles. Of these he’s found some minor difficulties with intellectual property, though usually there’s workarounds available. Instead the main problems have been in dealing with regulatory agencies. (Note I’m relying on my notes of McHugen’s description, not having time to read the original paper yet). One of the main problems public institutions have in getting approval is having the resources to go through the whole process. Dr. Quernada mentioned there is the the group Specialty Crop Regulatory Assistance that can help navigate this process.

AAAS Day 1 – Learning Research and Educational Practice

Here’s my first post of my first day at AAAS, with lots of interesting topics topics that probably deserve their own posts I’m going to have to split this up. A reminder if you want more current info about what I’m up to I’m updating our twitter account.

As tends to be the case here the first day started with a tough decision about which panels to try to attend. I started out with Learning Research and Educational Practice: How Can We Make Better Connections. This dealt with the basic research on learning and cognition feeds into the people who actually use that info for teaching, and how it feeds the other way back into basic research. This was the big theme that was the importance of the feedback loop illustrated by every talk using a cycle image at some point. Initially I came in expecting to see how educators are using basic science, but saw that basic science has as much to gain from learning how educators are using research.