Category Archives: Scientific Advances

Thought Experiments – Genetics and Synthetic Biology, A Report

Image from the Infinity Box Theater

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.

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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 19th 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 7th 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 30th 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. Continue reading

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.