Author Archives: David Jentsch

Of mice and mint: Animal research uncovers a previously unknown role for menthol in tobacco addiction

Cigarette addiction remains one of the common forms of drug addiction, worldwide; it is associated with remarkably elevated risk for heart disease, stroke and multiple types of cancer, explaining why nearly half a million Americans die each year from complications of smoking. A recent study by Brandon Henderson and his colleagues at the California Institute of Technology (Caltech) have revealed a startling new finding – that one of the most common flavorants added to some cigarettes may actually accelerate tobacco addiction. Dr. Henderson, now an Assistant Professor at Marshall University, answered some questions from Speaking of Research about his most recent discoveries.

 

What is menthol and why is it important to study its effects?

Menthol is the most popular flavor additive in tobacco products and the only non-banned flavor in traditional cigarettes (not e-cigarettes) sold in the US. Over time, reports have indicated that smokers of menthol cigarettes quit smoking at lower rates than those that smoke non-menthol cigarettes. Therefore, we are trying to identify the changes in the brain that occur with menthol that may indicate if menthol increases the addictive potential of nicotine (the primary addictive component in tobacco products). As an aside, menthol cigarettes are heavily used by African American smokers (75 – 90%). As a black scientist, this was another reason why I was attracted to studying menthol.

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Menthol is a naturally occurring chemical found in a number of plants, including mints

 

Can you give us a thumbnail sketch of your study and your findings?

Our goal was to examine well-known effects of nicotine on the brain and determine if they are enhanced by menthol. Two of the ‘well-known’ effects of nicotine are an increase in the number of nicotinic receptors (the proteins that bind nicotine) and an increase in the activity of neurons that release the neurotransmitter dopamine. These two events typically occur following long-term exposure (7 – 10 days) to nicotine, contributing directly to nicotine addiction.

Neuroscientists have known that nicotine, by itself, alters the brain to release more dopamine and that is one of the reasons why it is addictive. In this study, we focused on dopamine neurons of the ventral tegmental area, a part of the brain stem. The dopamine neurons that originate in this region are part of the mesolimbic dopamine system. This region is well-characterized for its importance in mediating the rewarding effects of drugs.

When we examined the combination of menthol with nicotine, we found that the combination increases the number of nicotinic receptors to a level that is significantly greater than is produced by nicotine alone. We also found that the combination of menthol and nicotine increased the activity of dopamine neurons to a degree that was significantly greater than what we observed with nicotine alone.

Since we observed that menthol promotes the pro-addictive effects of nicotine in the brain, we believe this may provide part of an answer to why smokers of menthol cigarettes have a much harder time quitting.

 

Mice were involved in your studies. In what ways are they similar and/or dissimilar from human smokers?

The mesolimbic dopamine system of mice is very similar to humans. Like humans, mice will self-administer (voluntarily consume) many drugs of abuse, including cocaine, opioids, and nicotine. Given that mice experience drug reward, similar to humans, they make an excellent model for studying addiction. Two experimental methods are commonly used in rodent models: intravenous self-administration and conditioned place preference, both of which reveal the degree to which nicotine is rewarding in the animal.

One hurdle associated with using mice to study drugs of abuse is that their bodies break down many drugs much more rapidly than humans. Therefore, proper dosing becomes a big concern so that our studies are relevant to humans. For nicotine, the guidelines for dosing were established long before I started science so this was a great benefit to my work with mice.

 

What are the medical or societal implications of your results?

Years ago, the FDA issued a request of information regarding menthol to determine if it should be banned similarly to other flavors that were banned following the Family Smoking Prevention and Tobacco Control Act (2009). This, and other scientific reports, will hopefully be examined by the FDA in determining the future regulations of menthol in cigarettes and e-cigarettes.

 

You just started a new lab as an Assistant Professor at Marshall University. Can you tell us about your future plans for your research and career?

I will continue to study menthol for a few more years because there is still much we need to understand. In the tristate area of Kentucky, West Virginia, and Ohio (where I am originally from), there is a large opioid addiction problem. Most opiate addicts (~80%) also are heavy smokers. I intend to begin studying how opioids and tobacco act together in the brain to promote addictive behaviors.

Henderson_Brandon_Marshall-headshot

Dr. Brian Henderson is an Assistant Professor in the Joan C. Edwards School of Medicine within Marshall University in Huntington, West Virginia

Dr. Brandon Henderson can be found on Twitter at @Dr_BHenderson and on the web at https://www.hendersonlab.org/

Camron Bryant: Triangulating the genes leading to binge eating

The following post is the first in a series of question and answer exchanges with biomedical researchers about recent high-impact neuroscience discoveries from their labs. Animal research will be central to many of these posts, with the goal being to explain the importance and implications of this research. We welcome suggestions for future posts, which can be emailed to jdavidjentsch@gmail.com

A recent article in the journal Biological Psychiatry reveals new information about the possible genetic factors that may lead to excessive overeating and its health consequences. The team was led by Dr. Camron Bryant, Assistant Professor of Pharmacology at the Boston University School of Medicine who has agreed to answer some questions about the group’s research and the significance of their exciting new findings.

Help us to understand what binge eating is and why it is important to study this behavior?

Binge eating is defined as the uncontrolled consumption of a large amount of food (typically high energy foods) over a very short time period. Key features include the lack of control over eating, i.e., the compulsion to start eating and difficulties with stopping. Also central to this behavior, in humans, is the feeling of guilt or remorse following a binge episode. Binge eating is a symptom that can be observed in patients with any one of the three main eating disorders, including Binge Eating Disorder, Bulimia Nervosa and (in some cases) Anorexia Nervosa. Binge eating is both a cause and consequence of disordered eating patterns and can be a component of a larger pattern of repeated cycles of bingeing followed by food restriction. It can lead to severe health complications, including weight gain, malnutrition (e.g., with cycles of food restriction), anxiety, and depression. A better understanding of the neurobiological basis of this key behavioral symptom could lead to treatments that normalize eating patterns and thus, improve outcomes for eating disorders, which are currently among the most lethal of all neuropsychiatric disorders.

Take us through your research. What did you do, and what did you discover?

We know that binge eating has a genetic component, based on decades of human research. However, the specific genes that influence it remain completely unknown. We utilized a large group of mice that exhibited differences in their eating behavior; using an unbiased approach, we mapped and validated a relationship between binge eating and the gene, Cyfip2 (cytoplasmic FMR1-interacting protein 2). We hope that this finding will facilitate the search for binge eating related genes in human, an effort that is currently limited in its power to detect statistically reliable results. We also found that the increased susceptibility to binge eating as a consequence of a mutation in Cyfip2 was associated with a binge-induced decrease in the expression of myelination genes in the white matter of the brain. This was an unexpected finding and suggests that promoting remyelination in the brain could represent a novel strategy to lessen binge-eating behavior.

Mouse

When intermittently offered flavorful foods rich in sugars and fats, some mice binge eat in a manner very similar to humans

Why did you choose to study binge eating in mice? In what ways is the mouse genetically similar, or dissimilar, from humans who overeat?

Mice remain the premier mammalian model organism for genetic studies. Greater than 90% of human genes have a mouse homolog, and mice and humans share many of the same basic features of the dopaminergic reward circuitry in the brain that is thought to be critical for binge eating behavior. Mice, like humans, will readily binge on high sugar/fat foods when it is intermittently available in limited amounts. This is not unlike humans who typically binge after periods of either normal or restricted eating.

In humans, binge eating is not always associated with obesity and can be distinguished from more constant patterns of overeating that are frequently associated with excess body weights. This is similar to our model; the mice bingeing on palatable food do not gain any additional weight relative to normally eating mice. In fact, recent data from our lab indicate that some mice may actually lose a little bit of weight after demonstrating robust binge eating behavior., These observations suggest that the bingeing mice actually reject the standard food they receive in their home cages in anticipation of the more rewarding palatable food they are occasionally offered.

What is the social significance of your findings?

There is a growing appreciation that maladaptive eating behaviors associated with eating disorders, including binge eating, share some of the same psychological features as drug or alcohol addictions, including loss of control, compulsive behavior, an inability to refrain from the behavior in spite of known detrimental health consequences, anxiety, depression, and relapse.

Furthermore, research is beginning to show that the same genes can lead to multiple neuropsychiatric disorders. Of direct relevance to our study, the binge-eating related gene that we found had been earlier reported to affect sensitivity to cocaine-induced behaviors. Thus, the concept of food “addiction”, while not identical to “substance use disorders”, is very real and has implications for understanding the biology and how we might develop effective treatments for maladaptive feeding behaviors such as binge eating.

What are the next steps for your research?

We are currently applying our mouse model of binge eating to other genetic crosses and populations to identify additional genes and adaptations in the brain that underlie binge eating. We know that many genes likely contribute to binge-eating, and a more comprehensive set of discoveries are needed. We hope to continue to provide new insight that will inform human genetic studies and potential pharmacotherapeutic treatments for binge-eating which, at the moment, are limited to amphetamine-like compounds that themselves have the potential for addiction liability.

Thank you for your research, Dr. Bryant, and for participating in this interview. In closing, I wonder if you could share with us what inspired you to become a scientist and what fuels your passion to continue this kind of research?

My scientific interest began in high school when I started to learn more about psychiatric disorders. I thought I wanted to become a psychologist or psychiatrist so I chose to major in psychology when I began my undergraduate career at the University of Illinois. I took a class called The Brain and the Mind and was blown away by what I was learning, including a series of psychopharmacology lectures by Jeff Mogil who would eventually become my undergraduate mentor. Jeff is an incredibly inspirational and enthusiastic scientist and got me excited not only about drugs but the scientific process in general. I worked in his lab for two years and was exposed for the first time to behavioral neuroscience and behavioral pharmacology and I immediately began to appreciate the power of how observing animal behavior can actually provide insight into what happens in the human brain. At that point I decided that this is how I want to make a living.

Dr. Camron Bryant can be found on twitter @CamronBryantPhD

Animal rights campaigns: When free speech takes a hideous turn

An important principle of American democracy is that the free exchange of ideas is crucial to social progress. We accept that protected speech can be often be ugly, provoke social unrest and include acts of civil disobedience. Yet, as far as possible, we must ensure that people are free to express their ideas – this cannot happen when individuals on one side of the debate are harassed and threatened. We’ve seen this happen in the abortion debate. Now, we see it unfold in the animal rights debate.

Organized harassment, intimidation, threats and firebombs directed at individuals involved in biomedical research involving animals, as well as other animal-related industries, and their families, are neither uncommon, nor are they protected forms of free speech.  While these are the tactics are used by a relatively small group of animal rights extremists who work under the motto — “animal liberation by all means necessary”, the escalation of violence from radical elements of the movement has been fueled in recent years by a larger group of activists who sit by the sidelines celebrating these criminal acts and inciting individuals to more violence. There is an even larger majority which appears at least to silently approve.  Only a disappointingly tiny group of animal rights philosophers and organizations have been vocal in condemning the violence from the fringes of the animal rights movement.

Some of the activists have taken to the internet in order to publish the addresses of their “targets” along with carefully worded incitements to violence; others have initiated campaigns of hate against their victims; yet others have shown up outside the targets’ front doors at night, wearing ski-masks, and frightening children inside with chants like “we know where you sleep”. This is, in good part, the free speech so many activists want to defend.

Protesters scream outside a researcher's home, routinely harassing the entire neighborhood

The behavior of animal rights extremists parallels that of radical, anti-abortion groups that targeted physicians who provided abortions to women who needed or requested them.  To seek a remedy to the escalating violence from these groups, President Bill Clinton passed the Freedom of Access to Clinic Entrances Act, that prohibits trespassing, vandalism, threats of violence, stalking, arson and bombings directed at reproductive health care clinics or their personnel.  The Animal Enterprise Terrorism Act simply attempts to control the criminal acts of animal rights extremists in a similar fashion.

The Animal Enterprise Terrorism Act (AETA) contains a clause indicating that nothing within it should be construed to “prohibit any expressive conduct (including peaceful picketing or other peaceful demonstration) protected from legal prohibition by the First Amendment to the Constitution.”  It is clear that only illegal conduct that is not covered under the First Amendment can be construed as violating the Act. Animal activists and advocates willing to express their views and educate the public regarding them can do so freely.

It is those that support campaigns of intimidation, threats and hatred that want to challenge it. It is those that want to use their speech to frighten and torment into submission others that dislike the enhanced punishments. It is those that want to enforce their views on society by force (which defines terrorism) that want it struck down.

We applaud Senator Feinstein for her stance in supporting legislation whose only goal is to respond to terrorist activities of a few and allow the rest of society to hold a civil debate on these the moral relationship between humans and non-human animals.

Regards,

David Jentsch and Dario Ringach

Fanning the flames of fear

Over the New Year’s weekend, the people of Los Angeles were gripped by a rash of arsons that targeted vehicles and homes. The fires sent people scurrying from bed in the middle of the night, with children in arms, in a desperate attempt to avoid harm. An understandable fear gripped the community, with people parking their cars down the street so that, if the arsonist came, the resulting fire would not spread to their house, risking the safety of their sleeping families.

The string of arsons was, apparently, the action of a single hate-filled man who was determined to inflict his anger on helpless targets. He went out into the night, applied accelerant to cars and set them on fire.

I, like other biomedical researchers in Los Angeles, had a powerful, personal response to viewing these events unfold. It was only 30 months ago that an animal rights extremist, morally blinded by hate and rage, walked through the gates of my yard at 4 am and set my car on fire, risking my life and that of those who lived around me. I can still see the flames when I close my eyes, and I can sometimes still feel the heat of the fire on my face, so I knew very well what these new victims that I watched on television were feeling: fear, panic, sadness and total confusion.

Animal rights extremists torched my car in 2009

The extremist elements that claim responsibility for these actions often indicate that they cause no harm to people; they say that they limit their actions to economic damage (WARNING: link takes you to an animal extremist website). They claim to break windows, steal documents, free animals and – yes – set cars and homes on fire, but they often insist that they do not hurt or injure people.

The claims that they cause no harm are proved hollow by the looks on the faces of people fleeing their burning homes on New Year’s eve. Extremist animal rights elements, like the man who set the New Year’s Eve fires, have one goal – not to cause financial losses to their targets – but to inflict psychological damage in the form of terror. In that sense, their targets are as much the people who have yet to be attacked as they are the individual whose car is on fire.

The events of last weekend underscore the fact that hatred is not unique to animal rights extremists. But it does demonstrate how powerful and insidious these forms of attack can be and how essential it is for our broader civil society to reject the actions of those who use thuggish tactics to achieve their ends of their movement.

Regards,

David Jentsch

On Friday, January 6, KCET, a Southern California PBS station, will re-air the story (‘Testing the Limits’) that addresses the harassment of Los Angeles researchers by local animal rights activists. You can watch it as it broadcasts (2/6 at 830 PM PST; 2/7 at 6 PM PST; 2/8 at 630 PM PST or 2/9 at 1030 PM PST); the program is also archived on their website (click here).

Afterthoughts on IoM report on the use of chimps in scientific research

Thursday marked an important moment in the history of animal research.  The long-anticipated report of a committee convened by the Institute of Medicine (IoM) to consider whether chimpanzee research is scientifically necessary released its report, quickly followed by a statement from Dr. Francis Collins, Director of NIH, the director accepting the committee’s recommendations.

The report acknowledged that chimpanzees were vital to past progress, but that at present there is limited necessity and justification for them in research.  It did not endorse a ban on chimpanzee research, nor the continuation of the moratorium on breeding, stating that these could potentially cause “unacceptable losses to the public’s health”.  It also made clear that “animal research remains a critical tool in protecting and advancing the public’s health”.   Both animal activists and biomedical researchers were simultaneously pleased and disappointed by different aspects of the report.

Speaking of Research believes there are many positive elements in the IoM report and to the surrounding discussion.  Above all, the report encouraged public dialogue, education, and serious civil conversation about the scientific and ethical (as well as practical and political) issues that surround animal research.  The IoM report provides a thoughtful, expert review of a range of issues involved in the consideration of the use of chimpanzees in biomedical and behavioral research.

There were, however, a couple important points to note within the IoM report and its deliberations.

First, the charge of the IoM committee to assess the “scientific necessity” of the work, while specifically avoiding ethical issues, was clearly ill-posed, and – as the committee quickly realized – nearly impossible to carry out.

We acknowledge the committee held serious discussions about the science of chimpanzee research and the availability of alternative methods, but it is notable that these were guided by principles that are ethical in nature.  Namely:

  1. The knowledge gained must be necessary to advance the public’s health.
  2. There must be no other research model by which the knowledge could be obtained, and the research cannot be ethically performed on human subjects.
  3. The animals used in the proposed research must be maintained in either ethologically appropriate physical and social environments or in natural habitats.

Moreover, the IoM committee explicitly recognized that “ethics was at the core of any discussion […] on the continued used of chimpanzees in research”.

It is evident that the tension about the use of chimpanzees in research is not merely about science.  In fact, it is not even primarily about science, as arguably chimps can stand as valid scientific models in many areas of research.  It isn’t even about the cost of research.

It is largely about ethics.

Consequently, the panel appears to have felt, at points, uncomfortable in their own shoes.  On one hand it maintained that considering ethical issues was not part of its charge; on the other, it produced a list of guiding principles that reflect ethical rather than scientific considerations, finally concluding that it did not have the required expertise to evaluate the ethical dimensions of chimpanzee research.

We believe discussions on the science and ethics of animal research are inextricably linked and both should be part of any public discussion on animal research. An honest, open and civil discussion on both the science and ethics of animal research that includes animal advocates, animal welfare organizations, scientists, patients and their families, patient advocacy groups, public health officials and the medical leadership of the country.

We would like emphasize that the guiding principles “adopted” by the panel are in fact very similar to the three Rs and current NIH guidelines that already guide decision-making regarding animal research.  By quickly adopting the IoM committee’s recommendations without additional comment, NIH may be sending the unintentional message that such principles are not at play in work with other species.  We think this issue needs to be addressed and clarified by the NIH.

The IOM panel clearly demonstrated the power of a comprehensive and critical analysis that accounts for progress in research, changes in technologies, models, and questions.  However, proceeding in critical analysis on a species-by-species basis is problematic for a number of reasons. We argue that a more general appraisal of the ethics and science of animal research is warranted.

a)     As illustrated by the IOM report and surrounding discussion, the “species-wise” approach ignores the more basic and important questions that are at the heart of the issue (the ethical dimension) and that this deserves a much more thorough and broader public discussion based upon empirical data and facts.

b)     There is no reason to think that changes in the technology, questions, and need for certain projects that contributed to a reduction in the requirement for chimpanzees in research might not also apply to other types of animals.  One may productively ask, for example, whether some studies currently conducted using mice might turn to zebra fish or drosophila instead?

c)     A broad review, beyond a single species, is also requisite to addressing the value of comparative studies, which are an integral part of strong science. Repeating work in more than one species is sometimes essential. Just because a finding is demonstrated in one species doesn’t mean it is a commonality in all.  Whereas the US Guiding Principles require that the lowest possible species be used, there are legitimate scientific reasons to repeat some studies in multiple species.

We believe that conducting a broader review of animal research could significantly advance public understanding of the role that it plays in medical and scientific progress.  In many ways, such an exercise is long overdue. The report’s conclusions clearly show the value of a rigorous, thoughtful, and public review of even the most controversial type of research. But public interest in animal studies extends far beyond chimpanzee research.

Addendum: There is an interesting discussion of the implications of the IOM report in Nature News this week, which highlights the fact that the majority of biomedical research projects that currently use Chimpanzees are likely to meet the new criteria proposed by the IOM panel  http://www.nature.com/news/chimp-research-under-scrutiny-1.9693

Speaking of Research

This is the fifth of a series of posts aimed at encouraging thoughtful and fact-based consideration of the full range of complex issues associated with chimpanzee research and both short- and long-term responsibility for their welfare, care and housing. Previous Speaking of Research posts on chimpanzee research include:

08/12/11: Facts must inform discussion of future of chimpanzee research.

10/13/11: Joseph M. Erwin, PhD Efforts to ban chimpanzee research are misguided.

11/21/11: A closer look at the Great Ape Protection Act.

12/08/11: What cost savings?  A closer look at the Great Ape Protection and Cost Savings Act of 2011

All in a day’s work: Scientists promote alternatives

Once upon a time, the medication BoTox (made by a company called Allergan) was tested for its potency, on a batch by batch basis, in living animals. This medication, which is really a protein derived from bacteria, has many important therapeutic purposes. For example, it has been shown to be very effective in the treatment of chronic migraine headaches – a condition that can have disabling effects on those who suffer from it. It is used to treat disorders in which people sweat profusely (hyperhidrosis) or have overactive bladders, both of which affect people’s qualities of life by impairing normal social functioning. It has also been used in the treatment of motor disorders like spasticity and dystonia, preventing the irregular and disruptive involuntary movements that are found in these disorders, thereby reducing the physical pain that is so often a consequence of them. Of course, it has also been used for aesthetic reasons, an arguably less compelling medical use.

BoTox is used to treat patients with spastic cerebral palsy, lesseing the pain they suffer as a result of their uncontrolled movements

Because the potency of individual batches of BoTox produced vary, the Food and Drug Administration (FDA) in the United States required Allergan to test each batch on live animals. For each batch, studies were conducted in which the amount of BoTox that was required to produce a specific toxic effect was evaluated in live animals, and the dose was adjusted to ensure that the potency of the drug across batches could be accounted for (roughly, if the batch was half as potent, this can be accounted for by giving twice the dose, ensuring that clinical effects were stable over time). This testing involved a lot of animals, mostly mice.

However, earlier this summer, the FDA changed its mind. It was approached by an organization that had – at considerable expense – developed a test that could determine BoTox potency just as well as the animal tests – but without involving live animals. The test is conducted on cells in a dish.

The organization spent millions of dollars to develop the test and to petition the FDA to consider this replacement for live animal use based upon its empirical results. They were successful.

Who was this organization? Was it the Humane Society of the United States? Perhaps it was People for the Ethical Treatment of Animals, or the Physicians Committee for Responsible Medicine?

It was none of these. Indeed, since none of these organizations spend their operating budgets on the laboratory research that is required to develop alternatives to live animal studies, it couldn’t have been any of them.

So, who accomplished this? It was Allergan itself. Biomedical researchers at the company who used animals in their tests became determined to find a model system that could replace living animals, and they didn’t stop until they found one. They did this though it came at a huge expense to the company. They were committed to producing medicines that people need and to use the fewest animals in the process, and they accomplished that. As the Allergen press release notes, there have been several attempts, using a variety of methods, over the past two decades to develop a replacement for the LD50 test, but until now all these have fallen short.  A report from a 2008 scientific workshop convened by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM)  and the National Toxicology Program Interagency Program for the Evaluation of Alternative Toxicological Methods (NICEATM) provides a good overview of many of the challenges involved in delevoling a replacement for the LD50 test, and the different approaches used to address them.

As always, the alternatives that exist for animal use in biomedical science came from the very scientists who are otherwise roundly criticized by the anti-animal research movement. Maybe the irony is lost on organizations like PCRM, HSUS and PeTA, but not on us. At UCLA, our administration has instituted a funding program that provides seed funding to scientists to promote work on refinement, reduction and replacement. What have the leading anti-research groups done? Nothing, but complain. Perhaps instead of criticizing scientists, these organizations should join with us in attempting to discover alternatives and reduce animal use.

Regards,

David Jentsch

Lighting the Way to New Treatments

A variety of diseases in humans happen when proteins with important cellular functions are lacking or are produced in abnormally low amounts. One example is type-2 diabetes mellitus which is caused by a complex set of problems involving the use of sugars (mostly, glucose) as an energy source. After eating, sugars in food are taken up by the body, and a set of biochemical events in the gut and metabolic organs (pancreas, liver) that control the levels of sugar in the blood and that allow cells to take up and use the sugar properly are activated. When those mechanisms do not function properly, blood sugar levels can become very high (hyperglycemia) and other forms of toxicity can result. Because there are many proteins involved in this process, type-2 diabetes can result from multiple different defects in different molecular pathways. This often makes type-2 diabetes difficult to treat, in some cases it can be reversed by lifestyle and dietary modification, while in many others the use of insulin or an anti-diabetic drugs such as metformin is required alongside dietary modification in order to achieve adequate control over glucose levels. In a significant minority of cases even the combination of medication and lifestyle changes is not effective enough to prevent the consequences of type-2 diabetes, such as cardiovascular and kidney disease.

A variety of novel treatments have been proposed, ranging from drugs that alter the functions of the defective proteins, to gene and/or protein therapy. In each case, the idea is to cause the proteins to be expressed and/or function normally, allowing sugar metabolism to progress optimally. Gene therapy involves causing a patient’s cells to express an artificial gene with the hope that it will, in turn, make more of a needed protein. Alternatively, therapies can involve direct administration of the protein, after it has been made by cells growing in a dish or by genetically-engineered animals (insulin treatment for type-1 diabetes is a good example). Gene therapy has many potential limitations, ranging from difficulties with the methods used to get the genes into the cells, to the fact that the cells may not express the protein in a normal amount and/or manner. Protein therapy suffers from the fact that it is very difficult to produce proteins suitable for drug treatment in large amounts or with sufficient potency and purity, meaning that these agents can be very expensive and have their own potential adverse effects.

A blended approach involves creating human cells that express proteins of interest in a laboratory, seeding them into an implantable “bio-reactor” and then placing the reactor into the patient’s body. Ideally, however, the expression of the protein by the cells in this bio-reactor would be controllable by the supervising physician, who could adjust it according to the patient’s needs and response to the treatment. This requires a “trigger” that turns up or down the activity of the cells. In a paper appearing in the journal Science, Swiss scientists have now demonstrated a method for controlling the production of proteins by an implanted bio-reactor; the trigger they developed is one free of any potential side effects of its own: namely, light.

To do this, they took advantage of an amazing mechanism – created by nature – that is buried deep in our eyes. Cells in our retina have proteins that sense light; when light strikes the proteins in these cells, a biochemical signal results which affects the physiology of the cell. This is the beginnings of how we see. In their article, Ye and colleagues report that theythat they used the light-sensitivity of the protein melanopsin to create cells in the laboratory that are capable of responding to light by producing a protein called glucagon like peptide-1, which promotes normal sugar balance and metabolism. They seeded these cells into a bio-reactor which they implanted just under the skin into mice that are type-2 diabetic. When they shined blue light onto the mice, some of it passed through the skin, reaching the bio-reactor. The cells released the protein, exactly as they were designed to do, and the secreted protein normalized the high blood sugar exhibited by the diabetic mice.

Blue light activates cells that express melanopsin proteins

Because different proteins are responsible for diabetes in different patients, it will eventually be possible to create individualized bio-reactors that restore the protein that is particularly important for that person; but in all cases, blue light can be the trigger. With that light comes the ability to control the levels of protein production according to the needs and response of the patient.

None of this would have been possible without decades of basic research into the biology of the eye (including studies in frogs which enabled the discovery of the critical light-sensitive protein melanopsin), into sugar metabolism  (in particular the studies in rats which identified glucagon like peptide-1 as an important regulator of insulin secretion ) and molecular genetics (which made it possible to modify the genetic structure of cells in the manner required here). Scientists working on these problems were not necessarily conducting research to cure human disease, but their discoveries laid the ground-work for these treatments anyway. Because of their enormous efforts, the new approach described by Ye and colleagues has potential for the treatment of a whole range of diseases where protein therapy is required, including cancer, liver disease and neurological problems. Once again, the future is “bright” for those suffering from those illnesses, thanks to the amazing combination of animal models and new technology.

Regards,

David Jentsch