Isotopes Beyond PET

Being in a lab that uses short-lived radioactive isotopes to study the human brain, we sometimes forget the utility of long-lived isotopes in other scientific fields. Reading the recent report of Bell et al. that indicates a potential for life developing on Earth as early as 4.1 Billion years ago,¹ I was reminded of the vast historical knowledge humans have gained through isotopic measurement. In this study, zircons from the Jack Hills in Australia, known for containing the oldest terrestrial-formed material on Earth,² were uranium-lead dated (4.1 Ga) and analyzed for the presence of partially disordered graphite (i.e. carbon, the atom of life). Zircons with graphite were analyzed for the presence of > 40 nm cracks—thanks to synchrotron transmission X-ray microscopy—to avoid regions that may have gathered carbon-based material after zircon formation. Crack-less regions were analyzed for evidence of biogenic carbon through ¹²C/¹³C isotopic ratio measurement.³ The ¹²C/¹³C ratio found in carbon-based inclusions in the Jack Hills zircon was consistent with the known biogenic carbon signature, suggesting that life may have had its start as early as 4.1 billion years ago, 300 million years earlier than previous reports.⁴ If earlier development of planetary life is the norm, it would increase current estimates of the prevalence of life throughout the universe. Bring on the aliens!

~GV

1)      Bell, E. A. et al. (2015). "Potentially biogenic carbon preserved in a 4.1 billion-year-old zircon". PNAS, doi: 10.1073/pnas.1517557112.

2)      Wilde, S. A.; et al. (2001). "Evidence from detrital zircons for the existence of continental crust and oceans on the Earth 4.4 Gyr ago." Nature 409 (6817):175–178.

3)      Schopf JW, Kudryavtsev AB (2014) Biogenicity of Earth’s earliest fossils. Evolution of Archean Crust and Early Life, Modern Approaches in Solid Earth Sciences, eds Dilek Y, Furnes H (Springer, Dordrecht, The Netherlands), Vol 7, pp 333–349.

4)      Mojzsis SJ, et al. (1996) Evidence for life on Earth before 3,800 million years ago. Nature 384 (6604):55–59.

Consumers can expect more accessible explanation of risks in pharmaceutical advertisements

Whether they are in print or some other broadcast medium, we are constantly bombarded with pharmaceutical advertisements. We are all too familiar with the format in which these advertisements appear: captivating images and/or compassionate and motivating speech with large text to draw your attention, convincing us that a particular agent can improve our lives in some otherwise ailing capacity. This is followed by a line of fine print, or the remaining few seconds of a commercial, rambling off a list of risks and side effects described in scientific jargon most viewers/listeners cannot understand. Even if we are able to comprehend the science, the risks are presented too quickly or in print too small to take in. Sure, most of these ads say to speak with your doctor about the risks before taking X drug, but why aren’t these risks easily and initially accessible to us? When we purchase food items, we may find printed cautions such that the food had been handled/manufactured with other products containing soy or peanuts (important for individuals with allergies or sensitivities to consider). If we as consumers are to take the drug into our bodies, then we should be fairly presented with the risks as well.

This may soon change, as the FDA is beginning to put into place regulations about how risks are displayed in direct-to-consumer advertising (DTCA) since the administration acknowledges that the way in which they are presented currently are not effective. The FDA proposes to use language more likely to be understood by consumers. However, there are other questions that are being raised: how to determine if the language is too technical or too simplistic for delivering information to consumers? How much information should ads contain so that they are sufficient without being too lengthy? Should all known risks and side effects be included or only those more likely to occur or those most serious? In the 30 years of DTCA, there have been a number of efforts to improve the way in which important information is conveyed to consumers. Questions such as those brought up above in addition to other issues and concerns will need to be addressed to improve message delivery in DTCA. What is clear is that companies should put in as much effort into delivering information about risks as they do into selling their products. 

-AB

Greene, J. A., & Watkins, E. S. (2015). The Vernacular of Risk—Rethinking Direct-to-Consumer Advertising of Pharmaceuticals. New England journal of medicine, 373 (12), 1087-1089.

Responsible Conduct of Research – Why?

A large percentage of the research done at prestigious institutions like Harvard, MGH or MIT is funded by federal money through the NIH, NSF or similar agencies. We all work hard to get the best possible results and give back to society – be it through publication of our results or licencing of newly developed tools that can improve people’s lives in various ways. We work under a number of regulations with that money. In order to conduct research on an NIH grant for example, the fundees are asked to participate in “Responsible Conduct of Research” seminars, which will not always elicit an excited response from busy scientists who have enough on their plate without another obligatory seminar series. I once was one of the students who had to sign up for such lectures, and starting out I was not exactly excited.

That was, until I started going and learned about reasons those very seminars existed. Academic misconduct being one major issue even today, for example a surprisingly large number of scientists fabricating or falsifying data to publish in a very competitive environment. The fact that this is not only disruptive with respect to the readers who base their research on incorrect data found in the literature,  it occurred to me clearer than ever before that such behavior is actively wasting, stealing tax money for the sake of personal benefit. This is an example for relatively obvious ethic choices one has to make as a researcher, when other issues that arose during the seminars were not as straight forward to think about. One major human cell line used in numerous labs today is known as “HeLa”. What fewer people are aware of is the origin of this cell line: it was created from cancerous tissue taken from a black woman called Henrietta Lacks. For many years, not even her name was commonly known, she would be referred to as “Helen Lane”. She died without ever knowing what her cells had done for science. Neither did her family for many years. The cells were licenced, produced and sold making scientists rich, while Henrietta’s family lived in poor conditions in Baltimore county. At the time, no protective measures ensured that patients could not be exploited – like Henrietta. Her story was published in a great book, which I highly recommend to anyone working in the medical sciences¹.

Many regulations that seem bothersome or exaggerated to new researchers have been developed over many years to protect the public from exploitation through unethical research. Knowing the historic background of these regulations, they suddenly really make sense and certain decisions become much easier to make.  I am now grateful that I was exposed to this very different perspective on scientific research. We aren’t graded in college for our ethical behavior, now will it necessarily earn us a PhD, but it is an absolutely essential prerequisite for science to function as a whole. We are consuming public money to do our work, we have to understand that it comes with a responsibility: To earn the trust of the public that enables our research, and treat them with respect.

-MGS-

¹Skloot, Rebecca (2010), The Immortal Life of Henrietta Lacks, New York City: Random House, ISBN 978-1-4000-5217-2

The disciplines I am most interested in are neuroscience and psychiatry, which are still distinct, though scientists hope to bridge the gap between these two fields. There are a number of neuroscience-based investigations conducted on psychiatric disease, but as Dr. Paulus mentions in a recent JAMA Psychiatry opinion piece, there is yet to exist a definitive biological explanation for any particular psychiatric illness. Yes, it is true that psychiatry deals with complex conditions, which are influenced by genetic and environmental factors exerting effects at the neuronal to systems levels.  Understandably, this makes it difficult to determine exactly what happens in different psychiatric illnesses. For medical conditions pertaining to other body systems (e.g., cardiovascular and infectious diseases), the biological determinants for disease manifestation and treatment efficacy are better understood. It would be great if psychiatric status could be examined in ways similar to monitoring for abnormal blood test results (e.g., CRP, HDL and LDL cholesterol, triglycerides, etc.) to minimize the chances of developing heart disease or MRI imaging to view a brightly-enhanced area likely to represent a tumor), but this approach to psychiatric diagnosis is too simplistic. Dr. Paulus believes that many scientific investigations focus on “mechanisms” and “mechanistic explanations” (admittedly vague expressions wildly thrown around in scientific publications) to study disease and that this way of conducting research is contributing to the rarity of biological breakthroughs in psychiatry.

In her opinion piece, Dr. Paulus also brings up the problem of reverse inference in neuroscience research. Yes, when discussing brain structure and function, you will frequently hear of a certain brain area being implicated in a particular behavior, emotion, affect, etc. Unfortunately, almost always secondary is the elaboration on the conditions in which the association was found. For example, if during resting state patients with a disease show increased activity in a brain region previously found to be active during tasks aimed at assessing reward-related behaviors, would you say there is heightened reward-associated activity in a disease? No, this is not necessarily true since brain areas are involved in multiple processes.

Dr. Paulus advocates for a prediction-based approach to solve clinical problems. However, is there sufficient information available on predictors to make estimates of diagnoses and prognoses for psychiatric illnesses, as she proposes to the neuropsychiatric research community?  I believe that there is need for computational predictive models to help determine the likelihood of developing a particular condition based on different factors, but we must also remain cautionary of an absolute utility of such models. How can a computational predictive model explain why a patient develops a disease despite expressing a neurobiological or genetic propensity for that disease?  What reasoning do you provide to the patient? Another vital piece of this puzzle is appropriate avenues for effective patient treatment.  How do you address the question of why something like CBT works for one patient but not another? What are the processes taking place in the brain leading to these outcomes? “Best practice” models for effective treatment are still subject to each patient’s unique biological makeup and environmental circumstances.

Furthermore, psychiatry is a field in which prescribed medications often have a variety of side effects, which can vary from person to person. Reliance on prediction models is unlikely to bring about novel understanding of disease or major improvements in therapeutic treatments. Neuroscience investigations should continue studying what exactly is altered in the brain of patients with a particular disease, and to what extent these changes are present. Research on!

-AB

Paulus, M.P. Pragmatism Instead of Mechanism: A Call for Impactful Biological Psychiatry. JAMA Psychiatry.2015; 72(7): 631-632.

Shadowing physicians and the impact of imaging on patients

Through collaborations with the Hooker Lab, I have been fortunate enough to shadow doctors who have specialized in different fields of medicine.  I am often asked what I learn from these observational visits. Besides witnessing doctor-patient encounters and getting a glimpse into what being a doctor entails, I have noticed how key components in clinical medicine overlap with ongoing research projects within the Hooker Lab. Clinical research plays a critical role in medical advances.  I know that I certainly enjoy reading the latest findings in medical research, but I was surprised to see the frequency in which patients come to doctors with newspaper clippings or printouts on recent studies.  For instance, a patient mentioned a newspaper article promoting the wonders of a recently published study in which tetanus vaccine in glioblastoma patients increased survival time and slowed tumor progression. The news article did not address the limitations of the research, including the issue of a small sample size and the fact that participants were required to have met strict eligibility criteria.  Therefore, it is important for doctors to be aware of the latest medical developments to help patients understand the limitations to the generalizability and realistic implications of research findings.

Many of the studies being conducted within our research group involve imaging techniques, which are widely used in medicine for making diagnoses, as tools during surgical or interventional procedures, and for monitoring specific cancers and other medical conditions.  The images obtained from scans can also evoke emotional responses from patients. This was the case when a patient, who had previously undergone surgery and treatments for a brain tumor, viewed an MRI brain scan revealing that the cancer was still kept at bay ten years later.

The role of imaging in medicine benefits both clinicians and patients, but there are still limitations to these techniques (e.g., with MRI, it is difficult to distinguish recurrent cancer cells from those of inflammation due to treatment).  This is why it is important to continue research aimed at improving imaging methods, particularly through designing radiotracers with targets that will help improve diagnostic and therapeutic techniques. 

-AB