Tuesday
Aug222017

First-in-Human: the moment research turns to medicine

 If you have not been watching the recent three-part series on the Discovery channel entitled “First-in-human,” I highly recommend checking it out. As a medical researcher who works in a translational lab, it is both refreshing and inspiring to get a glimpse into the moment where all of the basic research and development translates into a treatment for human disease. The documentary, which is targeted for a wide audience, provides rare insight into this critical first stage of drug development when a drug is first put into a human body, and includes the point of view of clinicians, researchers, and patients.

Three patients are introduced in the first episode who each have been left with little to no treatment options for their incurable diseases, two of which are types of cancer. Each patient has traveled to the hospital in building 10 at the NIH, which houses labs and clinical treatment facilities to support bench-to-bedside, first-in-human clinical trials. While these patients are quite sick, their remarkable courage is apparent as they listen to the doctor explain the risks and unknowns associated with taking part in a first-in-human study. The episode then offers an intimate portrait of how dynamic and emotional this first drug treatment can be for both the clinicians and the family members present, with the patient’s desire to maximize the potential for treatment success battling with the clinician’s oath to keep the patient out of unnecessary harm. This humanization of the scientific process of drug development was eye opening. As researchers, it is easy to hyper focus on the data and the statistics of drug success, so it is important to see the other side of the development process.

In addition to portraying the patient/clinician experience in a first-in-human trial, the documentary highlighted two novel immuno-oncology treatments, CAR-T (chimeric antigen receptor) therapy and TILS (tumor infiltrating lymphocytes). Both of these new technologies utilize the patient’s own immune cells to fight their cancer using a true bench-to-bedside technique. In CAR-T therapy, blood cells are harvested from a patient (in the documentary, the patient has relapsing leukemia), engineered and grown in the lab to recognize a target specifically expressed on leukemia cells, CD22, and then reintroduced into the patient’s body to attack the leukemia. Similarly, TIL therapy works by extracting a tumor from a patient’s body, slicing up the tumor and amplifying the endogenous immune cells already working to fight the tumor (lymphocytes), and reintroducing the immune cells back into the body to fight the cancer. Both of these therapeutic mechanisms amplify the patients’ own immune system responses to tackle the malignancy in their bodies. There is a unique aspect compared to small molecule treatments as these therapeutics require a concerted effort between the lab and the clinicians to develop a patient-specific treatment that will be successful.

It is no small feat to drive these types of projects forward in medicine, and it takes the researchers, clinicians, families, and patients to succeed.

 

MMR

Watch full episodes of First in Human here https://www.discovery.com/tv-shows/first-in-human/

Friday
Jul212017

Gut Instinct

Anatomy of a pycnogonid: A: head; B: thorax; C: abdomen 1: proboscis; 2: chelifores; 3: palps; 4: ovigers; 5: egg sacs; 6a–6d: four pairs of legsWhen an animal is all legs and almost no body, questions abound - and one question in particular springs to mind - where do they keep all their essential biological parts? Most mammals have plenty of internal space for the heart, lungs, and gastrointestinal organs. Not so for sea spiders! Some species are as large as a dinner plate (i.e., Antarctic sea spiders), with legs-for-days, but others have a tiny “torso” that is basically an attachment site for legs. So, how do they manage to reproduce or circulate blood, not to mention, process their food?

Sea spiders manage these important functions with their long legs. Interestingly, females grow ovaries on their legs and release them through pores. During mating, the male climbs over the female to fertilize her eggs and then carries them until they hatch. Similar to seahorses, male sea spiders carry their offspring until birth –and while the male seahorse swims away soon after - male sea spider cares for the young after they are born!

Not only are sea spiders’ reproductive organs located in their legs, but so are their guts. The distance between the mouth and anus is so small that the intestines reach down each leg so that food can be adequately processed. The guts contract to move food along just like our intestines do.

Sea spiders do not have any respiratory organs, instead, they receive oxygen through passive diffusion across their 4-6 pairs of legs. But because these pycnogonids can become so large, scientists wondered how they get the amount of oxygen they need to survive. Larger animals need to get plenty of oxygen into their bloodstreams and need to be able to pump that blood around their bodies. Passive diffusion might be fine in a small body, but Atlantic sea spiders tip the scale for size. Drs. Amy Moran and Arthur Woods, of the University of Hawaii at Manoa, recently discovered that sea spider hearts are not large enough to efficiently pump blood throughout their whole body. Instead, they circulate blood using their guts!

Each leg contains blood vessels as well as intestines, so as food is processed, blood is also circulated through the legs and into the body. However, the legs of a sea spider are not expandable, so, when digestive fluid is pushed in one direction, it forces blood to flow in the opposite direction. After oxygen diffuses in the legs, it travels to the creature’s body cavity through contractions of the guts. Once the blood reaches the body cavity, the heart is then able to circulate it around the body and head.

Sea spiders are able to live without having a specialized system for pumping blood because they effectively use their legs as gills and their guts as hearts – a gut check for all of us – we are not the only complicated creatures on the planet!  

-BGH

 

Sources:

https://www.theatlantic.com/science/archive/2017/07/sea-spiders-pump-blood-with-their-guts-not-their-hearts/533088/?utm_source=fbia

Woods, H. Arthur, Lane, Steven J., Shishido, Caitlin, Tobalske, Bret, Arango, Claudia P., Moran, Amy L. 2017. Respiratory gut peristalsis by sea spiders. Current Biology, Volume 27, Issue 13, R638 - R639

External anatomy of Nymphon sea spider. After G. O. Sars (1895).

https://upload.wikimedia.org/wikipedia/commons/7/73/Pycnogonida_Nymphon_s_Sars.png

Friday
Jul142017

Neural activity may differ between males and females with Adolescent Major Depressive Disorder

In a recent study, evidence of a sex difference in neural activation during a cognitive task was demonstrated in relation to adolescent major depressive disorder (MDD), with a novel focus on males [1]. There are differences between men and women in symptom presentation in MDD, and men are more likely to experience persistent, and women, recurrent, forms of depression [2]. By the age of 15, girls are two times as likely to experience depression compared to their male counterparts [3], whereas in adulthood, men are more likely to become suicidal [4].     

A recent study published in Frontiers in Psychiatry investigated depression in male and female adolescents between the ages of 11 and 17 [1]. Cognitive control of emotion, which also appears to differ between males and females, was tested using functional magnetic resonance imaging (fMRI) during an affective Go/No-Go task [1]. The participants’ responses to happy, sad or neutral words were measured during image acquisition. Neural activity in response to the sad words differed in the supramarginal gyrus in adolescent males compared to females [1]. Interestingly, depressed adolescent males showed decreased cerebellar activation and an age related decrease in its connectivity with the superior frontal gyrus compared to healthy adolescent males [1].

A number of brain regions found to be affected in adolescent males are involved in the default mode network, which is of interest as this network may be involved in the decline in cognition that occurs in MDD [5]. In light of sex differences related to MDD, the results of this study suggest that preventative and therapeutic interventions may be improved if neural differences are taken into consideration. It remains unknown whether developmental neural changes are involved in the etiology of this illness. As an important caveat, the study did encounter issues with enrollment, as fewer males participated compared to females, highlighting the need for matched sample sizes in future studies.

-MCC

 

[1] Chuang J-Y, Hagan CC, Murray GK, Graham JME, Ooi C, Tait R, Holt RJ, Elliott R, van Nieuwenhuizen AO, Bullmore ET, Lennox BR, Sahakian BJ, Goodyer IM and Suckling J (2017) Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task. Front. Psychiatry 8:119. doi: 10.3389/fpsyt.2017.00119

 

[2] Dunn V, Goodyer IM. Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in early adulthood. Br J Psychiatry (2006) 188:216–22.

 

[3] Cyranowski JM, Frank E, Young E, Shear MK. Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. Arch Gen Psychiatry (2000) 57(1):21–7.

 

[4] Blair-West GW, Cantor CH, Mellsop GW, Eveson-Annan ML. Lifetime suicide risk in major depression: sex and age determinants.  J Affect Disord. 1999 Oct: 55 (2-3): 171-8.  

Monday
Jul102017

Childhood epilepsy may be associated with increased β-amyloid accumulation in adulthood

Adults with childhood-onset epilepsy appear to have increased β-amyloid (Aβ) plaque accumulation compared to healthy controls, according to a recently published study conducted in Finland [1]. Brain Aβ plaque deposition was analyzed in 41 participants from a cohort of late middle- aged individuals with childhood-onset epilepsy and 46 matched controls using carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography (PET) [1].  Aβ plaque accumulation, a well- known hallmark of Alzheimer’s disease (AD), occurs in the brain years before the appearance of the first cognitive symptoms [2]. The participants with childhood-onset epilepsy are involved in the Turku Adult Childhood Onset Epilepsy TACOE study [3], which has followed them for 5 decades.

Childhood epilepsy was associated with increased PiB uptake compared to controls [1]. In a semi-quantitative analysis, the AD risk gene, APO ε4, together with idiopathic epilepsy, was also found to be associated with increased PiB uptake [1]. The findings are noteworthy as the effects of childhood epilepsy on the brain and cognition later in life are not well understood. Future studies are needed to examine whether childhood epilepsy might be a risk factor for AD. Well known risk factors for AD include Down syndrome, genetic abnormalities, cardiovascular disease and traumatic brain injury [2, 4]. AD is the most common form of dementia and there is no treatment [2]. At present, an estimated 5.4 million Americans have Alzheimer's disease [2].

-JKR

 

 [1] Joutsa J, Rinne JO, Hermann B, Karrasch M, Anttinen A, Shinnar S, Sillanpää M. Association Between Childhood-Onset Epilepsy and Amyloid Burden 5 Decades Later. JAMA Neurol. 2017;74(5):583-590.

[2] Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12(4):459-509.

[3] Sillanpää M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338(24):1715-22.

[4] Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev. 2007;13(3):237-46.

Friday
Jul072017

New Hope for Careers in Science

Check out http://sciencemag.org/careers for interesting articles and links to material covering all stages of careers in science. 

There are interesting blogs and articles as well as links to additional articles and publications on topics including the challenges of being a PhD student and the utility of pursuing a postdoc. You will also find content offering insight into a career as a staff scientist, promotion, mentoring, and work life balance as well as discussion of timely issues such as gender differences and diversity in science.

A recently posted Q&A with Stanford Professor and Nobel laureate Michael Levitt discussed his study in PNAS regarding funding trends of the National Institutes of Health (NIH). The study draws attention to the fact that over a 32 year period there has been a decrease in the number of younger (<46 years) basic science principal investigators and the need for NIH to become more pro-active in the context of increasing funding for younger researchers [1]. The good news is that given policies first implemented in 2008 addressing funding issues experienced by new investigators, Levitt does foresee career possibilities opening up for younger scientists in the near future.  

See http://www.sciencemag.org/careers/2017/06/why-it-might-be-good-time-start-career-science

 

-NRZ

 

References

Levitt and Levitt. Future of fundamental discovery in US biomedical research. PNAS. June 20, 2017