Archive for December, 2016


Dec 27 2016

An injection of optimism into biomedical research – Part 2: Improved management for two textbook diseases

by at 8:54 pm

This is Part 2 of my Injection of Optimism into Biomedical Research Series.  To read Part 1, click here.

Two diseases which have not (yet) been virtually eliminated – as phenylketonuria and congenital hypothyroidism have – but for which sufferers have seen huge benefits from early diagnosis and improved management are cystic fibrosis (CF) and sickle cell disease (SCD). Both of these diseases are caused by mutations in a single gene and inherited in an autosomal recessive manner. Though rare overall, they are among the most common genetic disorders in the world. As such, they are often “textbook examples” in introductory genetics classes. They are both now included in newborn screening programs in all 50 US states.

CF is present in 1 in between 2.500 and 3,500 births in Caucasians in the US, being the most common life-limiting genetic disorder amongst Caucasians. It leads to damage to multiple organ systems through the buildup of sticky mucus due to an abnormality in a chloride channel. In particular, it can result in severe nutritional and respiratory problems. While no curative treatment exists for this still-devastating disease, improved management has played a huge role in both quality of life and lifespan. This includes dietary recommendations to prevent malnutrition, therapeutic approaches to clear out the airways from thick secretions, and proactive use of antibiotics for treating airway infections. It is difficult to precisely understand the effect of this improved management on life expectancy, as when CF was first recognized as a stand-alone disorder in 1938 it was through autopsies of malnourished infants who had a life expectancy of 6 months. Less severe cases started being identified in the 1950s with the introduction of standardized “sweat tests” which led to comprehensive programs and improved survival. The responsible gene was finally identified in 1989. In the early 1970s the life expectancy for these “milder” cases was only in the teens, increasing to 25 years in 1985 and 37 years in 2008. There is increased hope that targeted gene therapy will provide a curative treatment, and the progress obtained in the last few decades must still not be overlooked.

SCD is a group of disorders which are characterized by hemoglobin – the protein in red blood cells that carries oxygen from the lungs throughout the body and returns carbon dioxide back to the lungs – having an abnormal and stiff shape. This leads to red blood cells (RBCs) which are sickle shaped instead of the usual flexible disc shape. The abnormal RBCs can stick to the vessel walls, leading to a lack of oxygen in surrounding tissues. This can result in severe “pain crises,” as well as anemia, increased susceptibility and impaired response to infections, and progressive organ damage.  SCD is the most common inherited blood disorder in the US and occurs in 1 in 365500 African Americans. The use of screening and other management strategies in early childhood, including penicillin prophylaxis and pneumococcal vaccines have led to an increase in life expectancy from < 20 years in the 1970s to the 30s or 40s since the early 1990s. Adult patients may also be prescribed hydroxyurea, which may reduce the frequency of the pain crises and the need of blood transfusions – this medication was initially approved in 1967 by the FDA to treat cancer and received a new indication for SCD in 1998 and is thus a great example of drug repurposing.

As the sickle cell trait is associated with protection against malaria when the disease-causing allele is present in a single copy, SCD is also very common in sub-Saharan Africa, estimated to affect 3% of all births in some regions. Indeed, it appears to be a major but often ignored cause of early childhood mortality, with some estimates ranging from 50-90% of individuals with SCD dying in early childhood and SCD accounting for 5-16% of under-5 mortality in certain regions. Similarly to CF, there is hope in using modern targeted approaches, including CRISPR, however the impact of improved management has been tremendous and indeed, its adoption in sub-Saharan Africa could substantially lower childhood mortality. Even in the US, there are limitations in terms of access to care for many SCD patients, meaning that improving overall management could improve outcomes even further.

Acknowledgment: Dr. Jacob Corn from UC Berkeley, the senior author of this paper on using CRISPR for SCD, was a keynote speaker at the 2016 ICBI Symposium. I learned a lot about SCD from talking to him, which made it very easy for me to look up the references for the second part of this post.


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Dec 16 2016

An injection of optimism into biomedical research – Part 1: Newborn screening success!

by at 1:03 pm

With headlines questioning whether science is broken, the skyrocketing costs of drug development, the high rates of obesity, and the recent decrease (though by only 0.1 years!) in life expectancy in the US, it can be tough to be an optimist in biomedical research – gloom and doom lurk just about everywhere. This is doubly so for someone like myself who is both an innate and a trained pessimist, what with my training in Biostatistics. However, I have been coming across numerous examples of successes in biomedical research and public health implementation from the past 60 years, and therefore want to share them in a multipart series here – my first foray into blogging – in order to spread cheer and hope in time for the holidays.

Research is hard and the only problems we tackle are those for which no solutions have yet been found. There are reasons why no longer look for cures for smallpox and polio! The prevention of many infectious diseases is well recognized as a huge public health success. I want to shed a bit more light on quieter success stories – There are many other examples which, though not as dramatic, show that science works and for many lesser known diseases that nonetheless affect many people in total, there is less suffering and more hope. I will be focusing on US examples, because these are the ones I am most familiar with, and welcome other examples in the comments.

Newborn screening programs for congenital diseases are valuable public health interventions, currently implemented in every state in the US – though the exact diseases considered are different in each state – and many other countries around the world via a blood test performed shortly after birth. In case of a positive result for one of the screened diseases, follow-up testing is performed to confirm the presence of the disease. The “poster diseases” for screening are phenylketonuria (PKU) – a recessive disease affecting 1 in 13,000 births – and congenital hypothyroidism (CH) – affecting 1 in 4000 births – for which screening has existed since the 1960s, respectively 1970s. In the absence of management, they both generally result in severe intellectual disabilities along with other potential health issues. The impact of these diseases can now be functionally eliminated via, respectively, a restricted diet, and a hormone supplement, both of which must be started shortly after birth. To give an idea of the human cost, consider the writer Pearl Buck, a novelist who won the Pulitzer prize in 1932 and became the first American woman to win the Nobel Prize for Literature in 1938. Her daughter Carol, born in 1920, had PKU and was institutionalized for most of her life. Part of the reason why she wrote her famous novel “The Good Earth” was to help pay for her daughter’s care. She would also write to her friend Polly Small “I would gladly have written nothing if I could have just an average child in Carol. Average children seem such a wonderful joy to me – I wouldn’t ask for a clever, bright child if I could have had her just average.” Buck would later publish the book “The Child Who Never Grew” in 1950, which is considered one of the first books to openly discuss intellectual disability.

Newborn screening panels are actively evolving, with a Recommended Uniform Screening Panel developed by the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) of the Department of Health and Human Services currently encompassing 34 core conditions. In general, diseases are included only if a treatment or management plan is expected to substantially alter the disease course if started before symptoms appear – this can be a difficult evidence-based medicine question and as such there is not always complete agreement. Other biomedical and ethical concerns – also see here and here – including issues such as:

  • Does the screening test have good performance in terms of false positives and false negatives? What are the costs of a false positive?
  • Should screening be performed for diseases without treatment or for carrier status so that families could be informed of risk to future pregnancies or be prepared for caring for a special-needs child?

While more work needs to be done in this area (I wouldn’t be a researcher if I didn’t end on this note), it is important to keep in mind that many children are already being substantially helped by this screening. In 2014, 3,988,076 babies were born in the US, which means that approximately 1,300 lives were fundamentally transformed by CH and PKU screening alone.


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