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Perspective interview - Harvey Levy (newborn screening)

Perspective interview - Harvey Levy (newborn screening)

2014 PKU Perspectives Harvey L. Levy

Prof Harvey Levy shares his hopes for the future of newborn screening

Prof Harvey Levy1 of the Boston Children’s Hospital and Harvard Medical School, Boston (USA) is widely associated with the development and advancement of newborn screening. Among his many awards he is a past recipient of both the Robert Guthrie award (1997) from the International Society for Neonatal Screening and the Asbjørn Følling Award (2012) from the PKU Academy. He addressed delegates at the 2014 Annual Multidisciplinary European PKU Symposium on use of BH4 in children under four years old.

As well as being a practicing clinical biochemical geneticist, Prof Levy is an active researcher. His recent publications, including Levy (2014)2 and Landau et al (2014)3 have continued his long association with screening for inborn errors of metabolism (IEM), asking the questions, 'Where is newborn screening going?' and 'Where should it be going?' We asked him the same questions.

The future is genomic

'It is quite clear', Prof Levy told us, 'that we now have the ability to take the newborn blood specimen; the filter paper containing circles saturated with blood we collect to test for PKU and other metabolic disorders, and to go further with it. Thanks to new developments in genomic sequencing we now have the opportunity to use that blood specimen to look at all of the different base pairs of the baby’s DNA. It’s not likely that we’re going to be sequencing the DNA of a baby to the point where we’ll be identifying tens of thousands of diseases in the near future, although perhaps in the distant future that may be a possibility.

'This is both an exhilarating and a frightening possibility. With genomic screening you can theoretically identify virtually any genetic disease as well as variations within those disorders that may be important for the baby.

'But in the course of looking at all of the different areas of the DNA there is a risk that we could also misinterpret what we see. We could think that the baby has a disease because we find a variation in the DNA that in actuality is simply a harmless difference. We do not yet know all of the normal variations within the world’s population of individuals. However, we do know that everybody has a different configuration of DNA from everyone else. So therein lies both the promise and the possible complications.'

You’ve got to eliminate the false-positive

He added: 'The promise is that we will be able to identify far more diseases by newborn screening than we are now identifying, many of which are important to identify because we might be able to use early treatments to prevent the complications. Even when we don’t have treatments it would still be of great benefit to the family to have a diagnosis as early as possible in the course of the child’s life.

'On the other hand we may be saying things to families about their children that are totally untrue because we don’t really know the implications of many of these variations. This could cause anxiety, uncertainty and possibly harm, including unnecessary treatment. These promises and concerns are being examined in a multicenter research effort funded by the National Institutes of Health (NIH) in the USA. Four centers are involved. Boston is one of them. We will be examining these questions for five years.  Hopefully, at the end we will all know much more about what to expect if genomic sequencing is added to newborn screening.'

Data overload

Aside from the ethical considerations arising from misdiagnosis (false-positive results), surely, we thought, there is also a danger that genomic screening could generate an overwhelming quantity of data.

Prof Levy commented that ‘Genomic sequencing has the potential to generate an extraordinary amount of data, so we’ll need to decide how wide we open the 'aperture.' Perhaps we will initially focus our search on just a few genes but then later open up the aperture wider to examine many more genes. Questions such as 'How many genes should we look at?' and 'Which genes should we look at?' are encompassed within our study’

Are there benefits to the genomic approach that go beyond screening, we asked. 'If we understand disorders in terms of both their basic genomic aspects and their biochemical aspects we will have more information on which to base our thinking for new therapies,' Prof Levy answered.

'If we know, for example precisely how an enzyme works, we might be in a position to develop therapies capable of restoring activity to that enzyme in a patient with an IEM, converting a disease to a non-disease. Work to develop chaperone therapies for PKU and other diseases would be more successful with a greater understanding of the molecular and biochemical base of the diseases being targeted.'

Tailored treatments

'My hope for the future in PKU therapy is really that we will not only have better treatments for PKU but also that we’re going to have a much better understanding of PKU and other IEMs. Research into PKU could benefit other, rarer, diseases, because there are many similarities among the various diseases that result from abnormalities in the genes of crucial metabolic enzymes or other critical proteins such as those that control cellular transport or immunity. We have already found that discoveries that help one disorder can often benefit others.

'When I first entered the field of biochemical genetics, we knew that these diseases were inherited, that they had some sort of genetic basis. But we had no idea what the genetic basis was or what the genes looked like. Today, we can identify the mutations of just about every individual with an IEM and we can even begin to look at using this information to design, develop and tailor treatments. I am more excited about working with PKU and other IEMs today than when I first began. It’s what keeps me going.'

 

1 - Prof Harvey L. Levy (Department of Pediatrics, Harvard Medical School Boston, Boston, MA, USA)

2 - Levy HL. Newborn screening: the genomic challenge. Mol Genet Genomic Med 2014;2:81-4

3 - Landau YE et al. Genomics in newborn screening. J Pediatr 2014;164:14-9

Harvey Levy

Department of Pediatrics
Harvard Medical School
Boston, United States