Lysosomes have diverse roles in defense and immunity, cellular nutrition and energy balance as well as
the recycling of critical building blocks for repair and reconstruction. While the lysosome is implicated in
numerous diseases, including those that are acquired, the study of Cell Biology owes much to the inborn
errors of lysosomal metabolism. These disorders continue to attract the most intense gaze and attention:
driven by the need for definitive diagnosis and therapeutic advance, medical research into more than 90
such disorders has also generated prodigious discoveries in Biology.
The close relationship of Cell Science to Medicine has revealed specialized activities of the organelle that
are critical for the development of the senses, resistance to microbial infection (including viruses), and
the recognition of self- and non-self in the innate immune response. Lysosomal metabolism of
endogenous and exogenous nucleic acids is a critical component of a thematic mechanism for the
homeostatic regulation of immunity, prevention of autoimmune activation, and control of the
inflammatory responses.
Here we will trace the intermingled science of the lysosome within medicine – and show that beyond the
classical lysosomal components identified by De Duve, our burgeoning understanding of lysosomal
proteins identified through pathological research by others, can have far-reaching clinical consequences.
Beyond the diseases of the past, we will also survey newly discovered genetic disorders of lysosomal
function, including those that affect membrane trafficking.
Lysosomes occupy a position of commanding importance in Cell Biology but once understood, this
humble genome-deficient organelle is peculiarly susceptible to therapeutic attack. The conceptual links
are so close that every successful treatment reflects not only the triumph of scientific thought in
clinical practice but a true debt of Science to Medicine.

In 1983 when my 4 year old son Brian was diagnosed with Gaucher Disease, we were told he did not have much time to live.

Two weeks and many tears later, my mother contacted the Weitzman Institute and was told that Dr. Roscoe Brady of NIH was the world expert and NIH was 10 minutes from my home.

I left my integrative family medicine practice and went to work gratis in Dr. Brady’s lab.

4 months later, Brian was severely anemic and on the edge of cardiac failure. Dec 22,1983 he was the first person in the world to receive the modified GCase developed in concert by NIH and the fledgling Genzyme Corporation. He was on and off the enzyme for 3 cycles of 7 weeks each and it became clear the enzyme was reversing all of his symptoms.

2 larger trials later, Ceredase was approved by the FDA in 1991. Subsequently, I went to Israel and with Dr. Ari Zimran we got approval.

Back in 1984 my family started the National Gaucher Foundation which supported research and patient education. Subsequently other foundations formed abroad.

Since then, the field of LSD’s has expanded tremendously based on the experience of one child- and seeing that something formerly impossible was indeed possible. Had all the bureaucracy, gold standard insistence, and ponderous regulation in today’s world been in place then, it is difficult to say what would have happened to my 3 (6 kids) with Gaucher and countless others.

Moderator: Uma Ramaswami, UK

Very Important: Aimee Donald, UK
Overrated: Majdolen Istaiti, Israel
Discussion

Moderator: Atul Mehta, UK

Very Important: Derralynn Hughes, UK
Very Concerning: Tanya Collin-Histed
Discussion

First you should read the NIH definition of a disease for which you want to find a suitable biomarker. For example, sometimes described is an enzyme deficiency that has clear consequences in biochemical pathways in the body (e.g. Fabry, Gaucher). In this case you have to search for defined molecules and hopefully you can find one or more substances that can be useful as biomarkers for diagnosis or prognosis or indicate therapeutic intervention. If this route is out of question an untargeted biomarker search would be necessary. With HPLC-Orbitrap MS you could use a separation and detection system that,  under optimised conditions, is able to see about 100.000 signals (=substances) from blood or urine. These signals you can print out as chromatograms e.g. as 1 m/z in the range of e.g. 80 – 1200 m/z (as I do). Usually I compare five cases versus five controls (or ten versus ten) by eye and can find differences between these groups. Then I look deeper and can find an ion like 254.178. The chromatogram with this ion is extracted in all measured patient and control samples. Then the peak area or peak height is compared. Often there is no clear difference for case versus control and you can disregard this ion = signal = substance. But if you are lucky you will find a substance where a huge difference between case and control indeed exists. The next question must be: Does this difference come from the specific disease or was the selection of control samples imperfect (e.g. differences in diet, genetic background, sex, …). More samples often have to be analysed before the magic word “fitting biomarker” can be used.