(All images in this article were made available by Prof. Henning Stahlberg and the Stahlberg group at C-CINA, Biozentrum, University of Basel. Scroll to the bottom for more detailed descriptions of them).

Click here for Part 1 of this series – Back to the Future.

Part 2: Coping with Biology

It cannot be overstated how complex our biology is. Each cell within us has tens of billions of moving parts spurred by innumerable chemical reactions that enable each one to communicate, respond to their environment, self-replicate and much more. They are the most sophisticated machines in the known universe, and we are made of over 37 trillion of them.

For most of our history, we didn’t even know they were there, yet there they were, driving our every thought, feeling and action. Now, finally, we can zoom in and get a birds-eye view of their worlds to better understand how they do all that they do, and how that impacts all that we do.

This image above is a cluster of cells inside a deceased human brain magnified roughly 10,000 times. When alive, every little blob that you see would have been in constant motion, each playing a role in keeping the person alive.

But from time to time things go wrong, some blobs break down, others stick to one another forming unhealthy clumps. But almost every time our cells figure out how to either fix or contain the problem.

However, there are rare occasions when damage spirals out of control…

Here something has caused the nucleus of the cell to become misshapen. The boundary separating the now Africa-shaped nucleus from the rest of the cell is starting to break down. Before long the disorder will snowball and result in the death of the entire cell.

But that is normal, cells die all the time. In the time it has taken you to read up to this line, an estimated 300 million in you have died.

However, unlike most other cells, the neurons shown above do not get replaced, so as we age their numbers dwindle. In some people that happens faster than in others causing a variety of motor and non-motor problems. We call those cases neurodegenerative disease.

Understanding why this happens and what can be done about it are what researchers studying these diseases try to answer. But getting there is as complex a problem as any we know of.

The good news is we are starting to get a handle on the problem thanks in part to new tools that can show us these basic building blocks of biology in unprecedented detail. Powerful electron microscopes now allow us to study our cells and the molecules within them in 3D at a resolution like never before….

But, we still have a long way to go before we can even dream of fully understanding what is going on inside us. We may not even be equipped with the language necessary to describe in enough detail something so complicated.

Yet, we try to make sense of it anyway, often leaving us rushing to hasty conclusions. We are predisposed to look for order, patterns and meaning, often seeing them where none exist. We are uncomfortable with uncertainty and get drawn towards simple explanations over complex truths.

So it is only natural that when confronted with a challenge as daunting as the biology of neurodegenerative disease that we fall into the trap of confusing evidence for reason. Looking back at our past attempts to treat neurodegeneration, almost all ended in failure because we did not properly account for the complexity we face.

But we should not despair. While understanding the scale of the problem may make the solution seem out of reach, there is a valuable lesson that an appreciation of the complexity of biology has for us.

That is simply that while there are things going wrong inside some of us that can make life more challenging than it used to be, there are trillions upon trillions of things going right that make life at all possible.

Life is the greatest story the universe has ever told. At one time it was just a single microscopic blob floating in a primordial ocean somewhere. Now it blankets almost every square inch of earth and fills each of us with a vast symphony of cells that let us see, touch, hear, smell and experience the world.

One day, when just enough of our cells die, this experience will end. But we should not despair, nor should we get too discouraged by our failures to intervene. Instead, we should embrace the complexity and the uncertainty inherent in the challenges life presents and remember all that has to be going right just to be able to confront these challenges in the first place.

The images in this article are from diseased, post-mortem human brain tissue that has been fixed and resin embedded.

The featured image contains a nucleus in yellow, mitochondria in green, endoplasmic reticulum in purple and vesicles in orange – light orange vesicles are empty, dark orange vesicles are filled (but we can’t specify with exactly what).

In the image of the dying cell, the process of degeneration can be seen. The nucleus becomes misshapen, the DNA condenses and clumps together and the nuclear membrane is disrupted. The cytoplasm surrounding the nucleus shows many disrupted cellular components such as mitochondria, various vesicles as well as fragmented membranes.

The image of an axon shows a cross section through the nerve where the myelin sheath (the insulation that wraps around the length of the axon to speed up the electrical impulses) is visible, as well as various vesicles, mitochondria and neurofilaments that are contained within the axon.

(The descriptions above were written by Amanda Lewis, PhD, postdoctoral researcher in the Stahlberg group)

The video is a reconstructed and color-segmented 3D transmission electron tomogram of aSyn-immunopositive inclusion (Lewy Body). The thickness of tissue section imaged is 150 nm. You can view many more such videos from Prof. Henning Stahlberg’s lab by clicking here.

Special thanks to Prof. Henning Stahlberg, Dr. Sarah Shahmoradian and Dr. Amanda Lewis for the images above and for all their valuable input in writing this.

Coming up in this series...(tentative schedule)

Part 3: What a Cure will be

Part 4: Understanding Drug Development

Part 5: Obstacles to Overcome

Part 6: The Bigger Problems

Part 7: Technology to the Rescue

Part 8: The Promise of Precision Medicine

Part 9: The Role of Patients

Part 10: Where Hope Springs

Part 11: The End of PD – Not with a bang, but a whimper