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Healthy Joint
p
q(S,D)
S
rr
S D
q=q
0
FIGURE 8.29 A front-line tissue with feedback for homeostasis produces damped oscillations of
S
D
D
time
cell numbers.
rp
FIGURE 8.30 Fraction of stem cells rises as the disease onset point is approached.
crash
r proliferation, p
FIGURE 8.31 Dierentiated cell numbers reach zero as disease threshold is approached.
S
D
is feedback process shows damped oscillations and settles down to a proper steady
state. As an aside, we can expect, as in Chapter 3, that such damped oscillations might
entrain to the seasons and lead to seasonal changes in alveolar composition, with more S
cells and thus more surfactant in some seasons and less in others.
We can also solve the model for various proliferation rates p to observe the rise in S
and then the crash as p approaches r. In simulations we use a simple form for the feedback
SD, = qS0D.
q
()
Let’s see what happens when the maximal proliferation rate, p, drops to approach the
stem-cell removal rate, r. By adding Equations 8.2 and 8.3 the dierentiation rate drops out
and we remain with
+=Dd/ tp
()
−−rS rD. At steady-state, therefore, we have:
()
S
D
r
st
=
pr−
st
dS
a result that is independent of the nature of the feedback q(D,S). When proliferation rate p
drops, the ratio of stem to dierentiated cells S/D rises (Figure 8.30) – to keep homeostasis, the
feedback loop increases the number of S cells in order to compensate for the reduction in their
proliferation rate. e fraction of S cells in the tissue diverges as proliferation p drops toward
the removal rate
r (Figure 8.30). When p < r, both S and D cells reach zero (Figure 8.31).
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Exercise 8.3: Stem-cell feedback that keeps constant S.
Consider the following feedback loop. Both stem cells S and D cells secrete factors that
increase dierentiation rate. e dierentiation rate is q
SD, = qS0D.
()
a. Write down the equations for this circuit.
b. Simulate this circuit (or use linear stability analysis) and test whether the steady-state
is stable.
c. Show that the steady-state concentration of S cells is independent of S proliferation
rate p.
d. What is the concentration of D cells as a function of p?
e. Is the eect of this feedback biologically useful?
Exercise 8.4: Oscillations in front-line tissue circuit.
Consider a feedback loop in which D increases dierentiation rate q
SD, = qS0D.
()
a. Write the equations and simulate them.
b. Explain the resulting oscillations in S and D numbers intuitively.
c. Read about the predator-prey model in ecology called the Lotka–Volterra model.
What is the analogy?
d. Why are ecological population models for species population an interesting resource
for modeling cell circuits?
Exercise 8.5: Protected stem cells.
Consider a tissue in which the stem-cell removal rate r
have a sizable removal rate r
.
2
is negligible, whereas the D cells
1
a. Suppose that a feedback loop provides a stable-steady state. What happens to the S/D
ratio as S proliferation p is lowered? Is there a point of collapse?
b. What diseases might characterize such tissues, more oen than tissues with stem
cells at the front line (high r
)?
1
c. Design a feedback loop that provides D levels that are insensitive to variations in
stem-cell proliferation p.
Exercise 8.6: NK cell homeostasis circuit.
NK cells are produced by stem cells in the bone marrow. ey have a high removal rate
, with a lifetime of hours, unless they go into the body’s tissues and nd cells that
r
2
make a survival signal (IL15-IL15R). Most cells of the body produce this survival signal.
When NK cells touch the donor cells, they receive the signal, and their death rate drops
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to zero. NK cells constantly patrol the body and go into and out of the bloodstream and
into the tissues.
a. Write equations for NK cell numbers.
b. What determines the NK cell lifetime of about a week in humans?
c. NK cells were introduced into a mouse mutant that cannot produce its own NK cells.
ese cells lasted for at least 6 months. Explain this result.
d. Explain how this homeostasis mechanism ensures that the number of NK cells
matches the number of cells in the tissues that require NK cell surveillance.
Exercise 8.7: Stem-cell symmetric and asymmetric divisions.
Consider the case where a stem cell can divide to form either two stem cells or two dierentiated cells, 2S or 2D. is is called symmetric division. Asymmetric division is the case
where there is also a third possibility of dividing to produce one D and one S cell.
a. What is the dierence in the mathematical equations for the S and D populations in
the two cases?
b. How does this aect the S/D ratio as proliferation p approaches removal
r?
1
Exercise 8.8: Reducing sickspan and enhancing healthspan
Healthspan is the duration of life spent in good health; the remaining time spent in poor
health and disability is called the sickspan. e sickspan is a heavy burden in terms of
human well being and economic expenditure. Here we use the saturating removal model
to analyze the eect of longevity interventions on the sickspan.
Suppose that poor health begins when senescent cells X cross a threshold X
occurs at threshold X
> Xd.
c
, and death
d
a. Use the saturating removal model Equation 7.5 for the mean damage at a given age to
calculate the mean healthspan and sickspan.
b. Show that longevity interventions that scale the survival curve increase lifespan and
sickspan proportionally. us, sickspan is extended. Relative sickspan, namely sickspan divided by lifespan, is unchanged by the intervention. Hint: interventions that
η
scale are interventions that aect damage production rate
.
c. Show that longevity interventions that steepen the survival curve reduce relative
sickspan. ey extend life mainly by extending healthspan. Hint: these interventions
increase
β
, decrease noise amplitude, or increase both thresholds Xd and Xc.
d. Which type of longevity intervention would you recommend, all things being equal?
e. Senolytics steepen the survival curve whereas caloric restriction scales it. Explain
intuitively from biological principles why senolytics might compress the sickspan
whereas caloric restriction might extend it by scaling it proportionally to lifespan.
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FURTHER READING
Senescent cells and the incidence of age-related diseases. (Katzir et al. 2021)
e Geroscience Hypothesis: Is It Possible to Change the Rate of Aging? (Austad 2016)
A Disease or Not a Disease? Aging As a Pathology. (Gladyshev and Gladyshev 2016)
Pursuing the Longevity Dividend. (Olshansky et al. 2007)
REFERENCES
Armitage, P., and R. Doll. 1954. “e Age Distribution of Cancer and a Multi-Stage eory of
Carcinogenesis.” British Journal of Cancer 8 (1): 1–12.
Austad, Steven N. 2016. “e Geroscience Hypothesis: Is It Possible to Change the Rate of Aging?”
In Advances in Geroscience, edited by Felipe Sierra and Ronald Kohanski, 1–36. Springer
International Publishing. https://doi.org/10.1007/978-3-319-23246-1_1.
Gladyshev, Timothy V., and Vadim N. Gladyshev. 2016. “A Disease or Not a Disease? Aging
As a Pathology.” Trends in Molecular Medicine 22 (12): 995–6. https://doi.org/10.1016/j.
molmed.2016.09.009.
Hernandez-Gonzalez, Fernanda, Rosa Faner, Mauricio Rojas, Alvar Agustí, Manuel Serrano, and
Jacobo Sellarés. 2021. “Cellular Senescence in Lung Fibrosis.” International Journal of Molecular
Sciences 22 (13): 7012. https://doi.org/10.3390/ijms22137012.
Katzir, I., M. Adler, O. Karin, N. Mendelsohn-Cohen, A. Mayo, and U. Alon. 2021. “Senescent Cells
and the Incidence of Age-Related Diseases.” Aging Cell 20 (3): e13314. https://doi.org/10.1111/
acel.13314.
Koelling, Sebastian, Jenny Kruegel, Malte Irmer, Jan Ragnar Path, Boguslawa Sadowski, Xavier Miro,
and Nicolai Miosge. 2009. “Migratory Chondrogenic Progenitor Cells from Repair Tissue
during the Later Stages of Human Osteoarthritis.” Cell Stem Cell 4 (4): 324–35. https://doi.
org/10.1016/j.stem.2009.01.015.
Lander, Arthur D., Kimberly K. Gokoski, Frederic Y. M. Wan, Qing Nie, and Anne L. Calof. 2009.
“Cell Lineages and the Logic of Proliferative Control.” PLOS Biology 7 (1): e1000015. https://
doi.org/10.1371/journal.pbio.1000015.
Lopes-Paciencia, Stéphane, Emmanuelle Saint-Germain, Marie-Camille Rowell, Ana Fernández
Ruiz, Paloma Kalegari, and Gerardo Ferbeyre. 2019. “e Senescence-Associated Secretory
Phenotype and Its Regulation.” Cytokine 117 (May): 15–22. https://doi.org/10.1016/j.
cyto.2019.01.013.
Martel-Pelletier, Johanne, Andrew J. Barr, Flavia M. Cicuttini, Philip G. Conaghan, Cyrus Cooper,
Mary B. Goldring, Steven R. Goldring, Graeme Jones, Andrew J. Teichtahl, and Jean-Pierre
Pelletier. 2016. “Osteoarthritis.” Nature Reviews. Disease Primers 2 (October): 16072. https://
doi.org/10.1038/nrdp.2016.72.
Martinez, Fernando J., Harold R. Collard, Annie Pardo, Ganesh Raghu, Luca Richeldi, Moises
Selman, Jerey J. Swigris, Hiroyuki Taniguchi, and Athol U. Wells. 2017. “Idiopathic Pulmonary
Fibrosis.” Nature Reviews. Disease Primers 3 (October): 17074. https://doi.org/10.1038/
nrdp.2017.74.
Nordling, C. O. 1953. “A New eory on the Cancer-Inducing Mechanism.” British Journal of Cancer
7 (1): 68–72.
Olshansky, S. Jay, Daniel Perry, Richard A. Miller, and Robert N. Butler. 2007. “Pursuing the
Longevity Dividend.” Annals of the New York Academy of Sciences 1114 (1): 11–13. https://doi.
org/10.1196/annals.1396.050.
Chapter 9
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Periodic Table of Diseases
! W o . T celebrate, let’s take a nice
C
deep sigh of relief. Here, we tie together the themes and principles of this book in a
periodic table of diseases.
PERIODIC TABLE OF DISEASES
As a metaphor, consider Mendeleev’s periodic table of elements. In 1869, while preparing a
chemistry textbook, Dmitry Mendeleev noticed patterns in the chemical properties of the
elements known at the time as a function of their molecular weight (Figure 9.1).
ese patterns allowed Mendeleev to predict several new elements (Figure 9.2 white
squares). For example, there was an empty space below aluminum that suggested an element
similar to aluminum but heavier, with a low melting point and a density of about
g/cm3.
FIGURE 9.1 One of the original versions of Mendeleev’s periodic table.
220
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H
BeLi
MgNa
FIGURE 9.2 A modern periodic table with Mendeleev’s four predicted elements in white squares.
N
He
NeFOCB
ArClSPSiAl
KrBrSeAsGeGaZnCuNiCoFeMnCrVTiScCaK
XeITeSbSnInCdAgPdRhRuTcMoNbZrYSrRb
RnAtPoBiPbBaCs TlHgAuPtIrOsReWTaHf
e predicted element, Gallium, was discovered 6 years later with the correct density and
melting point. e other three predicted elements were also discovered in due course.
e periodicity of the table remained a mystery for several decades, until quantum
mechanics oered the explanation in terms of orbitals.
Metaphors are crucial in science. ey let us make inferences about something that is
unknown based on something we know. When we say light is a wave or light is a particle,
we entail certain features of waves or particles on light. If that seems interesting, I recommend the book Metaphors We Live By by Lako and Johnson (2008).
So, let’s use the periodic table metaphor to organize cell types and diseases. Of course,
physiology is much more complex than atoms. e metaphor is imperfect. For example,
it won’t be a periodic table (no repeating period). But there will be patterns and predicted
diseases.
CELL TYPES CAN BE CLASSIFIED BY ABUNDANCE AND TURNOVER
Diseases are traditionally classied in four ways: (1) anatomically, by organ or tissue, such
as heart diseases and liver diseases; (2) physiologically, by function, such as respiratory diseases and metabolic diseases; (3) pathologically, by the nature of the disease process such
as neoplastic diseases (tumors) and inammatory diseases; and (4) etiologically, by their
cause, such as fungal or streptococcal infections.
ese classications are embedded in the international disease code system used to
catalog diseases. More recently, diseases have been arranged as networks, where diseases
with shared genetic risk factors or symptoms are connected by links (Barabási, Gulbahce
and Loscalzo, 2010).
Here, we propose a new classication inspired by the physiological circuit motifs we have
studied. e circuits describe the dynamics of cell numbers and cell turnover. We therefore
arrange cell types in a table by their number (abundance) and their turnover rate. We will
then see how this table reveals patterns of diseases that correspond to each cell type.
Every “element” in the table is thus a cell type (Figure 9.3). e rows go by the number
of cells of that type in the body. is ranges from rare cell types, like the parathyroid gland
8
whose size is like a grain of rice with 10
cells called keratinocytes that make up the several kilos of skin tissue.
cells, to very numerous cell types like the 1012 skin
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Permanent
Periodic Table of Diseases
Tu rnover
Years
Front-line
Years-months
Secretory
Months-days
Barrier
>10
10
10
Number of cells
10
10
10
11
11
10
9
8
7
Bone
Osteocytes
Osteoporosis
Muscle
Myocytes
Sarcopenia
Brain
Neurons
Alzheimer
Brain
Basal ganglia
neurons
Parkinson
Eye
Retina
Macular
degeneration
Eye
Lens
Cataract
s
s
Small blood
vessel
Endothelium
Vascular Fibrosis
Liver
Hepatocytes
Cirrhosis
Heart
Cardiomyocytes
Joint,
Chondrocyte
Osteoarthritis
Kidney
Podocytes
Glomerulosclerosis
Lung
Alveoli
IPF
Liver,
Cholangiocyte
PSC, PBCHeart Failure
Large artery
Endothelium
Atherosclerosis
Vasculitis
Eye
Cornea
Pterygium
Fat,
Adipocytes
Lipoma
Thryoid,
Thyrocyte
Hashimoto
Toxicnodules
Pancreas
Beta cells
Type I Diabetes
Pituitary,
Somatotropes
Acromegaly
Pituitary
Corticotropes
Cushing
s
s
Breast,
Ductal cells
Ductal
carcinoma
Adrenal cortex
Epithelium
Addison
s
s
Cushing
Skin
Melanocytes
Vitiligo
Parathyroid
Chief cells
Hyperparathyroidismthyroidism
Pituitary
Gonadotropes
Hypergonadismgonadism
Skin,
Keratinocytes
Dermatitis
Intestine,
Epithelium
Inflammatory
Bowel Disease
Lung
Bronchial
Epithelium
Asthma
Stomach
Parietal cells
Pernicious
Anemia
Nasal
Epithelium
Rhinitis
Organ
Cell type
Disease
Cell numbers for some organs are shifted for visual clarity
FIGURE 9.3 Periodic table of cell types and diseases. Selected cell types with major non-commu-
nicable diseases are arranged according to cell number and cell turnover/tissue function. Disease
class is indicated in color. Cell numbers for basal ganglia are shied for clarity.
To be more tangible, a billion cells weigh about a gram. Exceptions are large cells like
neurons, fat cells, and muscle cells which are each 100 times bigger than most cells, so that
the 1 kg brain has about 10
e columns go by the turnover time of the cell types. Some cell types, like neurons,
have no turnover in adulthood. ey are called permanent cell types. Other cell types, like
fat cells, have turnover times of many years. Still others, like liver hepatocytes, turn over
10
neurons.
Degenerative
Disease class
Autoimmune
Toxic adenoma
Immune
hypersensitivity
Tumorprevalence
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with a timescale of a year. Most organs have turnover times of months, with an average
cell turnover of about 100 days in the body (Sender and Milo 2021). Barrier tissues which
stand between the outside and inside typically have the fastest turnover, such as 50d for
skin keratinocytes and a few days for the gut epithelium.
e position of a cell type in the table, namely its abundance and turnover, is determined by its physiological function. For example, the size of an endocrine gland is roughly
proportional to the size of the target organs. Glands that supply a hormone to the entire
10
body weigh about 10 g, like the thyroid and adrenal. eir 10
cells can make the required
amounts of hormones. In contrast, glands that need to supply only a relatively small target
organ have fewer cells. Pituitary gland cell types, like those that make ACTH for the adre-
7
nal, weigh about 0.01 g, or about 10
cells. is is perfect for supplying enough hormone for
their 10 g target organ.
e same goes for larger secretory organs. At 1 kg are the liver hepatocytes that produce
massive amounts of proteins and metabolites. In the 10 kg range are the skin and fat, all
according to their purposes. Skin covers a large area, fat stores fuel.
Turnover is likewise determined by function. Neuron circuits which encode information are permanent and do not replace their neurons. In contrast, barrier cells like skin
cells face damage and need to be replaced oen.
THE TABLE SHOWS BROAD PATTERNS OF DISEASES
We now consider the main diseases of each cell type, listed in red in each element box
(Figure 9.3). e point is that the diseases show patterns in the table. Each column has its
own class or classes of diseases. ese classes are shown in color, corresponding to degenerative diseases, progressive brotic diseases, autoimmune diseases, toxic adenomas, and
immune hypersensitivity diseases. e orange triangles represent the prevalence of benign
tumors and cancers (Figure 9.3).
e rst hint of this way of arranging diseases arrived when Yael Korem and I asked
which endocrine organs get autoimmune diseases and which do not. We saw a pattern
9
in which organs with less than 10
9
cells get autoimmune diseases, as discussed in Chapter 4. I then began experimenting
10
with the relation between diseases and cell number and turnover around 2019, and the
table slowly took. Its current graphical form arose in discussion with several scientists,
especially Michael Elowitz.
Is it a table of diseases or cell types? Because we consider cell-type-specic diseases, it is
both, where each disease has a cell type, and each cell type can have several diseases.
In this chapter, we will analyze the patterns in the table and their origins in the circuit
motifs.
First, however, there are some caveats. e table in Figure 9.3 includes only a small fraction of the cell types in the human body, and only the most prevalent diseases. It is a working dra for us to see patterns. Some classes of diseases do not t easily into the table. is
includes systemic diseases such as lupus and psychiatric diseases such as bipolar disorder,
schizophrenia, and depression.
cells get toxic adenomas while organs with more than
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CANCER RISK RISES ALONG THE DIAGONAL OF THE TABLE
To explore the patterns in the table, let’s start with cancer prevalence (including benign
tumors). e lifetime risk of cancer in a given cell type rises along the diagonal of the
table: the more cells and the more exposure, the more mutations in a lifetime and the
higher the cancer risk (Figure 9.4).
e main eect is the number of cells. Cells accumulate about 50 mutations per year,
regardless of their division rate (Cagan et al. 2022; Miller 2022). Each cell division adds
several additional random mutations. e more cells, the more the risk of a cell with oncogenic mutations. e dependence on total cell number is evident in the increasing risk of
cancer with height. Each 10 cm of height raises the risk of cancer by a factor of about 1.1.
Males have overall 20% more risk of cancer than females, due in part to height dierence.
is picture modies previous notions that the main determinant of cancer risk is the
number of lifetime stem-cell divisions (Tomasetti and Vogelstein 2015; Tomasetti, Li and
Vogelstein 2017), a theory that could not explain prevalent tumors in slowly dividing tissues. Abundant but slowly dividing cell types get common tumors; these tumors, thankfully, are benign – they don’t spread to make metastases and are not lethal. is includes
fat cells that have a turnover of years but show lipomas in at least 2% of people. Small blood
vessels (capillary endothelial cells) are also very abundant, amounting to 2 kg in a 70 kg
person, and get benign angiomas in most people with age.
>10
10
10
11
11
10
Permanent
∞
Front-line
years
Turnover
Secretory
Yeary-months
Barrier
months-days
Cancer
9
10
Number of cells
8
10
7
10
FIGURE 9.4 Risk of cancer, represented by the orange triangles, rises with cell number, cell turn-
over, and exposure to environmental toxins and mutagens.
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Exposure to toxins and mutagens further enhances risk, which is why the risk is highest in
barrier tissues – the rightmost column in the table. Barrier tissues are exposed to factors that
cause mutations and inammation, such as UV in the skin, smoking in the bronchi of the lung,
and toxins in the gut. ey hide their stem cells in a protected niche, as far from the damaging
factors as possible. ese tissues get prevalent tumors: skin basal cells result in benign tumors
in 30% of people; colon and bronchi give rise to colon cancer and lung cancer, each in about 3%
of the population; these two currently account for most of the deaths from cancer.
In contrast, permanent tissues cease to divide in adulthood and almost never get cancer
in adults; their rare cancers occur in childhood, such as neuroblastomas and osteosarcomas
(bone).
SECRETORY CELLS SHOW THREE ZONES: TOXIC
ADENOMAS, AUTOIMMUNE DISEASES, AND CANCER
Each column in the table has its own pattern of diseases. Let’s start with the column of
secretory cells (Figure 9.5), because we have seen it before in Chapter 4.
e secretory cells have a turnover time on the order of weeks to months, except for
some cell types like beta cells which have slower turnover in adulthood. Listing the most
common diseases of these cell types indicates a striking pattern with three zones of diseases according to cell number.
Turnover
Permanent
∞
11
>10
11
10
10
10
9
10
Number of cells
8
10
7
10
Front-line
years
Cancer
Autoimmune
diseases
Toxic
adenomas
Secretory
Yeary-months
Fat,
Adipocytes
Lipoma
Thryoid,
Thyrocyte
Hashimoto’s
Toxic nodules
Pancreas
Beta cells
Type I Diabetes
Pituitary,
Somatotropes
Acromegaly
Pituitary
Corticotropes
Cushing’s
Breast,
Ductal cells
Ductal
carcinoma
Adrenal cortex
Epithelium
Addison’s
Cushing’s
Skin
Melanocytes
Vitiligo
Parathyroid
Chief cells
Hyperparathryoidism
Pituitary
Gonadotropes
Hypergonadism
Barrier
months-days
FIGURE 9.5 Secretory cells show three zones: toxic adenomas at the smallest cell numbers, auto-
immune diseases between a billion and 10 billion cells, and cancer at higher numbers of cells.
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