We're finishing our discussion of oncogenes and moving into stem cells.
The presence of an oncogene, such as Sark, causes cancer.
This was discovered by Temin in 1910 with Rous sarcoma virus.
Later studies in the 1970s-1980s used recombinant DNA to create Delta RSV.
Sark was present in all chicken cells, so the mutation of C-Sarc (a normal tyrosine kinase regulating cell growth) into V-Sarc (a constitutive kinase with constitutive signaling) causes cancer.
Michael Bishop and Harold Barmus won the Nobel Prize for discovering this.
Examples of proto-oncogenes being converted into oncogenes -- genes that you turn on, but don't turn off, like Ras.
Another type of mutation that causes cancer is the loss of a tumor suppressor gene like p53, which prevents damaged DNA from being replicated.
Losing p53 functionality is bad for both initial cancer development and making it worse.
Tumors acquire multiple mutations by the time cancer kills you.
Half of cancer patients have lost p53.
We have 2 copies of every gene so we don't have a problem until we lose both functional copies of p53.
Tumor suppressor genes are recessive, while oncogenes are dominant.
Mutations that Cause Cancer
Types of mutations that generate cancer:
Coding mutation: changes the sequence of the gene.
Introduce a mutation in the DNA.
The RNA sequence is incorrect.
The protein is hyperactive (e.g., Ras never turns off).
Gene amplification: more copies of the DNA.
Nothing wrong with the gene sequence.
More copies of DNA result in more RNA and more protein.
Chromosome rearrangement: a new promoter is placed in front of the DNA.
The gene itself is not mutated, nor is its quantity.
The new promoter is more active, resulting in more RNA and more protein.
Fusion protein: recombination in the DNA causes chunks of DNA to move around, resulting in two proteins glued together.
RNA comprises two proteins glued together.
A new piece gets glued on yielding a hyperactive protein.
Too much growth signal could be sent by proteins in some cases with other cases involving merely too much protein.
Overexpression of the Egf Receptor
Instead of a normal density of Egf receptors, you get many.
You can have 10 to 50 times the normal levels of Egf receptor.
The receptors are super crowded, leading to autophosphorylation even without the Egf ligand present.
This cross-phosphorylation turns on the cell and tells it to grow, even without Egf, leading to growth factor independence
Autocrine signaling is another growth factor independence mechanism.
A cell gains the ability to secrete its own mitogen (Egf), telling itself to grow regardless of neighbors' signals.
Truncated Egf Receptor
A truncated Egf receptor has a mutation without the part that binds the Egf ligand.
The truncated Egf receptor turns on regardless of whether Egf is there and this receptor cannot even bind to Egf.
Erisa is a lung cancer drug that targets a specific type of truncated Egf receptor, turning it off.
Erisa works great in 10% of patients, there is a dramatic reduction in the tumor, but does nothing for the other 90%.
We can analyze the genetics of a tumor to see if the patient has this mutation and would benefit from Erisa, an example of patient-specific medication.
Stem Cells
Stem cells were first understood in the 1960s with the discovery of hematopoietic stem cells.
Radiation effects were studied after nuclear bombs were created, when scientists realized they didn't know the effects of radiation exposure.
Mice were irradiated and died in around 30 days. Bone marrow transplants were discovered and rescued the irradiated mice so that they didn't die.
As few as 10,000 bone marrow cells were enough to rescue a mouse.
Sometimes it worked with fewer than 10,000 cells, but sometimes those transplants failed, it was very binary.
Just one cell was enough to rescue the mouse.
Clones of this single cell could also rescue other mice.
This magic cell is the hematopoietic stem cell, which can turn into long-term and short-term hematopoietic stem cells.
The short-term hematopoietic stem cells will create the myeloid lineage (red blood cells, platelets, granulocytes, macrophages) and the lymphoid lineage (B cells, T cells, natural killer cells) and the dendritic cells -- every single blood cell type.
The single transplanted cell can rescue the entire blood supply.
The long-term hematopoietic stem cell can differentiate into the short-term, and then the myeloid and lymphoid lines of cells, and it can also clone itself via self-renewal.
The short-term hematopoietic stem cells can also self-renew, but do it faster.
Hematopoietic stem cells are needed to make new blood; without them, you can't make new blood.
Blood cells, especially red blood cells, last about 120 days before they are replaced.
Stem Cell Balance
Stem cells make new differentiated cells, which are the myeloid and lymphoid cells.
Stem cells must also self-renew.
The stem cells need to maintain a 1:1 balance between self-renewal and differentiation.
Too much self-renewal leads to a buildup of stem cells, if there too little self renewal, we risk losing the population.
The hematopoietic stem cells have slow cycling (copy DNA less often), while short-term hematopoietic stem cells undergo fast cycling in the rapidly dividing state.
Fast cycling means racing through the cell cycle as fast as possible.
A typical human cell completes a cell cycle in about 24 hours.
Every time DNA is copied, there is a chance of error.
Even with error-checking machinery, one to three errors can be missed each duplication.
Errors can lead to uncontrolled growth and cancer.
Stem cells use slow cycling to maintain high-quality DNA.
Short term stem cells are produced to take care of any short fall of not replenishing the blood supply sufficiently.
Other Stem Cell Types
Stem cells exist in many tissues, aiding in healing when there is damage.
Other stem cell types include:
Intestines
Skin and hair (generated by the same stem cell)
Bone and cartilage (mesenchymal stem cell)
Neural stem cells (limited ability to make new neurons)
Cardiac stem cells (limited ability to renew heart tissue)
Hematopoietic stem cells and mesenchymal stem cells are multipotent, making a bunch of different cell types.
Pluripotent stem cells can make anything.
The intestinal lining takes a lot of damage due to consumption of various foods and exposure to carcinogens, and requires renewal every 3 to 4 days.
Intestinal Stem Cells
In the intestines, intestinal crypts exist with a handful of stem cells at the bottom, away from the surface.
Next to the stem cells are other cells that help the stem cells stay as themselves.
Further up the crypt, the stem cells turn into transit amplifying cells that cycle quickly.
The stem cells cycle slowly, while the transit amplifiers cycle quickly.
The villi are finger-like protrusions that stick up into the intestines to absorb nutrients.
Mucus-secreting cells create a lining of mucus.
Absorptive cells absorb nutrients.
Both mucus-secreting cells and nutrient absorbers come from the stem cell in absorptive cells.
The cells start off on the bottom, move up, become transit amplifiers, and then differentiate into fully differentiated cells.
The cells walk up the villi, and when they get to the end, they undergo programmed cell death.
Colon cancer has a chance to develop, but these defense mechanisms are in place to prevent it from happening.
Homeostasis
Maintaining proper cell number requires homeostasis.
Feedback control mechanisms are important for cell number regulation, like maintaining blood volume or intestine size.
Blood Regulation
The body has about 10 liters of blood, with 5 \times 10^{12} red blood cells per liter.
The process of making 10^{10} red blood cells every hour maintains this system.
At sea level, the amount of oxygen is normal; at higher altitudes the concentration declines.
If people spend a few days in a location with low oxygen concentration such as in the mountains in Mammoth, California, their body adjusts.
Denver, Colorado is known as the 'mile high city'. The people from Denver practice and live in low oxygen concentrations, thus conditioning them when competing with athletes in sea level conditions.
Erythropoietin (Epo) is an endocrine signal secreted into the blood for red blood cell control.
If blood oxygen is low, the kidneys release Epo.
Epo slows down the rate at which red blood cells decompose, increasing the blood oxygen level, giving the body time to adjust and acclimate to the higher altitudes.
Injecting recombinant Epo is a form of illegal doping, particularly among endurance athletes, thus, Epo is banned in many events.