Personalized Medicine: A Cure for HIV

Personalized Medicine – finding the right treatment for the right patient at the right time – is quickly becoming a buzzword both in the medical field but also to the public. But is it just hype? No!  I discussed a number of examples of how personalized medicine is currently be used in breast cancer in a previous post. In this and future posts, I’ll talk about a few fascinating emerging examples of the promise of personalized medicine.  These are NOT currently being used for patient treatment as part of standard of care, but could be someday.

HIV

HIV lentivirus

The Human Immunodeficiency Virus (HIV), the cause of AIDS, is a virus that attacks the immune system.  This attack prevents immune cells from fighting other infections.  The result of this is that the patient is more likely to acquire other infections and cancers that ultimately kill them.  When first discovered in the early 1980s, HIV infection was a death sentence. Untreated, survival is 9 to 11 years.  In the past 30 years, antiviral treatments have been developed that, when taken as prescribed, essentially make HIV infection a chronic disease, extending life to 25-50 years. But there is no cure for HIV, and as of 2012, over 35.3 million people were infected with the virus.

The lack of a vaccine to prevent the disease or of a cure to treat those infected isn’t because no one is trying. Since the virus was identified as the cause of the disease, scientists have been working to find a prevention or cure (along with developing all of the antiretroviral drugs that delay/treat the disease). I’m not going to discuss all of this interesting research (though it is worthy of discussion), instead I’m going to talk about one patient, Timothy Ray Brown, who was cured of HIV/AIDS through a stroke of genetic understanding and luck!

Brown was HIV positive and had been on antiretroviral therapy for over 10 years when he was diagnosed with leukemia in 2007. His leukemia – Acute Myeloid Leukemia (AML) – is caused by too many white blood cells in the bone marrow, which interferes with the creation of red blood cells, platelets and normal white blood cells. Chemotherapy and radiation are used to treat AML by wiping out all of the cells in the bone marrow – both the cancer cells and the normal cells. Brown’s doctors then replaced the cells in the bone marrow with non-cancerous bone marrow cells of a donor.  This is called a stem cell transplant, and it is commonly used to treat leukemia – often resulting in long term remission or a cure of the disease.

But the really cool part of this story isn’t the treatment itself.  Rather it’s that that Brown’s doctor selected bone marrow from a donor that had a mutation in the gene CCR5. So what? The CCR5 protein is found on the outside of the cells that the HIV virus infects. CCR5 is REQUIRED for the virus to get inside the cell, replicate, and kill the cell. Without CCR5, HIV is harmless. There is a deletion mutation in CCR5 called delta32 that prevents HIV from binding to the cell and infecting it.  Blocking HIV from getting into the cell prevents HIV infection.  In fact, it’s been found that some people are naturally resistant to HIV infection because they have this deletion. Two copies of the gene are found in 1% of the Caucasian population, and it’s thought that this mutation was selected for because it also prevents smallpox infection.
HIV_ccr5So Brown’s doctors repopulated his bone marrow with cells that had the CCR5-delta32 mutation.  This didn’t just cure his leukemia but it also prevented the HIV from infecting his new blood cells, curing his HIV. He is still cured from HIV today!

What does this mean for others who are infected with HIV? Is a stem cell transplant going to work for everyone?  Unfortunately, no. This mutation is very rare, so finding donors with this mutation isn’t feasible.  Plus, this is a very expensive therapy that comes with risks such as graft-versus-host disease from the mismatch between the person receiving the transplant and the transplanted cells themselves. However, there are possible options to overcoming these challenges, including “gene editing.” In this method, T cells from HIV-positive patients would be removed from the body and then gene editing would be used to to make the CCR5-delta32 mutation in these cells.  These cells could then be re-introduced into the patient.  With the mutation, HIV won’t be able to infect these T cells, which would hopefully cure the disease, while avoiding some of the major graft-versus-host side effects. A small clinical trial tested this idea in 2014 (full article can be found in the New England Journal of Medicine), and HIV couldn’t be detected in one out of four patients who could be evaluated. Although this is a preliminary study using an older gene-editing technique, it shows promise for “personalized gene therapy” to potentially cure HIV.

How scientists “cured” melanoma

When talking about Personalized Medicine, one of the recent shining examples of this concept in practice is in the treatment of melanoma. Melanoma is a cancer of the pigment cells called melanocytes and is most commonly diagnosed as a skin cancer. The prognosis for melanoma is dismal when caught at later stages where the cancer cells have spread into lower layer of the skin or throughout the body (see the stats in the image below). Treatment typically involves surgery to remove the cancer cells, followed by chemotherapy and/or radiation therapy, but the response to these treatments is low.

melanoma

There are two interesting personalized medicine examples for melanoma.  The first is in determining whether a low stage (I or II) melanoma has a likelihood of spreading.  Once a low stage melanoma has been removed by surgery, there is still a 14% chance that these patients will develop metastatic (melanoma that spreads) disease. To determine which patients are more at risk, a biotech company developed DecisionDx-Melanoma. This test looks at the expression of 31 genes and separates the patients into two groups based on the gene expression profiles.  One group only has a 3% risk of developing invasive melanoma within 5 years whereas the other group has a 69% chance.

However, whether the cancer progresses or not, treatment is still an issue. That is, it was until a few years ago when scientists found that  50-60% of all melanoma patients have a mutation in the gene called “BRAF.” This mutation tells the cancer cells to grow faster, so you can imagine that if you stop this signal telling the cancer cells to GROW, then they might stop growing and die. This is exactly what the drug PLX4032 (vemurafenib) does – it inhibits this mutated BRAF and stops the cancer cells from growing in 81% of the patients with this mutation (see the photo at the bottom of the post to see how dramatic this effect is).  On the other hand, in patients without this mutation, the drug has severe adverse effects and shouldn’t be used.  Because of this, doctors don’t want to prescribe this treatment to patients without the mutation.  Therefore, scientists created a companion diagnostic.  These are tests that are used to identify specific mutations before treatment to help decide what treatment to give (see image below). In the case of melanoma, this companion diagnostic tests if the patient has the BRAF mutation, and the patient is only treated with vemurafenib if they have this mutation.

This treatment was revolutionary with an incredible ability to cure melanoma. It was like melanoma was previously being treated with the destruction of a nuclear bomb, and now it is being treated with the precision of a sniper rifle – targeting the exact source of the cancer. So why is the word “cure” so obviously in quotes? Unfortunately, after continued therapy, the cancer relapses (see the image below). Imagine treating cancer cells being like closing a road- it’ll block up traffic (kill the cancer cells), but then you’ll be able to find back roads that get you to the same place.  In the case of cancer, the drug is targeting mutations in BRAF, and BRAF finds ways to evade the drug by mutating again (effectively removing the roadblock).  Or the cancer cells themselves may have other routes besides mutated BRAF making the cancer grow. So although this drug is a life extender, scientists have been working to combine it with other targeted drugs (blocking off alternative routes) to make it a long-term life saver.

melanoma_relapse

From the Journal of Clinical Oncology

What is a biomarker? A cornerstone of personalized medicine.

What is a biomarker? Biomarkers are biological measures of health or disease and are a cornerstone for personalized medicine.Historically, diagnosing a disease was based on symptoms. This reminds me of a joke.  A patient goes to see the doctor and tells him “Doctor, I hurt everywhere.” The patients touches his head “I hurt here”, he touches his arm “I hurt here”, he touches his stomach “I hurt here” and on and on.  The doctor looks at him and says “I know what’s wrong with you!  You have a broken finger!”

No one wants to be diagnosed or misdiagnosed with a broken finger. This isn’t to say understanding symptoms and using this information to contribute to a diagnosis isn’t important.  But what if…
…symptoms don’t lead to an obvious diagnosis?
…two patients have the same symptoms, but different diseases?
…two patients have the same disease, but different causes – either the root cause is different or they both have lung cancer but the genetic mutations in each cancer is different.  In this case different treatments would be are needed.
…two patients have different diseases, but similar causes – maybe they both have the same genetic mutation in two different kinds of cancer –  so the same treatment can be used?

biomarkerThis is where biomarkers come in.  Biomarkers are things in the body that can be measured to give us information about a disease or other condition.  Biomarkers can be a variety of things including

  • Imaging methods
  • Genes (presence or absence)
  • Specific gene mutations
  • Proteins or antibodies
  • Metabolites
  • Microbes?

And these things can be measured to in some way indicate if the person is healthy or has a disease.  Other biomarkers may be used to detect a disease earlier than when the patient is showing symptoms.  Detecting a disease early may allow the patient to change a behavior to decrease the likelihood of developing the disease or to start treating a patient earlier when it is easier to successfully treat a disease. Biomarkers may also be used to determine the severity of a disease or whether or not the disease is progressing.

biomarker_types
Some biomarkers that you may be familiar with are cholesterol, temperature, and blood pressure.  There are a number of biomarkers for pregnancy. Home pregnancy tests look for the presence of the protein beta human chorionic gonadotropin (also called beta-HCG) in the urine.  This protein biomarker is in the blood after the zygote implants 6-12 days after fertilization.  Other biomarkers such as serum creatinine and liver enzymes are markers for kidney and liver function, respectively.

So what makes a good biomarker?  First, it needs to be different if the patients has a disease.  For example, higher than normal blood glucose levels may indicate that a patient has diabetes and these levels of blood glucose would not be found in a patient who didn’t have diabetes.  Second, the biomarker would have to correlate with the outcome.  What this means is that as the patient’s condition changes, the biomarker would also change. In the case of the patient with high blood glucose and diabetes, when the patient starts regulating their diet or taking insulin, the blood glucose levels will go down.  Third, biomarkers should be easy to access, and one of the main reasons for this is so that testing for the biomarkers isn’t too expensive.  Blood is a common location for biomarkers, including in our example of blood glucose levels.  Finally, biomarkers should be consistent.  It wouldn’t be useful to have a biomarker that changes based on whether it’s noon or midnight.  It needs to be dependent on the health of the patient.

Biomarkers are a cornerstone of personalized medicine because they allow clinicians to use symptoms along with measurable and quantifiable factors in the body (the biomarkers) to diagnose, track, and treat disease. Learn more about biomarkers in this YouTube video

What is a biobank? And why do scientists collect human tissue for research?

To understand what a biobank is and why they exist, it helps first to understand what type of “currency” is stored in the “bank” and what this “currency” will be used to purchase. Biobanks are a collection of “biospecimens” (the “currency”) and knowledge through research or preservation is often what can be “purchased” with this currency.  And as a quick FYI, biobank and biorepository are words that can be used interchangeably to describe the same thing.

Biospecimens can be any type of biological sample or material.  Seed biobanks, like the Svalbard Global Seed Bank in Norway, hold tens of thousands of seeds from over 4000 essential food crops.  The purpose of this biobank is to function as a back-up for seeds being stored in various countries. If a crop is wiped out because of disease or a zombie apocalypse, these seeds can be used to grow these crops again a biobank.

butterflies

photo credit Christian Guthier

The collection of birds, insects, butterflies, spiders and other animals and plants stored at the National Museum of Natural History at the Smithsonian Institute are also considered a biorepository.  There are a few reasons that these types of collections exist.  First, they are interesting to the public to show off the diversity of animals and plants found around the world and throughout time (I mean, who doesn’t like dinosaurs?).  But more than that, they are also immensely useful to scientists interesting in studying the animals themselves – including extinct animals, diversity, and evolution.

Biobanks that contain human tissue are most applicable to the study of humans and disease.  The biospecimens stored in these biobanks may include urine, blood, tissue (for example, extra tumor tissue removed during a surgery), feces (aka poop), cells (for example, cells scraped from the inside of the cheek or skin cells), cerebral spinal fluid, DNA or RNA.   The purpose of repositories that store tissue and fluids from people is to better understand diseases and use this understanding to develop molecular diagnostics and treatments. How is this done? Generally, scientists will compare biospecimens from many patients with a particular disease (for example, tumor tissue removed during surgery from patients with breast cancer or blood from patients with diabetes) to samples from patients who do not have that disease using one of those “-omic” analyses. Through understanding what causes the disease, methods can be devised to better detect the disease early or treatments can be developed to target the cause.

biobank_purpose

But you may be wondering how tissue biorepositories exist at all?  It is all because patients have been gracious enough to contribute some tissue, blood, skin, or nails for researchers to use in their research.  Biorepositories do not own this tissue and neither do the researchers – we are merely custodians of the tissue with the ultimate purpose to use the biospecimens for research.  The patient always comes first. Therefore, the first thing that is done before collecting tissue for research is to talk to the patient and explain why it is biobankers would like to collect and store their tissue.  The risks are explained and we ask for their permission through a process called informed consent (more on this in future posts).  If a patient does not consent to donate tissue for research, this does not affect their care in any way whatsoever.  It is the patients choice.  However, if they do agree to donate tissue, it will either be collected in the operating room (in the case of tumor tissue) or in pathology.  This tissue collection never disrupts medical care or diagnosis.  If all of the tissue is needed for diagnosing the patient, then that’s what happens and none is collected for research. Again, the patient and their medical care always come first.  If we are able to collect samples, they are stored in liquid nitrogen tanks until they are requested by a researcher.  We then make sure that the samples safely get to the researcher.biobank_workflow

Thousands (likely hundreds of thousands) of studies have relied on biospecimens to better understand the underlying disease in or to develop treatments.  For example, tissue from melanoma patients was used to identify a mutation found ~50% of patients who have melanoma.  This mutation can be specifically targeted by a drug that significantly improved progression-free survival in patients who typically have a dismal prognosis.  Even more studies on ongoing, with the goal of using knowledge gained from these priceless biospecimens to reach the promise of personalized medicine.

How do mutations change proteins?

We’ve talked about mutations and how they can be good, bad or neutral, but how does that work exactly?  This is the nitty gritty. Remember back to how DNA is transcribed into messenger RNA which is then translated into the protein?  This is based on a three letter code – where each 3 letters of the RNA makes on amino acid. (If you’re interested in knowing how 4 nucleotides, which have 64 possible combinations makes only 20 amino acids, see my Answers page). If you change one of these amino acids a number of things can happen.

To make it easier, let’s pretend that these codons make the sentence “DNA HAS ALL YOU CAN ASK FOR” (see the picture below).  You may change one letter and it doesn’t change the meaning of the sentence (or the function of the protein) at all, making it a “silent” mutation. You may change one letter and it does change the meaning, but maybe not significantly – this is a missense mutation.  You may have a mutation that stops the sentence early – this would make a protein that is shorter than it’s supposed to be and probably will cause the protein to function improperly.  This is a nonsense mutation. Finally, you may add or remove one or many nucleotides which shifts the letter of the sentence so that they no longer make any sense.  These frameshift mutations also will affect the protein, and likely not in a good way.

protein_mutationsNow you can see how small changes may or may not affect the protein.    It’s interesting because it helps really explain how ONE nucleotide change can affect a protein and cause disease.  Also, if you think about the effect one nucelotide change can have, it helps us understand how finding and understanding these changes can be important for diagnosing disease.