In the Lab

On Cancer: Memorial Sloan Kettering Investigators Synthesize Vital Biological Molecule Erythropoietin for the First Time

By Julie Grisham, MS, Science Writer/Editor  |  Monday, October 8, 2012
Pictured: Structure of Synthesized Erythropoietin A ribbon structure of synthesized erythropoietin. The green represents the protein portion, and the blue, yellow, and pink shapes represent the carbohydrates.

For the first time, a team of Memorial Sloan Kettering investigators has synthesized erythropoietin (also known as EPO), the hormone that controls the production of red blood cells. The researchers, led by Samuel J. Danishefsky, a member of the Molecular Pharmacology and Chemistry Program in the Sloan Kettering Institute, have also shown that the molecule they produced in the laboratory functions in the manner of natural erythropoietin.

A culmination of ten years of work, the accomplishment is a significant advance in the chemical synthesis of complex biological molecules from basic building blocks: simple amino acids and carbohydrates. Furthermore, the researchers believe that being able to synthesize this vital molecule will enable them to learn more about how EPO functions as well as how the body makes proteins with complicated structures.

“This work opens up a new chapter in protein chemistry because we can now use chemical synthesis to make very complex molecules that have previously been thought to be producible only by nature,” says Dr. Danishefsky, senior author of the study published online September 25 in the chemistry journal Angewandte Chemie. “Being able to make large biological molecules such as hormones in the laboratory can lead to many new avenues of research.”

A Hormone Essential to Life

Erythropoietin, which is produced in the kidneys, is critical to life because it controls the production and performance of red blood cells. As a commercial drug, EPO  — which is currently manufactured in cell cultures — is used primarily for the treatment of anemia in people with chronic kidney disease and in patients who have undergone chemotherapy or radiation therapy for cancer.

Erythropoietin as it is now produced is not actually one compound but a mix of a large family of molecules. Known as glycoproteins, the structures are composed of a protein with four sectors of carbohydrates attached, known as carbohydrate domains. The protein portion is always the same, as are the locations where the carbohydrate domains attach.

The variation in these structures is also seen in the vast range of different carbohydrates found in natural EPO. In this new study, however, the investigators were able to make for the first time a pure EPO, in which all the carbohydrates were specifically selected.

Confirmation That the Molecule Functions

After the molecule was synthesized, the investigators had to determine whether it would induce the formation of red blood cells. Study co-author and cell biologist Malcolm A. S. Moore and his laboratory at Memorial Sloan Kettering combined stem cells from umbilical cord blood with the pure hormone synthesized in the Memorial Sloan Kettering laboratory and confirmed that the molecule functioned as expected. “We showed that the synthesized erythropoietin was causing the stem cells to differentiate into red blood cells and proliferate,” Dr. Moore explains.

In addition, Ronald Hendrickson, Head of Memorial Sloan Kettering’s Proteomics and Microchemistry Core Facility, used a highly sophisticated version of a technique called mass spectrometry, which separates the parts of a molecule based on their masses, to verify that the structure created by the Memorial Sloan Kettering team was the same as the natural glycoprotein.

Stepping Stone to Additional Studies

Part of the team’s motivation for generating fully synthetic erythropoietin came from the desire to gain access, for the first time, to a pure form of the natural molecule. The ability to generate pure versions of EPO will enable scientists to make numerous versions of the molecule and study whether differences in the sizes of the carbohydrate domains attached affect how the glycoprotein induces the production of red blood cells.

“This is a major development in the field of chemistry,” Dr. Moore says. “It will help us immensely in understanding the complexity of this molecule.”

This research was supported by the National Cancer Institute of the National Institutes of Health (NIH) under award number CA28824 and by the NIH under award number HL025848.

Comments

Great appreciation for your tireless efforts in securing this vital information.

Is there any connection in finding a solution for CLL as red cells diminish?

Thanks for your comment, Anna Marie. According to our hematologists, EPO is often successful in treating chemotherapy-induced anemia and decreasing the need for red cell transfusions in a variety of cancers. However, data published a few years ago suggests that EPO can facilitate the growth of certain cancers and its use is not recommended when the goal of treatment is cure. It is not clear if EPO stimulates CLL cells significantly. Since CLL usually cannot be cured, administering EPO to treat chemotherapy-induced anemia in this disease is acceptable and typically effective.

The research being reported in this study is still at an early stage and will not change the way that pharmaceutical EPO is manufactured.

Thank you for prroviding me with this useful information. I have a son who will be 55 years old in January. He suffers from Sickle Cell - Thalassemia and pulmonary hypertension. His younger brother recently underwent a Stem Cell Transplant at NIH using as his donor his sister's Stem Cells. She was a 100% match. So far the transplant has been successful. My older son does not have a sibling that is a 100% match. Can this production of red cells be used to increase my son's red blood cells in the future?

Hi Anne, thanks for your comment. We are not able to answer specific medical questions on our blog, but according to our hematologists, EPO is not an established treatment for people with sickle cell disease.

I have Coombs positive hemolytic anemia. Will this discovery have any bearing on my ability to keep my red count normal?

Hi Lou, thanks for your comment. We are not able to answer specific medical questions on our blog, but according to our hematologists EPO is not routinely used to treat autoimmune hemolytic anemia. There are other effective treatments for this type of condition.

In addition, the research being reported in this study is still at an early stage and will not change the way that pharmaceutical EPO is manufactured.

I have a grandson who suffers from Diamond Blackfan Syndrom, His body makes no red blood cells at all. He has lived all of his life on cortisone except for his teen years when he had blood transfusions. He is now 30 years old.
can this new discovery help him?

Thanks for your comment, Katherine. Unfortunately we are not able to answer specific medical questions on our blog, but according to our hematologists EPO is not an established treatment for Diamond-Blackfan anemia.

In addition, the research being reported in this study is still at an early stage and will not change the way that pharmaceutical EPO is manufactured.

I have donated monthly payments to Memorial Sloan- Kettering Cancer Center, for many years. Today I have read the most AWESOME news of finding a cure for some kind of cancer.

Will this new discovery help with liver cancer?

Thank you for your comment, John. According to our experts, EPO is sometimes given to patients with liver cancer to treat chemotherapy-associated anemia. However, the research being reported in this study is still at an early stage and does not change the way that pharmaceutical EPO currently is manufactured.

Where can one get this? I am a prostate cancer patient at MSKCC.

Can this boost hemoglobin level?

Thank you for your comment, Joel. The research being reported in this study is still at an early stage and does not change the way that pharmaceutical EPO currently is manufactured. We recommend that you talk to your doctor about whether EPO should be part of your treatment.

Add a Comment

We welcome your questions and comments. Because this is a public forum, please do not include contact information or other personal details. Also, keep in mind that while we can provide general information and resources, we cannot offer personal medical advice. To make an appointment with one of our experts, contact our Physician Referral Service at 800-525-2225 or online.
Your e-mail address is kept private and will not be shown publicly.

More information about formatting options