Does Human Fat Contain Stem Cells?

Aeon Magazine recently published my longform essay on our research with human liposuction samples and our attempts to use fat for regenerative and therapeutic purposes. Many research groups, including our own group, have been able to isolate stem cells from human fat. However, when it came to using this cells for treating cardiovascular disease, the cells behaved in a manner that we had not anticipated.

Undifferentiated mesenchymal stem cells (left) and their fat neighbors (right)
Undifferentiated mesenchymal stem cells (left) and their fat neighbors (right) – From our PLOS One paper

We were unable to convert them into heart muscle cells or blood vessel endothelial cells, but we found that they could help build large networks of blood vessels by releasing important growth factors. Within a few years of our initial publication, clinical trials with patients with blocked arteries or legs were already being planned, and are currently underway.

We decided to call the cells “adipose stromal cells” because we wanted to emphasize that they were acting as a “stroma” (i.e. supportive environment for blood vessels) and not necessarily as stem cells (i.e. cells that convert from an undifferentiated state into mature cell types). In other contexts, these same cells were indeed able to act like “stem cells”, because they could be converted into bone-forming or cartilage-forming cells, thus showing the enormous versatility and value of the cells that reside within our fat tissues.

The answer to the question “Does Human Fat Contain Stem Cells?” is Yes, but these cells cannot be converted into all desired tissues. Instead, they have important supportive functions that can be used to engineer new blood vessels, which is a critical step in organ engineering.

In addition to describing our scientific work, the essay also mentions the vagaries of research, the frustrations I had as a postdoctoral fellow when my results were not turning out as I had expected, and how some predatory private clinics are already marketing “fat-derived stem cell therapies” to paying customers, even though the clinical results are still rather preliminary.

 

For the readers who want to dig a bit deeper, here are some references and links:

 

1. The original paper by Patricia Zuk and colleagues which described the presence of stem cells in human liposuction fat:

Zuk, P et al (2001) “Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies

 

2. Our work on how the cells can help grow blood vessels by releasing proteins:

Rehman, J et al (2004) “Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells

 

3. Preliminary findings from ongoing clinical studies in which heart attack patients receive infusions of fat derived cells into their hearts to improve heart function and blood flow to the heart:

Houtgraf, J et al (2012) “First Experience in Humans Using Adipose Tissue–Derived Regenerative Cells in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction

 

4. Preliminary results from an ongoing trial using the fat-derived cells in patients with severe blockages of leg arteries:

Bura, A et al (2014) “Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia

 

5. Example of how “cell therapies” (in this case bone marrow cells) are sometimes marketed as “stem cells” but hardly contain any stem cells:

The Largest Cell Therapy Trial in Heart Attack Patients Uses Hardly Any Stem Cells

 

6. The major scientific society devoted to studying the science of fat and its cells as novel therapies is called International Federation for Adipose Therapeutics and Science (IFATS).

I am not kidding, it is I-FATS!

Explore their website if you want to learn about all the exciting new research with fat derived cells.

 

7. Some of our newer work on how bone marrow mesenchymal stem cells turn into fat cells and what role their metabolism plays during this process:

Zhang, Y et al (2013) “Mitochondrial Respiration Regulates Adipogenic Differentiation of Human Mesenchymal Stem Cells

 

ResearchBlogging.org

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, & Hedrick MH (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering, 7 (2), 211-28 PMID: 11304456

 

 

 

ResearchBlogging.org
Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, & March KL (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109 (10), 1292-8 PMID: 14993122

Advertisements

Should Doctors ‘Google’ Their Patients?

Here is an excerpt from my latest post on the 3Quarksdaily blog:

 

Beware of what you share. Employers now routinely utilize internet search engines or social network searches to obtain information about job applicants. A survey of 2,184 hiring managers and human resource professionals conducted by the online employment website CareerBuilder.com revealed that 39% use social networking sites to research job candidates. Of the group who used social networks to evaluate job applicants, 43% found content on a social networking site that caused them to not hire a candidate, whereas only 19% found information that that has caused them to hire a candidate. The top reasons for rejecting a candidate based on information gleaned from social networking sites were provocative or inappropriate photos/information, including information about the job applicants’ history of substance abuse. This should not come as a surprise to job applicants in the US. After all, it is not uncommon for employers to invade the privacy of job applicants by conducting extensive background searches, ranging from the applicant’s employment history and credit rating to checking up on any history of lawsuits or run-ins with law enforcement agencies. Some employers also require drug testing of job applicants. The internet and social networking websites merely offer employers an additional array of tools to scrutinize their applicants. But how do we feel about digital sleuthing when it comes to relationship that is very different than the employer-applicant relationship – one which is characterized by profound trust, intimacy and respect, such as the relationship between healthcare providers and their patients?


The Hastings Center Report is a peer-reviewed academic bioethics journal which discusses the ethics of “Googling a Patient” in its most recent issue. It first describes a specific case of a twenty-six year old patient who sees a surgeon and requests a prophylactic mastectomy of both breasts. She says that she does not have breast cancer yet, but that her family is at very high risk for cancer. Her mother, sister, aunts, and a cousin have all had breast cancer; a teenage cousin had ovarian cancer at the age of nineteen; and that her brother was treated for esophageal cancer at the age of fifteen. She also says that she herself has suffered from a form of skin cancer (melanoma) at the age of twenty-five and that she wants to undergo the removal of her breasts without further workup because she wants to avoid developing breast cancer. She says that her prior mammogram had already shown abnormalities and she had been told by another surgeon that she needed the mastectomy.

Such prophylactic mastectomies, i.e. removal of both breasts, are indeed performed if young women are considered to be at very high risk for breast cancer based on their genetic profile and family history. The patient’s family history – her mother, sister and aunts being diagnosed with breast cancer – are indicative of a very high risk, but other aspects of the history such as her brother developing esophageal cancer at the age of fifteen are rather unusual. The surgeon confers with the patient’s primary care physician prior to performing the mastectomy and is puzzled by the fact that the primary care physician cannot confirm many of the claims made by the patient regarding her prior medical history or her family history. The physicians find no evidence of the patient ever having been diagnosed with a melanoma and they also cannot find documentation of the prior workup. The surgeon then asks a genetic counselor to meet with the patient and help resolve the discrepancies. During the evaluation process, the genetic counselor decides to ‘google’ the patient.

The genetic counselor finds two Facebook pages that are linked to the patient. One page appears to be a personal profile of the patient, stating that in addition to battling stage four melanoma (a very advanced stage of skin cancer with very low survival rates), she has recently been diagnosed with breast cancer. She also provides a link to a website soliciting donations to attend a summit for young cancer patients. The other Facebook page shows multiple pictures of the patient with a bald head, suggesting that she is undergoing chemotherapy, which is obviously not true according to what the genetic counselor and the surgeon have observed. Once this information is forwarded to the surgeon, he decides to cancel the planned surgery. It is not clear why the patient was intent on having the mastectomy and what she would gain from it, but the obtained information from the Facebook pages and the previously noted discrepancies are reason enough for the surgeon to rebuff the patient’s request for the surgery.

 

If you want to learn more about how ethics experts analyzed the situation and how common it is for psychologists enrolled in doctoral programs to use search engines or social networking sites in order to obtain more information about their patients/clients, please read the complete article at 3Quarksdaily.com.  

Inspired By Snake Venom

When I remember the 80s, I think of Nena’s 99 Luftballons, Duran Duran’s Wild Boys and ….snake venom. Back in those days, I used to be a typical high school science nerd. My science nerdiness interfered with my ability to socialize with non-nerds and it was characterized by an unnecessary desire to read science books and articles that I did not really understand, just so that I could show off with some fancy science terminology. I did not have much of an audience to impress, because my class-mates usually ignored me. My high school biology teacher, Herr Sperr, was the only one who had the patience to listen to me. One of the science books that I purchased was called “Gehirn und Nervensystem” (i.e. “Brain and Nervous System”), published by Spektrum der Wissenschaft, the German publisher of Scientific American. It was a collection of Scientific American articles in the field of neuroscience that had been translated into German. I was thumbing through it, looking for some new neurobiology idea or expression that I could use to impress Herr Sperr. While browsing the book, I came across the article “Der Nervenwachstumsfaktor” (originally published in Scientific American as “The Nerve-Growth Factor” in 1979) by Rita Levi-Montalcini and Pietro Calissano.

My curiosity was piqued by this article, because I did not realize that nerves had “growth factors” and because one of the authors, Rita Levi-Montalcini, had just won the Nobel Prize in the preceding year. I started reading the article and loved it, reading it over and over again. I liked the article so much, that I did not even try to show off about it and kept the newly discovered inspiration to myself. There are many reasons why I loved the article and I will just mention two of them:

1. Scientific discovery is an exciting journey, starting and ending with unanswered questions

Levi-Montalcini and Calissano started off by describing the state of knowledge and the unanswered questions in the field of developmental neurobiology and neuronal differentiation in the 1940s, when Levi-Montalcini was about to launch her career as a scientist. They commented on how the simple yet brilliant idea to test whether tumors could influence the growth of nerves sparked a whole new field of investigation. They narrated a beautiful story of scientific discovery, from postulating a “nerve growth factor” to actually isolating and sequencing it. Despite all the advances that Levi-Montalcini and her colleagues had made, the article ended with a new mystery, that the role of the nerve growth factor may be much bigger than all the researchers suspected. The nerve growth factor was able to act on cells that were not neurons and it was unclear why this was the case. By hinting at these yet to be defined roles, the article made it clear that so much more work was necessary and I felt that an invitation was being extended to the readers to participate in the future discovery.

2. Scientific tools can harbor surprises and important clues

The article mentioned one important coincidence that helped shape the progress of discovering the sequence of the nerve growth factor. To assess whether the putative nerve growth factor contained nucleic acids, Levi-Montalcini and her colleagues exposed the “soup” that was inducing the growth of nerves to snake venom. The rationale was that snake venom (by the way, the German expression “Schlangengift” sounds even more impressive than the English “snake venom”) would degrade nucleic acids and if the growth enhancing properties disappeared, it would mean that the nerve growth inducing factor contained nucleic acids. It turned out that the snake venom unexpectedly magnified the nerve growth enhancing effects, because the venom contained large quantities of the nerve growth factor itself. This unexpected finding made it much easier for the researchers to sequence the nerve growth factor, because the snake venom now provided access to a large source of the nerve growth factor and it resulted in a new mystery: Why would snake venom contain a nerve growth factor?

In the subsequent decades, as I embarked on my own career as a scientist, I often thought about this article that I read back in high school. It inspired me to become a cell biologist and many of the projects in my laboratory today focus on the effects of growth factors on blood vessels and stem cells. The article also made me think about the importance of continuously re-evaluating the tools that we use. Sometimes our tools are not as neutral or straight-forward as we think, and this lesson is just as valid today as it was half a century ago. For example, a recent paper in Cell found that the virus used for reprogramming adult cells into stem cells is not merely a tool that allows entry of the reprogramming factors, as was previously thought. The virus tool can actually activate the stem cell reprogramming itself, reminiscent of how the “snake venom” tool was able to induce nerve growth.

Rita Levi-Montalcini was one of the world’s greatest biologists and passed away on December 30, 2012. In addition to her outstanding scientific work, she was also a shining example of an activist scientist with a conscience, who fought for education and research. I never had the opportunity to meet her in person, but I was inspired by her work and I will always see her as a role model.

Image credit: Cover of the book “Gehirn und Nervensystem” by Spektrum der Wissenschaft

“It Is An Opportunity For Great Joy”

I was about 12 years old when I found out that my grandfather was born on 12/12/12. If he were alive, he would be exactly 100 years old today. I found out about his birthday, when he came to stay with us in Munich for an eye surgery. He was a diabetic and had been experiencing deterioration in his vision. At that time, it was very difficult to find an eye surgeon in Pakistan who would be able to perform the surgery. My grandfather spoke many languages, such as Punjabi, Urdu, Persian, English, Arabic and some Sanskrit, but he could not speak German. His visit occurred during my school holidays, so I was designated to be his official translator for the doctor visits and his hospital stay.


On the afternoon before his surgery, we went to the hospital and I was filling out the registration forms, when I asked my grandfather about his birthday and he said 12/12/12. I was quite surprised to find out that he had such a wonderful combination of numbers, when the lady at the registration desk saw the date and asked me whether he was absolutely sure this was the correct date. I translated this for my grandfather and he smiled and said something along the lines of, “It is more or less the correct date. Nobody is exactly sure, but it is definitely very easy to remember”. I knew that I was supposed be a translator, but this required a bit more finesse than a straightforward translation. One cannot tell a German civil servant that a date is more or less correct. If we introduced uncertainty at this juncture, who knows what the consequences would be.

I therefore paraphrased my grandfather’s response as, “Yes, it is absolutely correct!”

She then said, “Eine Schnapszahl!”

My grandfather wanted me to translate this, and I was again at a loss for words. Schnapszahl literally means Schnapsnumber and is a German expression for repeated digits, such as 33 or 555. The origin of the word probably lies in either the fact that a drunken person may have transient double vision or in a drinking game where one drinks Schnaps after reaching repeated digits when adding up numbers. I was not quite sure how to translate this into Urdu without having to go into the whole background of how German idioms often jokingly refer to alcohol.

I decided to translate her comment as “What a memorable date”, and my grandfather nodded.

We were then seen by a medical resident who also pointed out the unique birthday.

His comment was “Darauf sollten wir einen trinken!”, which is another German idiom and translates to „we should all have a drink to celebrate this”, but really just means “Hooray!”  or “Great!”

My grandfather wanted to know what the doctor had said and I was again in a quandary. Should I give him accurate translation and explain that this is just another German idiom and is not intended as a cultural insult to a Pakistani Muslim? Or should I just skip the whole alcohol bit? Translation between languages is tough enough, but translating and showing cultural sensitivity was more than I could handle. My Urdu was not very good to begin with, and all I could come up with the rather silly Urdu translation “It is an opportunity for great joy”. My grandfather gave me a puzzled look, but did not ask any questions.

 

*****

On the day after my grand-father’s eye surgery, the ophthalmologist and the residents came by for morning rounds.  They removed his eye-patch, inspected the eye and told me that everything looked great. He just needed a few more days of recovery and would soon be able to go home. After putting the gauze and eye-patch back on, the doctors moved on to the next patient.

 

Once the doctors had completed rounds, I made the acquaintance of the head nurse. She seemed to think that the eye ward was her military regiment and was running it like a drill-sergeant. She walked into every room and ordered all the patients to get out of bed and walk to the common area. Only lazy people stayed in bed, she said. The best way to recuperate was to move about.

 

I told her that I did not think my grandfather was ready to get up.

“Did any doctor forbid him to get up?”

“No, not really”, I replied.

“If he has two legs, he can walk to the common room. If not, we will provide a wheelchair.”

“He just had surgery yesterday and needs to rest”, I protested and pointed to my grandfather’s eye-patch.

“Yesterday was yesterday and today is today!” was the response from the drill-sergeant.

This statement did not seem very profound to me and I was waiting for a further explanation, but the drill-sergeant had already moved on, ordering the patients from the neighboring rooms to get up.

My grandfather and I did not have much of a choice, so we joined the procession of one-eyed men who looked like retired, frail pirates. They were slowly shuffling out of their rooms towards the common area.

The common area consisted of chairs and sofas as well as a couple of tables. I sat down in a corner with my grandfather, and we started talking. He told me stories from his life, including vivid descriptions of how he and his friends proudly defied the British colonialists. My grandfather recited poems from the Gulistan of the Persian poet Saadi for me in Persian and translated them into Urdu. He wanted to know about German history and what I was learning at school. He asked me if I knew any poems by Goethe, because the Indian poet Iqbal had been such a great admirer of Goethe’s poetry.

We talked for hours. Like most children, I did not realize how much I enjoyed the conversations. It was only years later when my grandfather passed away that I wished I had taken notes of my conversations with him. All I currently have are fragmented memories of our conversations, but I treasure these few fragments.

I then pulled out a tiny travel chess set that I had brought along, and we started playing chess. I knew that he had trouble distinguishing some of the pieces because of his eye surgery. I took advantage of his visual disability and won every game. During my conversations with my grandfather and our chess games, I noticed that some of the other men were staring at us. Perhaps they were irritated by having a child around. Maybe they did not like our continuous chatting or perhaps they just did not like us foreign-looking folks. I tried to ignore their stares, but they still made me quite uncomfortable.

On the next day, we went through the same procedure. Morning rounds, drill sergeant ordering everyone to the common area, conversations with my grandfather and our chess games. The stares of the other patients were now really bothering me. I was wondering whether I should walk up to one of the men and ask him whether they had a problem with me and my grandfather. Before I could muster the courage, one of the men got up and walked towards us. I was a bit worried, not knowing what the man was going to do or say to us.

 

“Can you ask your grandfather, if I can borrow you?”

“Borrow me?”, I asked, taken aback.

“He gets to tell you all these stories and play chess with you for hours and hours, and I also want to have someone to talk to.”

Once he had said that, another patient who was silently observing us chimed in and said that he would like to know if he could “borrow” me for a game of chess. I felt really stupid. The other patients who had been staring at me and my grandfather were not at all racist or angry towards us, they were simply envious of the fact that my grandfather had someone who would listen to him.

I tried to translate this for my grandfather, but I did not know how to translate “borrow”. My grandfather smiled and understood immediately what the men wanted, and told me that I should talk to as many of the patients as possible. He told me that the opportunity to listen to others was a mutual blessing, both for the narrator as well as the listener.

On that day and the next few days that my grandfather spent in the hospital, I spoke to many of the men and listened to their stories about their lives, their health, their work and even stories about World War 2 and life in post-war Germany. I also remember how I agreed to play chess, but when I pulled out my puny little travel chess set, my opponent laughed and brought a huge chess set from a cupboard in the common area. He beat me and so did my grandfather who then also played chess with me on this giant-size chess board which obliterated the visual advantage that my travel set had offered.

***********

Since that time I spent with my grandfather and the other patients on the eye ward, I have associated medicine with narration. All humans want to be narrators, but many have difficulties finding listeners. Illness is often a time of vulnerability and loneliness. Narrating stories during this time of vulnerability is a way to connect to fellow human beings, which helps overcome the loneliness. The listeners can be family members, friends or even strangers. Unfortunately, many people who are ill do not have access to family members or friends who are willing to listen. This is the reason why healthcare professionals such as nurses or physicians can serve a very important role. We listen to patients so that we can obtain clues about their health, searching for symptoms that can lead to a diagnosis. However, sometimes the process of listening itself can be therapeutic in the sense that it provides comfort to the patient.

Even though I mostly work as a cell biologist, I still devote some time to the practice of medicine. What I like about being a physician is the opportunity to listen to patients or their family members. I prescribe all the necessary medications and tests according to the cardiology guidelines, but I have noticed that my listening to the patients and giving them an opportunity to narrate their story provides an immediate relief.

It is an indeed an  “an opportunity for great joy”, when the patient experiences the joy of having an audience and the healthcare provider experiences the joy of connecting with the patient. I have often wondered whether there is any good surrogate for listening to the patient. Medicine is moving towards reducing face-to-face time between healthcare providers and patients in order to cut costs or maximize profits. The telemedicine approach in which patients are assessed by physicians who are in other geographic locations is gaining ground. Patients now often fill out checklists about their history instead of narrating it to the physicians or nurses. All of these developments are reducing the opportunity for the narrator-listener interaction between patients and healthcare providers. However, social networks, blogs and online discussion groups may provide patients the opportunities to narrate their stories (those directly related to their health as well as other stories) and find an audience. I personally prefer the old-fashioned style of narration. The listener can give instant feedback and the facial expressions and subtle nuances can help reassure the narrator. The key is to respect the narrative process in medicine and to help the patients find ways to narrate their stories in a manner that they are comfortable with.