Small molecules as therapeutics
The identification of active compounds holds the key to the future development of therapeutic agents. Upon synthesis of the analogs of these compounds, derivatives of the initially identified compound could be selected for increased activity.
Initially, scientists investigated peptides or oligonucleotides, hoping they would have some therapeutic qualities. However, poor oral activities, rapid clearance from the body, and limited bioavailability meant that peptides were not good candidates.
Small molecules, however, which generally have molecular weights smaller than 600-700, presented themselves as interesting candidates for therapeutic use. Screening these small molecules and forming a catalog of them become a major goal in molecular biology, with the hopes of developing new treatments for various diseases.
Small molecule stimulation of nerve stem cells to maturation
It had been believed for decades that the adult mammalian brain could not grow new brain cells. Thus, learning and memory were thought to be due to new connections created between existing cells in the brain. It is now well-established that new nerve cells are being constantly created in the brain. Scientists know that when a nerve cell sends a neurotransmitter to a stem cell it generates new nerve cells, but researchers are not sure which signaling pathways or genes are involved in this process.
Researchers at University of Texas Southwestern Medical Center at Dallas have discovered a small molecule called Isx-9 that stimulates nerve stem cells to maturate into nerve cells. Dr. Hsieh and her colleagues demonstrated that Isx-9 behaves like a neurotransmitter signal. Compared to other commonly used neurogenic simulators, Isx-9 was three times more efficient in the generation of nerve cells while also preventing the stem cells from transforming into non-nerve cells. When they cultured cells from the hippocampus with Isx-9, the researchers found that stem cells formed clusters along with the development of spiky appendages called neuritis. Their finding provides a new opportunity to investigate the signaling circuitry specifying the fate of neuronal cells and offers potential new approaches for neuro-regenerative drugs. Using this approach, it might someday be possible to do a stem cell therapy using a patient’s own stem cells that could be grown in a culture and transformed into mature nerve cells by using small molecule induction. These could then be transplanted back into patients to treat various neurological disorders.
Development of neuroprotective small molecules
The degeneration of the hippocampus and loss of neurons occurs in the early phases of Alzheimer’s disease. Current approaches are often inadequate to treat symptoms associated with Alzheimer’s. As such, scientists are frantically searching for novel therapeutics.
The hippocampus plays a critical role in learning and memory. Researchers screened a library of 1,000 different molecules to identify the ones that can enhance neuron formation in the hippocampus of mice. This quest for a drug that could keep brain cells from dying led to the discovery of a compound: a study by doctors McKnight and Pieper found that a small molecule called P7C3 may protect newborn neurons from dying.
One advantage of such a small molecule as a drug is the availability of means to modify the compound to improve its actions. Further studies are needed, however, to see if P7C3 can block the death of mature nerve cells. Modifications may allow its usage in treating different types of diseases such as Huntington’s disease and amyotrophic lateral sclerosis. As a small molecule, P7C3 has the ability to penetrate the blood-brain barrier. It achieved stability in animal models and cell culture settings, and activity even at nanomolar concentrations.

Cardiogenic small molecules for heart regeneration
The current treatment for heart failure is transplantation. Unfortunately, only about 30% of patients survive until they can get new hearts. The major problem in cardiac dysfunction is the death of muscle cells after a heart attack. Cardiac regeneration is the key to a non-transplantation form of treatment for heart failure following myocardial infarctions. Use of novel small molecules could help to fight one of the deadliest diseases of modern times.
The search for small molecules that enhance myocardial repair has led to the discovery of a number of potential cardiogenic small molecules. Stem cell therapies for heart regeneration rely on understanding how cells differentiate into cardiac genes from stem cells. Researchers identified small molecules that involve the activation of a cardiac gene called Nkx2.5 in various mouse stem cells, including human mobilized peripheral blood cells. This family of small molecules, called sulfonylhydrazone (Shz), was tested in bone marrow cells and transplanted into rat hearts. This procedure improved heart function after cardiac injuries.
Fighting cancer using small molecules
Some cancers are known to depend on certain genes for their survival. Pancreatic and a particular lung cancer known as non-small cell lung cancer are particularly dependent on TBK-1 activity for growth. Researchers believe that a number of lung and pancreas cancer patients would benefit from the inhibition of TBK-1 activity. The researchers tested about 250,000 compounds for their effectiveness at fighting tumors in mice. Three and half years of investigation led to the discovery of a highly effective compound called 6-aminopyrazolopyrimidine. This small compound inhibited the activity of TBK-1 by about 50 percent in lung cancer and pancreatic cancer tissue cultures, resulting in a reduction of cancer growth. This is an important finding for the future of fighting cancer, as this could potentially turn off a gene that cancer cells hijack to survive. Though it happened to be effective in reaching different parts of a mouse’s tumor, researchers are not yet sure whether it will penetrate solid tumors in a human body.
Quest for drug sensitizers: microRNA inhibitors            
MicroRNAs are non-coding small RNAs that regulate protein expression. These RNAs form tiny RNA strands that make complexes with proteins and target another mRNA to negatively regulate its translation (its generation of protein). MiRNAs are involved in various cellular pathways, and a miRNA can elicit multiple effects in a cell.
Aberrant microRNA expression in cancer has been well studied. MicroRNAs are involved in tumor progression and metastasis through various mechanisms involving migration, invasion, cell proliferation, angiogenesis, and apoptosis (cell death). MicroRNAs are thought to be potential therapeutic targets for personalized cancer treatments. Different cancer types and patients demonstrate different levels of response/resistance to chemotherapies. This resistance could be correlated with the expression of a microRNA profile, and studies are being performed to increase drug sensitivity toward the treatment of cancer. For example, paclitaxel, a mitotic inhibitor used in chemotherapy, is used, along with a library of chemically synthesized inhibitors that contains all known microRNAs, in non-small cell cancer cell lines. This will hopefully identify microRNAs and microRNA inhibitors that modulate cellular viability and sensitivity.
As humans, we inevitably face diseases, some of which do not have any treatment options. To understand the epidemiology of these diseases, as well as to develop treatments, researchers have pursued different approaches. Understanding and discovering novel compounds, especially small molecules, may help us to better treat disease in the future.

References
1. Pieper et al. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51.
2. Ou et al. TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation. Molecular Cell. February 2011.
3. Sadek et al. Cardiogenic small molecules that enhance myocardial repair by stem cells. PNAS. April 22, 2008 vol. 105 no. 16.
4. White et al. Metastamirs: a stepping stone towards improved cancer management. Nature Reviews Clinical Oncology 8, 75-84 (February 2011).
5. Paclitaxel. Wikipedia. http://en.wikipedia.org/wiki/Paclitaxel
6. Schneider et al. Small-molecule activation of neuronal cell fate. Nature Chemical Biology, 15 June 2008.
7. Researchers create molecule that nudges nerve stem cells to mature. http://www.utsouthwestern.edu/utsw/cda/dept353744/files/468005.html
8. Small Molecule. http://en.wikipedia.org/wiki/Small-molecule
9. Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.)
10. Pertsemlidis Lab. http://compbio.swmed.edu/

Heart Failure

The heart is basically a pump that provides the force needed to circulate blood and its contents to the body. It consists of four chambers: left ventricle, left atrium, right ventricle, and right atrium. The right ventricle and atrium collect the blood from the whole body and pump it to the lungs for removal of carbon dioxide and replenishment of oxygen. On the other hand, the left ventricle and atrium are responsible for collecting the blood from the lungs and pumping it to the body through the aorta (main artery). Non-stop blood circulation requires life-long and unfailing heart muscle power. Common symptoms of heart failure include waking up at the middle of night with shortness of breath and decreased ability to walk a few steps upstairs. Heart failure could arise due to any condition that decreases efficiency of the myocardium (heart muscle – Figure 1) through myocardial infarctions (death of muscles due to lack of oxygen, also known as heart attack) or overloading, such as hypertension, that requires increased contraction force. Loss of function in the ventricles (lower chamber of the heart) may require the use of ventricular assist devices (VAD).

Ventricular assist devices

A VAD is a mechanical pump that is implanted into the chest of patients to support the heart function through bridging the blood flow from the lower chamber to the aorta (Figure 2).^2,3 A VAD is usually useful during or after cardiac surgeries until recovery of the heart or while waiting for a heart transplant. VADs could also be used long term if the patient is not eligible for a heart transplant due to other complications. A VAD has several components, including a tube carrying blood out of the heart into a pump, a pump with another tube carrying blood to the aorta, and a power supply connecting to a control unit that monitors the VAD`s functionality.

There are different designs of VADs such as HeartMate, HeartWare, DuraHeart, and so on. Some VADs pump like the heart does, using a pumping action, and others use continuous blood flow. Intriguingly, VADs with continuous flow lead to a loss of normal pulse, but this has been found to decrease complications and increase survival. Two types of VADs include left ventricular assist device (LVAD) or right VAD (RVAD). LVADs are the most commonly used ones due to higher incidence of left ventricular function loss. If both LVAD and RVADs are used together, they are called a biventricular assist device (BVAC). VADs nowadays could be used not only for people with end stage heart failure, but also earlier stages of heart failure, including children. A VAD takes ninety percent of the pumping function of the heart. When using a VAD, your heart will still beat and have a rhythm. If none of these works for a patient, this requires the use of a mechanical or artificial heart, also known as total artificial heart (TAH).

Total artificial hearts

An artificial heart is a mechanical device that substitutes for the failing heart.^4,5,6 They are commonly used during heart transplantations to bridge the blood flow temporarily or to replace the heart permanently during a shortage of transplantable hearts. Early studies with artificial heart trials go back to the 1940s. Since then, various groups worldwide have invested in development of artificial heart prototypes and performed animal and human trials. Total artificial heart prototypes include, but are not limited to, SynCardia, ABIOMed (AbioCor), and Carpentier (CARMAT).6

SynCardia is developed from the Jarvik-7. It was first implanted in 1982. Dr. Robert Jarvik originally designed the Jarvik-7 (Figure 3). Barney Clark underwent the first artificial heart implantation at the University of Utah and survived for 112 days. This was followed by other implants. The longest survival with the Jarvik-7 is 620 days. However, the device is more commonly used on patients as a bridge during heart transplants. It has two pumps that resemble the two ventricles of the heart and is pneumatically (air) powered. The pump of SynCardia is covered with polyurethane. A pneumatic driver used in the US is a non-portable console, and requires patients to stay in the hospital. However, a portable version has been developed in Europe that could be carried a backpack while a patient waits for a donor heart.

The ABIOMed (AbioCor) is a completely self-contained, total artificial heart, which avoids the need for an external console or having wires or tubes piercing the skin to power the device. It uses a wireless energy transfer system, also known as a transcutaneous energy transmission system. This decreases the risk of developing infections due to implants.

CARMAT, on the other hand, is designed by Alain F. Carpentier.⁷ It is a fully implantable artificial heart with embedded biomaterials that make the device more biocompatible. In addition, the CARMAT includes valves made from cow heart tissue and has internal pressure sensors. This allows a person to adjust the flow rate in response to increased demand, such as during exercise. This feature distinguishes the CARMAT from other artificial hearts that provides a constant flow rate.

Biological artificial hearts

Synthetic replacement of organs is one of the long-sought dreams of modern medicine. To this end, there are efforts to develop biological artificial hearts in the laboratory. One recent study took the approach of producing a decellurized (empty from cells) scaffold of a mouse heart and recellurized it with human cardiac cells, and showed that lab-grown human heart tissue can beat on its own (about 40-50 beats per minute) in as short as a few weeks (Figure 4).⁸ They took the advantage of induced pluripotent cell (iPS cells) technology to produce multi-potential cardiovascular progenitor (MCP) cells, which could give rise to all three types of cardiac cells found in the heart. This area of research is still in its infancy but in the future, at least, it may provide tools to generate patches of heart tissue to replace damaged parts of the hearts. Given the success of a mouse heart cellurized with human cardiac cells, it’s possible that scientists will also try to decellurize the heart of a monkey or another animal and then cellurize it with human cardiac cells to produce a beating human heart in the laboratory as an alternative source to a full heart transplant.

Another approach to a biological artificial heart is to genetically modify animals in a way that their hearts will be compatible with a human body. Genetic engineering is a rapidly evolving field that one day could provide such tools for scientist to grow necessary organs in monkeys, dogs, or maybe even horses. Genetic modification may overcome tissue rejection issues when they are transplanted into a human body. For instance, one study tested the possibility of a heart transplant from genetically modified pigs into monkeys and showed the applicability of heart transplants between different species.^9,10

Until the development of biological artificial hearts, ventricular assist devices and mechanical artificial hearts seem to the best options. However, artificial heart implants have had various complications, including infections, pneumonia, high fevers, and multiple organ failures with variable survival rates based on the type of device and materials used. Another issue is the necessity of artificial heart to meet requirements of the body in terms of heart flow rate. For instance, the required flow rate of someone walking or exercising is different than someone at rest. In addition, the possibility of mechanical or computerized systems to fail may be a source of distress in patients implanted with artificial hearts or assist devices. This reminds us of that as long as we take care of our heart’s health, we won’t have worry whether its battery could fail – and what a mercy that is.

It is stunning that even with so much need and effort we are still not able to develop something that completely replaces all the functions of a heart. This clearly points that the heart is a marvelous gift granted to us. We are counting on every beat of the heart for our survival, and we should give thanks, with every beat, for what an incredible gift we’ve been given.

References

1. Bui, A. L., Horwich, T. B. & Fonarow, G. C. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 8, 30-41 (2010).

2. What Is a Ventricular Assist Device? NHLBI, NIH. Retrieved from www.nhlbi.nih.gov/health/health-topics/topics/vad/ on 1/2/14.

3. Ventricular assist devices (VADs) Definition – Tests and Procedures – Mayo Clinic. Retrieved from www.mayoclinic.org/tests-procedures/ventricular-assist-devices/basics/definition/PRC-20020578 on 1/2/14.

4. Artificial Hearts. Retrived from www.umasswiki.com/wiki/Artificial_Hearts on 1/2/14.

5. Artificial heart. Retrieved from en.wikipedia.org/wiki/Artificial_heart on 1/2/14.

6. Heart Assist Devices. Texas Heart Institute. Retrieved from http://texasheart.org/Research/Devices/index.cfm on 1/12/14

7. Carmat artificial heart patient in good condition: hospital. Retrieved from www.reuters.com/article/2013/12/30/us-carmat-patient-idUSBRE9BS07O20131230 on 1/2/14.

8. Lu, Tung-Ying, Bo Lin, Jong Kim, Mara Sullivan, Kimimasa Tobita, Guy Salama, and Lei Yang. “Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells.” Nature communications 4 (2013).

9. Heart of genetically modified pig ‘successfully transplanted into monkey’, South Korea scientists claim. Retrieved from http://www.dailymail.co.uk/news/article-2164964/South-Korea-scientists-successfully-transplant-heart-genetically-modified-pig-monkey.html on 12/1/14

10. Pig to human transplants. Retrieved from http://www.theguardian.com/world/2002/jan/03/qanda.simonjeffery on 12/1/14